WHO Vaccine Manual PDF

VACCINE SAFETY AND
FALSE CONTRAINDICATIONS
TO VACCINATION
Training manual
VACCINE SAFETY AND
FALSE CONTRAINDICATIONS
TO VACCINATION
Training manual
Abstract
Health professionals are the single most important influence on whether individuals decide to have
themselves or their children vaccinated; therefore, information and education for health professionals are
essential. The aim of this training manual is to present “state-of-the-art”, authoritative, scientifically valid
advice to counter common misperceptions of vaccination.
Keywords
IMMUNIZATION
VACCINE SAFETY
VACCINE SIDE EFFECTS
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Table of contents
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
1. Scope and purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Safety of vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2.1.1. Pre-licensure testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2.1.2. Post-licensure testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1.3. Manufacture of vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1.4. Addition of a vaccine to a recommended immunization schedule . . . . . . . . . . . . 4
2.1.5. Continuous monitoring of the safety of vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.6. Role of clinicians in vaccine safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.7. Predictable pattern of behaviour when a new vaccine is introduced . . . . . . . . . . 5
2.2. Vaccine safety institutions and mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.2.1. National regulatory authorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.2.2. Immunization safety surveillance system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3. Adverse events after vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3.1. Vaccine reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3.2. Reactions associated with defective vaccine quality . . . . . . . . . . . . . . . . . . . . . . 12
2.3.3. Reactions due to vaccination errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.3.4. Reactions due to anxiety about vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.3.5. Coincidental events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.4. Case definitions and treatment of adverse events after vaccination . . . . . . . . . . . 14
2.5. Reporting of adverse events after vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.5.1. Events to be reported . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.5.2. Timing of reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.5.3. Mode of reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.5.4. Reporting adverse events during immunization campaigns . . . . . . . . . . . . . . . 20
2.5.5. Barriers to reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.5.6. Vaccine Adverse Events Information Management System (VAEIMS) . . . . . . . 21
3. Valid and false contraindications to vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.1. When to vaccinate safely . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.1.1. Contraindications to commonly used vaccines and precautions to be taken . 22
3.1.2. Precautions for administration of rotavirus vaccine . . . . . . . . . . . . . . . . . . . . . . 25
3.2. Misperceptions about vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4. Facts and myths about vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.2. Reasons given for refusing vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.2.1. Barriers to vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.2.2. Objections to vaccines based on religious beliefs . . . . . . . . . . . . . . . . . . . . . . . . . 30
iii
4.3. Responding to concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.3.1. Vaccine manufacture and testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.3.2. The immune system and the host response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.3.3. Are vaccines really necessary? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
4.3.4. Relations between vaccination and neurological disease . . . . . . . . . . . . . . . . . . 38
4.3.5. Relation with other diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
5.1. Conservation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
5.1.1. The cold chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
5.1.2. Vaccine storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.1.3. Vaccine vial monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.2. Vaccine administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5.2.1. Which, when, where and how . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.2.2. Simultaneous administration of several vaccines . . . . . . . . . . . . . . . . . . . . . . . . 50
5.3. Vaccination records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.3.1. Records of health care providers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.3.2. Patient records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.3.3. Vaccination information systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.4. Advice on vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
5.4.1. Before vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
5.4.2. At the doctor’s office . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
5.4.3. After vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6. Vaccination in special situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6.1. Altered immunocompetence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6.1.1. Immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.1.2. Vaccination of contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.2. Conditions that might cause immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.2.1. HIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.2.2. Congenital immunodeficiency in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.2.3. Recipients of haematopoietic cell transplants . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
6.2.4. Recipients of solid organ transplants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.2.5. Anatomical or functional asplenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.2.6. Bleeding disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.2.7. Chronic illnesses in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
6.3. Drugs that might cause immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
6.3.1. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
6.3.2. Other immunosuppressive drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
6.3.3. Antibody-containing products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
6.3.4. Concurrent administration of antimicrobial agents and vaccines . . . . . . . . . . 62
6.4. Vaccination of preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
6.5. Vaccination during breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
6.6. Vaccination during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
6.7. Vaccination of patients with tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
6.7.1. Tuberculosis skin test reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
6.7.2. Screening of people vaccinated with bacille Calmette-Guérin (BCG) . . . . . . . . 67
iv
6.7.3. Efficacy of BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
6.7.4. Revaccination with BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
6.7.5. Screening for severe combined immunodeficiency disease in countries with
universal BCG vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
6.8. Vaccination of people with lapsed or unknown immunity . . . . . . . . . . . . . . . . . . . . 69
6.8.1. Interchangeability of brands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.8.2. Catch-up vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.10 Vaccination for travellers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8. Clinical cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8.1. Case 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8.2. Case 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Annex. Frequency of adverse reactions to commonly used vaccines . . . . . . . . . . . . . . . . 99
v
Acknowledgements
The authors of the training manual are listed below. They received guidance from WHO Regional
Office for Europe.
Professor Federico Martinón-Torres, the Head of Translational Paediatrics and Infectious Diseases
Service of Hospital Clínico of the University of Santiago, the Associate Professor of Paediatrics of
the University of Santiago, and the Coordinator of Genetics, Vaccines, Infections and Paediatrics
Research Group of the Health Care Research Institute of Santiago, Spain.
Dr Irene Rivero Calle, the Consultant in Paediatrics of Translational Paediatrics and Infectious
Diseases Service of the Hospital Clínico of the University of Santiago, Spain.
vi Vaccine Safety and False Contraindications to Vaccination – Training manual

Abbreviations
AEFI Adverse effects after vaccination
AIDS Acquired ImmunoDeficiency Syndrome
BCG bacille Calmette-Guérin
CIOMS Council for International Organizations of Medical Sciences
DT diphtheria and tetanus toxoids
DTP diphtheria, tetanus and pertussis
DTaP diphtheria and tetanus toxoids and acellular pertussis
DTwP diphtheria and tetanus toxoids and whole-cell pertussis
GACVS Global Advisory Committee on Vaccine Safety
GBS Guillian-Barré syndrome
HBsAg hepatitis B surface antigen
Hib Haemophilus influenzae type b
HIV human immunodeficiency virus
HPV human papillomavirus
Ig immunoglobulin
IL interleukin
IPV inactivated poliovirus vaccine
Men meningococcus
NK cells natural killer cells
NRA National Regulatory Authority
OPV oral poliovirus vaccine
PCV pneumococcal conjugate vaccine
PIDM Programme for International Drug Monitoring
PS23 23-valent pneumococcal polysaccharide vaccine
RV1 rotavirus vaccine RotaTeq®
RV5 rotavirus vaccine Rotarix®
SCID severe combined immunodeficiency
SIV Simian Immunodeficiency Virus
TB Tuberculosis
Td tetanus and diphtheria toxoids
Tdap tetanus toxoid, reduced diphtheria toxoid and acellular pertussis
Tdwp tetanus toxoid, reduced diphtheria toxoid and whole-cell pertussis
TIV trivalent inactivated vaccine
TST tuberculin skin test
TT tetanus toxoid
USA United States of America
VAEIMS Vaccine Adverse Event Information Management System
VAERS Vaccine Adverse Event Reporting System
Vi typhoid capsular polysaccharide typhoid vaccine
VVM vaccine vial monitor
WHO World Health Organization
vii
1. Scope and purpose
Vaccination has been demonstrated repeatedly to be one of the most effective interventions for
preventing disease worldwide. Ironically, the fact that vaccines are administered to healthy people
to prevent diseases that have become rare, largely thanks to vaccination, contributes to concern
about vaccine safety. Because the devastating effects of the diseases are no longer prominent,
public attention is focused on side-effects of vaccination. This influences how people weigh up
the risks and benefits of vaccination, leading in some instances to reduced vaccination rates
and outbreaks of disease; however, the minimal risks associated with vaccination are totally
overshadowed by the health risks associated with non-vaccination.
Health professionals are the single most important influence on whether individuals decide to
have themselves or their children vaccinated; therefore, information and education for health
professionals are essential. The aim of this training manual is to present “state-of-the-art”,
authoritative, scientifically valid advice to counter common misperceptions of vaccination.
2. Safety of vaccines
2.1. Introduction
The vaccines used in national immunization programmes are safe and effective; however, like
other pharmaceutical products, vaccines are not completely risk-free, and adverse events occur
occasionally after vaccination. Although most such events are minor (e.g. redness at the injection
site, fever), more serious reactions (e.g. seizures, anaphylaxis) can occur at a very low frequency
(Annex 1).
The general public has low tolerance for any adverse events after vaccination, because vaccines
are given to healthy people to prevent disease. Therefore, vaccines are expected to have a
higher standard of safety than the medications used to treat people who are sick (e.g. antibiotics
and insulin)1,2. The lower public tolerance for risk after vaccination means that a greater effort
must be made to detect and investigate any adverse event than is generally expected for other
pharmaceutical products.
National regulatory authorities are responsible for ensuring the quality, safety and effectiveness
of vaccines and other pharmaceutical products3. Before vaccines are introduced into an
immunization programme, they are evaluated for their safety and efficacy in clinical trials. Once
they are introduced, their manufacturing process undergoes thorough, continuous review, and the
national regulatory authorities continue to monitor and investigate adverse events to ensure that
the vaccines are safe for the entire population.
2.1.1. Pre-licensure testing

The national regulatory authority of the country in which a vaccine is manufactured tests it before
licensing it3. First, the vaccine is tested in the laboratory and in computer models that inform
Scope and purpose 1

scientists about the disease the vaccine is intended to prevent and its genetic codes. Secondly, it is
tested in animals with immune systems that are similar to those of humans to help predict effects
in people and to make sure that the vaccine has no major side-effects. Then, a series of clinical
trials is performed in humans.
National regulatory authorities set the rules for three phases of clinical trials in order to ensure
the safety of the volunteers. Researchers test vaccines in adults first.
• Phase 1: 20–100 healthy volunteers are tested to determine whether a vaccine is safe, appears
to work and has any serious adverse effects.
• Phase 2: Several hundred volunteers are tested to determine the commonest short-term side-
effects, whether the size of the dose is related to any side-effects and how the volunteers’
immune systems respond to the vaccine.
• Phase 3: Hundreds or thousands of volunteers are tested to determine whether the people who
receive the vaccine are similar to those who don’t, whether the vaccine is safe and effective
and the commonest side-effects.
Once a vaccine has been determined to be safe and effective, the regulatory authority grants a license
to allow its sale and distribution. It is at this point that post-licensure monitoring of the vaccine begins.
2.1.2. Post-licensure testing

Phase 4 clinical trials, also known as “post-marketing surveillance”, involve surveillance of the
vaccine for safety (pharmacovigilance) and continuous technical support after it has been licensed
for sale. Phase IV studies may be required by regulatory authorities or may be undertaken by a
sponsoring company for competitive (finding a new market for the drug) or other reasons (for
example, the drug might not have been tested for interactions with other drugs or in certain
population groups, such as pregnant women, who are unlikely to volunteer for trials). Surveillance
is designed to detect any rare or long-term adverse effects in a much larger patient population
and over a longer period than was possible in phases I–III. If harmful effects are detected in phase
IV trials, the vaccine might be banned from sale or restricted to certain uses.
A national regulatory authority licenses a vaccine only if it is safe and effective and if the benefits
outweigh the risks1-3. Vaccines are then made in batches, called “lots”. Manufacturers must test
all lots to make sure that they are safe, pure and potent. Lots can be released only after the
national regulatory authority has reviewed their safety and quality by inspecting manufacturing
facilities regularly. Every lot of vaccine must be tested and double-checked for safety, potency
and purity to assure the uniformity of every dose of vaccine given. Each lot is precisely identified
to allow follow-up.
2.1.3. Manufacture of vaccines

Fig. 1 shows the steps in producing and distributing a vaccine. The first step is generation of the
antigen used to induce an immune response. This step includes the growth and harvesting of
the pathogen itself (for later inactivation or isolation of a subunit) or generation of a recombinant
protein (a protein made with DNA technology) derived from that pathogen. Recombinant proteins
2 Vaccine Safety and False Contraindications to Vaccination – Training manual

can be manufactured in cultures of bacterial cells or yeast. Viruses are grown in cell cultures.
Bacterial pathogens are grown in devices with a growth medium designed to optimize the yield of
the antigen while maintaining its integrity.
Fig. 1. Stages in vaccine production and distribution
PRODUCTION
VIRUS
VESSEL
GENERATE ANTIGEN,
PURIFY STRENGTHEN VIALS
RELEASE & ISOLATE
BACTERIA
DISTRIBUTE
Viruses: For many viral vaccines, the process begins with small amounts of a specific virus that
can be grown in cell cultures. Various cell types may be used, such as cells from chicken embryos
and cell lines that reproduce repeatedly.
Bacteria: Bacteria can be grown in bioreactors. Some antigens can be manufactured within
bacteria or yeast.
The second step is to release the antigen from the cells and isolate it from the material in which
it is grown. As proteins and other parts of the growth medium may still be present, they must be
removed in the next step. The goal in this stage is to release as much virus or bacteria as possible.
The third step is purification of the antigen. For vaccines that are made from recombinant proteins,
this may involve chromatography and ultrafiltration.
The fourth step may be addition of an adjuvant, which is a material that nonspecifically enhances
immune responses. Vaccines may also include stabilizers to prolong shelf-life or preservatives to
allow safe use of multi-dose vials.
In the final step, all the components of the final vaccine are combined and mixed uniformly in
a single vessel. Then, the vaccine is placed into vials or syringe packages, sealed with sterile
Safety of vaccines 3
stoppers or plungers and labelled for distribution. Some vaccines are freeze-dried and then
rehydrated at the time of administration.
Additives are used in vaccines for several reasons, such as to stabilize vaccines in adverse conditions
(e.g. extreme temperatures of heat and freeze-drying), to improve the immune response to the
vaccine, to prevent the vaccine components from adhering to the sides of the vial and to prevent
fungal or bacterial contamination4, 5. Examples of additives include lactose and sucrose (sugars),
glycine and monosodium glutamate (amino acids or salts of amino acids), human or bovine serum
albumin (proteins) and gelatin. These additives ensure that vaccines remain safe and effective.
Some vaccines contain stabilizers to maintain the vaccine’s safety and effectiveness under various
conditions and temperatures. Gelatin and lactose–sorbitol are examples of stabilizers.
Adjuvants are chemicals added to enhance the body’s immune response to a vaccine. Various
forms of aluminium salts are commonly used. A recent review of all the available studies
of aluminium-containing diphtheria, tetanus and pertussis (DTP) vaccines (either alone or in
combination) provided no evidence that aluminium salts in vaccines cause any serious or long-
term adverse events6-9.
A diluent is a liquid used to dilute a vaccine to the proper concentration. In vaccines, it is usually
sterile saline or water.
Preservatives are included in some vaccines to prevent fungal or bacterial contamination, mostly
in vaccines that are manufactured in multi-dose vials.
Remnants after manufacture: Often, chemicals are used during vaccine manufacture and then
removed from the final product. For example, formaldehyde might be used to kill a vaccine virus,
or antibiotics might be used to prevent bacterial contamination while viruses are growing in the
laboratory. When these chemicals are removed, trace amounts might remain. While some of
these chemicals might be harmful in large doses, the trace amounts left are too small to have any
toxic effect4,5.
2.1.4. Addition of a vaccine to a recommended immunization schedule

A national immunization technical advisory group consists of a group of experts who provide
independent, evidence-based advice to ministries of health on the introduction of new vaccines.
They include experts in the rea of peadiatrics, infectiouse diseases, public health, epidemiology,
immunology, and other disciplins, who carefully review all the available evidence about the
vaccine from the clinical trials and other studies and prepare recommendations for use of the
vaccine. When making recommendations, they consider how safe the vaccine is at specific
ages, how well it works at specific ages, how serious is the disease that the vaccine prevents
and how many children would get the disease the vaccine prevents if they were not vaccinated.
They also consider pharmaco-economic aspects. Although the national immunization technical
advisory group makes recommendations, the ministry of health makes the final decision. The
recommendations become part of the national vaccination schedule.

2.1.5. Continuous monitoring of the safety of vaccines
National regulatory authorities such as the European Medicines Agency in Europe and the Food
and Drug Administration in the USA, and WHO globally, monitor the safety of vaccines after their
introduction10. The purpose of monitoring is to detect adverse events and to evaluate possible
side-effects, to ensure that any risks associated with the vaccine are identified, especially if the
adverse events occur at very low frequency and were therefore not excluded during clinical
development. Scientists conduct studies to evaluate the safety of vaccines and determine whether
any observed side-effects were actually associated with vaccination. Vaccine recommendations
may change according to the results of such safety monitoring.
A “vaccine adverse event information management system” (VAEIMS) is used to collect and
analyse reports of adverse events after vaccination11. For example, in the USA, anyone can submit
such a report, including parents, patients and health care professionals. A vaccine safety datalink
is a network of health care organizations, through which information is made available to the
population.
2.1.6. Role of clinicians in vaccine safety

Clinicians are responsible for proper storage and administration of vaccines, identification of
contraindications, providing information and education to patients, reporting and treating any
reactions, referring patients as appropriate and following them up.
The vaccinee should be informed or motivated to receive the vaccine and educated by receiving
clear facts. The person delivering the vaccine should then screen the vaccinee for potential
contraindications, including pre-existing health conditions, allergies, previous adverse events,
antecedents of fainting (syncope) and pregnancy. The vaccinee should be asked to sit or lie down
and should be observed for at least 30 min. The person giving the vaccine should be ready in
advance for common events such as fainting and rare anaphylactic reactions.
2.1.7. Predictable pattern of behaviour when a new vaccine is introduced

Can vaccines have side-effects? Yes, but very rarely. Reactogenicity (local or systemic) is the
usual, expected side-effect of vaccination. Vaccines are, however, often wrongly linked to adverse
events: a coincidence in time is commonly misperceived as a causal relation.
The success of vaccination makes it its own worst enemy. Owing to effective vaccination
programmes, most people in industrialized countries have never experienced the devastating
vaccine-preventable diseases, and many people believe that these diseases no longer pose a
threat, as they are no longer visible. Now, some people consider that vaccines are more dangerous
than the diseases they prevent. In some countries, such misperceptions have led to decreased
coverage and a resurgence of contagious diseases12, as viruses do not respect borders.
Vaccination is a changing science, and, like all aspects of public health, it has social, political and
economic implications. The behaviour towards introduction of a new vaccine is cyclical, with a
similar pattern observed in the past, the present and probably again in the future (Fig. 2).
Fig. 2. Pattern of perception of vaccination
Source: Adapted from Chen RT, Rastogi SC, Mullen JR, Hayes SW, Cochi SL, Donlon JA, et al. The Vaccine Adverse Event Reporting
System (VAERS). Vaccine. 1994 May;12(6):542-50
As vaccination coverage increases, the prevalence, and thus the fear, of the disease decreases. The
rate of adverse events remains constant until very high coverage has been achieved, when more
adverse effects are seen globally, with a rapid effect on the mass media, which leads to doubts,
fears and finally denial of vaccination. Coverage rapidly decreases, and the disease reappears.
Resurgence of the disease usually recalls fear of the disease, and vaccination is resumed. Ideally,
the disease is eradicated, and the vaccine is no longer necessary.
Fig. 3 illustrates this pattern. When vaccine coverage is 80%, about 2000 cases may be found;
when coverage falls to 20%, the number of cases increases dramatically, to 45 00013. Subsequently,
vaccination is resumed, and the disease is again controlled.
Fig. 3. Reappearance of pertussis in the United Kingdom due to reduced vaccination coverage
Notifications Vaccine
coverage (%)
200,000 100
Notifications Vaccine coverage (%)
180,000
Immunisation 80
160,000
140,000 60
120,000
40
100,000
20
80,000
60,000 0
40,000
20,000
0
1940 1950 1960 1970 1980 1990 2000
Year
Source: Immunisation against infectious disease 1996, Eds. Salisbury DM and Begg NT. En: Edward Jenner, Bicentenary Edition

2.2. Vaccine safety institutions and mechanisms
The general principles for the surveillance of adverse events after vaccination are similar in all
countries, although the approaches may differ due to factors such as the organization of immunization
services and the resources available. Different organizations serve different purposes in vaccine
safety and in monitoring and supporting national responses to adverse events (Fig. 4).
Fig. 4. Components of a global vaccine safety monitoring, investigation and response system
Global capacity Global advice and response

building and
harmonized tools Other global or regional
GACVS
advisory bodies
Brighton
Collaboration
CIOMS/WHO National AEFI surveillance, Global signal,

working group investigation and response evaluation and
detection
National
Nationalregulatory
regulato authority
ry authority
Training
providers Nationalimmunization programme WHO PIDM
AEFI review committee

Global Vaccine
Other support groups
Safety DataNet
Other partners
Product monitoring
Vaccine Licensing authorities in Procurement
manufacturers country of manufacture agencies
GACVS, Global Advisory Committee on Vaccine Safety; CIOMS, Council for International Organizations of Medical Sciences; AEFI,
adverse effects after vaccination; PIDM, Programme for International Drug Monitoring
2.2.1. National regulatory authorities

The safety of vaccines is assured by national regulatory authorities3. All countries should have
such an authority to ensure that all medicines, including vaccines, used in the country are safe,
effective and of good quality. The authority must abide by the principles of transparency, fairness
and accountability (Figs 5–7). After a vaccine has been licensed and introduced, the authority is
responsible for strong surveillance for adverse events to ensure its safety and to ensure exchange
of information with the system of vaccination delivery or the national immunization programme10,11.
The national regulatory authority and the national immunization programme together are
responsible for seting up and maintaining a national surveillance system for adverse events
after vaccination, often with a review committee and other support groups, such as academic
institutions and technical agencies1-3, 10, 11. In countries that produce their own vaccines, vaccine
manufacturers and national control laboratories may be part of the surveillance system.
Fig. 5. Functions of a national regulatory authority, depending on the source of vaccines15
Areas of activity by NRA (or WHO) depending on source of vaccines

Vaccine-specific NRA
functions needed Vaccine procured by Vaccine manufactured in
Vaccine procured by NRA
United Nations agency country
FUNCTION 1
Marketing authorization
and licensing activities
FUNCTION 2
AEFI surveillance
FUNCTION 3
NRA lot release
FUNCTION 4 NRA functions

Laboratory access undertaken by WHO
on behalf of United
FUNCTION 5 Nations agencies or
Regulatory inspections NRA functions
producing countries.
undertaken by
FUNCTION 6 producing country.
Oversight of clinical trials
Fig. 6. Functions of national regulatory authorities relating to vaccines15

Fig. 7. Key functions of a national regulatory authority15
2.2.2. Immunization safety surveillance system

Immunization safety involves ensuring and monitoring the safety of all aspects of immunization,
including vaccine quality, adverse events, vaccine storage and handling, vaccine administration,
disposal of sharps and management of waste14. Vaccination safety may be monitored by:
• passive surveillance, or reporting all spontaneous adverse events after vaccination. Its main
strength is early detection of previously undetected serious adverse events (signals), but it
has many limitations, including underreporting.
• active surveillance, used primarily to characterize the rates of adverse events and risk factors.
Countries may conduct active surveillance for only selected adverse events at selected
institutions (sentinel sites) or in the community (e.g. cohort event monitoring).
• ad hoc studies, in which epidemiological studies are conducted to extend specific aspects of
vaccination safety surveillance, such as testing hypotheses of causality.
2.3. Adverse events after vaccination

An adverse event after vaccination is any untoward medical occurrence that follows vaccination,
which is not necessarily causally related to administration of the vaccine. The event may be any
unfavourable or unintended sign, abnormal laboratory finding, symptom or disease16. Although all
vaccines used in national immunization programmes are safe and effective if used correctly, no
vaccine is completely risk-free, and some adverse events will occasionally occur after vaccination.
The frequency of adverse reactions of commonly used vaccines is listed in Annex 1.
Adverse events after vaccination are grouped into five categories17, depending on whether they are
due to:
• the vaccine product: an adverse event caused or precipitated by a vaccine due to one or more of
its inherent properties. Example: extensive limb swelling after administration of DTP vaccine
• quality: an adverse event caused or precipitated by a vaccine with one or more defects, including
the administration device provided by the manufacturer. Example: paralytic poliomyelitis due
to failure by a manufacturer to completely inactivate a lot of poliovirus vaccine
• vaccination error: an adverse event due to inappropriate handling, prescription or administration
of a vaccine. Example: transmission of infection from a contaminated multidose vial
• anxiety: an adverse events arising from anxiety about the procedure. Example: vasovagal
syncope in an adolescent during or after vaccination
• a coincidental event: an adverse event caused by an event other than the vaccine, vaccination
error or anxiety. Example: a fever occurring at the time of vaccination (temporal association)
that is in fact due to a viral infection
2.3.1. Vaccine reactions

A vaccine reaction is an individual’s response to the inherent properties of the vaccine, even when
the vaccine has been prepared, handled and administered correctly (Table 1).
Table 1. Main minor and severe reactions associated with vaccination
Minor reaction Severe reaction

Usually occurs within a few hours of injection Usually does not result in long-term problems
Resolves after a short time, and poses little danger Can be disabling
Local, including pain, swelling or redness at the site Includes seizures and allergic reaction of the body
of injection to a component of the vaccine
Systemic, including fever, malaise, muscle pain,
headache or loss of appetite
Vaccine reactions are due to either the vaccine product or the quality of the vaccine quality.
Vaccination induces immunity by causing the recipient’s immune system to react to the antigens
contained in the vaccine. Local and systemic reactions such as pain or fever may be part of the
immune response. Other vaccine components (e.g. adjuvants, stabilizers and preservatives) can
also trigger reactions17. In a successful vaccine, even minor reactions are kept to a minimum while
the best possible immune response is elicited.
Vaccine reactions likely to be observed with some of the most commonly used vaccines, their
frequency and their treatment are listed in Table 218. Reactions typically occur within 1–2 days of
vaccination (except for rash reactions after measles vaccination, which can arise 6–12 days after
vaccination) and persist for 1–2 days19.

Table 2. Commonly observed vaccine reactions, frequency and treatment
Vaccine Local reaction (pain, Specific reaction

swelling, redness)
Fever > 38 °C Irritability, malaise
and systemic
symptoms
BCG 90–95% None None
Adults, ≤ 15% 1–6% None
Hepatitis B
Children, ≤ 5%
Haemophilus influenza 5–15% 2–10% None
type b
Measles, mumps and 10% 5–15% 5% (rash)
rubella
Oral poliovirus None < 1% < 1%
Pertussis (DTP) ≤ 50% ≤ 50% ≤ 55%
Pneumococcal 20% 20% 20%
conjugate
Tetanus, diphtheria 10% 10% 25%
toxoids adsorbed
Cold cloth on injection Extra oral fluids Extra oral fluids
site
Cool clothing
Treatment Paracetamol
Tepid sponge or bath
Paracetamol
BCG, bacille Calmette-Guérin
Severe vaccine reactions include seizures, thrombocytopenia, hypotonic hyporesponsive episodes and
prolonged crying (Table 3), all of which should be reported. Most severe vaccine reactions do not result
in long-term problems. Anaphylaxis, while potentially fatal, is treatable without long-term effects.
Table 3. Frequency and delay to onset of severe reactions to commonly used vaccines
Vaccine Reaction Delay to onset Frequency per no. of

doses given person
Fatal dissemination of 1–12 months 0.19–1.56/1 000 000
BCG20
BCG infection
Vaccine-associated 4–30 days 2–4/1 000 000
Oral poliovirus vaccine21
paralytic poliomyelitis
Prolonged crying and 0–24 h < 1/100
DTP22
seizures
Hypotonic 0–24 h < 1–2/1000
hyporesponsive
episodes
Measles23 Febrile seizures 6–12 days 1/3000
Thrombocytopenia 15–35 days 1/30 000
Anaphylaxis 1h 1/100 000
BCG, bacille Calmette-Guérin; DTP, diphtheria and tetanus toxoids and pertussis
2.3.2. Reactions associated with defective vaccine quality
These adverse events are caused or precipitated by a vaccine that has one or more defects, including the
administration device provided by the manufacturer. An example would be failure by the manufacturer
to completely inactivate a lot of poliovirus vaccine. If the reaction is related to a particular lot or batch,
the distribution of the lot or batch should be ascertained and instructions provided on its use. The
national regulatory authority and the marketing authorization holder should be notified about the
adverse event, and these bodies should communicate the information to the manufacturer18.
2.3.3. Reactions due to vaccination errors

Vaccination errors result from errors in vaccine preparation, handling, storage or administration
(Table 4)18,24. These errors are preventable. As they detract from the overall benefit of an
immunization programme, identification and correction of these practices are of great importance.
Table 4. Vaccination errors resulting from errors in vaccine preparation, handling, storage or administration
Vaccination error Possible adverse event

Non-sterile injection Local injection-site reaction (e.g. abcess, swelling, cellulitis)
Reuse of disposable syringe or needle, Sepsis
resulting in contamination of a vial,
Toxic shock syndrome
especially in the case of a multi-dose vial
Bloodborne transmission of disease (e.g. hepatitis B, HIV infection)
Improper sterilization of a syringe or needle
Death
Contaminated vaccine or diluent
Reconstitution error Local abcess
Inadequate shaking of vaccine vial Vaccine ineffective
Use of incorrect diluent Effect of drug (e.g. insulin, oxytocin, muscle relaxant)
Drug substituted for vaccine or diluent Toxic shock syndrome
Reuse of reconstituted vaccine at Death
subsequent session
Incorrect injection Abcess or other local reaction
BCG given subcutaneously Damage to sciatic nerve
Diphtheria, tetanus and/or pertussis
vaccine given too superficially
Injection into buttocks
Vaccine transported or stored incorrectly Local reaction to frozen vaccine
Vaccine ineffective
Contraindication ignored Avoidable severe reaction
Vaccination errors can result in a cluster of events, i.e. two or more cases of the same adverse
event related in time, place or the vaccine administered. Clusters are usually associated with a
particular provider or health facility or a vial of vaccine that has been inappropriately prepared or
contaminated. Errors may affect many vials; for example, freezing vaccine during transport may
increase the number of local reactions.
To avoid programme errors24:

• vaccines must be reconstituted only with the diluent supplied by the manufacturer;
• reconstituted vaccines must be discarded at the end of each vaccination session and never
kept longer than 6 h;
• no other drugs or substances should be stored in the refrigerator containing the vaccine; and
• vaccination workers must be adequately trained and closely supervised.
2.3.4. Reactions due to anxiety about vaccination

Individuals may react in anticipation and as a result of any injection. Such reactions are not related to the
vaccine itself or its components but to fear of the injection. The four main reactions are listed below18.
• Fainting is relatively common, mainly among older children and adults. This vasovagal reaction may
lead to loss of postural tone and consciousness. Patients recover spontaneously, and the main risks
are related to falling and not to the underlying mechanism or syncope. Fainting can be prevented by
adequate explanation, vaccination of a patient when he or she is seated or lying down (to avoid injury
caused by falling) and placing patients in a recumbent position after the injection, particularly if they
are prone to fainting (such as adolescents and people with a previous history of fainting).
• Hyperventilation due to anxiety about vaccination can cause light-headedness, dizziness and tingling
around the mouth and in the hands.
• Vomiting: Vomiting is a common anxiety symptom in young children. Breath-holding spells may
occur, which can result in brief unconsciousness, during which breathing resumes.
• Convulsions: An anxiety reaction to injection can, on rare cases, include convulsions. Convulsions
usually occur in the context of a vasovagal reaction and syncope, soon after or with the loss of
postural tone and consciousness that characterizes syncope. Such seizures are due to anoxia, are
usually self-limited and benign and do not require antiepileptic drug therapy.
Mass vaccination events can generate a mass psychogenic reaction25, which is the collective
occurrence of symptoms (e.g. headache, dizziness, loss of consciousness) suggestive of organic
illness in a group with shared beliefs about the cause of the symptoms. Adolescents are particularly
prone, resulting in fainting, sometimes accompanied by tonic–clonic seizure-like movements (not
seizures). Clear explanation of vaccination and calm, confident delivery will decrease the level of
anxiety and reduce the likelihood of an occurrence.
2.3.5. Coincidental events

The majority of problems thought to be related to the administration of a vaccine are actually
not due to the vaccine itself17,18. Many are events that occur at the same time as vaccination. For
example, if a 6-month-old infant has a seizure starting 1 h after a vaccination, it would naturally
be considered differently from one that started 1 h before the vaccination.
Coincidental events are inevitable when children in these age groups are vaccinated, especially
during mass campaigns. The commonest mistake is to establish a causal link between vaccination
and the coincidental event because of the temporal relation. Individual case ascertaiment is not
always easy for a frontline physician, and epidemiological surveillance is essential. The expected
numbers of coincidental events after vaccination can be obtained by comparing the normal
incidences of disease and death in these age groups with the coverage and timing of vaccination.
2.4. Case definitions and treatment of adverse events after
vaccination
Health workers should know how to recognize and treat adverse events after vaccination,
immediately if they are serious. Common adverse events and their treatment are listed below17,18,24,25.
• Fever
Fever can be classified (on the basis of rectal temperature) as mild (38–38.9 °C), high (39-40.4 °C) and
extreme (≥40.5°C). Fever on its own need not be reported. Treatment is symptomatic with paracetamol.
• Local infection
A fluctuant or draining fluid-filled lesion at the site of injection is of bacterial origin if there is
evidence of infection (e.g. purulent, inflammatory signs, fever, culture) and a sterile abscess if not.
Treatment involves incision and drainage; antibiotics should be given if the infection is bacterial.
• Severe local reaction

Redness and/or swelling at the site of injection and one or more of the following:
• swelling beyond the nearest joint;

• pain, redness and swelling of more than 3 days’ duration;
• requires hospitalization.
Local reactions of lesser intensity occur commonly and and need not be reported. They resolve
spontaneously within a few days to a week, and symptomatic treatment with analgesics or
antibiotics is inappropriate.
• Seizures
These comprise generalized convulsions that are not accompanied by focal neurological signs or
symptoms. Febrile seizures occur if the rectal temperature is >38°C (rectal) and afebrile seizures
if the temperature is normal. Seizures are self-limiting; supportive care with paracetamol and
cooling may be given if the patient is febrile. Anticonvulsants are rarely required.
• Encephalopathy
Acute onset of major illness characterized by any two of the following:
• seizures,
• evere alteration in the level of consciousness lasting for ≥ 1 day,
• distinct change in behaviour lasting ≥ 1 day.
If it is related to vaccination, it should occur 7–12 days after administration. No specific treatment
is available; supportive care should be given.
• Thrombocytopenia
Serum platelet count < 50 000/mL, leading to bruising and/or bleeding. The condition is usually
mild and self-limiting; occasionally, steroids or platelet transfusion is required.

• Anaphylactic reaction (acute hypersensitivity reaction)
Exaggerated acute allergic reaction, within 2 h of vaccation, characterized by one or more of the following:
• wheezing and shortness of breath due to bronchospasm,

• laryngospasm or laryngeal oedema,
• skin manifestations, e.g. hives, facial or generalized oedema.
Less severe allergic reactions need not be reported. Self-limiting; antihistamines may be helpful.
• Anaphylaxis
Anaphylaxis is very rare (estimated as once every million doses of vaccine given) but is a severe,
potentially life-threatening allergic reaction. When anaphylaxis occurs, it must be diagnosed
properly and the patient treated and managed urgently by trained staff and transferred to hospital.
Health workers who lack training are highly likely to misdiagnose fainting (vasovagal syncope)
and dizziness after vaccination as the onset on anaphylaxis; most episodes of malaise or fainting
that occur immediately after vaccination are not due to the onset of anaphylaxis.
Programme managers must take these aspects into consideration before deciding at which level of
the health system treatment for anaphylaxis will be provided during a campaign. Once a decision is
made, the appropriate staff should receive training and equipment for the management of anaphylaxis.
Vaccinators should be able to distinguish anaphylaxis from fainting, anxiety and breath-holding
spells, which are common benign reactions (Table 5). A person who is fainting suddenly becomes
pale, loses consciousness and collapses (unless supported). Fainting is sometimes accompanied by
brief clonic seizure activity (i.e. rhythmic jerking of the limbs), which requires no specific treatment
or investigation. Fainting is relatively common after vaccination of adults and adolescents but
very rare in young children. It is managed by simply placing the patient in a recumbent position.
Consciousness is recovered within 1–2 min, but the patient may take more time to recover fully.
An anxiety spell can lead to a pale, fearful appearance and symptoms of hyperventilation (light-headed,
dizziness, tingling in the hands and around the mouth). Breath-holding occurs in young children, leading
to facial flushing and cyanosis, and may end in unconsciousness, during which breathing resumes.
Table 5. Differential diagnosis of fainting and anaphylaxis
Characteristic Fainting (syncope) Anaphylaxis

Onset Usually during or soon after injection Usually after 5–30 min
Skin Pale, sweaty, cold and clammy Generalized red, raised, itchy
rash; swollen eyes and face
Breathing Normal-to-deep breaths Noisy breathing (wheeze or
Symptoms
stridor) due to airway obstruction

Cardiovascular Bradycardia Tachycardia
Transient hypotension Hypotension
Gastrointestinal Nausea and vomiting Abdominal cramps
Neurological Transient loss of consciousness; good Loss of consciousness; little
response when prone response when prone
Recognition of anaphylaxis
Anaphylaxis is a severe reaction of rapid onset (usually 5–30 min after the injection), characterized
by circulatory collapse. The early signs of anaphylaxis are generalized erythema and urticaria and
upper and/or lower respiratory tract obstruction. In more severe cases, limpness, pallor, loss of
consciousness and hypotension are also seen.
Vaccinators should be able to recognize the signs and symptoms of anaphylaxis. In general, the
more severe the reaction, the more rapid the onset. As most life-threatening reactions begin
within 10 min of vaccination, recipients should be kept under observation for at least 30 min after
the injection18,24,25. The clinical progression of anaphylaxis from mild, early-warning signs to late,
life-threatening symtoms is as follows:
• urticaria, rash and swelling around the injection site;

• dizziness and a general feeling of warmth;
• painless swelling, e.g. of the face or mouth;
• flushed, itchy skin, nasal congestion, sneezing and tears;
• hoarseness, neausea and vomiting;
• swelling in the throat, difficulty in breathing and abdominal pain; and
• wheezing, noisy, diffult breathing, collapse, low blood pressure and an irregular, weak pulse.
Unconsciousness is rarely the sole manifestation of anaphylaxis and occurs only as a late event
in severe cases. A strong central pulse (e.g. in the carotid) is maintained during a faint but not in
anaphylaxis. Although anaphylaxis usually involves multiple body systems, symptoms may be
seen in only one body system (e.g. skin), leading to delayed diagnosis. Occasional reports have
been made of symptoms recurring 8–12 h after the onset of the original attack and of prolonged
attacks lasting up to 48 h18,25.
Treatment of anaphylaxis
Once anaphylaxis has been diagnosed, the patient should be considered as having a potentially fatal
condition, regardless of the severity of the symptoms. Treatment should be started immediately
and plans made to transfer the patient swiftly to hospital (if he or she is not already in hospital).
Adrenaline stimulates the heart, reverses spasm in the lung passages and reduces oedema and
urticaria, thus countering anaphylaxis. This very potent agent can, however, cause an irregular
heartbeat, heart failure, severe hypertension and tissue necrosis if used at an inappropriate dose.
Administration of adrenaline for fainting is not only contraindicated but is very dangerous.
Vaccinators trained in the treatment of anaphylaxis should have rapid access to an emergency
kit with adrenaline and be familiar with its dosage and administration24,25. The expiry date of the
adrenaline should be written on the outside of the emergency kit, and the whole kit should be
checked three or four times a year. Adrenaline that has a brown tinge must be discarded18.
2.5. Reporting of adverse events after vaccination

Case detection is the first step in surveillance of adverse events after vaccination. The person who
first reports an adverse event may be a field health worker, clinic or hospital staff, a volunteer, a

parent or another person. Suspicion alone is a valid reason for reporting: the primary reporter is
not expected to assess causality. Rapid detection and evaluation of a possible link to the vaccine
is essential to ensure its continued safety. Thus, a report on a suspected adverse event after
vaccination should preferably be submitted rapidly to a suitable technical authority rather than
waiting until all aspects of the investigation are completed, particularly if the event is serious17,24,25.
In many settings, the primary reporter submits a report to the immediate authority, which is
generally a local public health authority. The report is then transferred through the intermediate
level to national level and to the central immunization programme and/or national regulatory
authority. Recipients at each level may seek clarification or request additional information before
sending the report onwards. The chain depends on the government structure.
To improve detection of adverse events, the primary reporter should have good knowledge of
the types of events and the purpose of surveillance. Regular orientation, training and awareness
programmes can be used to update knowledge and maintain willingness among primary
reporters24,25.
Parents of infants and children to be vaccinated, health workers in vaccination facilities and the
staff of hospital accident and emergency departments are most likely to recognize or detect
adverse events after vaccination when they first occur. Health workers are responsible for
detecting adverse events after vaccination and reporting them when appropriate; they are also
responsible for treating or referring patients17,24,25. All vaccination staff and medical workers must
be capable of diagnosing adverse events. This requires effective training and education to ensure
accurate diagnosis based on clear case definitions, which can be included on the reporting form
and in national guidelines for adverse events after vaccination.
2.5.1. Events to be reported

Any adverse event that is of concern to parents or health care workers must be reported, in
particular24,25:
• serious adverse events,

• signs and events associated with a newly introduced vaccine,
• events after vaccination that might be due vaccination error,
• significant events of unexplained origin that occur within 30 days of vaccination and
• events that raise significant concern for parents or the community.
Reporting of minor adverse events, such as high fever and minor local reactions, is optional.
These are expected vaccine reactions; if all were reported, the reports would overwhelm the
system with information of limited value17. It is nevertheless helpful to record crude numbers of
events and compare them with background rates, which might indicate a product quality defects,
vaccination errors or even increased susceptibility for vaccine reactions in a particular population.
Table 6 lists suggested reportable events24,25. Each country should decide which events should
appropriately be included in its reporting system; however, they are encouraged to include a
broad range of events for the purposes of global harmonization of data.
Table 6. Adverse events after vaccination that it is suggested be reported
Adverse event after vaccination Onset after vaccination

Acute flaccid paralysis in a recipient of oral 4–30 days
poliovirus vaccine
Acute flaccid paralysis after contact with a recipient 4–75 days
of oral poliovirus vaccine
Anaphylaxis (after any vaccine) Within 48 h
Brachial neuritis in a recipient of a tetanus- 2–26 days
containing vaccine
Disseminated BCG infection in a recipient of BCG 1–2 months
vaccine
Encephalopathy in a recipient of
measles or MMR vaccine 6–12 days
DTP vaccine 0–2 days
Hypotonic hyporesponsive episode in a recipient of Median, 3–4 h; range, immediate to 48 h; even after
DTP or pentavalent vaccine 48 h
Bacterial or sterile injection-site abscess in a Not specific; commonly within first 14 days
recipient of any injectable vaccine
Intussusception in a recipient of rotavirus vaccine Commonly within 21 days; risk increased after the
first 7 days and usually the first dose
Lymphadenitis, osteitis or osteomyelitis in a 1–12 months
recipient of BCG vaccine
Persistent (> 3 h) inconsolable screaming in a Common immediately and up to 48 h; can occur
recipient of DTP or pentavalent vaccine after 48 h
Sepsis in a recipient of any injectable vaccine Within 7 days
Seizures, including febrile seizures in a recipient of
measles or MMR vaccine 6-12 days following imunization
DTP vaccine 0-2 days following immunization
Severe local reaction in a recipient of any injectable Within 7 days
vaccine
Thrombocytopenia in a recipient of measles or MMR Median, 12–25 days; range, 1–83 days
vaccine
Toxic shock syndrome in a recipient of any Commonly within 72 h
injectable vaccine
BCG, bacille Calmette-Guérin; MMR, measles, mumps and rubella; DTP, diphtheria, tetanus toxoids and pertussis
The interval between vaccination and the onset of an event may not always be precise or well
established. Consequently, an interval is included in case definitions only for selected adverse
reactions. Case definitions should be simple. Those of the Brighton Collaboration provide different
levels of diagnostic certainty and are widely used27. Countries that find it difficult to adapt them
to their situations can, however, adopt other, valid case definitions for reporting purposes. Local
reactions that occur at increased frequency, even if they are not severe, should also be reported,
as they may indicate vaccination errors or inadequate quality of specific lots.

2.5.2. Timing of reporting
Immediately. A report must be made as quickly as possible so that an immediate decision can be made
on action and investigation. When there are many cases or widespread community concern, a telephone
call, fax or e-mail to the administrative or operational level at which a decision can be made is appropriate.
2.5.3. Mode of reporting

Reports should be made on a standard form (Table 7)17,24,25, which should be supplied by the
immunization service. The form should be simple but should ensure that health workers provide
the essential information: the minimum required information must be entered onto the reporting
form, as it is the basis for decisions about further investigation.
Table 7. Example of a standard form for reporting adverse events after vaccination
Date report first received at the national centre

Identity
Country in which the event was reported

Location (address)
Patient identification
Case
Date of birth or age at time of onset or age group at time of onset

Sex
Medical history
Primary suspected vaccine (generic name)
Vaccine
Other vaccines given just before the adverse event

Batch number and expiry date
Vaccine dose number
Date and time of vaccination
Event
Date and time of onset of adverse event

Adverse event
Outcome
Name of first reporter of adverse event
Reporter
Institution and location

Position and department
E-mail address
Telephone number
Comments (if any) by a national officer before the report is sent to the global database
Other
For optimal monitoring of vaccine safety and meaningful analysis of adverse events after
vaccination, systematic, standard collection of critical data is essential. A limited number of
variables are required to manage adverse events properly, including the unique identifier of
the report, the primary source of information, patient characteristics, details of the event, the
vaccine(s) of interest and the possibility for collecting additional information if needed.
2.5.4. Reporting adverse events during immunization campaigns
In a campaign, a large number of doses are given during a short period, so that there will be
more vaccine reactions and coincidental events26. The rate of events remains unchanged, but the
increased number is readily apparent to both staff and the public, particularly when injectable
vaccines are used and especially at a time of intensive social mobilization26. Programme errors
may also increase during campaigns.
Careful planning will limit negative publicity about an adverse event after vaccination. During
a mass or a special vaccination programme, it is of utmost importance to ensure that adverse
events are reported, for two reasons26:
• Unless an event that occurs during a mass vaccination campaign is properly investigated and
analysed, it may raise concern in the public and may affect the vaccination programme.
• In special immunization programmes, a new vaccine may be introduced for which there is no prior
experience of or little information on adverse reactions. Signs can be detected by strengthening
surveillance during such programmes and may be used to improve the quality of the vaccine.
Even if a national programme does not yet have a functioning adverse events surveillance system,
some form of monitoring is essential in mass campaigns. Otherwise, the public is likely to hear of
an adverse event before the programme manager does, and the situation may become difficult to
control. Surveillance should be simple, flexible and rapid.
One person should be assigned overall responsibility for surveillance of adverse events, who
should be the focal point and the spokesperson. The person may be the manager of the Expanded
Programme on Immunization, the person in charge of surveillance at national level or a staff
member at the national regulatory authority. This is particularly important if surveillance is
conducted by a structure other than the Expanded Programme, if there is a national regulatory
authority or if there is a common monitoring scheme for drugs and vaccines26. Decisions should
be made on what to report, how to report and who is to receive reports. The list of events to
be reported should not be complicated. Countries with limited reporting capacity should decide
which events should be reported during a campaign26.
2.5.5. Barriers to reporting

Immunization service providers may not report adverse events after vaccination for a number of
reasons,17,25 such as:
• deciding that the event was not due to vaccination (however, all events after vaccination as per
the definition should be reported);
• lack of knowledge about the reporting system and process;
• apathy, procrastination, lack of interest or time; inability to find the reporting form;
• fear that the report will have personal consequences; and
• guilt for having caused harm and being held responsible for the event and diffidence about
reporting an event for which the reporter is not confident about the diagnosis.

Unless immunization service providers and units at community level report appropriately, the
safety surveillance system will not be adequate17,24,25. Staff must be encouraged to report adverse
events without fear of penalty. The aim is to improve the system or provide further training and
not to blame individuals. Positive feedback to health workers is essential. It should include the
outcome of investigations or causality assessments, if conducted, and recommendations for
managing the vaccinee, particularly with regard to future vaccination. There must be an adequate
supply of reporting forms. Pre-addressed, postage-paid forms may improve reporting in some
countries, especially by private physicians17,24,25.
2.5.6. Vaccine Adverse Events Information Management System (VAEIMS)

The VAEIMS consists of software developed by the International Vaccine Institute in collaboration
with WHO25. Its purpose is for the transfer of core variables on adverse events after vaccination
efficiently and effectively from the periphery of a health care system to a central database for
processing and conversion into information to guide actions. The design of VAEIMS takes into
account the diverse systems of data collection, transmission, analysis and feedback in different
countries25. It is tailored to local conditions and provides quick, reliable information to decision-
makers in a country at all levels and globally.
VAEIMS allows transfer of data from a national database to the global database (Vigibase), as it is
E2B-compatible, for sharing information on adverse events after vaccination25. Both a web-based
and an offline version of VAEIMS are available free of charge. The web-based version includes real-
time data uploading, data sharing and analysis. Later, reporting of adverse events after vaccination
from the periphery to national level will be facilitated by the collection of data on mobile telephones.
3. Valid and false contraindications

to vaccination
3.1. When to vaccinate safely
National standards for paediatric vaccination include descriptions of valid contraindica¬tions
to vaccination and precautions to be taken. The people who administer vaccines should screen
patients for contraindications and take precautions before giving each dose of vaccine. Screening
is facilitated by consistent use of questionnaires available from certain state vaccination
programmes and other sources18.
A contraindication to vaccination is a rare characteristic of a recipient that increases their risk for a
serious adverse reaction. Ignoring contraindications can lead to vaccine reactions. One of the most
serious reactions after vaccination is anaphylaxis, which is the only absolute contraindication to
subsequent doses of the same vaccine25. Most contraindications, such as severe acute illness (e.g.
acute respiratory tract infection) or treatment with steroids, are temporary, and the vaccination can
be administered later. These are known as “temporary” or “relative” contraindications. In addition,
people who are severely immunocompromised generally should not receive live vaccines25.
Children who experience encephalopathy within 7 days of a dose of diphtheria and tetanus toxoids,
Valid and false contraindications to vaccination 21

whole-cell pertussis vaccine, DTP, DTaP or Tdap that is not attributable to another identifiable
cause should not receive an additional dose of a vaccine that contains pertussis bacteria25.
There is no evidence that the fetuses of pregnant women vaccinated with inactivated virus, bacterial
vaccines or toxoids are at risk28,29. Live attenuated vaccines administered to a pregnant woman pose
a theoretical risk to the fetus, but the benefits of vaccinating pregnant women usually outweigh the
potential risks when the likelihood of exposure to the disease-causing agent is high, when infection
would pose a risk to the mother or the fetus and when the vaccine is unlikely to cause harm29.
The safety and effectiveness of vaccines in immunocompromised persons are determined by the
type of immunodeficiency and degree of immunosuppression. Each person is different and should
be considered unique with regard to vaccination. Under-immunized people are at risk for serious
illness and death, and every effort should be made to ensure adequate protection through vaccination.
Nevertheless, inappropriate use of live attenuated vaccine can cause serious adverse events in some
immunocompromised people due to uncontrolled replication of the vaccine virus or bacterium29.
Precautions should be taken when a recipient has a condition that might increase his or her risk for
a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity;
examples are administration of measles vaccine to a person who is passively immune to measles due
to exposure during a blood transfusion, or administration of influenza vaccine to a person with a history
of Guillain-Barré syndrome within 6 weeks of a previous influenza vaccination. Such people might
experience more severe reactions to the vaccine than would otherwise have been expected; however,
the risk is lower than that expected with a contraindication. In general, vaccination should be deferred
if precaution is indicated. Vaccination might be indicated, however, if the benefit of protection outweighs
the risk for an adverse reaction. For example, a dose of DTaP should be considered for a person in a
community with a pertussis outbreak, even if he or she had Guillain-Barré syndrome after a dose. The
presence of a moderate or severe acute illness with or without a fever calls for caution in administering
any vaccine, and a personal or family history of seizures calls for caution in giving MMR vaccine29.
3.1.1. Contraindications to commonly used vaccines and precautions to be taken

The main contraindications to commonly used vaccines are listed in Table 8, with precautions to
be taken29.

Table 8. Main contraindications to commonly used vaccines and indications for precautions to be taken
Vaccine Contraindications Indications for precautions

DTwP Severe allergic reaction (e.g. Progressive neurological disorder, including
anaphylaxis) after a previous dose or infantile spasms, uncontrolled epilepsy, progressive
to a vaccine component encephalopathy: defer DTwP until neurological status
known and stabilized
Encephalopathy (e.g. coma,
decreased level of conscious¬ness, or Temperature of ≥ 40.5 °C within 48 h of vaccination
prolonged seizures), not attributable with a DTP or DTaP
to another identifiable cause, within
Collapse or shock-like state (i.e. hypotonic
7 days of administration of a dose of
hyporesponsive episode) within 48 h of a dose of DTP
DTP or DTwP
or DTwP
Seizure ≤ 3 days of a dose of DTP or DTwP
Persistent, inconsolable crying lasting ≥ 3 h within 48
h of a dose of DTP or DTwP
GBS < 6 weeks after a dose of tetanus toxoid-
containing vaccine
History of arthus-type hypersensitivity reaction
after a dose of tetanus toxoid-containing vaccine:
defer vaccination until at least 10 years since the last
tetanus toxoid-containing vaccine
Moderate or severe acute illness with or without fever
DT, Td Severe allergic reaction (e.g. GBS < 6 weeks after a dose of tetanus toxoid-
anaphylaxis) after a previous dose or containing vaccine
to a vaccine component
History of arthus-type hypersensitivity reaction
Tdwp Severe allergic reaction (e.g. GBS < 6 weeks after a dose of tetanus toxoid-
anaphylaxis) after a previous dose or containing vaccine
Progressive or unstable neurological disorder,
Encephalopathy (e.g. coma, uncontrolled seizures or progressive encephalopathy
decreased conscious¬ness or until a treatment regimen has been established and
prolonged seizures) not attributable the condition has stabilized
to another identifiable cause within 7
History of arthus-type hypersensitivity reactions
days of a dose of DTP, DTwP or Tdwp
MMRa,b Severe allergic reaction (e.g. Recent (≤ 11 months) receipt of antibody-containing
anaphylaxis) after a previous dose or blood product (interval depends on product)
History of thrombocytopenia or thrombocytopenic
Pregnancy purpura
Known severe immunodeficiency Indication for tuberculin skin testing
(due e.g. to a haematological or solid
tumour, chemotherapy, congenital
immunodeficiency or long-term
immunosuppressive therapyc or in
patients with HIV infection who are
severely immunocompromised)b

Hib Severe allergic reaction (e.g. Moderate or severe acute illness with or without fever
anaphylaxis) after a previous dose or
Age < 6 weeks
Hepatitis Severe allergic reaction (e.g. Infant weight < 2000 gd
B anaphylaxis) after a previous dose or
OPV Severe allergic reaction (e.g. Pregnancy
Varicella Severe allergic reaction (e.g. Recent (≤ 11 months) receipt of antibody-containing
anaphylaxis) after a previous dose or blood product (interval depends on product)e
Known severe immunodeficiency
(due e.g. to a haematological or solid
tumour, chemotherapy, congenital
immunodeficiency or long-term
immunosuppressive therapyc or in
patients with HIV infection who are
severely immunocompromised)b
Pregnancy
PCV Severe allergic reaction (e.g. Moderate or severe acute illness with or without fever
to a component of PCV7, PCV13 or any
diphtheria toxoid-contain¬ing vaccine
HPV Severe allergic reaction (e.g. Pregnancy
DT, diphtheria and tetanus toxoids; DTwP, diphtheria and tetanus toxoids and whole-cell pertussis; GBS, Guillian-Barré syndrome;
HBsAg, hepatitis B surface antigen; Hib, Haemophilus influenzae type b; HIV, human immunodeficiency virus; HPV, human
papillomavirus; OPV, oral poliovirus vaccine; MMR, measles, mumps and rubella; PCV, pneumococcal conjugate vaccine; SCID,
severe combined immunodeficiency; Td, tetanus and diphtheria toxoids; Tdwp, tetanus toxoid, reduced diphtheria toxoid and whole-
cell pertussis.
Events or conditions listed as indications for precautions should be reviewed carefully, and the benefits and risks of administering
a specific vaccine to a person under these circum¬stances should be considered. If the risk of adverse events from the vaccine is
considered to outweigh the benefits, the vaccine should not be administered. If the benefit of vaccination is considered to outweigh
the risk, the vaccine should be administered. Whether and when to administer DTaP to children with a proven or suspected
underlying neurological disorder should be decided case by case.
a HIV-infected children may receive varicella and measles vaccine if their CD4+ T-lymphocyte count is > 15%30
b MMR and varicella vaccines may be administered on the same day. If not, vaccination with these products should be separated
by at least 28 days. Measles vaccine might temporarily suppress tuberculin reactivity. Measles-containing vaccine can be
administered on the same day as tuberculin skin testing. If testing cannot be performed until after MMR vaccination, it should
be postponed for ≥ 4 weeks after vaccination. If skin testing is urgently required, it should be done on the understanding that
reactivity might be reduced by the vaccine.
c A substantially immunosuppressive steroid dose is considered to be 20 mg or 2 mg/kg body weight per day of prednisone or
equivalent for ≥ 2 weeks.
d Hepatitis B vaccination should be deferred for infants weighing < 2000 g if the mother is documented as HBsAg-negative at
the time of the infant’s birth. Vaccination can commence at a chronological age of 1 month or at hospital discharge. For infants
born to HBsAg-positive women, hepatitis B immune globulin and hepatitis B vaccine should be administered within 12 h of
birth, regardless of their weight.
e Vaccination should be deferred for an appropriate interval if replacement immune globulin products are being administered.

3.1.2. Precautions for administration of rotavirus vaccine
Altered immunocompetence
Children and adults who are immunocompromised due to congenital immunodeficiency or
haematopoietic or solid organ transplantation sometimes experience severe or prolonged
rotaviral gastroenteritis31,32. No data are available, however, on the safety or efficacy of rotavirus
vaccine in infants who are immunocompromised or potentially immunocompromised.
In the case of infants who are exposed to or infected with HIV, two considerations support
vaccination31,32:
• A diagnosis of infection might not be established in infants born to HIV-infected mothers before
the age at which they receive the first dose of rotavirus vaccine (for example, only 1.5–3% of
HIV-exposed infants in the USA are found to be HIV-infected).
• Vaccine strains of rotavirus are considerably attenuated.
Acute gastroenteritis
Under usual circumstances, rotavirus vaccine should not be administered to infants with acute
moderate or severe gastroenteritis until the condition improves; however, infants with mild acute
gastroenteritis can be vaccinated, particularly if the delay in vaccination would be substantial,
making the infant ineligible for vaccination (e.g. aged > 15 weeks and 0 days before the vaccine
series is started)31,32.
Moderate or severe acute illness

As for all vaccines, the presence of moderate or severe acute illness with or without fever
warrants precaution in administering rotavirus vaccine. Infants with moderate or severe acute
illness should be vaccinated as soon as they have recovered from the acute phase of the illness.
Vaccination should not be delayed because of the presence of mild respiratory tract illness or
other mild acute illness with or without fever31,32.
Pre-existing chronic gastrointestinal disease

Infants with pre-existing gastrointestinal conditions (e.g. congenital malabsorption syndromes,
Hirschsprung disease or short-gut syndrome) who are not undergoing immunosuppressive
therapy should receive rotavirus vaccine, as the benefits outweigh the theoretical risks31,32.
History of intussusception
Practitioners should consider the potential risks and benefits of administering rotavirus vaccine
to infants with a history of intussusception, who are at higher risk for a repeat episode than
infants who have never had intussusception31,32.
Infants with spina bifida or bladder exstrophy

The RV1 oral applicator contains latex rubber, whereas the RV5 dosing tube is latex-free. If RV1 is
the only rotavirus vaccine available, it should be administered, because the benefit of vaccination
is considered to be greater than the risk for sensitization31,32.

3.2. Misperceptions about vaccination
Clinicians and other health-care providers might misperceive certain conditions or circumstances
as valid contraindications or indications of precaution for vaccination when they actually do not
preclude vaccination (Table 9). These misperceptions result in missed opportunities to administer
recommended vaccines33. Among the most common conditions mistakenly considered to be
contraindications are diarrhoea, minor upper respiratory tract illnesses (including otitis media)
with or without fever, mild to moderate local reactions to a previous dose of vaccine, current
antimicrobial therapy and being in the convalescent phase of an acute illness.
Table 9. Conditions commonly misperceived as contraindications to vaccination29
Vaccine Conditions commonly misperceived as contraindications (i.e. vaccine may be

administered under these conditions)
For all vaccines: Mild acute illness with or without fever
DTwP, DT, Tdwp,
Mild-to-moderate local reaction (i.e. swelling, redness, soreness); low-grade or
OPV, MMR,
moderate fever after previous dose
Hib, hepatitis
B, varicella, No previous physical examination of a person appearing to be well
rotavirus, PCV,
Current antimicrobial therapya
HPV
Convalescent phase of illness
Preterm birth (except hepatitis B vaccine in certain circumstances)b
Recent exposure to an infectious disease
History of penicillin allergy, other non-vaccine allergies, relatives with allergies or
receiving allergen extract immunotherapy
DTwP Fever of < 40.5 °C, fussiness or mild drowsiness after a previous dose of DTP or DTwP
Family history of seizures
Family history of sudden infant death syndrome
Family history of an adverse event after DTP or DTaP
Stable neurological condition (e.g. cerebral palsy, well-controlled seizures or
developmental delay)
Tdwp Fever of ≥ 40.5 °C for < 48 h after vaccination with a previous dose of DTP or DTwP
Collapse or shock-like state (i.e. hypotonic hyporesponsive episode) within 48 h of
receiving a previous dose of DTP or DTwP
Seizure < 3 days after receiving a previous dose of DTP or DTwP
Persistent, inconsolable crying lasting > 3 h within 48 h of receiving a previous dose of
DTP or DTwP
History of extensive limb swelling after DTP, DTwP or Td that is not an arthus-type
reaction
Stable neurological disorder
History of brachial neuritis
Latex allergy that is not anaphylactic
Breastfeeding
Immunosuppression
OPV Previous receipt of one or more doses of oral poliovirus vaccine

MMRc,d Positive tuberculin skin test
Simultaneous tuberculin skin testinge
Breastfeeding
Pregnancy of recipient’s mother or other close or household contact
Female recipient of child-bearing age
Immunodeficient family member or household contact
Asymptomatic or mildly symptomatic HIV infection
Allergy to eggs
Hepatitis B Pregnancy
Autoimmune disease (e.g. systemic lupus erythematosis or rheumatoid arthritis)
Varicella Pregnancy of recipient’s mother or other close or household contact
Immunodeficient family member or household contactf
Asymptomatic or mildly symptomatic HIV infection
Humoral immunodeficiency (e.g. agammaglobulinaemia)
HPV Immunosuppression
Previous equivocal or abnormal Papanicolaou test
Known HPV infection
Breastfeeding
History of genital warts
Rotavirus Prematurity
Immunosuppressed household contacts
Pregnant household contacts
DT, diphtheria and tetanus toxoids; DTP, diphtheria toxoid, tetanus toxoid and pertussis; DTwP, diphtheria and tetanus toxoids and
whole-cell pertussis; HBsAg, hepatitis B surface antigen; Hib, Haemophilus influenzae type b; HPV, human papillomavirus; OPV, oral
poliovirus; MMR, measles, mumps and rubella; PCV, pneumococcal conjugate vaccine; Td, tetanus and diphtheria toxoids; Tdwp,
tetanus toxoid, reduced diphtheria toxoid and whole-cell pertussis
a Antibacterial agents have no effect on the response to live, attenuated vaccines, except for live oral typhoid vaccine, and
have no effect on inactivated, recombinant subunit or polysaccharide vaccines or toxoids. Typhoid vaccine should not be
administered to people receiving antimicrobial agents until 24 h after the last dose. If feasible, to avoid a possible reduction
in vaccine effectiveness, antibacterial drugs should not be started or resumed until 1 week after the last dose of oral typhoid
vaccine.
b Hepatitis B vaccination should be deferred for infants weighing < 2000 g if the mother is documented as HBsAg-negative at
the time of the infant’s birth. Vaccination can done at a chronological age of 1 month or at hospital discharge. For infants born
to HBsAg-positive women, hepatitis B immune globulin and hepatitis B vaccine should be administered within 12 h of birth,
regardless of weight.
c MMR and varicella vaccines can be administered on the same day. If not, the two vaccinations should be separated by at least
28 days.
d HIV-infected children should receive immune globulin after exposure to measles. They may receive varicella and measles
vaccines if their CD4+ T-lymphocyte count is > 15%.
e Measles vaccination might suppress tuberculin reactivity temporarily. Measles-containing vaccine can be administered on
the same day as tuberculin skin testing. If testing cannot be performed on the same day, it should be postponed for at least 4
weeks after vaccination. If a skin test is urgent, it should be understood that reactivity might be reduced by the vaccine.
f If a vaccinee experiences a presumed vaccine-related rash 7–25 days after vaccination, he or she should avoid direct contact
with immunocompromised people for the duration of the rash.

A decision to administer or delay vaccination because of a current or recent acute illness depends
on the severity of symptoms and the etiology of the condition. Vaccines have been shown to be safe
and effective in people who have mild illness. Vaccination should not be delayed because of the
presence of a mild respiratory tract illness or other acute illness with or without fever but should
be deferred in cases of moderate or severe acute illness29. This precaution avoids diagnostic
confusion between manifestations of the underlying illness and possible adverse effects of
vaccination and avoids superimposing adverse effects of the vaccine on the underlying illness.
After people with moderate or severe acute illness have been screened for contraindications, they
should be vaccinated as soon as their condition has improved. Failure to vaccinate children with
minor illnesses can impede vaccination efforts. For people whose compliance with medical care
cannot be ensured, every opportunity should be taken to administer appropriate vaccines.
Routine physical examinations and procedures such as measur¬ing temperature are not necessary
for vaccinating people who appear to be healthy. The provider should ask the parent or guardian
of a child whether he or she is ill. If the child has a moderate or severe illness, vaccination should
be postponed.
The conditions commonly misperceived as contraindications to vaccination with injectable vaccines

are neurological diseases, neonatal jaundice, low haemoglobin concentration, haemangioma,
encephalopathy and low birth weight29.
4. Facts and myths about

vaccination
4.1. Introduction
Vaccination has been shown repeatedly to be one of the most (if not the most) effective
interventions for preventing disease worldwide. Readers of The British Medical Journal in 2007
voted vaccination as one of the four most important developments in medicine of the previous 150
years, with sanitation, antibiotics and anaesthesia34.
Modern vaccines provide high levels of protection against an increasing number of diseases and
the symptoms, disability and death that may occur. At the same time, serious reactions to vaccines
are rare. The fact that vaccines are administered to healthy people to prevent diseases that have
become rare, largely thanks to vaccination, contributes to concern about vaccine safety35. Because
the devastating effects of these diseases are no longer so evident, public attention is focused on
the side-effects of vaccination, which influences how people weigh up the risks and benefits of
vaccination.
In some instances, concerns about the safety of certain vaccines have led to downturns in
vaccination rates and outbreaks of disease13. Most of the arguments against vaccination appeal
to parents’ understandable, deep concern for the health of their children, particularly very young
infants. Unfounded allegations of adverse effects of vaccines typically relate to feared diseases

and syndromes or conditions of unknown or uncertain cause, such as autism, sudden infant death
syndrome and multiple sclerosis.
Three anti-vaccine profiles have been identified.
• Uninformed, ignorant, passive objectors: Such people have no objective reasons or good
objective information about vaccines. They are not aware that a decision not to vaccinate is an
active decision with consequences. They can be addressed with education and information.
• Conspiracy freaks: Such people have hilarious reasons or have built up their own theories
of how vaccines are made and the side-effects that can occur, with no supporting rationale.
They spread their messages through blogs, web pages and books with no scientific basis and
offer alternative explanations for the outstanding benefits of vaccines. This group is difficult
to address, and investing time on them is usually not efficient, as they do not listen to reason.
• Pseudo-intellectuals and alternative life-style parents: This group is generally made up of
parents with a medium or high level of education. They have read or heard information with no
scientific basis but have built their own theories about vaccination. They rely on herd protection
from vaccinated children around their own children. This group requires education and
information to make them change their minds. They usually use homeopathy and “alternative”
or “natural” medicine and have a pure, ecological life-style.
4.2. Reasons given for refusing vaccination

Some people believe that vaccine-preventable diseases have been almost entirely eliminated
and that the risk for exposure to infectious disease is minimal; therefore, they conclude that no
vaccination programme is needed. The public may receive mixed, often confusing messages that
leave them feeling ambivalent about vaccination. The majority are supportive of vaccination, and
only a minority of parents refuse vaccination of their children. Their rejection may be related to
wider scepticism about orthodox medical interventions and support for alternative approaches
to health. Others may have had a personal experience in which they, their child or an immediate
family member had an adverse event that they consider was attributable to vaccination, or they
may be generally concerned about the safety of vaccines for other reasons. Some people become
vocal opponents of vaccination, spreading messages against it in the mass and social media and
through grassroots lobbying.
4.2.1. Barriers to vaccination

The first step is to identify barriers, which include lack of information, doubts about vaccine
efficacy or about the evidence, moral barriers, cost, pressure from the mass media, concern
about safety and exposure to anti-vaccine groups. The only means to overcome these barriers
is information. A number of web sites provide scientific information on vaccination, such as
http://onlinenursepractitionerprograms.com/vaccine-immunization/.
Anti-vaccination movements aren’t new. Newspaper articles on false concerns about the safety
of vaccines can be very harmful, as they tend to appear on the first page! Many publishers are not
concerned about whether the information has been countered or confirmed, and the consequences
of such statements can reduce vaccine dose distribution rapidly.
Facts and myths about vaccination 29

What parents want to know about vaccines
Parents need information to answer their questions:
• What are the risks?

• Does it hurt?
• How much does it cost?
• What will it protect my child against?
• Does the disease still exist?
• What’s a vaccination programme?
• “I have read that...”
Good examples of vaccination information sheets for parents are available on the WHO web site:
• Seven key reasons for immunization: http://www.euro.who.int/__data/assets/pdf_

file/0017/84302/Seven_Key_Reasons.pdf
• New immunization resources launched in 2013: http://www.euro.who.int/en/what-we-do/health-
topics/disease-prevention/vaccines-andimmunization/european-immunization-week/
european-immunization-week-2013/new-immunization-resources-launched-in-eiw-2013
At the same time, general practitioners and paediatricians should be trained. Many web sites offer
this kind of training, information and fact sheets, including those of WHO, the Centers for Disease
Control and Prevention in the USA, the European Centre for Disease Prevention and Control and
local and national authorities.
Not to vaccinate is an active decision

Vaccine-preventable diseases or, worse, deaths are unacceptable. The minimal risks of vaccination
are completely overshadowed by the health risks of non-vaccination. The most important misbelief
of parents who refuse to vaccinate their children is that vaccination is an active decision while not
to vaccinate is not.
A successful vaccination programme requires acceptance, communication, information and

education, and collaboration between national public health authorities, health care professionals,
patients and parents is crucial.
4.2.2. Objections to vaccines based on religious beliefs

Some religious groups are concerned about the origin or characteristics of some vaccine
ingredients, such as gelatin, which is partially hydrolysed collagen, usually of bovine or porcine
origin4,5,36. Gelatin is added to some vaccines as a stabilizer in adverse conditions, such as
temperature extremes, which may affect vaccine quality. Some people of the Islamic and
Jewish faiths object to vaccination because vaccines may contain pork products4,5,36. Scholars
of the Islamic Organization for Medical Sciences, however, have decided that transformation of
the original pork product into gelatin alters it sufficiently to make vaccination permissible for
observant Muslims37. Likewise, leaders of the Jewish faith also permit pork-derived (transformed)
additives in medicines.

Concern has been raised about the ethics of receiving a vaccine when the cells in which the
vaccine virus was grown were obtained from an aborted fetus. Although, under the right
supportive conditions, bacteria can survive and replicate on their own, viruses require cells in
order to replicate and can be grown only in the laboratory in cells or “cell lines”. A cell line is a
specific population of cells that is maintained in culture for an extended period. Cell lines have
an unlimited lifespan and represent a renewable, predictable system for growing viruses used
in the production of vaccines. The best cell types in which to grow human-specific viruses are
often derived originally from a sample of human tissue. It is very hard to grow some viruses
that infect humans in any other type of cell. Certain cell lines (human diploid cell lines WI-38 and
MRC-5) originated from fetal tissue were obtained from three elective abortions indicated for
medical reasons in the 1960s39. These cell lines have been growing under laboratory conditions
for more than 40 years. No tissue has been obtained from fetuses since that time. Abortions have
not been conducted specifically for the purpose of harvesting cell lines. The vaccines that are
manufactured in cell lines originally derived from fetal tissue include rubella-containing vaccines
(MMR and MMRV), hepatitis A vaccines, varicella vaccines and rabies vaccine40-46.
Some people with religious objections to abortion have questioned the use of these vaccines. A
statement from the Vatican47 includes the comment that “as regards the disease against which
there is no alternative … if the latter [population as a whole] are exposed to considerable dangers
to their health, vaccines with moral problems pertaining to them may also be used on a temporary
basis … this is particularly true in the case of vaccination against German measles [rubella]”.
4.3. Responding to concerns

Health professionals are the single most important, powerful influence on a people’s decision to
vaccinate themselves or their children48. Health professionals must be well informed about common
concerns associated with vaccination so they can provide authoritative, scientifically valid advice49.
To obtain consent to vaccinate, the people delivering vaccines must honestly discuss the benefits
and risks associated with vaccination and the risks for disease and complications that might
result from withholding vaccination. If patients or parents raise arguments against vaccination,
the best approach of health professionals is to listen to their concerns, explore their reasoning
and then provide information appropriate to the person’s circumstances and educational level49.
A decision about vaccination should be made in partnership between the patient or client and
the health professional. Information is best provided in a credible written format and presented
in an objective way. Health professionals should avoid downplaying concerns or offering overtly
personal opinions, respect differences of opinion and consider the personal, cultural and religious
factors that might influence a person’s decision about vaccination49.
4.3.1. Vaccine manufacture and testing

Vaaccines must be safe, as they are given to prevent disease; immunization programmes are
targeted at all or many members of a population, most of whom are healthy. Concern about the
manufacture and testing of vaccines is related mainly to the possibility that vaccines contain toxic
or harmful substances or biological agents used in the manufacturing process4,5,36. The most
common questions and the related facts are summarized below.

• “Vaccines contain foreign proteins.”
Depending on their purpose and composition, vaccines can contain live viruses, killed viruses,
purified viral proteins, inactivated bacterial toxins or bacterial polysaccharides. Vaccines are
complex pharmaceutical products that must be able to withstand transport, storage and adverse
environmental factors. To ensure that they are stable over time, vaccines may contain additives,
such as gelatin or albumin4,5,36. Furthermore, some vaccines contain trace residual quantities
of substances used during the manufacturing process, such as formaldehyde, antibiotics, egg
proteins and yeast proteins4,5,36.
A question that arises about vaccines that contain foreign material is the presence of egg proteins.
Some vaccines are grown in eggs and should be given with caution to people with known egg
allergy. The risk for an allergic reaction to these vaccines depends on the amount of egg protein
(ovalbumin) in the vaccine and the severity of the allergy50,51. Most influenza vaccines currently
in use have only trace amounts of ovalbumin (< 1 µg) per dose and can be given safely to most
people who are allergic to eggs51. Nevertheless, individuals with a severe allergy should seek
specialist advice. Yellow fever and one of the rabies vaccines contain larger amounts of ovalbumin
and generally should not be given to people with a severe allergy to eggs52.
The measles and mumps viruses used in vaccines are grown in chick embryo cell lines, not in
eggs50. It is now recognized that measles- and mumps-containing vaccines (MMR and MMRV)
contain negligible amounts of egg protein and can be given to children with an egg allergy, even
those who respond with anaphylaxis to egg50. If parents ask for reassurance about vaccination of
a child with an egg or other allergy, the child can be referred to a specialist immunization clinic,
paediatrician or infectious diseases specialist with an interest in immunization. Specialist advice
can also be obtained from state or territorial health authorities.
4.3.2. The immune system and the host response
• “Vaccines weaken or overwhelm the immune system.”
Healthy people can mount a response to any infection they encounter. Vaccines do not weaken
their immune system but strengthen it by stimulating the defence mechanisms that provide
protection against diseases53,54. The body’s immune system begins developing before birth. During
and soon after birth, when the immune system is still maturing, newborns are protected against
many, but not all, serious infections by antibodies from their mothers (maternal antibodies). This
protection usually lasts about 4 months55. National immunization programmes are planned to
balance the capacity of the infant’s immune system to respond to a vaccine against their risk for
infection. Vaccines contain many fewer antigens than those that children encounter every day in
their environment while eating, drinking and playing, and they do not overwhelm or “use up” the
immune system53,54.
If the administration of multiple vaccines overwhelmed the immune system, much weaker
immune responses might be expected than when they are given at different times. During the

development of vaccines, however, tests are conducted to confirm that addition of a new vaccine to
combinations given at the same time does not change the immune response or the safety profile54.
In addition, combination vaccines, such as the five- or six-in-one DTPw-containing vaccines and
the combination MMRV vaccine, are all rigorously tested during research and development to
ensure that the immune response to each vaccine antigen is adequate54.
• “Is natural immunity better than vaccine-acquired immunity?”
Vaccines stimulate the natural immune response, so that exposure to the same pathogen in the
future triggers the immune system to “remember” it and mount an effective response to stop the
disease from developing or to reduce the severity of disease53-55.
Some people consider that vaccination is unnatural and that contracting a disease provides optimal
protection, as well as benefits to overall health56. Tied to this is the belief that vaccination interferes
with the body’s natural processes53. Choosing to remain unvaccinated and have the disease rather
than prevent it can, however, have serious consequences. Diseases such as tetanus and meningitis
can kill and maim, whereas the vaccines against these diseases are generally well tolerated, with
minor side-effects. Vaccines provide the same stimulus to the immune system as an infection and
can offer more effective protection against certain pathogens. Most importantly, protection through
vaccination avoids the complications associated with the disease. For example, infection with wild
measles virus causes encephalitis (inflammation of the brain) in one in 1000 infected individuals,
and measles infection kills two of every 1000 infected individuals. In contrast, the combination
MMR vaccine causes a severe allergic reaction only once in every 1 000 000 vaccinated individuals,
while preventing measles infection25,26. The benefits of vaccine-acquired immunity heavily outweigh
the serious risks associated with natural infection. The Haemophilus influenzae type b (Hib) and
tetanus vaccines actually provide more effective immunity than natural infection53-55. The benefits of
vaccination far outweigh those of infection with a vaccine-preventable disease.
• “Homeopathic preparations are an alternative to conventional vaccines.”
There is no scientific evidence that any homoeopathic preparation can prevent the diseases
targeted by conventional vaccines, whereas the effectiveness of conventional vaccines is well
established by large-scale studies57. Homoeopathic preparations have been subjected to scientific
scrutiny in very few studies57. As none included a preparation for use against a disease on the
current national immunization schedule, the efficacy of these preparations against those diseases
has not been established57.
Several homoeopathic substances are marketed as “vaccines”. Most are manufactured by serial
dilutions of a disease-causing organism, tissue or plant extract, to the point where only an
infinitesimal amount of the original material is present. This process of “succussion” is said to
transfer the protective activity of the original material to the diluting water; however, there is no
physically plausible mechanism by which ingestion of such preparations could prevent infection
and/or the related diseases. These preparations are unfortunately widely diffused and accepted
even by some health care professionals on the basis of their “placebo” effect.

• “Vaccines cause or worsen asthma and allergies.”
There is no evidence that vaccines cause or worsen allergic diseases such as asthma or
eczema58-62. Many studies have been conducted to determine whether wheezing occurs more
commonly in children after they have received a vaccine, and it is clear that this is not the case58-
62
. It is especially important that children with asthma are given all the recommended vaccines,
as a disease like pertussis or influenza can worsen asthma. Influenza vaccination is particularly
recommended for children with asthma because of this risk62.
Vaccines or their components can cause allergic reactions in some people; however, the risk is
low18. For example, the risk for anaphylaxis after a single vaccine dose has been estimated as less
than one in a million63. The risk depends, however, on the vaccine type. Components of vaccines
that can trigger an allergic reaction include gelatin, yeast and egg protein50-52. (Vaccination of
people who are allergic to eggs is discussed above.) It is important to determine the presence
of an allergy and the exact nature of the allergic response, if present. Children and adults with
most food or environmental allergies, such as dust mite or hayfever, can be safely vaccinated18.
Vaccination is contraindicated for people who have experienced anaphylaxis after a previous dose
of a particular vaccine or any vaccine component18,36.
If a health care provider is unsure about vaccinating a person with a history of an allergic reaction
after a vaccine or vaccine component, he or she should contact a specialist immunization clinic, a
paediatrician or an infectious diseases specialist with an interest in immunization.
4.3.3. Are vaccines really necessary?
• “Infectious diseases are not serious.”
Some people argue that infections are a normal, healthy part of growing up; however, the infectious
diseases targeted by vaccines can be serious and even fatal64-67. These diseases were common in
many countries before vaccination, but the number of cases of these diseases has been reduced
with the introduction of vaccines and very high vaccination rates in the community64-67. Current
generations of parents are unlikely to have seen a child paralysed by poliomyelitis, who requires an
“iron-lung” to breathe, a child with obstructed breathing due to diphtheria or someone with brain
damage due to measles. Other diseases like varicella (chickenpox) are generally considered mild
childhood diseases; however, varicella can be severe or fatal, particularly in immunocompromised
children and adults68. Influenza is sometimes dismissed as not being serious: many people refer
to the common cold as “the flu”; however, influenza is not the same as the common cold and can
be a serious infection, particularly in elderly people, causing dozens of deaths every year69-73.
Other vaccine-preventable diseases, such as meningitis due to Hib, meningococcus or

pneumococcus, while not seen very commonly in some countries, can also be associated with
serious health consequences74,75.

• “Improved living standards, not vaccination, have reduced infectious diseases.”
Some people argue that improved health and hygiene were the reasons for the dramatic decrease
in infectious diseases during the past century, not vaccines12. To support this argument, they use
graphs showing decreasing death rates from disease before the introduction of vaccines and
no visible impact of vaccination. All these graphs show overall death rates rather than disease
incidence, thus hiding the true effect of vaccines.
While overall improvements in living standards, health care and treatment have reduced the
numbers of deaths from all diseases, the additional impact of vaccines is illustrated by the near
disappearance of deaths from diphtheria, tetanus, pertussis, poliomyelitis and measles64-67. Such
dramatic decreases after the introduction of vaccines, often over a short period, could not be due
to improved living conditions or medical treatment alone.
Examples that demonstrate that vaccines have had a marked impact on the incidence of infectious
diseases are listed below.
• Smallpox, which used to kill 5 million people worldwide every year, was eradicated in 1978
and is now all but forgotten12.
• The WHO Region of the Americas eliminated measles in 2002, only 12 years after a large
measles outbreak in 1990, which resulted in more than 250.000 cases and over 10,000
deaths12,76.
• In the WHO European Region, all Member States agreed upon the target of measles and rubella
elimination by 2015. There is still a large burden of measles in the Region, but the number of
cases reported has decreased by more than 96%, from 215,767 in 1997 to 7,499 cases in 201012,76.
• The WHO European Region was declared free from polio (no endemic polio transmission) in 2002
and reported no cases for 7 years. While the Region has experienced outbreaks of imported
wild poliovirus in 2010, it has been interrupted, and the goal of global polio eradication lies
within reach. Four countries globally remain endemic for poliovirus (Afghanistan, India, Nigeria
and Pakistan). So far, the global fight against polio has saved 5 million people from paralysis12
One of the best ways to demonstrate the impact of a vaccination programme on the incidence of a
vaccine-preventable disease is to study a community in which the vaccination rate is low but living
standards are high. For example:
• Two major epidemics of poliomyelitis occurred in the Netherlands, in 1984 and 1991, in a
religious community that refused vaccination. The disease did not spread to the rest of the
population, which was well covered with polio vaccine77.
• The acceptance of pertussis vaccine decreased in the United Kingdom in the mid-1970s.
Between 1977 and 1979, there was an epidemic of 102 500 cases of pertussis, during which
27 children died as a direct consequence of pertussis and 17 had permanent neurological
damage13. Acceptance of pertussis vaccine has now improved to about 93%, and the incidence
of pertussis has fallen. Similar large epidemics occurred in Japan and Sweden at about the
same time, due to low acceptance of pertussis vaccine78.

• A resurgence of measles occurred in the United Kingdom after a decrease in measles
immunization rates in the wake of now discredited claims of a link between MMR vaccine and
autism79. Thousands of cases of measles occurred, with some deaths, and the United Kingdom
lost its previous measles elimination status.
Some countries with high vaccine coverage and known to have no local measles, having eliminated
the disease, are now experiencing measles outbreaks due to imported cases from countries in
which measles vaccine coverage rates are low12. Higher standards of living and sanitation alone
do not ensure protection from infectious diseases. With short travel times over large distances,
infectious diseases can be carried from countries with a high disease prevalence. Cases have
occurred in unvaccinated people all over the world as a result of travel to and from areas where
vaccine-preventable diseases are still common.
• As the diseases are virtually eliminated, vaccination is not needed.”
Some people believe that vaccine-preventable diseases have been almost entirely eliminated
and that the risk for exposure to infectious disease is minimal. Therefore, they conclude that
a vaccination programme is unnecessary. Although many people around the world have been
immunized, resulting in a marked reduction in the targeted diseases, it is important that
the vaccination rates be kept as high as possible, mainly to protect the wider community and
vulnerable people with medical problems who cannot be vaccinated12.
When a significant proportion of individuals in a population is protected against a disease by

immunization, those who are still susceptible are indirectly protected, as they are less likely
to come into contact with someone with the disease or infection. This effect is known as “herd
immunity”12. For herd immunity to be effective, however, vaccination rates must be high.
Although many vaccine-preventable diseases are rarely seen in some countries today, they are
still common in many other countries. Travellers returning from such countries have been known
to bring home diseases such as measles, increasing the potential for an outbreak in communities
in which the vaccination rates are low. Reductions in vaccination rates can lead to recurrence of
diseases, as seen with regard to polio in many developed countries, diphtheria in eastern Europe
and more recently in Spain, and measles in Germany80-82.
• “Vaccines cause or spread the diseases they are supposed to prevent.”
The majority of vaccines are inactivated or prepared from only part of the pathogen. The components
of the vaccine are therefore not living and therefore cannot cause disease18. Exceptions are live
attenuated viral vaccines, which contain weakened (“attenuated”) forms of the virus against which
the vaccine is meant to protect people. The weakened virus replicates in the host to create an
immune response but cannot cause disease, except on very rare occasions18. Other types of live
vaccine contain a naturally occurring organism that does not itself cause the disease in humans but
which is closely related to the pathogen that causes the disease and can therefore induce protection
against it. Some of the available live vaccines are MMR and MMRV, varicella (chickenpox) and BCG.

After most natural infections and vaccination with most live attenuated vaccines, the infecting
organism or antigen does not persist in the body because it is eliminated in the immune response
they induce. An exception is the virus that causes chickenpox, which remains dormant in sensory
nerves and is sometimes reactivated later in life to cause usually mild herpes zoster (shingles)12.
This also occurs after natural infection but at a much higher rate. Furthermore, a vesicular
skin rash at the injection site of a varicella vaccine (which occurs in five of every 100 people
who receive the vaccine) can transmit the vaccine virus to someone else by direct contact with
the rash, although this is extremely rare68. In the USA, where more than 56 million doses of
varicella vaccine have been administered over 10 years, there were only six documented cases of
transmission of the vaccine virus from an immunocompetent vaccinated person to others83. The
MMR vaccine can also cause a transient rash 7–10 days after vaccination, but it is not infectious68.
• “People who are vaccinated can still get the disease.”
It has been argued that, as cases of vaccine-preventable disease occur in people who have been
vaccinated, vaccines are not effective. This is not completely true, although there is a relation
between vaccination rates, vaccine effectiveness and apparent vaccine failures. Thus, where
vaccination rates are high and a disease breaks out, the numbers of cases in vaccinated people
may appear high in relation to the number of cases among people who were not vaccinated, for
two reasons. First, no vaccine is 100% effective. In order to ensure that vaccines are safer than
the disease they are designed to prevent, the vaccine bacteria or virus is killed or attenuated.
Furthermore, individual genetic make-up means that not all vaccinated people develop immunity.
Most routine childhood vaccines are effective in 85–95% of recipients; therefore, 5–15 of every
100 people who receive a vaccine do not develop protective immunity. Secondly, in a country such
as Spain, people who have been vaccinated against the common childhood vaccine-preventable
diseases vastly outnumber those who have not.
How these two factors bring about a situation in which the majority of cases in an outbreak occur
among people who have been vaccinated is illustrated in the following hypothetical scenario. In a
school with 1000 pupils, none has had measles. All but five of the pupils have received two doses
of measles vaccine and are fully vaccinated. The entire student body is exposed to measles, and
every susceptible student becomes infected, including the five unvaccinated pupils. Of the 995
who were vaccinated, several can be expected not to have responded to the vaccine. If the efficacy
rate of two doses of measles vaccine is as high as 99%, in this school, 10 pupils will not have
responded to the vaccine and will become infected. Therefore, 10 of 15 (67%) of the cases will
occur in pupils who were fully vaccinated.
This does not, however, prove that the vaccine did not work. As most of the children in the school
had been vaccinated, those who were vaccinated and did not respond outnumbered those who
had not been vaccinated. In other words, 100% of the children who had not been vaccinated and
only about 1% of those who were vaccinated got measles. Measles vaccine protected most of the
pupils. If none of the pupils in the school had been vaccinated, there would probably have been
1000 cases of measles.

4.3.4. Relations between vaccination and neurological disease
Families who refuse vaccination often cite safety as their major concern, particularly the risk
for neurological disease, including seizures and epilepsy84. Indeed, febrile seizures have been
shown to occur at an increased rate after vaccination85; however, there is no evidence to suggest
that fever caused by a vaccine predisposes the person to seizures, any more than fevers due to
other causes86. Thus, children who have seizures after vaccination are no more likely to have
afebrile seizures or developmental problems than children who have febrile seizures due to other
causes86. Overall, there is no evidence to suggest that vaccines cause central nervous system
injury, epilepsy or infantile spasms86.
Vaccine-associated encephalopathy has been shown to be caused by a genetic mutation in a sodium

channel87,88. These gene mutations arise spontaneously and are only rarely inherited. The cases
resemble another disorder, severe myoclonic epilepsy of infancy (Dravet syndrome), and may be
wrongly attributed to the vaccine. The mutation explains seizures and developmental regression
in these patients, and vaccines are extremely unlikely to be the cause87,88. Mitochondrial disorders
are rare, predominantly genetic diseases, which can cause encephalopathy and, rarely, autistic
features in affected patients89. While these patients may have exacerbated symptoms with febrile
illnesses, there is no clear evidence that vaccines trigger these exacerbations86,90.
Other general and vaccine-specific misperceptions of causality between vaccination and

neurological disease development are discussed below.
• Lack of association between MMR vaccine and autism and inflammatory bowel disease
The MMR vaccine does not cause autism or inflammatory bowel disease91-125. These associations
were proposed by researchers in the United Kingdom in 1998, who suggested that measles virus
in the gut caused a new syndrome of inflammatory bowel disease that resulted in decreased
absorption of essential vitamins and nutrients through the intestinal tract126. They suggested that
this, in turn, caused developmental disorders such as autism or worsened symptoms in children
with already diagnosed autism, so-called “regressive autism”126.
Although this report generated much media attention, the few studies on which it was based127-130
had a number of significant weaknesses that have been highlighted by a plethora of letters to the
editor91-100 and have since been retracted. Ten of the 13 authors of the original study (published
in The Lancet) published a statement in 2004 retracting the paper’s findings, stating that the
data were insufficient to establish a causal link between MMR vaccine and autism. The Lancet
subsequently retracted the original paper131, and an investigation into the original data showed it
to be fraudulent.
Numerous well-conducted studies and expert panel reviews since 1998 have now provided
conclusive evidence that there is no link between MMR vaccine and autism or inflammatory bowel
disease132-139 (4, 5), WHO concluded that current scientific data do not show a causal link between
the measles virus and autism or inflammatory bowel disease137. Extensive reviews published by
the Institute of Medicine, an independent expert body in the United States, also concluded that

there is no association between the MMR vaccine and the development of autism. Reviews by
the American Academy of Pediatrics, the Chief Medical Officer and the Medical Research Council
in the United Kingdom132 and Canadian139 experts have also shown no link between autism or
inflammatory bowel disease and measles-containing vaccines.
It has been suggested that it would be better to give each component of the MMR vaccine separately
rather than giving it as a combination vaccine; however, there is no scientific support for this
suggestion140. In fact, giving each component separately might be harmful, because vaccination
against each disease would be delayed, leaving the child (and, in turn, the population) susceptible
to the disease12. National and international expert bodies all recommend that MMR vaccine should
continue to be used132-139.
• Lack of association between mercury in vaccines and autism
There is no evidence that thiomersal (also known as thimerosal), a mercury-based preservative,

in vaccines has caused any health problems, except perhaps minor reactions such as redness
at the injection site4,5,8. Thiomersal has been used in very small amounts in some vaccines since
the 1930s to prevent bacterial and fungal contamination7. The form of mercury in thiomersal is
organic ethyl mercury, which does not accumulate in the body, unlike the closely related methyl
mercury, which accumulates and is neurotoxic. These forms of mercury occur naturally in the
environment (in the air, earth and ocean) and in fish.
Mercury is used in industrial processes, dental fillings and thermometers. It is harmful to the body
only after it reaches a certain level, and its toxicity depends on the amount consumed, the form of
mercury, body weight and the length of exposure. Although methyl mercury has clear neurotoxic
effects in humans after absorption, well-designed toxicity studies of the accumulation of ethyl
mercury suggest that a relation between ethyl mercury in vaccines and neurological toxicity is
biologically implausible6,7. Many well-conducted studies and reviews by expert panels have shown
that there is no evidence of developmental or neurological abnormalities, such as autism, due to
administration of vaccines containing thiomersal141-148.
Thiomersal has not been used in vaccines since 2000, as they are now produced in single-use sealed
vials that do not require addition of a preservative. This reduces the total exposure of young children
to any form of mercury in a world where other environmental sources (particularly food such as fish)
may be more difficult to eliminate. Some vaccines, such as pneumococcal vaccines, MMR vaccine
and other live attenuated viral vaccines, never contained thiomersal141-148. Thiomersal may be used
as a preservative to prevent the growth of bacteria in vaccines produced in multi-dose vials after the
vial has been opened for the first time, for example, as an emergency measure during a pandemic.
• Pertussis vaccine and brain damage
The pertussis vaccine does not cause brain damage149-152. The pertussis component of DTP vaccine
was originally manufactured from inactivated whole pertussis organisms, designated DTPw.
DTPw (or whole-cell) vaccines were commonly associated with local reactions such as redness,

swelling and pain at the injection site, fever and mild-to-moderate systemic side-effects such as
drowsiness, fretfulness and loss of appetite. In a study of more than 2 million children in the USA,
administration of DTPw was not associated with an increased risk for encephalopathy150. In a study
of all suspected cases of encephalopathy in Canada over 10 years151, the authors concluded that
all the cases were related to a pre-existing medical condition or infection and not to vaccination.
• Link between vaccines and Guillain-Barré syndrome
Guillain-Barré syndrome is a rare neurological disorder due to inflammatory demyelination of

peripheral nerves. It is estimated that one to two newly diagnosed cases per 100 000 population
(0.001–0.002%) occur annually. The most severe cases result in paralysis, requiring respiratory
support if the chest wall muscles are affected. Guillain-Barré syndrome can occur spontaneously
(with no identified cause) or after events such as infections, including infection with Campylobacter
jejuni, a bacterium that causes gastroenteritis.
In the USA in 1976, the seasonal influenza vaccine formulation was associated with an increased
risk for Guillain-Barré syndrome. Several long-term studies to determine whether influenza
vaccines since 1976 were associated with this syndrome found only a very small increase after
influenza vaccination, with approximately one case among every one million people vaccinated
against influenza additional to the number that would have occurred without vaccination153-155.
Isolated case reports have suggested a possible association between Guillain-Barré syndrome
and several other vaccines, including oral poliovirus, MMR, tetanus toxoid-containing and hepatitis
B vaccines156. Robust epidemiological studies have not, however, demonstrated a link157. In the USA,
a possible association with quadrivalent meningococcal conjugate vaccine used in adolescents
was reported to the adverse events reporting system, but a subsequent investigation found no
increased risk158.
• Seizures after vaccination in young children
Febrile convulsions (sometimes referred to as seizures) are a relatively common response to fever
of any cause in young children159. In most cases, the seizures are mild and resolve spontaneously.
Overall, by the age of 5 years, about three in every 100 children will have experienced a febrile
convulsion, irrespective of whether they received a vaccine159. As fever is a well-documented
adverse event after the administration of many common childhood vaccines, it is not unexpected
that febrile convulsions may occur after vaccination, although it is still very rare.
The risk is higher after administration of certain vaccines, such as influenza, MMR and MMRV
vaccines18. For example, MMR and MMRV vaccines are associated with a higher risk for a febrile
convulsion 7–12 days after the first dose of vaccine than at other times18,160. It is estimated that
one child of every 3000 who receive MMR vaccine will experience a febrile convulsion during this
period18,160. When MMRV vaccine is given as the first MMR-containing vaccine, the risk for fever
and febrile convulsions during this period is approximately two times higher than when MMR and
varicella vaccines are given separately160. Therefore, MMRV vaccines are not recommended as the

first MMR-containing vaccine in children under 4 years of age, who are more likely to experience
convulsions when they have a high fever160.
• Autoimmune inflammatory syndrome induced by vaccine adjuvants
The development and increasing use of new vaccines and global vaccination protocols have
stimulated burning debates about the safety of adjuvants and whether they enhance the
immunogenicity of vaccines4,5,8. An adjuvant is a substance that enhances the antigen-specific
immune response, induces the release of inflammatory cytokines and interacts with toll-like
receptors and the NALP3 inflammasome161. The immunological consequence is stimulation of the
innate and adaptive immune responses. Activation of the immune system by adjuvants, a desirable
effect, could, however, trigger manifestations of autoimmunity or autoimmune disease161.
Shoenfeld and Agmon-Levin used the term “autoimmune inflammatory syndrome induced by
adjuvants” to describe a complex of variable signs and symptoms that may occur after previous
exposure to adjuvants and external environmental triggers and may elicit specific, overt immune-
mediated disorders162. This entity subsumes five medical conditions: post-vaccination phenomena,
Gulf War syndrome, macrophagic myofasciitis syndrome, siliconosis and “sick building” syndrome,
but the relevance and extent of the syndrome in children is limited mainly to post-vaccination
autoimmune or inflammatory disorders162.
The main substances associated with autoimmune inflammatory syndrome are squalene (Gulf War
syndrome), aluminium hydroxide (post-vaccination phenomena, macrophagic myofasciitis) and
silicone (siliconosis)161,162. Aluminium hydroxide is the adjuvant used most often in vaccines, but the
mechanisms by which it works are complex and little known. Alum adjuvants are good humoral
immune potentiators in vaccine formulations, and this property has recently been attributed to
NLRP3 inflammasome activation163. The inflammasome is an intracellular multiprotein complex
that mediates caspase-1 cleavage of the inactive precursor of the pro-inflammatory cytokine
interleukin-1β, leading to the release of mature cytokine161-163. Inflammasome-mediated cleavage
of pro-interleukin-1β in vitro depends on signals that activate both toll-like receptor and nucleotide
oligomerization domain-like receptors, such as NLRP3163. Activation of these innate immune
system receptors is now recognized as a step in effective adaptive immunity in a combination of
stimuli for naive T cells. Aluminium salts induce humoral immunity via Th2 responses but have
less effect on cell-mediated immunity and are therefore not useful in vaccines against intracellular
pathogens163.
The occurrence of vaccine-triggered phenomena represents a diagnostic challenge for clinicians

and a research conundrum for many investigators. In the presence of a favourable genetic
background, many autoimmune and inflammatory responses can be triggered by adjuvants and
external factors, showing how each person might breach immune tolerance and drive many
pathogenetic aspects of human diseases164.

• H1N1 vaccine and narcolepsy
Narcolepsy is a chronic disorder presenting as excessive daytime sleepiness, and its variant with
cataplexy, referred to as type 1 narcolepsy, is closely associated with HLA-DQB1*0602, which
plays a central role in the immune system by presenting peptides derived from extracellular
proteins165, 166. Investigations of patients with narcolepsy–cataplexy show that the neuropeptide
orexin, which regulates arousal, wakefulness and appetite, is deficient in the cerebrospinal fluid of
the majority of these patients167,168. More than 1300 cases of narcolepsy had been reported to the
European Medicines Agency by January 2015 associated with an AS03-adjuvant influenza vaccine
that was distributed to more than 30.5 million people in countries of the European Union and the
European Economic Area during the outbreak of A(H1N1)pdm09 influenza169. In 2012, studies in
Finland and Sweden showed an association between narcolepsy and vaccination with a European
A(H1N1)pdm09 vaccine with AS03 adjuvant, an oil-in-water emulsion170.
With regard to squalene-based adjuvants, no increased risk has been associated with the A(H1N1)
pdm09 vaccine in which the adjuvant is MF59, with an estimated 6.5 million doses distributed in
Europe and 25 million doses used in Europe and Latin America170. A lower risk for narcolepsy was
found with an AS03 adjuvant pandemic vaccine, Arepanrix, in Canada than with a similar vaccine,
Pandemrix, used in Europe169. These observations indicate that vaccine-associated narcolepsy is
not due solely to the characteristics of the adjuvant165-170.
4.3.5. Relation with other diseases
• Haemangioma
A haemangioma is a benign, usually self-involuting swelling or growth that most commonly

appears as a rubbery, bright-red nodule of extra blood vessels in the skin171-173. Sometimes
called a “strawberry mark”, a haemangioma usually appears in the first weeks of life and grows
most rapidly during the first 6 months171,174-177. Usually, growth is complete and involution has
commenced by 12 months171, 174-177. A haemangioma can occur anywhere on the body but is most
common on the face, scalp, chest or back171.
The vast majority of infantile haemangiomas do not require medical or surgical intervention, unless
they interfere with vision or breathing178. Medical care of clinically significant haemangiomas is
limited to a few medications178, including glucocorticosteroids179-181 (topical, intralesional and oral),
interferon α and, rarely, vincristine and topical imiquimod. Beta-blockers, specifically propranolol,
were found serendipitously to induce involution of infantile haemangiomas182-184.
If treatment with glucocorticosteroids is initiated, especially at a high dose (2 mg/kg body weight per
day for more than 14 days), the immune system is weakened, resulting in increased susceptibility to
infection. Therefore, it is important to reduce exposure to infections during treatment. No live virus
vaccines should be given to people on steroid medication until treatment has been discontinued for at
least 1 month18, 179-181. There are no other contraindications to vaccination. Non-live vaccines may be
administered179-181. The beta blocker propanolol does not appear to affect the immune system182-184.

Thus, glucocorticoesteroids are immunosupressants, and treatment with these agents requires a
temporary delay in administration of live vaccines; however, haemangiomas are not modified by
vaccines, and they do not grow or pose any problem to vaccination178-184.
• Sudden infant death syndrome
Sudden infant death syndrome is the sudden, otherwise unexplained death of an infant. The
incidence of the syndrome peaks at 2 months of age, at which most infants receive their first
vaccinations. The apparent association between the timing of vaccination and sudden infant death
syndrome has been examined to determine whether there is a causal link. Almost all the well-
controlled studies in the past 20 years showed that the number of deaths associated in time with
DTP vaccination was within the range expected to occur by chance, irrespective of vaccination185-192.
To date, all the published evidence suggests that vaccination does not increase the risk for sudden
infant death syndrome, and some studies suggest that vaccination may lower the risk187, 190-192.
The well-established risk factors for sudden infant death syndrome include gender (more likely in
boys), age (2–3 months), race (in the USA, Black, American Indian and Alaskan Native infants are
at higher risk), having siblings or cousins, prematurity, low birth weight, prone face-down sleeping
position and parental smoking185-192. Major reductions in deaths from this syndrome followed
successful campaigns to reduce the risk factors.
• Diabetes
Despite research throughout the world, there is no evidence that vaccines cause diabetes193-202.
The incidence of type 1 diabetes began to increase in developed countries at a similar time to the
introduction of widespread childhood vaccination. It was postulated in two studies that vaccination
before 2 months of age protected against type 1 diabetes, whereas vaccination after that age
increased the risk203, 204. The claim implicated hepatitis B and Hib vaccines and later included BCG
and more recently MMR and pertussis-containing vaccines203,204.
Subsequent to those reports, large, well-conducted studies found no link between any of the
recommended childhood vaccines and type 1 diabetes, nor could they verify the findings of the
earlier studies193-202. Changes in the timing of vaccination have not been shown to alter the risk for
diabetes193.
It is recommended that people with diabetes be vaccinated according to the national immunization
programme schedule193. Furthermore, annual influenza vaccination is currently recommended for
people with diabetes205.
• Cancer
Two vaccines, hepatitis B and human papillomavirus (HPV) vaccine directly prevent cancer, as
opposed to modifying the risk for cancer by attention to factors such as diet, exposure to tobacco
smoke and lifestyle behaviour206,207. The hepatitis B vaccine prevents liver cancer (associated

with hepatitis B infection), and the HPV vaccine prevents cervical and other anogenital cancers
(associated with HPV infection)207. Both these vaccines are inactivated; thus, they do not contain
live virus and could not biologically cause cancer.
Some people believe that vaccines can cause cancer, because some batches of injectable polio
vaccine produced between 1957 and 1963 were contaminated with a simian virus (SV40) that may
be linked to the development of some cancers208-209. SV40 is found in some species of monkey
and may be involved in causing cancer208. Between 1955 and 1963, some of the poliovirus vaccine
administered in the USA was unknowingly contaminated with SV40 from the monkey kidney
cell lines used to produce the vaccine208-210. Because SV40 was not identified until 1960, no one
was aware that poliovirus vaccines made in the 1950s could have been contaminated208-210. All
poliovirus vaccines manufactured since the early 1960s have been screened for SV40.
None of the current poliomyelitis vaccines contains SV40. SV40 is found in certain types of human
cancer, such as mesothelioma (rare tumours located in the lungs), brain and bone tumours and
some types of non-Hodgkin lymphoma208-209. The role of SV40 in human cancers is not, however, fully
understood and is the topic of continued research. Most information, including many large studies in
Europe and the USA208, strongly suggests that people given vaccine containing SV40 between 1955 and
1963 were at no higher risk for cancer than people who did not receive poliovirus vaccine at that time.
• Poliovirus vaccines and HIV/AIDS
Some people have argued that an oral poliovirus vaccine used in the 1950s was contaminated
with simian immunodeficiency virus (SIV), a primate virus that gave rise to HIV-1 that infects
humans and causes AIDS211. A number of factors counter this argument:
• Testing of the vaccine showed no contamination with either SIV or HIV.

• The vaccine was not given to the people in whom AIDS was first identified.
• The vaccine was given to people in Europe and Africa, but early AIDS cases were seen only in
Central Africa.
• The vaccine was produced in cells from Asian monkeys, which do not carry the viruses thought
to be responsible for AIDS.
Even if a rumour of unofficial use of cells from chimpanzees in the Belgian Congo were true,
recent molecular epidemiological research shows that the form of SIV in these animals did not
match the HIV-1 strains that affect humans212. The argument that the Koprowski polivrus vaccine
contained HIV is therefore thoroughly discredited212.
• Hepatitis B vaccine and multiple sclerosis
There is no evidence that hepatitis B vaccine, or any other vaccine, causes multiple sclerosis, a
chronic illness resulting from inflammation of myelin, the protective covering nerves in the brain
and spinal cord213-217. The cause of multiple sclerosis is unknown, but genetic and environmental
factors appear to be important214.

In the 1990s, concern about hepatitis B vaccination was raised in France after reports of multiple
sclerosis or multiple sclerosis-like illness after a large-scale programme of administration
of hepatitis B vaccine to adolescents and young adults, in whom multiple sclerosis often first
presents218. The French Government initially stopped the vaccination programme but resumed
it when the rate of multiple sclerosis in vaccinated people was found to be similar to that in the
general population.
Numerous other studies around the world and expert panels of WHO and the Institute of Medicine
and the Centers for Disease Control and Prevention in the USA agree that there is no evidence to
support the theory that vaccination with hepatitis B vaccine, or any other vaccine, is associated
with an increased risk for multiple sclerosis213-217. There is also evidence that vaccination does not
worsen the symptoms or cause relapses of multiple sclerosis217.
• HPV vaccines and safety, infertility or problems with pregnancy
HPV vaccines were developed primarily to prevent cervical cancer; however, they also provide
protection against other cancers in both men and women, including anal cancer, penile cancer and
head-and neck-cancers219,220. HPV vaccines have been evaluated for safety and efficacy in the same
way as all other vaccines. The European Medicines Agency, the Food and Drug Administration in
the USA and WHO have concluded that HPV vaccines are safe and effective219-229.
In clinical trials222-226, the main side-effect of HPV vaccines was a local reaction at the injection site
(pain, redness and swelling) in about 80% of those who received the vaccine. Other reported side-
effects were fever, headache and fatigue but these were no more common in recipients of vaccine
and of placebo222-226. Very few serious adverse events were reported after vaccination (in < 0.1%),
and they were no more frequent than in those receiving the placebo vaccine222-226. Participants in
the clinical trials were evaluated for up to 4 years after vaccination to determine whether they had
experienced higher rates of new medical conditions, including autoimmune diseases227. No trends
or patterns of new medical conditions or safety concerns were identified during the follow-up
period221-229. As with all vaccines, adverse events after vaccination are still being monitored now
that the vaccine is in use. Post-licensure surveillance data from various regulatory agencies in
different countries confirm these reassuring findings223, 224, 226.
There is no biologically plausible way in which HPV vaccine could cause infertility in either women
or men219-230. HPV infection, unlike some other sexually transmitted infections such as chlamydia,
is not a cause of infertility. Studies with high doses of HPV vaccine in female and male rats showed
no effect on fertility229,230. Some Internet sites report a disturbing claim that one ingredient of the
vaccine, polysorbate 80, caused infertility in rats. This claim is based on one study of newborn
rats (weighing 10–17 g) that were injected in the abdomen with doses of polysorbate 80 that were
20–200 times the amount in Gardasil® HPV vaccine231. Several health institutions have reviewed
the evidence and concluded that there is no evidence that polysorbate 80 at the level of 50 µg per
0.5-mL dose in Gardasil® poses a hazard to human reproduction or fertility232. Polysorbate 80 is
found in numerous medications, including other vaccines, and is used as an additive in foods and
cosmetics233.

While it is recommended that vaccination be avoided during pregnancy, there is no evidence that
inadvertent administration of HPV vaccine to a pregnant woman will increase her risk for adverse
pregnancy outcomes234,235. Although participants were requested to avoid pregnancy during
phase-3 trials of Gardasil®, 1796 women who received Gardasil® and 1824 who received a placebo
became pregnant, and the rate of adverse pregnancy outcomes was similar in the two groups224.
5. Practical tips for vaccination

5.1. Conservation
Failure to adhere to the recommended specifications for storage and handling of immunobiological
material can reduce or destroy their potency, resulting in inadequate or no immune response in the
recipient. Recommendations given in product package inserts, including methods for reconstituting
the vaccine, should be followed carefully. Maintenance of vaccine quality is the shared responsibility
of all handlers of vaccines, from the time a vaccine is manufactured until its administration. All
vaccines should be inspected on delivery and monitored during storage to ensure that the
recommended temperatures have been maintained. Inadequate vaccine storage can result in the
loss of thousands of dollars’ worth of vaccine and the cost of inventory replacement.
5.1.1. The cold chain

Maintaining the vaccine cold chain is essential for a successful immunization programme236. Vaccine
manufacturers clearly state that they do not guarantee the potency of the vaccines if they are not
stored at the temperatures recommended on the data sheet, which for most vaccines is 2–8 °C for
short-term storage and –20 °C for long-term storage of live vaccines (BCG, OPV, measles and MMR
(Table 10)237. The “T vaccines” (DPT, DT, TT) should not be frozen, as this may interfere with their
efficacy. Some adjuvants (e.g. aluminium) can act as irritants and produce sterile abscesses238.
Table 10. Recommended vaccine storage and transport temperatures
Vaccine At state At zone level At district At primary and During transport

level level community health
centre level
OPV –15 to –25 –15 to –25 –15 to –25 +2 to +8 °C up to 1 In cold boxes with
°C up to 6 °C up to 3 °C up to 3 month hard frozen icepacks
months months months or dry ice
Measles +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up to 1 In cold boxes with
to 6 months to 3 months to 3 months month icepacks
BCG +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up to 1 In cold boxes with
to 6 months to 3 months to 3 months month icepacks
DPT +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up to 1 In cold boxes with
to 6 months to 3 months to 3 months month conditioned icepacks
Tetanus +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up to 1 In cold boxes with
toxoid to 6 months to 3 months to 3 months month conditioned icepacks
Hepatitis +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up +2 to +8 °C up to 1 In cold boxes with
B to 6 months to 3 months to 3 months month conditioned icepacks
OPV, oral poliovirus vaccine; BCG, bacille Calmette-Guérin; DPT, diphtheria, pertussis and tetanus

5.1.2. Vaccine storage
Refrigerators and freezers used for vaccine storage must maintain the required temperature range
around the year, be large enough to hold the year’s largest inventory and be dedicated to storage
of vaccines239. Vaccine storage units must be carefully selected, used properly and consistently
monitored to ensure that the recommended temperatures are maintained. Refrigerators without
freezers and stand-alone freezers (manually or automatically defrosted) are usually the most
effective at maintain¬ing the precise temperatures required for vaccine storage. Single-purpose
units sold for home use are less expensive than special medical equipment and are preferable to
combination units. A combination refrigerator–freezer unit sold for home use might be adequate
for storing limited quan¬tities of vaccine if the refrigerator and freezer compartments have
separate external doors. Before a refrigerator is used for vaccine storage, the temperature should
be allowed to stabilize and then be measured in various locations within the compartment to
ensure that a consistent temperature can be maintained. New units might have to be operated for
≥ 2 days to establish a stable operating temperature, and vaccine should not be stored in the unit
until it maintains this temperature239. Refrigerator temperatures reflect the actual compartment
temperature after the door has remained closed and undisturbed for several hours (e.g. overnight).
The refrigerator temperature should be set at the midpoint of the recommended rang239. A
storage unit should be sufficiently large that vaccines can be placed away from the walls in the
part of the unit that best maintains the required temperature. Combination units with separate
smaller compartments can be used to store only limited quantities of vaccine. Frequent opening
and closing of doors can cause fluctuations in compartment temperature; food, beverages and
clinical specimens should not be stored in vaccine storage units239. If it becomes necessary to
store clinical specimens in the same unit as vaccines, the clinical specimens should be on a shelf
below the vaccine to prevent contamination if the specimens leak.
5.1.3. Vaccine vial monitors

A vaccine vial monitor is a thermochromic label placed on vials containing vaccine, which gives
a visual indication of whether the vaccine has been kept at the temperature that preserves its
potency239. The labels were designed to respond to the problem of delivering vaccines to countries
where the cold chain was difficult to preserve and where vaccines were formerly rendered
inactive and administered ineffectively because they had been denatured by exposure to ambient
temperature, especially for OPV, the most thermolabile vaccine239. The vial monitor consists of a
heat-sensitive square within a circle. When the monitor is exposed to heat, it changes colour over
time and at increasing speed in hotter conditions. If the square becomes the same colour as the
circle or darker than the circle, the vaccine contained in the vial is damaged and the vial should
be discarded (Fig. 8).
Practical tips for vaccination 47

Fig. 8. Vaccine vial monitors: usable and unusable stages
Usable Stages Unusable Stages
Reading the Stages of the VVM Discard Point:

The inner square is lighter than the outer circle. The color of the inner square matches that of the outer
circle: DO NOT use the vaccine.
If the expiry date has not been passed:
If the color of the inner square is darker than the outer
USE the vaccine.
circle, DO NOT use the vaccine.
VVM, vaccine vial monitor
5.2. Vaccine administration

The route of administration is the path by which a vaccine (or drug) is brought into contact with the
body (Fig. 9). This is a critical factor for successful vaccination. A substance must be transported
from the site of entry to the part of the body at which is to act. Using the body’s transport
mechanisms for this purpose is not, however, trivial.
Fig. 9. Routes of administration of vaccines
OPV, oral poliovirus vaccine; DTwP, diphtheria and tetanus toxoids and whole-cell pertussis; DTaP, diphtheria and tetanus toxoids
and acellular pertussis; DT, diphtheria and tetanus toxoids; Td, tetanus and diphtheria toxoids; TT, tetanus toxoid; IPV, inactivated
poliovirus vaccine; Hib, Haemophilus influenzae type b; PCV-7, pneumococcal conjugate vaccine; BCG, bacille Calmette-Guérin
OPV, oral poliovirus vaccine; DTwP, diphtheria and tetanus toxoids and whole-cell pertussis; DTaP,
diphtheria and tetanus toxoids and acellular pertussis; DT, diphtheria and tetanus toxoids; Td, tetanus
and diphtheria toxoids; TT, tetanus toxoid; IPV, inactivated poliovirus vaccine; Hib, Haemophilus
influenzae type b; PCV-7, pneumococcal conjugate vaccine; BCG, bacille Calmette-Guérin

• Intramuscular injection is used to administer a vaccine into the muscle mass. Vaccines containing
adjuvants should be injected intramuscularly to reduce the risk for local adverse effects237,239.
• Subcutaneous injection is used to administer a vaccine into the subcutaneous layer above the
muscle and below the skin.
• Intradermal injection is used to administer a vaccine into the topmost layer of the skin. BCG
and IDflu are given by this route237. Intradermal injection of BCG vaccine reduces the risk for
neurovascular injury237,239. A short, narrow needle (15 mm, 26-gauge) is required for injecting BCG
vaccine, while other vaccines are given with a longer, wider needle (commonly 25 mm, 23 gauge)
either subcutaneously or intramuscularly237,239.
• Intranasal administration is performed with the patient in an upright position, and the tip is placed
just inside the nostril to ensure that the vaccine is delivered into the nose. The patient should
breathe normally.
• Oral administration of vaccine eliminated the requirement for a needle and syringe.
5.2.1. Which, when, where and how

Table 12 lists various vaccines, where should they be administered, when and by which route.
Table 12. Main vaccines doses, intervals and routes of administration237,239
Vaccine Time of vaccination Dose Route Site

BCG At or as soon as possible 0.1 mL (0.05 Intradermal Left upper arm
after birth mL until 1
month of age)
Hepatitis B At birth or as soon as 0.5 mL Intramuscular Antero-
possible within 24 h lateral side of
mid-thigh
OPV-0 At birth or as soon as 2 drops Oral Oral
possible within first 15 days
Infants
OPV 1, 2 and 3 At 6, 10 and 14 weeks 2 drops Oral Oral

DPT 1, 2 and 3 At 6, 10 and 14 weeks 0.5 mL Intramuscular Antero-
lateral side of
mid-thigh
Hepatitis B 1, At 6, 10 and 14 weeks 0.5 mL Intramuscular Antero-
2 and 3 lateral side of
mid-thigh
Measles 9 completed months, 12 0.5 mL Subcutaneous Right upper arm
months (give up to 5 years if
not received at 9–12 months)
DPT booster 16–24 months 0.5 mL Intramuscular Antero-
lateral side of
Children
mid-thigh
OPV booster 16–24 months 2 drops Oral Oral
DPT booster 5–6 years 0.5 mL Intramuscular Upper arm
Tetanus toxoid 10 and 16 years 0.5 mL Intramuscular Upper arm
BCG, bacille Calmette-Guérin; OPV, oral poliovirus vaccine; DPT, diphtheria, pertussis and tetanus

5.2.2. Simultaneous administration of several vaccines
All vaccines can be administered at the same visit as all other vaccines237. The exception is
for asplenic children, to whom pneumococcal conjugate and Menactra brand meningococcal
conjugate vaccines should not be administered at the same visit but should be separated by at
least 4 weeks237.
For many years, there has been a recommendation that when two live vaccines are required in the
same individual, then the vaccines should either be given on the same day, or separated by an interval
of at least four weeks237. This was based on early studies with measles and smallpox vaccines240,
and supported by the theory that interferon production stimulated by the replication of first vaccine
prevented replication of the second agent, thus leading to a poor response to the second vaccine.
Based upon the available evidence and on the different immune mechanisms used by the various
vaccines, in February 2014 the JCVI agreed that the guidance to either administer the vaccines on
the same day or at four week interval period should not be generalised to all live vaccines241. They
concluded therefore, that intervals between vaccines should be based only upon specific evidence
for any interference of those vaccines (Table 13).
Table 13. Recommendations for giving more than one live attenuated vaccine
Vaccine combinations Recommendations

Yellow Fever and MMR 242
A four week minimum interval period should be
observed between the administration of these two
vaccines. Yellow Fever and MMR should not be
administered on the same day.
Varicella (and zoster) vaccine and MMR243 If these vaccines are not administered on the same day,
then a four week minimum interval should be observed
between vaccines.
Tuberculin skin testing (Mantoux) and MMR244 If a tuberculin skin test has already been initiated, then
MMR should be delayed until the skin test has been read
unless protection against measles is required urgently. If
a child has had a recent MMR, and requires a tuberculin
test, then a four week interval should be observed.
All currently used live vaccines (BCG, rotavirus, Apart from those combinations listed above, these live
live attenuated influenza vaccine (LAIV), oral vaccines can be administered at any time before or
typhoid vaccine, yellow fever, varicella, zoster after each other. This includes tuberculin (mantoux) skin
and MMR) and tuberculin (Mantoux) skin testing. testing
Increasing the interval between doses of a multidose vaccine does not diminish its effectiveness237.
Decreasing the interval between doses of a multidose vaccine may interfere with antibody
response and protection237. It is not necessary to restart the series or add doses because of an
extended interval between doses237.

5.3. Vaccination records
5.3.1. Records of health care providers
Documentation of appropriate, timely vaccination helps to ensure not only that the people who
should receive the recommended vaccine doses receive them but also that adequately vaccinated
patients do not receive excess doses. Curtailing the number of excess doses administered to
patients controls the costs incurred by patients, providers, insurers, vaccination programmes
and other stakeholders. In addition, excess doses of inactivated vaccines might increase the risk
for an adverse reaction237. Health care providers who administer vaccines are required to ensure
that the permanent medical record of the recipient (or a permanent office log or file) indicates the
date a vaccine was administered, the vaccine manufacturer, the vaccine lot number and the name,
address and title of the person administering the vaccine237. Providers and staff members should
systematically update the patient’s permanent medical record to reflect any documented adverse
events after vaccination and any serological test results related to vaccine-preventable diseases
(e.g. those for rubella screening and antibody to HBsAg)237.
5.3.2. Patient records

Patient records are used in vaccination education programmes to increase the awareness of
parents and patients of the need for vaccination. A permanent record card should be established
for each newborn infant and maintained by the parent or guardian, who should be informed about
the importance of keeping the record up to date and instructed to keep it indefinitely as part
of the child’s permanent medical record237. Cards should be distributed to new mothers before
they are discharged from hospital. Vaccination record cards for adolescents and adults are also
encouraged237.
5.3.3. Vaccination information systems

Formerly referred to as “immunization registries”, these are confidential, population-based,
computerized information systems for collecting and consolidating data on vaccination from
multiple health-care providers in a geographical area245. They can increase and sustain vaccination
coverage by consolidating the records from multiple providers, generating reminder and recall
notices for each person and providing official vaccination forms and vaccination coverage
assessments245.
Vaccination providers often change during a vaccination series, and these changes and the
vaccination records are often unavailable or not entered into an information system. Missing
or inaccurate information on the vaccines received can preclude accurate determination of
the vaccines required at the time of a visit, resulting in administration of extra doses245. A fully
operational information system prevents duplicate vaccination, missed appointments, vaccine
waste and staff time required to produce or locate vaccination records or certificates245. Most
health information systems also allow vaccine management, maintenance of lifetime vaccination
histories and interoperability with other systems245.

5.4. Advice on vaccination
Advice to parents and children determines a successful immunization programme246. Various
techniques can be used, but what is most important is that all questions or doubts are resolved and
the process is as un-traumatic as possible. Examples of information for parents are outlined below.
5.4.1. Before vaccination

Parents should come prepared. They should be advised to take the following steps before
vaccination of their child to help make the visit less stressful for both them and their children.
They should:
• read all the material about vaccination that they receive from their child’s health care
professional and write down any questions they may have;
• find their child’s vaccination record and bring it to the appointment to ensure that their doctor
knows exactly what vaccines their child has already received;
• pack a favourite toy, book or blanket that their child uses regularly for comfort;
• be honest with older children and explain that vaccination may pinch or sting but won’t hurt
for long;
• engage other family members, especially older siblings, in the support of the child; and
• avoid telling scary stories or making threats about injections.
5.4.2. At the doctor’s office

Any question about vaccination should be addressed to the child’s doctor or nurse, and the child’s
doctor should be approached for advice on using non-aspirin pain relievers and other steps that
can be takes at home to comfort the child. To make injections easier for a child:
• Distract and comfort the child by cuddling, singing or talking softly.

• Smile and make eye contact with the child; let the child know that everything is under control.
• Comfort the child with a favourite toy or book, such as a blanket that smells familiar.
• Hold the child firmly on the lap whenever possible.
For older children:
• Take deep breaths to help “blow out” the pain.

• Point out interesting things in the room to distract the child.
• Tell or read stories.
• Support the child if he or she cries. Never scold a child for not “being brave.”
Remember to schedule your next visit. Familiarization with a child’s vaccinations is the best
protection against disease. Support is important once a child has received all of the injections,
and infants should be held, cuddled, breastfed or offered a bottle. A soothing voice, praise and
hugs reassure a child that everything is under control.

5.4.3. After vaccination
Some children experience mild reactions to vaccines, such as pain at the injection site, a rash or
a fever. These reactions are normal and will soon resolve. The following tips will help identify and
minimize mild side-effects.
• Review any information from your doctor about the injections, especially vaccine information
statements and other information on what side-effects to expected.
• Use a cool, wet cloth to reduce redness, soreness and swelling at the place the injection was
given.
• Reduce any fever with a cool sponge bath. If your doctor approves, give a non-aspirin pain
reliever.
• Give your child lots of liquid. It’s normal for some children to eat less during the 24 h after
vaccination.
• Pay extra attention to your child for a few days. If you see something that concerns you, call
your doctor.
6. Vaccination in special situations

6.1. Altered immunocompetence
The term “altered immunocompetence” is often used synonymously with “immunosuppression”
and “immunocompromise”. Primary immunodeficiency is generally inherited and includes
conditions defined by the absence or quantitative deficiency of cellular or humoral components
of immunity (e.g. X-linked agammaglobulinaemia)247. Secondary immunodeficiency is generally
acquired and is defined by loss or qualitative deficiency in cellular or humoral immune
components as a result of a disease process or its treatment (e.g. HIV infection)247. The degree to
which immunosuppressive drugs cause clinically significant immunodeficiency is usually related
to dose and varies by drug237.
Determination of altered immunocompetence is important for vaccine providers because the

incidence or severity of some vaccine-preventable diseases is higher in such people; therefore,
certain vaccines (e.g. inactivated influenza vaccine and pneumococcal vaccines) are recommended
specifically for persons with these diseases237. Vaccines might be less effective during the period
of altered immunocompetence. Administration of live vaccines might have to be deferred until
immune function has improved, and administration of inactivated vaccines during the period of
altered immunocompetence might have to be repeated after immune function has improved237. In
addition, people with altered immunocompetence might be at increased risk for adverse reactions
after administration of live attenuated vaccines because of uninhibited replication247.
Clinicians and other health care providers must assess the safety and effectiveness of vaccines.
Laboratory studies can be useful for assessing the effects of a disease or drug on the immune
system. The general principles are:
Vaccination in special situations 53

• Assess whether the patient receive immunosuppressive therapy.
• Review and complete vaccination according to the routine immunization schedule.
• Consider additional vaccines indicated by the underlying disease.
• Order pre-vaccination serology before MMR, hepatitis A, hepatitis B and varicella vaccines.
6.1.1. Immunodeficiency
Before vaccination of a patient who is immunodeficient, consideration must be taken of whether
the vaccine is inactivated or live. All inactivated vaccines can be administered safely to people with
altered immunocompetence, and the usual doses and schedules are recommended; however,
the effectiveness of the vaccine might be suboptimal237,248. People with any of most forms of
altered immunocompetence should not receive live vaccines, and those with severe cell-mediated
immunodeficiency should not receive live attenuated viral or bacterial vaccines237,248.
6.1.2. Vaccination of contacts

Household and other close contacts of people with altered immunocompetence can receive all
the age-appropriate vaccines except smallpox vaccine237,248. MMR, varicella and rotavirus vaccines
may be administered without restriction, as MMR vaccine viruses are not transmitted to contacts,
and transmission of varicella vaccine is rare248. No specific precautions are required, unless
the varicella vaccine recipient has a rash after vaccination, in which case direct contact with
susceptible contacts should be avoided until the rash resolves248. All household contacts should
wash their hands after changing the diaper of an infant who has received rotavirus vaccine for
an undetermined number of weeks after vaccination. Household and other close contacts of
people with altered immunocompetence should be vaccinated against influenza annually237,248.
Live attenuated influenza vaccines may be administered to healthy household and other close
contacts of people with altered immunocompetence237,248.
6.2. Conditions that might cause immunodeficiency

6.2.1. HIV infection
Children infected with HIV are vulnerable to severe, recurrent or unusual infections with the
pathogens that cause vaccine-preventable diseases249. The efficacy and safety of vaccines depends
on the extent of their immunodeficiency249. In general, most vaccines are safe and efficacious in
early life, as the immune system is relatively well preserved, although the duration of protection
may be compromised, as the memory response is impaired with immune attrition249. Vaccines are
significantly less effective and safe in children with advanced disease, and consideration should
be given to re-administering childhood vaccines to such children when their immune status
has improved after antiretroviral therapy249. An infant born to an HIV-positive mother but with
an indeterminate HIV status should be vaccinated according to the normal schedule249. Table 14
summarizes recommendations for vaccination of HIV-infected children237,249.

Table 14. Recommendations for vaccination of HIV-infected children
Vaccine Asymptomatic child Symptomatic child

BCG Yes (at birth) No
DTwP/TT/Td/Tdwp Yes, as per routine schedule
Hib Yes, as per routine schedule
Polio vaccines IPV; OPV if IPV not affordable
Measles vaccine Yes Yes, if CD4 count > 200 (> 15%)
Inactivated influenza vaccine Yes, recommended if not part of routine schedule
Rotavirus Insufficient data
Hepatitis B Yes Yes, four doses, double dose, check
seroconversion, boosters
Hepatitis A Yes Yes, check seroconversion, boosters
Varicella Yes Yes, if CD4 count > 200 (> 15%)
Vi typhoid Yes Yes, if CD4 count > 200 (> 15%)
HPV Yes, as per routine schedule
Pneumococal Yes, 3+1 schedule (boosters may be needed)
Men ABCWY Yes, recommended if not in routine schedule
BCG, bacille Calmette-Guérin; DTwP, diphtheria and tetanus toxoids and whole-cell pertussis; TT, tetanus toxoid; Td, tetanus and
diphtheria toxoids; Tdwp, tetanus toxoid, reduced diphtheria toxoid and whole-cell pertussis; Hib, Haemophilus influenzae type b; Vi
typhoid, capsular polysaccharide typhoid vaccine; Men, meningococcal
6.2.2. Congenital immunodeficiency in children

Live vaccines, including OPV, BCG, oral typhoid and live attenuated influenza, are contraindicated in
patients with severe B-cell immunodeficiency (X-linked agammaglobulinaemia)237,249. Measles and
varicella vaccines may be given, but they may be ineffective due to concomitant immunoglobulin
therapy237,249. Inactivated vaccines may be given but are ineffective237,249. In less severe B-cell
deficiency, such as IgA and IgG subclass deficiency, only OPV is contraindicated237,249. In patients with
severe T-cell immunodeficiency (e.g. SCID), all live vaccines are contraindicated, and all vaccines
are ineffective237,249. Patients who have received live vaccine, especially BCG, before diagnosis
are at increased risk for complications, including disseminated BCG disease249. For patients with
combined immunodeficiency, such as Di George syndrome, Wiskott-Aldrich syndrome and ataxia
telangiectasia, inactivated vaccines may be given, but live vaccines are contraindicated249. All
vaccines may be safely given to children with complement deficiency, and pneumococcal, Hib and
meningococcal vaccines are particularly indicated249. In patients with phagocyte defects such as
chronic granulomatous disease, only live bacterial vaccines are contraindicated; other vaccines
may be given safely and effectively249. See Table 15 for more details.

Table 15. Recommendations for vaccination in cases of the main types of immunodeficiency
Vaccines
Type of immunodeficiency contraindicated Vaccines indicated Comments
Major antibody deficiency All live vaccines Influenza Vaccination with Men C
(agammaglobulinaemia, or Men ACWY (preferred)
Other inactivated
hypogammaglobulinaemia) recommended
vaccines on
immunization calendar
Minor antibody deficiency OPV All vaccines on Vaccination with Men C
(IgA deficiency of immunization calendar, or Men ACWY (preferred)
polysaccharide antibody including live vaccines recommended
deficiency)
Influenza Pneumococcal
vaccination in combined
schedule (PCV13 + PS23)
recommended
Complement deficiency No All vaccines on Vaccination with Men C or
(classical or alternative contraindications immunization calendar Men ACWY (preferred)
pathway)
Pneumococcal, Hib New Men B vaccine
and meningococcal are recommended
mandatory
Phagocytic system Live bacterial All vaccines on Pneumococcal
deficiencies (chronic vaccines (BCG, oral immunization calendar, vaccination in combined
granulomatous disease), typhoid vaccines) except all live vaccines schedule (PCV13 + PS23)
adhesion molecule defect, in chronic in adhesion molecule recommended
Chédiak–Higashi syndrome, granulomatous defect and Chédiak–
congenital neutropenia disease Higashi syndrome
All live vaccines in
adhesion molecule
defect and
Chédiak–Higashi
syndrome
Innate immune defects (IL- All live vaccines All vaccines on Pneumococcal
12, interferon-γ (BCG, oral typhoid, immunization calendar, vaccination in combined
MMR, varicella) except live vaccines schedule (PCV13 + PS23)
recommended
Influenza
Mixed or combined T-cell All live vaccines Some guidance does not Patients with incomplete
deficiency (complete (BCG, oral typhoid, recommend inactivated DiGeorge syndrome may
DiGeorge syndrome, ataxia MMR, varicella) vaccines if the patient receive MMR and varicella
telangiectasia, Wiskott- is receiving intravenous vaccines if their CD3
Aldrich syndrome, hyper- immunoglobulin count is > 500/m3, their
IgE syndrome) CD8 count ≥ 200/m3 and a
Influenza
normal mitogen response
Men, meningococcus; Ig, immunoglobulin; OPV, oral poliovirus vaccine; PCV, pneumococcal conjugate vaccine; PS23, 23-valent
pneumococcal polysaccharide vaccine; IL, interleukin; MMR, measles, mumps and rubella
6.2.3. Recipients of haematopoietic cell transplants

Recipients of haematopoietic stem cell transplants are no longer immunized, as they lose all
memory responses in marrow ablation250. Influenza vaccine should be given before the transplant,
6 months after the transplant and for life237,250. MMR and varicella vaccines may be given 24 months
after transplant if the recipient is judged to be immunocompetent237,250. Inactivated vaccines may
be given 6–12 months after transplant237,250.

All susceptible contacts of haematopoietic stem cell transplant recipients, including household
and health care worker contacts should be vaccinated against varicella and influenza 6 weeks
before the transplantation237,250.
6.2.4. Recipients of solid organ transplants

Recipients of solid organ transplants should complete all vaccinations before the transplant,
in accelerated schedules if necessary237,251. Vaccination with live vaccines should be completed
at least 4 weeks before the transplant and seroconversion should be documented237,251. After
transplantation, all live vaccines are contraindicated251. In patients who have not completed
vaccination before the transplant, inactivated vaccines can be given 6 months afterwards when
immunosuppression has been lowered237,251. Boosters for inactivated vaccines should be given
6 months after the transplant as per the schedule when antibody levels wane (hepatitis A and
B)237,251. Annual vaccination against influenza is recommended237,251. All household and health care
worker contacts should be vaccinated against influenza and varicella237.
6.2.5. Anatomical or functional asplenia

People with anatomical asplenia (e.g. after surgical removal or congenital absence of the spleen)
or functional asplenia (as in sickle-cell disease) are at increased risk for infection by encapsulated
bacteria, especially Streptococcus pneumoniae, Neisseria meningitidis and Hib252. Children aged <
5 years with anatomical or functional asplenia should receive the age-appropriate series of PCV,
and those aged ≥ 2 years should receive two doses of pneumococcal polysaccharide vaccine
separated by 5 years237,253.
Quadrivalent meningococcal polysaccharide vaccine also should be administered to asplenic

children greater than or equal to 2 years of age237,253. Immunization with Hib vaccine should be
initiated in infancy at the same dosage and schedule as recommended for otherwise healthy
children237,253.
Pneumococcal, meningococcal and Hib vaccines should be administered at least 14 days before
elective splenectomy, if possible237,253. If they are not administered before surgery, they should be
administered 2 weeks after the procedure, as soon as the patient’s condition is stable237.
6.2.6. Bleeding disorders

Because of the risk for haematoma formation after intramuscular injection, people with bleeding
disorders are often given vaccines that are usually administered by this route subcutaneously
or intradermally237,254. In one study, hepatitis B vaccine was administered intramuscularly to 153
people with haemophilia with a 23-gauge or smaller calibre needle, followed by application of
steady pressure to the site for 1–2 min255. The bruising rate was low (4%), and no patients required
factor supplements255. It is not known whether intramuscular administration of antigens that
produce more local reactions (e.g. pertussis) would result in an equally low rate of bruising.
When hepatitis B or another intramuscularly administered vaccine is indicated for a patient with a
bleeding disorder, it should be administered only if a physician familiar with the patient’s risk for
bleeding determines that the administration would be reasonably safe237. If the patient receives

antihaemophilia or similar therapy, intramuscularly administered vaccines can be scheduled
shortly after such therapy is administered237,254. A fine-gauge needle (23-gauge or smaller calibre)
should be used, followed by firm pressure on the site, without rubbing, for at least 2 min237,254. The
patient or family should be informed about the risk for haematoma from the injection.
Patients receiving anticoagulation therapy presumably have the same bleeding risk as patients
with clotting factor disorders, and the same guidelines for intramuscular administration should
be followed237,254.
6.2.7. Chronic illnesses in children

Children with chronic neurological, endocrinological (diabetes), hepatic, renal, haematological,
cardiac, pulmonary or gastrointestinal disease are at increased risk for infection and for
serious infections256. Live vaccines may be given safely to these children (except those
with immunosupression)237,257,258. They should be offered pneumococcal, hepatitis A and B,
meningococcal, varicella and influenza vaccines257,258. It is important to stress the role of hepatitis A
vaccine in patients with liver disease, pertussis boosting in those with stable neurological disease
and influenza in those with cardiac or pulmonary disease257,258. The main recommendations for
vaccination of children with chronic illnesses are summarized in Table 16.

Table 16. Recommendations for administration of vaccines to patients with chronic illnesses
Endocrine Chronic Non-malignant

Asplenia or Renal disease Neurological and metabolic inflammatory haematological
Vaccine hyposplenia or dialysis disorders Lung disease Liver disease diseases Heart disease diseases disorders
Inactivated
DTaP Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use
Hib Recommended (all Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use
ages)
Hepatitis A Recommended Recommended Recommended Recommended Recommended If indicated Recommended Recommended if Recommended in
before transfusions if not routine if not routine if not routine if not routine not routine haemophilia and
(sickle-cell repeated infusions
disease)
Hepatitis B Routine use, Recommended Routine use Routine use Recommended Routine use Routine use Routine use Recommended in
recommended haemophilia and
before transfusions repeated infusions
Influenza Recommended Recommended Recommended Recommended Recommended Recommended Recommended Recommended Recommended annu-
(TIV) annually annually annually annually annually annually annually annually if ally in anaemia or
immune-suppressed haemoglobinopathy
Meningococ- Recommended (all Recommended Recommended Recommended Recommended Recommended Recommended Recommended if Recommended if not
cal ages) if not routine if not routine if not routine if not routine if not routine if not routine not routine routine
Men ACYW
indicated
Pneumonia Recommended (all Recommended Recommended Recommended Recommended Recommended Recommended Recommended if Recommended in
13-V ages) immune-suppressed haemoglobinopathy
Pneumonia Recommended (> 2 Recommended Recommended Recommended Recommended Recommended Recommended Recommended if Recommended in
23-V years) (> 2 years) (> 2 years) (> 2 years) (> 2 years) in diabetes (> 2 years) immune-suppressed haemoglobinopathy
Live
BCG Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use
MMR Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use if not Routine use
immune-suppressed
OPV Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use if not Routine use
immune-suppressed
Rotavirus Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use if not Routine use
immune-suppressed
Varicella Routine use Routine use Routine use Routine use Routine use Routine use Routine use Routine use if not Routine use
immune-suppressed
DTaP, diphtheria and tetanus toxoids and acellular pertussis; Hib, Haemophilus influenzae type b; TIV, trivalent inactivated vaccine; V, valent; BCG, bacille Calmette-Guérin; MMR, measles, mumps and
Vaccination in special situations

rubella; OPV, oral poliovirus vaccine
59
6.3. Drugs that might cause immunodeficiency
6.3.1. Corticosteroids
Corticosteroid therapy is not usually a contraindication to administering live-virus vaccine when
it is given237,259:
• for < 14 days;

• at a low-to-moderate dose (< 20 mg of prednisone or equivalent per day);
• as long-term, alternate-day treatment with a short-acting preparation;
• as a physiological maintenance dose (replacement therapy) or
• topically (skin or eyes), inhaled or by intraarticular, bursal or tendon injection.
No severe reactions have been reported to live, attenuated viral vaccines in people receiving
corticosteroid therapy by aerosol, and this therapy should not delay vaccination237,259.
Although the immunosuppressive effects of steroid treatment vary, most clinicians consider that
a dose equivalent to ≥ 2 mg/kg body weight per day or ≥ 20 mg/day of prednisone or equivalent
to people who weigh > 10 kg administered for ≥ 14 days at ≥ 2 mg/kg body weight per day (or ≥
28 days at ≥ 1 mg/kg body weight per day) is sufficiently immunosuppressive to raise concern
about the safety of vaccination with live-virus vaccines237,259. Corticosteroids given at greater than
physiological doses can reduce the immune response to vaccines. Vaccination providers should
defer live-virus vaccination for at least 1 month after discontinuation of high-dose, systemically
absorbed corticosteroid therapy administered for > 14 days237,259.
6.3.2. Other immunosuppressive drugs

When feasible, clinicians should administer all the indicated vaccines to all patients before initiating
chemotherapy, before treatment with other immunosuppressive drugs and before radiation or
splenectomy237,260.
Chemo- and radiotherapy

Patients receiving chemotherapy or radiation for leukaemia and other haematopoietic
malignancies, for solid tumours or after solid organ transplant should be assumed to have altered
immunocompetence260. Live, attenuated vaccines should not be administered for at least 3 months
after such therapy261. Inactivated vaccines that are administered during chemotherapy should
be re-administered after immune competence is regained237,261. Children receiving chemotherapy
for leukaemia, lymphoma and other malignancies or radiation are generally considered to retain
immune memory after treatment, although revaccination with the common childhood vaccines
after chemotherapy for acute lymphoblastic leukaemia might be indicated237,260,261. In general,
revaccination of a person after chemotherapy or radiation therapy is considered unnecessary if
the previous vaccination was done before and not during therapy, with the exception of recipients
of haematopoietic cell transplantation, who should be revaccinated as recommended previously237.
Other immunosuppressive drugs

Several immunosuppressive drugs can be used in chronic autoinmune diseases. Methotrexate

at < 0.4 mg/kg body weight per week, 6-mercaptopurine at < 1.5 mg/kg body weight per day
and azathioprine at < 3 mg/kg body weight per day confer little immunosupression, whereas
anti-TNF (such as etanercept, infliximab and adalidumab), rituximab, anti-IL-1 (anakinra,
canakinumab), anti-IL-6 (tocilizumab), anti-IL-12 and anti-IL-23 (ustekinumab) confer high
immunosuppression137,262-266.
Inactivated vaccines may be administered during low-dose intermittent or maintenance

therapy with immunosuppressive drugs; however, the safety and efficacy of live, attenuated
vaccines during such therapy is unknown137,262-266. Physicians should carefully weigh the risks
and benefits of giving injectable live vaccines to adults receiving immunosuppressive therapy
for chronic autoimmune disease137,262-266. In general, vaccination is considered safe when done 1
month after discontinuation of immunosuppressive therapy with corticosteroids, 3 months after
discontinuation if they cause low immunosuppression and 6 months after discontinuation if they
cause high immunosupression137. Varicella vaccine can be given safely 4 weeks before starting
immunosuppressive drugs and MMR vaccine 6 weeks before treatment137.
Further recommendations include administration of hepatitis A vaccine to patients receiving

hepatotoxic drugs (methotrexate or tocilizumab), HPV vaccine to males and females receiving
immunosuppressive drugs and meningoccocal ABCWY, Hib and pneumococcal vaccine to patients
receiving eculizumab137,266.
6.3.3. Antibody-containing products

Inactivated vaccines can be safely administered simultaneously but at different sites or at any
time with antibody-containing products (whole blood, packed red cells, plasma, immunoglobulin)
with no loss of immunogenicity or efficacy137,267-269. The exception is administration of rabies
immunoglobulin 7 days after rabies vaccine137,267-269. Live vaccines, including MMR and varicella,
should be avoided for at least 3 months (Table 17) after reception of antibody-containing products,
and these products should be avoided for 2 weeks after receipt of these vaccines137,267-269. If
vaccination outside this prescribed period has been conducted, the serological response should
be checked and vaccination repeated if indicated137,267-269. Oral typhoid vaccine, live attentuated
influenza vaccine, OPV and yellow fever vaccine may be given at any time in relation to antibody-
containing products137,267-269. Rotavirus vaccine should be avoided for 6 weeks after such products
are given, although the vaccine may be given if deferral results in postponement of the first dose
of rotavirus vaccine beyond 15 weeks137,267-269.

Table 17. Recommended intervals for administration of MMR vaccine after immunoglobulin or blood
product transfusión
Timing of administration
Product of MMR vaccine (months)
Non-specific immunoglobulins 3
Polyvalent Ig at 0.02–0.06 mL/kg body weight 5
Polyvalent Ig at 0.25 mL/kg body weight 6
Polyvalent Ig at 0.50 mL/kg body weight 8
Polyvalent Ig immunodeficiency therapy at 300–400 mg/kg body weight 8–10
Polyvalent Ig immunodeficiency therapy at 400–1000 mg/kg body weight 8
Prophylaxis after exposure to varicella at 400 mg/kg body weight 11
Therapy for Kawasaki disease at 2 g/kg body weight 3
Anti-hepatitis B immunoglobulin 4
Anti-rabies immunoglobulin 3
Anti-tetanus immunoglobulin 5
Anti-varicella zoster immunoglobulin
Blood and blood products
Blood 6
Red cells 6
Plasma or platelets 7
6.3.4. Concurrent administration of antimicrobial agents and vaccines

With a few exceptions, administration of antimicrobial agents is not a contraindication to
vaccination137. Antibacterial agents have no effect on the response to live, attenuated vaccines,
except for live oral typhoid vaccine, and have no effect on inactivated, recombinant subunit or
polysaccharide vaccines or toxoids137,270. Typhoid vaccine should not be administered to people
receiving antimicrobial agents until 24 h after the last dose270. If feasible, to avoid a possible
reduction in vaccine effectiveness, antibacterial drugs should not be started or resumed until 1
week after the last dose of oral typhoid vaccine270.
Antiviral drugs used for treatment or prophylaxis of influenza virus infections have no effect
on the response to inactivated influenza vaccine; however, live, attenuated influenza vaccine
should not be administered until 48 h after cessation of therapy137,271. If feasible, to avoid possible
reduction in vaccine effectiveness, antiviral medication should not be administered for 14 days
after live attenuated influenza vaccine271. Antiviral drugs that are active against herpesviruses
(e.g. acyclovir and valacyclovir) might reduce the efficacy of live, attenuated varicella and zoster
vaccines, and these drugs should be discontinued at least 24 h before administration of vaccines
containing varicella zoster virus, including zoster vaccine, if possible137,272,273. Use or resumption of
antiviral therapy should be delayed for 14 days after vaccination137,272,273. There is no evidence that
commonly used antiviral drugs affect the efficacy or safety of rotavirus or MMR vaccine137.

6.4. Vaccination of preterm infants
In most cases, preterm infants (born before 37 weeks’ gestation), regardless of birth weight,
should be vaccinated at the same chronological age and according to the same schedule and with
the same precautions as for full-term infants and children (Table 18)137,274-279. Birth weight and size
do not determine whether a clinically stable preterm infant should be given the full recommended
dose of each vaccine; divided or reduced doses are not recommended274-279.
Table 18. Administration of vaccines to preterm infants
Vaccine Considerations for administrations to preterm infants

Tuberculosis Eligible infants born ≥ 34 weeks’ gestation can receive BCG vaccine soon after birth.
(BCG)
Eligible infants born before 34 weeks’ gestation should not receive BCG vaccine until
34 weeks’ gestational age.
DPT, polio and Hib Three doses beginning at 6 weeks of age
Invasive Preterm infants born < 32 weeks’ gestational age or with chronic lung disease are
pneumococcal eligible for:
disease (PCV)
• 13-valent pneumococcal conjugated vaccine (Prevenar13®): 3+1 vaccination
schedules, otherwise as per immunization calendar, followed by
• two 23-valent pneumococcal polysaccharide vaccine doses (Pneumovax® 23), the
first at ≥ 2 years of age and the second 5 years after the first
Rotavirus Medically stable preterm infants should be vaccinated according to the same schedule
as full-term infants.
There is a theoretical risk of disease resulting from horizontal transfer of the vaccine
virus.
The first dose to infants who are still hospitalized at 6 weeks of age:
• should be deferred until the day they are discharged if this is to occur before the
infant is 15 weeks of age or
• should be administered while the infant is still in hospital if discharge is not
anticipated before the infant is 15 weeks of age.
The main considerations in vaccinating preterm infants are as follows274-279.
• The preferred site for intramuscular injection is the vastus lateralis.

• A 23–25-gauge, 16-mm needle inserted at a 90° angle to the skin is usually adequate.
• Preterm infants may have a poor immune response to some vaccines, although evidence
suggests that the response is still protective274-283.
• Vaccination of these infants is safe and effective, although post-vaccination apnoea with or
without associated bradycardia up to 48 h after vaccination may occur more frequently in
some groups284.
If a child aged at least 6 weeks has been in hospital since birth, deferral of rotavirus vaccination
is recommended until the time of discharge285. The rotavirus vaccine series should not be initiated
for infants aged ≥ 15 weeks285.
Preterm infants weighing < 2000 g at birth may have decreased seroconversion rates after
administration of hepatitis B vaccine at birth. By a chronological age of 1 month, however, all

preterm infants, regardless of their birth weight, are likely to respond as adequately as larger
infants280-282. Preterm infants born to HBsAg-positive mothers and mothers with unknown HBsAg
status must receive immunoprophylaxis with hepatitis B vaccine within 12 h of birth286. The initial
vaccine dose should not be counted in completion of the series, and three additional doses of
hepatitis B vaccine should be administered, starting when the infant is 1 month of age.
6.5. Vaccination during breastfeeding

Neither inactivated nor live-virus vaccines administered to a lactating woman affects the safety of
women or their breastfeeding infants137. Although live viruses in vaccines can replicate in vaccine
recipients (i.e. the mother), most live viruses in vaccines, including varicella vaccine virus, are not
excreted in human milk288. Although rubella vaccine virus might be excreted, it usually does not
infect the infant. If infection does occur, it is well tolerated because the virus is attenuated289.
Inactivated, recombinant, subunit, polysaccharide and conjugate vaccines, as well as toxoids, pose
no risk for mothers who are breastfeeding or for their infants. Breastfeeding is a contraindication
for smallpox vaccination of the mother because of the theoretical risk for contact transmission
from mother to infant. Yellow fever vaccine should be not be given to breastfeeding women290;
however, if a nursing mother cannot avoid or postpone travel to areas endemic for yellow fever in
which risk for acquisition is high, she should be vaccinated.
Limited data indicate that breastfeeding enhances the response to certain vaccine antigens292. There
is no evidence that passive transfer of antibodies to human milk affects the efficacy of live-virus
vaccines. Breastfed infants should be vaccinated according to the recommended schedule292-294.
6.6. Vaccination during pregnancy

Developing fetuses are theoretically at risk from vaccination of the mother during pregnancy.
There is no evidence of risk to the fetus from vaccinating pregnant women with inactivated virus
or bacterial vaccines or toxoids295,296. As live vaccines administered to a pregnant woman pose
a theoretical risk to the fetus, live, attenuated virus and live bacterial vaccines are generally
contraindicated137. The benefits of vaccinating pregnant women usually outweigh the potential
risks when the likelihood of exposure to the disease is high, when infection would pose a risk to
the mother or fetus and when the vaccine is unlikely to cause harm137.
Pregnant women who received the last dose of tetanus toxoid-containing vaccine > 10 years
previously should generally receive tetanus and diphtheria toxoids while they are pregnant297. A
dose during pregnancy ensures adequate immunity to tetanus in the mother and prevents disease
in both the mother and infant. The dose of Td can be withheld if the provider is confident that the
pregnant woman is immune to tetanus298. Pregnant women who have not been vaccinated or are
only partly vaccinated against tetanus should complete the primary series297. Women for whom
Td is indicated but who did not complete the recommended three-dose series during pregnancy
should receive follow-up after delivery to ensure that the series is completed.
Women in the second and third trimesters of pregnancy are at increased risk for hospitalization for
influenza299,300. As vaccination against influenza before the season begins is critical and predicting

exactly when the season will begin is impossible, routine influenza vaccination is recommended
for all women who are or will be pregnant (in any trimester) during the influenza season299.
IPV can be administered to pregnant women who are at risk for exposure to wild-type
poliovirus infection. Hepatitis A, pneumococcal polysaccharide, meningococcal conjugate and
meningococcal polysaccharide vaccines should be considered for women at increased risk for
those infections301-303. Pregnant women who must travel to areas where the risk for yellow fever
is high should receive yellow fever vaccine because the limited theoretical risk from vaccination
is outweighed substantially by the risk for infection304. Hepatitis B vaccine is not contraindicated in
pregnancy and should be given to any pregnant woman for whom it is indicated305.
Pregnancy is a contraindication for smallpox vaccine and measles-, mumps-, rubella- and
varicella-containing vaccines137. Smallpox vaccine is the only vaccine known to harm the fetus when
administered to a pregnant woman137. In addition, smallpox vaccine should not be administered to
a household contact of a pregnant woman306.
Studies of children born to mothers vaccinated with rubella vaccine during pregnancy indicate
the presence of rubella antibodies in unvaccinated infants, which may represent passive transfer
of maternal antibody or a fetal antibody response to vaccine virus infection307-309. No cases of
congenital rubella, varicella syndrome or abnormalities attributable to fetal infection have been
observed in infants born to susceptible women who received rubella or varicella vaccines during
pregnancy307-309. Because of the importance of protecting women of childbearing age against
rubella and varicella, reasonable practices in any vaccination programme include asking women
whether they are pregnant or might become pregnant in the coming 4 weeks; not vaccinating
women who state that they are or plan to become pregnant; explaining the theoretical risk of the
fetus if MMR, varicella or MMRV vaccine is administered to the pregnant mother and counselling
women who are vaccinated not to become pregnant for 4 weeks after MMR, varicella or MMRV
vaccination137. Vaccination with MMRV is an unlikely option for a pregnant woman because the
vaccine is licensed only for children < 12 years of age. Routine pregnancy testing of women
of childbearing age before administration of a live-virus vaccine is not recommended137. If a
pregnant woman is inadvertently vaccinated or becomes pregnant within 4 weeks of MMR or
varicella vaccination, she should be counselled about the theoretical basis of concern for the
fetus; however, MMR or varicella vaccination during pregnancy should not be considered a reason
to terminate pregnancy310-311.
People who receive MMR vaccine do not transmit the vaccine viruses to contacts310, and
transmission of varicella vaccine virus to contacts is rare137. MMR and varicella vaccines should
be administered when indicated to children and other household contacts of pregnant women.
Infants living in households with pregnant women should be vaccinated with rotavirus vaccine
according to the same schedule as infants in households without pregnant women137,310.
Pertussis is a highly contagious, potentially fatal vaccine-preventable disease that continues

to emerge as outbreaks worldwide, despite high childhood vaccination rates312. The highest
incidence of pertussis, its associated complications and the majority of pertussis-related deaths

occur in infants who were too young to be vaccinated (aged < 2 months) or were incompletely
immunized (aged < 6 months)312,313. Infants too young to receive the primary DTP series as
recommended depend on passive maternal antibodies for protection against pertussis; however,
pregnant women have very low concentrations of pertussis antibodies315,316. To protect young
infants, tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine has been
recommended initially for postpartum women and close contacts of infants, for pregnant women
who have not previously received Tdap and then for all pregnant women during every pregnancy,
regardless of their history of Tdap vaccination315,316.
Vaccination of pregnant women with Tdap in the second and third trimester is well tolerated
and elicits immune responses similar to those in vaccinated nonpregnant women313. Preliminary
evaluation indicated no increased risk for adverse events among women who received Tdap
vaccine during gestation or in their infants313. Secondary assessments showed that maternal
vaccination with Tdap resulted in significantly higher concentrations of antibodies to all vaccine
antigens in their infants from birth until initiation of vaccination at 2 months of age and did not
substantially alter the infants’ response to DTaP313. As the kinetics of maternal antibodies might
differ by region according to the country’s epidemiology, vaccine strategy, vaccine brand used and
population targeted, larger studies should be conducted, with longer follow-up, to understand
the immunological responses of pregnant women, the required frequency of booster Tdap
administration and the consequences on neonatal immunity.
6.7. Vaccination of patients with tuberculosis

6.7.1. Tuberculosis skin test reactivity
Measles, severe acute or chronic infections, HIV infection and malnutrition can create a relatively
anergic state, during which the tuberculin skin test (TST) might show a false-negative reaction317-319.
Although any live, attenuated measles vaccine can theoretically suppress TST reactivity, the
degree of suppression will probably be less than that after acute infection with wild measles
virus317. Although routine TST screening of all children is no longer recommended, TST screening
is sometimes required (e.g. for child care, school entrance or employee health check-ups) at the
time of administration of a measles-containing vaccine. The TST and measles-containing vaccine
can be administered at the same visit (preferred option); simultaneous administration does
not interfere with reading the TST result at 48–72 h and ensures that the person has received
measles vaccine137,317. Otherwise, TST screening can be delayed for at least 4 weeks after
vaccination to remove concern about any theoretical but transient suppression of TST reactivity
from the vaccine317. The TST can also be performed and read before administration of measles-
containing vaccine317. This option is the least favoured because it delays receipt of the vaccine. If a
person has suspected TB, MMR vaccine should be withheld not only before the TST but until after
initiation of treatment, because a person with active TB who is moderately or severely ill should
not receive MMR vaccine137. In general, if TB is not suspected, a TST may be done simultaneously
with administration of live vaccine or deferred for 28 days after vaccination317.
No information is available about the extent of TST suppression that might be associated with
other live, attenuated virus vaccines (e.g. varicella or yellow fever). In the absence of information,

it is prudent to follow guidelines for measles-containing vaccine when scheduling TST screening
and administering other live, attenuated virus vaccines317. Vaccination should not be delayed only
because of these theoretical considerations137. Because of similar concerns about smallpox vaccine
and TST suppression, a TST should not be performed until 4 weeks after smallpox vaccination317,320.
A more specific test for diagnosis of TB or latent TB infection was licensed in 2005. The interferon-γ
release assay requires only one visit and is less sensitive to the effects of previous BCG vaccination.
The same timing guidelines that apply to the interval between a live vaccine and TST apply to this
assay (28 days if they are not done on the same day), because the interferon-γ release assay (like
TST) might be suppressed by immunological mechanisms321.
The potential that TST can boost results should be considered in patients who might have latent
TB and have a negative initial TST, and the two-step tuberculin test is recommended in certain
situations321. As this test consists of two TSTs (or a TST followed by interferon-γ release assay)
separated by an interval of 1–3 weeks, there is a longer time during which live vaccine replication
could suppress reactivity321. If a live vaccine is administered, the first dose of a two-step TST should
be delayed for 4 weeks, and, if additional doses of live vaccines are indicated thereafter, they should
be delayed until the second TST (or the interferon-γ release assay after an initial TST)321.
Reactivity to either assay in the absence of TB disease is not a contraindication to administration

of any vaccine, including live, attenuated virus vaccines137,317. TB is not a contraindication to
vaccination, unless the person is moderately or severely ill137. Although the effects of MMR vaccine
on people with untreated TB have not been studied, measles vaccine might theoretically exacerbate
it. Therefore, anti-TB therapy should be initiated before administration of MMR to people with
untreated active TB137. It is also prudent to consider whether concurrent immunosuppression (e.g.
due to HIV infection) is a concern before administering live, attenuated vaccines137.
6.7.2. Screening of people vaccinated with bacille Calmette-Guérin (BCG)

The sensitivity of people vaccinated with BCG to tuberculin is highly variable, depending on the
strain of BCG used and the group vaccinated322. The presence or size of a post-vaccination TST
reaction does not predict whether BCG provides protection against TB323. Furthermore, the size
of a TST reaction in a BCG-vaccinated person does not determine whether the reaction is due to
infection with Mycobacterium tuberculosis or the BCG vaccination323.
TST is not contraindicated for people who have been vaccinated with BCG, and the results are
used to diagnose M. tuberculosis infection324. A diagnosis of infection and treatment of latent TB
infection should be considered for any BCG-vaccinated person who has a TST reaction of > 15 mm
of induration, especially if the person137,322-324:
• is a contact of another person who has infectious TB, particularly if the infectious person has
transmitted M. tuberculosis to others;
• was born or has resided in a country in which the prevalence of TB is high; or
• is exposed continually to populations in which the prevalence of TB is high, such as health care
workers, employees and volunteers at homeless shelters and workers at drug-treatment centres.

Treatment of latent TB infection should be considered for BCG-vaccinated people with a TST
reaction of > 5 mm induration if they are infected with HIV and at risk for M. tuberculosis infection323.
BCG-vaccinated people who have a positive reaction in a TST but who do not have TB should be
evaluated for treatment of latent TB infection323. The possibility of TB should be considered for
BCG-vaccinated persons who have symptoms suggestive of TB323.
6.7.3. Efficacy of BCG

The effectiveness of BCG vaccination and its policy implications differ for countries with a high
and a low incidence of TB, especially in terms of cost–effectiveness324. Countries with a policy
of vaccination at birth tend to be those with a high incidence of TB (> 20/100 000 according to
the European Centre for Disease Prevention)324. Given the incomplete control of TB, especially
in high-burden countries, use of BCG should be optimized. The study324 indicates that children
should be vaccinated as soon as possible after birth to prevent infection and disease. The results
provide evidence that BCG protects against severe and disseminated TB infection in infants in
epidemiologically different settings, independently of the type of interferon-γ release assay used
to detect infection324. Future trials of candidate vaccines should address their efficacy against
infection and early and late progression to active disease.
6.7.4. Revaccination with BCG

A systematic review324 of nine studies showed no significant difference in the incidence rate ratio
(range, 0.57–1.74), relative risk (range, 0.39–0.59) or hazard ratio (1.20; 0.77–1.89) for TB. In addition,
there was no significant difference in the relative risk for an adverse reaction (2.3; 0.67–7.80) or
in vaccine efficacy (8; –77–52), but a significant increase in immune response was found in the
revaccinated group324. In general, the review concluded that BCG revaccination does not provide a
significant additional protective effect against TB, mortality from TB or adverse reactions324. The
findings support the 1995 WHO recommendation against BCG revaccination325.
Athough revaccination does not confer additional protection against TB, BCG provides protection
against the severe form of TB and TB in childhood326. Meta-analyses of studies on the protective
effect of a single dose of BCG showed an effect of 73–86%324. A study in Brazil of adolescents aged
15–20 years who received BCG vaccination at birth found a prolonged protective effect of the first
dose, of 9–58%327.
6.7.5. Screening for severe combined immunodeficiency disease in countries with

universal BCG vaccination
SCID comprises a heterogeneous group of genetic conditions characterized by profound
deficiencies in the numbers and function of T and, in some types, B and/or NK cells328. If untreated,
infants with typical SCID succumb early in life to severe and recurrent infections328. BCG, like
other live-attenuated vaccines, is contraindicated for SCID patients329. However, because BCG is
usually administered at birth, SCID patients are often vaccinated before their immune deficiency
is diagnosed. The prevalence of complications following vaccination with BCG has been estimated
to be higher in patients with SCID than in the general population329-331, although an effect has not
been established definitively. The cumulative experience of 28 centres in 17 countries in Africa,
the Americas, Asia and Europe confirms that (as expected) complications are more prevalent in

SCID patients than in the general population332. Recent studies have found that the total number
of T cells at the time of SCID diagnosis and the patient’s age at BCG vaccination are significantly
correlated with the increased prevalence of complications333.
The worldwide coverage of BCG vaccination is 88%334, and it is usually administered at birth335
Until safer, more efficient anti-TB vaccines become available, delaying BCG vaccination beyond 1
month of age is likely to be favourable for this highly vulnerable population and in neonates who
are susceptible due to e.g. HIV infection. Moreover, delaying BCG vaccination enhances the clinical
impact of neonatal SCID screening, obviating administration of a contraindicated vaccine before
the diagnosis is established. Two major drawbacks to delaying BCG vaccination can, however,
be foreseen: the “missed opportunity” of vaccinating infants after birth might lead to decreased
coverage, and there is a very low potential of increased risk for BCG-preventable diseases during
the “unprotected” interval. WHO data demonstrate BCG coverage of 89.2% in countries that
encourage vaccination at birth, similar to the 89% coverage with the third dose of DPT in the same
countries, which is typically given at 6 months of age336. This suggests little or no decrease in
coverage due to delaying BCG vaccination. In addition, BCG-preventable mycobacterial diseases
within the first 6 months of age are extremely uncommon. Studies on paediatric tuberculous
meningitis, a BCG-preventable disease, show that the mean age at which this life-threatening
disease occurs is 23–49 months, although a few cases have been described during the first
6 months of life, and the median is 12–24 months337-341. Modification of BCG vaccination policy
requires extensive discussion, balancing the needs of the immunocompetent general population
and highly vulnerable immunodeficient patients.
6.8. Vaccination of people with lapsed or unknown immunity

A vaccine series need not be re-started, regardless of the time elapsed between doses, because
of immune memory137. The next dose should be given as if the usual interval had elapsed, and
the immunization schedule should be completed at the next opportunity137. Doses should not be
given ≤ 4 days before the minimum interval137. If a dose is inadvertently given ≥ 5 days after the
minimum interval, it should not be counted137. Children of unknown immunization status should
be considered unimmunized and vaccinated accordingly137. Self-reports should not be accepted
in the absence of documentation, except for influenza vaccine and PPV137. Serological testing
may be conducted in patients with uncertain status but is usually not cost–effective, may reduce
compliance and may result in missed opportunities for vaccination137.
6.8.1. Interchangeability of brands

There is sufficient evidence that different brands of Hib, hepatitis B and hepatitis A vaccines can be
safely interchanged without compromising immunogenicity or efficacy343,344. Robust data on the
immunogenicity of vaccination with different brands of DTwP is lacking, however, and vaccination
with DTwP should be completed with the same brand unless the previous brand is unknown or no
longer available344. Vaccination should not be delayed or cancelled.
6.8.2. Catch-up vaccination

Catch-up vaccination regimens should preferably be individualized. Any number of live or
inactivated vaccines may be given on the same day, either singly or as combination, maintaining

a distance of 5 cm between injection sites. The exception is administration of BCG, measles and
MMR vaccines, which should not be given on the same day137,237,241. Inactivated vaccines can be
given at any interval with other live or inactivated vaccines137,237,241. If two live injectable vaccines,
especially MMR and varicella and also yellow fever and live attenuated influenza vaccines, are not
given on the same day, an interval of 4 weeks should be maintained137,237,241. OPV, rotavirus and
oral typhoid vaccines may be given at any interval with any live or inactivated vaccine137,237,241. In
catch-up vaccination, doses should preferably be given at the shortest interval to ensure early
protection.
Catch-up schedule tables are useful for planning the number of doses and the best way to
organize visits and coadministration for unimmunized children or children who have interrupted
the primary series137,237,241. Table 19 gives examples.
Table 19. Examples of catch-up schedules (Updated March

Table 3: Recommendations* for Interrupted or Delayed Routine Immunization Summary of WHO Position Papers 2017)
Doses in Primary Doses for those who start vaccination late

Interrupted primary
Antigen Age of 1st Dose Series (min interval Booster Dose
series***
between doses)** If ≤ 12 months of age If > 12 months of age
Recommendations for certain regions
Inactivated Vero cell- Resume without repeating
6 months 2 (4 weeks) generally 2 doses (generally) 2 doses (generally)
derived vaccine previous dose
Japanese
Not recommended
Encephalitis 11 Live attentuated 8 months 1 NA 1 dose 1 dose
Live recombinant vaccine 9 months 1 NA 1 dose 1 dose
1 dose with measles

Yellow Fever 12 9-12 months NA 1 dose 1 dose Not recommended
containing vaccine
3 doses (1st to 2nd 1-3 Resume without repeating

FSME-Immun & Encepur ≥ 1 yr 3 doses 3 doses At least 1 booster
Tick-Borne mos; 2nd to 3rd 12 mos) previous dose
Encephalitis 13
3 doses (1st to 2nd 1-7 Resume without repeating
TBE_Moscow & EnceVir ≥ 3 yr 3 doses 3 doses Every 3 years
mos; 2nd to 3rd 12 mos) previous dose
Recommendations for some high-risk populations

Vi PS 2 years (min) 1 dose NA Not recommended 1 dose Every 3 years
If interruption between
Typhoid 14 3-4 doses (1 day)
doses is < 21 days resume
Ty21a Capsules 5 years (min) (see footnote) without repeating previous Not recommended > 5 yrs: 3-4 doses Every 3-7 years
(see footnote)
dose; If > 21 days restart
primary series
2-5 yrs: 3 doses 2-5 yrs: every 6 months. If booster is

2-5 yrs: 3 doses
delayed > 6 months the primary series
must be repeated.
If interval since last dose ≥ 6
Dukoral (WC-rBS) 2 years (min) Not recommended
weeks restart primary series
Cholera 15 >6 yrs: every 2 years. If booster is
≥ 6 yrs: 2 doses delayed > 2 yrs the primary series must
> 6 yrs: 2 doses
(≥ 7 days) be repeated.
Resume without repeating

Shanchol and mORCVAX 1 year (min) 2 doses (2 weeks) Not recommended 2 doses After 2 years
previous dose
2 doses if < 9 months with 8

MenA conjugate (5µg) 9-18 months 1 NA 1 dose of 5µg up to 24 months Not recommended
week interval

2-11 months 2 (8 weeks min)
MenC conjugate previous dose 2 doses 1 dose 2-11 months of age after 1 year
Meningococcal
16 >12 months 1 NA

9-23 months 2 (12 weeks min)
Quadrivalent conjugate previous dose 2 doses 1 dose
≥ 2 years 1 NA
Hepatitis A 17 1 year (min) At least 1 dose Not recommended At least 1 dose Not recommended

3 doses (1st to 2nd 7 days; previous dose; Interval Only if occupation puts a frequent or
Rabies 18 As required 3 doses 3 doses
2nd to 3rd 14-21 days) between last two doses continual risk of exposure
should be 14 days minimum

Dengue ( CYD-TDV) 19 9 years (min) 3 doses (6 months) Not recommended 3 doses ≥ 9 years Not recommended
dose
Recommendations for immunization programmes with certain characteristics

2 doses with measles Resume without repeating
Mumps 20 12-18 months Not recommended 2 doses Not recommended
containing vaccine (4 weeks) previous dose
Seasonal influenza (inactivated tri- and < 9 yrs: 2 doses (4 weeks) Resume without repeating < 9 yrs: 2 doses
6 months (min) 2 doses Revaccinate annually 1 dose only
qudri-valent) 21 ≥ 9 yrs: 1 dose previous dose ≥ 9 yrs: 1 dose
1-2 (4 weeks – 3 months, Resume without repeating

Varicella 22 12-18 months Not recommended 1-2 doses
depending on manufacturer) previous dose
P.2 /9
BCG, bacille Calmette-Guérin; NA, not applicable; DTP, diphtheria and tetanus toxoids and pertussis; OPV, oral poliovirus vaccine;
IPV, inactivated poliovirus vaccine; HPV, human papillomavirus
Table 20 shows a suggested catch-up schedule. Other vaccines may be given after discussion
with parents.

Table 20. Suggested vaccination schedule for an unimmunized child
Visit Suggested vaccines

First Measles (MMR if > 12 months)
DTwP 1/DTaP 1 (Tdap if ≥ 7 years)
OPV 1/IPV 1 (only if < 5 years)
Hib 1 (only if < 5 years)
Hepatitis B 1
Second (1 month after first visit) BCG (only if < 5 years)
DTwP 2/DTaP 2 (Td if ≥ 7 years)
OPV 2 (if OPV given earlier)
Hepatitis B 2
Hib 2 (if< 15 months)
Third (1 month after second visit) OPV 3/IPV 2
MMR (if > 12 months)
Typhoid (if > 2 years)
Fourth visit (6 months after first visit) DTwP 3/DTaP 3 (Td if ≥ 7 years)
OPV 4/IPV 1
Hepatitis B 3
MMR, measles, mumps and rubella; DTwP, diphtheria and tetanus toxoids and whole-cell pertussis;
DTaP, diphtheria and tetanus toxoids and acellular pertussis; Tdap, tetanus toxoid and acellular
pertussis; OPV, oral poliovirus vaccine; IPV, inactivated poliovirus vaccine; Hib, Haemophilus
influenzae type b; Td, tetanus and diphtheria toxoids; IPV B1,
6.10 Vaccination for travellers

The vaccine recommendations for travellers depend on the epidemiology of endemic illnesses
in the countries they will visit, the duration of the trip and the nature and conditions of travel137.
Physicians should update routine vaccinations and provide vaccines specific for the destination. For
instance, vaccines commonly recommended for travellers from India include yellow fever vaccine
for those going to destinations in South America and sub-Saharan Africa, polio and meningococcal
vaccines for those on a hajj pilgrimage to Saudi Arabia and quadrivalent meningococcal vaccine
for those visiting countries in the African meningitis belt345-348. Visitors to India are usually advised
to be vaccinated against typhoid, hepatitis A, hepatitis B, rabies and Japanese encephalitis (if they
visit rural areas endemic for Japanese encephalitis in the relevant season)347.
Examples of the most frequent vaccine-preventable diseases and the dose schedules are shown
In Table 21.

Table 21. Most frequent vaccine-preventable diseases and dose schedules
Vaccine Travel destination Dose

Meningococcus United Kingdom, USA, endemic areas Two doses 4–8 weeks apart
Africa and Saudi Arabia
Yellow fever Endemic zones 10 days before travel
Cholera Endemic area or an outbreak Two doses of oral vaccine 1 week apart
Japanese B encephalitis Endemic areas Single dose (≤ 15 years)
Rabies (prophylaxis) Trekking 0, 7 and 28 days
7. Conclusion
Non-vaccination is an
ACTIVE decision
Minimal risks of vaccination are
completely overshadowed by the
health risks of non-vaccination
8. Clinical cases
8.1. Case 1
A 2-month-old infant born prematurely at 32 weeks of gestational age with cerebral palsy as
a sequel of ventricular leukomalacia visits a clinic for routine vaccination. The mother reports
that the infant has had diarrhoea for the past 2 days and has been taking antibiotic therapy for
pharyngoamigdalitis for 10 days. The physical examination shows increased bowel sounds but no
other acute major finding. Please choose among the following answers for this patient:
Q1. Can this patient be vaccinated with DTwp, Hib and hepatitis B vaccines at this
visit?
1. No, the patient has several absolute contraindications for vaccination (prematurity, cerebral
palsy).
2. No, vaccination should be re-scheduled once the acute episode of diarrhoea has resolved.
3. Yes, I would not lose the opportunity to vaccinate the patient.
4. No, because the antibiotic therapy might interfere the immune response.
Answer to Q1:
There is no evidence that acute illness reduces the efficacy of vaccines or increases the
incidence of adverse events after vaccination. As a precaution, however, in cases of moderate
or severe acute illness, all vaccines should be delayed until the illness has resolved. Mild

illnesses such as otitis media, upper respiratory infection and diarrhoea are not contraindications
to vaccination. Children with mild acute illnesses such as low-grade fever, upper respiratory
infection, colds, otitis media and mild diarrhoea should be vaccinated on schedule. Several large
studies137,349 have shown that young children with these conditions respond as well to measles
vaccine as those without them. There is no evidence that mild diarrhoea reduces the immune
response of infants. The temperature of infants and children need not be measured before
vaccination if they do not appear to be ill and the parent does not report that the child is currently
ill. The decision to vaccinate should be based on an overall evaluation of the person rather than
on arbitrary body temperature.
Vaccination should not be withheld for a person taking antibiotics. Antibiotics do not affect
the immune response to most vaccines. The only commonly used antimicrobial drug that will
inactivate a live-virus vaccine is a sulfonamide, which will inactivate the oral typhoid vaccine, which
should therefore be administered at least 72 h after a dose of sulfonamide. Antiviral drugs may
affect vaccine replication in some circumstances, and live attenuated influenza vaccine should not
be administered until 48 h after cessation of therapy with drugs against influenza (amantadine,
rimantadine, zanamivir, oseltamivir). Antiviral drugs against herpesviruses (acyclovir, famciclovir)
should be discontinued 24 h before administration of a varicella-containing vaccine, if possible.
Q2. Does prematurity pose any limitation or contraindication for vaccination?

1. Yes, a premature patient cannot receive rotavirus vaccine because of gastrointestinal
immaturity.
2. Yes, a premature patient should not receive the first dose of hepatitis B vaccine until his or her
weight is > 2500 g.
3. Yes, a premature patient should not receive pertussis-containing vaccines because of immune
immaturity.
4. All the previous answers are false.
Answer to Q2:
Prematurity is not a contraindication for vaccination. On the contrary, premature patients
are at increased risk for infectious diseases and for more severe disease than healthy children.
Timely vaccination of premature infants is therefore essential.
Q3. Can this premature patient receive rotavirus vaccine?

1. This patient is already experiencing an acute episode of gastroenteritis, and thus rotavirus
vaccination is no longer indicated.
2. As soon as the patient recovers, he or she should receive the first dose of rotavirus vaccine,
ideally before 15 weeks of age
3. The first dose of rotavirus vaccine should be administered only after 3 months of age.
4. The patient could be vaccinated, as the acute illness is mild,
Answer to Q3:
There are very few contraindications to rotavirus vaccines. These are:
Clinical cases 73
• a history of a severe allergic reaction (e.g. anaphylaxis) after a previous dose of either rotavirus
vaccine or any component of the vaccine being given;
• severe combined immunodeficiency; the risk–benefit ratio for children with known or suspected
altered immunocompetence should be assessed individually. Children and adults with
congenital immunodeficiency, haematopoietic transplantation or solid organ transplantation
sometimes experience severe or prolonged rotavirus gastroenteritis.
• a history of intussusception, which places children at greater risk than children who have
never had it.
Moderate or severe acute illness with or without a fever indicates precaution in administering
all vaccines, including rotavirus vaccine. Vaccination should not, however, be delayed due to mild
respiratory tract or other acute illness with or without fever. In the case described above, the patient
had diarrhoea, probably related to antibiotics, and rotavirus vaccine could be administered safely,
although some authors350 consider diarrhoea in acute gastroenteritis a reason for postponing
rotavirus vaccination. Usually, rotavirus vaccine should not be administered to infants with acute
moderate or severe gastroenteritis until the condition improves.
Infants with mild acute gastroenteritis can be vaccinated, particularly if the delay in vaccination
might be substantial and might make the infant ineligible to receive vaccine (e.g. age > 15 weeks
before the vaccine series is started). Even a documented episode of naturally occurring rotavirus
acute gastroenteritis after an episode of acute gastroenteritis does not contraindicate rotavirus
vaccination.
In some low- and middle-income countries, the window for rotavirus vaccination is wider (up to 3
years of age), as the additional lives saved by removing age restrictions on rotavirus vaccination
by far outnumber the excess vaccine-associated deaths due to intussusception. In other cases, a
restricted schedule (initiate by 15 weeks and complete by 32 weeks) should be followed strictly.
Q4. This patient has cerebral palsy as a sequel of prematurity. Which of the
following statements is true?
1. Cerebral palsy is an absolute contraindication for vaccination.
2. The vaccine is not contraindicated, but the schedule of vaccination is different.
3. The patient can be vaccinated normally.
4. The patient can be vaccinated normally except with any vaccine containing pertussis antigen.
Answer to Q4:
Chronic diseases may increase a person’s risk for infection or for more severe disease
if infection occurs, so that prevention by vaccination is essential. The patient is also at
increased risk for nosocomial infection with vaccine-preventable diseases because of the
increased likelihood of prolonged hospitalization and frequent outpatient visits. Therefore, it is
particularly important that people with chronic diseases who are immunocompetent be
immunized in a timely manner with both live and inactivated vaccines according to the
routine immunization schedule. Vaccines may be less immunogenic in this population. Ideally,
vaccination should be completed early in the disease course when the response is likely to be

similar to that of other people of a similar age with no chronic medical condition.
The vaccine requirements and recommendations may change for people with immunosuppression
or receiving immunosuppressive therapy, and the vaccination scheduled should be carefully
reviewed, particularly for live vaccines.
As our patient has a stable, chronic neurological disease, he or she should be vaccinated normally.
Q5. The mother is breastfeeding the preterm baby. Which of the following
statements is true?
1. Vaccination might interfere with the immune response of the infant but with no clinical
consequences.
2. Vaccination should be postponed until breastfeeding is finished.
3. Vaccination interferes only with rotavirus vaccine.
4. Breastfed infants should be vaccinated according to the recommended schedule.
Answer to Q5:
Breastfeeding does not decrease the responses to routine childhood vaccines and is not a
contraindication for any vaccine except smallpox. Yellow fever vaccine should be avoided;
however, if a nursing mother cannot avoid or postpone travel to areas endemic for yellow fever
in which risk for acquisition is high, they should be vaccinated. Breastfeeding does not extend or
improve the passive immunity to vaccine-preventable disease provided by maternal antibodies,
except possibly for Hib. Breastfed infants should be vaccinated according to the recommended
schedule. Although rubella vaccine virus might be shed in human milk, infection of infants is rare.
Breastfeeding and prematurity (< 37 weeks’ gestation) do not impair the immune response to
rotavirus vaccine, as proven in recent studies in Africa and Asia351-353.
8.2. Case 2
An 18-month-old boy is taken to a clinic because of a tonic–clonic seizure that lasted 2 min and
ceased spontaneously. He has fever of 38.5 °C. He had received DTwp-Hib-hepatitis B vaccine
the day before. After careful history-taking and a physical examination, no other findings are
detected. Please answer the following questions regarding this patient:
Q1. What is your interpretation of this case?

1. The child had a febrile seizure secondary to central nervous stimulation by vaccination.
2. The child had a febrile seizure due to fever, which was probably related to vaccination.
3. The child has epilepsy, and antiepileptic drugs should be started; further vaccines are
contraindicated.
4. The child has epilepsy secondary to vaccination.
Answers to Q1:
Febrile seizures can occur with any condition that causes fever. During a febrile seizure,
a child often has spasms or jerking movements and may lose consciousness. Febrile seizures
usually last 1–2 min, and they do not cause any permanent neurological damage. They are most
Clinical cases 75
common with fevers of ≥ 38.9 °C but can also occur at lower body temperatures or when a fever is
going down. One in three children who have one febrile seizure will have at least one more during
childhood; some are linked to the family health history.
The causes include common childhood illnesses like colds, influenza, an ear infection or roseola.
Vaccines sometimes cause fevers but rarely febrile seizures. Infants and young children are
at highest risk for febrile seizures: ≤ 5% of young children will have at least one febrile seizure,
usually associated with illness. Most febrile seizures occur in children aged 6 months to 5 years,
although the commonest age range is 14–18 months.
Vaccines prevent many febrile seizures. Vaccination of a child as recommended prevents

febrile seizures by protecting tham against measles, mumps, rubella, chickenpox, influenza,
pneumococcal infections and other diseases that can cause fever and febrile seizures. The risk–
benefit relation of vaccination and the onset of febrile seizures always favours vaccination.
Q2. How would you interpret the event with regards to the vaccine?
1. The seizure was caused by the vaccine.
2. The seizure was temporarily related to vaccination.
3. The seizure was totally unrelated to vaccination.
4. The vaccination caused epilepsy in the child.
Answer to Q2:
Vaccines, like any medication, can have side-effects; however, most are minor (for example, a
sore arm or low-grade fever) and resolve within a few days. Usually, there is only a temporary
link between vaccination and the event, which does not indicate a causal relation. Caution
should be exercised before a judgement is made or communicating it to the parent, as it may
affect future vaccination.
Studies have indicated that there is no increased risk for febrile seizures after administration
of acellular pertussis vaccine, DTaP, Hib, hepatitis B or varicella vaccine159,160,354,. DTwP has
been reported to be associated with a small increase in risk for febrile seizures the day after
administration355. This small or absent risk is, however, negligible in comparison with the benefits
that the vaccine may provide. Furthermore, the risk does not appear to be associated with any
long-term adverse consequences356.
Q3. How would you manage the patient with regard to future vaccination?
1. The patient shouldnot receive this or any other vaccine in the future.
2. The patient should not receive this vaccine but could receive other vaccines.
3. The patient can receive this vaccine only under surveillance in a special unit for vaccine allergy.
4. The patient can be vaccinated normally with this or any other vaccine.
Answer to Q3:
The parents should be informed that vaccines are prepared in accordance with the highest standards

of safety. Years of testing are required by law before a vaccine is licensed and distributed. Once
in use, vaccines are continually monitored for safety and efficacy. Like any medical procedure,
vaccination is associated with some risks as well as substantial, proven benefits. Individuals react
differently to vaccines, and the reaction of an individual to a particular vaccine cannot be predicted
precisely. Anyone who is vaccinated should be fully informed about both the benefits and the
risks, and any questions or concerns should be discussed with a physician or other health care
provider.
Febrile seizures can be frightening, but nearly all children who have a febrile seizure recover
quickly and are healthy afterwards. Even in the rare cases that an episode of febrile seizure can
be related to administration of DTwp-Hib-hepatitis B, future doses of this and other vaccines can
be administered safely.
Q4. If it is suspected that this case and any other unusual reaction or clinical
event is related to vaccination, what should be the procedure?
1. Don’t tell anyone, as this is bad publicity for vaccines.
2. Vaccines have no adverse effects.
3. The event should be reported to the local authorities, even if it is only suspected.
4. The event should be reported to the local authorities according to the procedure only if the
relation is proven.
Answer to Q4:
Anyone who administers vaccines is encouraged to report any significant health problem or
unexpected event, even if they are uncertain that the vaccine caused the event. Adverse events
listed on the manufacturer’s package insert and any other clinically significant or unexpected
event after vaccination should be reported. A report of an adverse event does not necessarily
mean that the vaccine caused the event. The report should include
• the type of vaccine received,

• the timing of vaccination,
• the onset of the adverse event,
• current illnesses or medication,
• history of adverse events after vaccination and
• demographic information about the recipient.
Q5. If in the same week that the child was vaccinated, two other children who
received the same type of vaccine in the same facilities present with the
same symptoms, how would you interpret the episode?
1. I would clearly associate the vaccine with seizures and never vaccinate other children with
DTwp-Hib-hepatitis B vaccine.
2. I would report the event for further investigations of the vaccine lot, transport and storage.
3. I would inform the parents that an increased rate of seizures due to DTwp-Hib-hepatitis B
vaccine has been confirmed.
4. I would assume that the event was coincidental and take no further measures.
Clinical cases 77
Answer to Q5:
It may be difficult to identify the causes of adverse events after vaccination. Once the adverse
event has been reported, caution should be exercised in making associations. Vaccination should
be continued; however, if further cases of the same adverse event occur with the same vaccine,
errors in its manufacture, transport and storage must be ruled out. Meanwhile, health care
professionals should remain alert for new cases but provide the same information to parents. No
alarm should be given until an official report of causality is available, as it is essential to build trust
in immunization programmes.

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Global manual on surveillance of adverse events following immunization
Annex. Frequency of adverse reactions to commonly used

vaccines
Annexes
annex 1. Frequency oF vAccine Adverse reActions oF commonly used
vAccines
BCG Vaccine Summary Hepatitis B Vaccines Summary

Vaccine Adverse Reactions Frequency category Vaccine Adverse Reactions Frequency category
n Injection site reaction ( Papule, Very common n Fever Common
mild ulceration orscar) n Headache Common
n Suppurative lymphadenitis Uncommon to Rare n Injection site pain Common to Very common
n BCG osteitis Uncommon to Very rare n Injection site redness Common
n Disseminated BCG disease or Very Rare n Injection site swelling Common
systemic BCG-itis
n Anaphylaxis Very rare
n Immunine Reconstitution Very Rare
Inflammatory Syndrome (IRIS)
DTP Vaccines Summary Human Papiloma Vaccines (HPV) Summary

Whole cell Pertussis vaccines Bivalent HPV Vaccine
n Fever 100.1oF - 102oF Very common n Fever Common
n Injection site Redness Very common n Headache Very common
n Swelling Very common n Injection site pain Very common
n Pain (Severe-Moderate) Very common n Redness Very common
n Fussiness (Severe-Moderate) Very common n Swelling Very common
n Drowsiness Very common n Rash Uncommon
n Anorexia Very common n Arthralgia Very common
n Vomiting Common n Myalgia Very common
n Persistent screaming Uncommon to Rare n Fatigue Very common
n HHE Very rare n Gastrointestinal disorders Very common
n Seizures Very rare
n Encephalopathy Very rare Quadrivalent HPV Vaccine
n Anaphylaxis n Fever 100.1oF - 101oF Very common
n Fever 100.1oF - 102oF Very Common
A cellullar Pertussis vaccines n Injection site Redness Common
n Fever 100.1oF - 101oF Very common n Injectionsite swelling Common
n Fever 100.1oF - 102oF Common n Pain (Severe-Moderate) Common
n Injection site Redness Common to Very common n Fussiness (Severe-Moderate) Common
n Injectionsite swelling Common to Very common n Drowsiness Common
n Pain (Severe-Moderate) Uncommon to Common n Anorexia Common
n Fussiness (Severe-Moderate) Common to Very common n Vomiting Common
n Drowsiness Very Common n Persistent screaming Common
n Anorexia Very Common n HHE Very common
n Vomiting Very Common n Seizures Very rare
n Persistent screaming Uncommon
n HHE Rare
n Seizures Very rare
Tetanus vaccines Summary Hib Vaccines Summary

n Brachial neuritis Very rare n Fever Common
n Anaphylaxis Very rare n Injection site reaction Very common
103
Annex. Frequency of adverse reactions to commonly used vaccines 99

September 2014
Polio Vaccines Summary Measles Vaccines Summary

Whole cell Pertussis vaccines n Fever Common to Very common
n VAPP n Rash Common
– Recipient VAPP Very Rare n Injection site reaction Very common
– Total VAPP Very Rare n Febrile seizures Rare
n Encephalomyelitis Very rare
Inactivated Polio Vaccine (IPV) n Thrombocytopenia Very rare
n Injection site erythema Un common to Common n Anaphylaxis Very rare
n Injection site induration Common to Very common
n Injection site tenderness Very Common
Pneumococcal vaccines Summary Rubella Vaccines Summary

Unconjugated vaccine (PPSV) n Fever Common
n Fever > 39oC Uncommon n Injection site reaction Very common
n Injection site reaction Very common n Acute Arthralgia (adults) Very common
n Acute Arthritis (adults) Very common
Conjugated vaccine (PCV)
n Fever > 39oC Uncommon
n Injection site reaction Very common
Varicella Vaccines Summary Mumps Vaccines Summary

n Febrile seizures Rare n Injection site reaction Very common
n Fever > 39oC Very Common n Parotid swelling Common
n Injection site reaction Common to Very Common n Aseptic meningitis Very common
n Site rash (local/generalized) Common
Rotavirus Vaccines Summary Yellow Fever vaccines Summary

n Intussusception Very rare n Vaccine-associated viscerotropic Very rare
disease
Source: WHO Fact sheets www/who.int/vaccines safety/initiative/tools/vaccinfosheets
Key
Very common > 1/10 > 10%
Common > 1/100 and < 1/10 > 1% and < 10% F
Uncommon > 1/1,000 and < 1/100 > 0.1% and < 1 %
Rare > 1/10,000 and < 1/1,000 > 0.01% and < 0.1%
Very rare < 1/10,000 < 0.01%
N
104 *

The WHO Regional
Office for Europe
The World Health Organization (WHO) is a specialized

agency of the United Nations created in 1948 with the
primary responsibility for international health matters
and public health. The WHO Regional Office for Europe
is one of six regional offices throughout the world,
each with its own programme geared to the particular
health conditions of the countries it serves.
Member States
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Finland
France
Georgia
Germany
Greece
Hungary
Iceland
Ireland
Israel
Italy
Kazakhstan
Kyrgyzstan
Latvia
Lithuania
Luxembourg
Malta
Monaco
Montenegro
Netherlands
Norway
Poland
Portugal
Republic of Moldova
Romania
Russian Federation
San Marino
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Slovakia
Slovenia
Spain
Sweden
Switzerland
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Republic of Macedonia
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VACCINE SAFETY AND

© World Health Organization 2017

vi Vaccine Safety and False Contraindications to Vaccination – Training manual

2.1.1. Pre-licensure testing

Scope and purpose 1

2.1.2. Post-licensure testing

2.1.3. Manufacture of vaccines

2 Vaccine Safety and False Contraindications to Vaccination – Training manual

Fig. 1. Stages in vaccine production and distribution

2.1.4. Addition of a vaccine to a recommended immunization schedule

4 Vaccine Safety and False Contraindications to Vaccination – Training manual

2.1.6. Role of clinicians in vaccine safety

2.1.7. Predictable pattern of behaviour when a new vaccine is introduced

6 Vaccine Safety and False Contraindications to Vaccination – Training manual

Global capacity Global advice and response

CIOMS/WHO National AEFI surveillance, Global signal,

AEFI review committee

2.2.1. National regulatory authorities

Areas of activity by NRA (or WHO) depending on source of vaccines

FUNCTION 4 NRA functions

Fig. 6. Functions of national regulatory authorities relating to vaccines15

8 Vaccine Safety and False Contraindications to Vaccination – Training manual

2.2.2. Immunization safety surveillance system

2.3. Adverse events after vaccination

2.3.1. Vaccine reactions

Table 1. Main minor and severe reactions associated with vaccination

Minor reaction Severe reaction

10 Vaccine Safety and False Contraindications to Vaccination – Training manual

Vaccine Local reaction (pain, Specific reaction

Vaccine Reaction Delay to onset Frequency per no. of

2.3.3. Reactions due to vaccination errors

Vaccination error Possible adverse event

To avoid programme errors24:

12 Vaccine Safety and False Contraindications to Vaccination – Training manual

2.3.4. Reactions due to anxiety about vaccination

2.3.5. Coincidental events

• Severe local reaction

• swelling beyond the nearest joint;

14 Vaccine Safety and False Contraindications to Vaccination – Training manual

• wheezing and shortness of breath due to bronchospasm,

Table 5. Differential diagnosis of fainting and anaphylaxis

Characteristic Fainting (syncope) Anaphylaxis

stridor) due to airway obstruction

• urticaria, rash and swelling around the injection site;

2.5. Reporting of adverse events after vaccination

16 Vaccine Safety and False Contraindications to Vaccination – Training manual

2.5.1. Events to be reported

• serious adverse events,

Adverse event after vaccination Onset after vaccination

18 Vaccine Safety and False Contraindications to Vaccination – Training manual

2.5.3. Mode of reporting

Date report first received at the national centre

Country in which the event was reported

Date of birth or age at time of onset or age group at time of onset

Other vaccines given just before the adverse event

Date and time of onset of adverse event

Institution and location

2.5.5. Barriers to reporting

20 Vaccine Safety and False Contraindications to Vaccination – Training manual

3. Valid and false contraindications

4. Facts and myths about