Inmunidad Vacunas Dengue

19 Dengue Vaccines
Scott B. Halstead, David W. Vaughn
INTRODUCTION Hemisphere in 1977, and was quickly followed by an out-

break of DHF/DSS accompanying the introduction of DENV
History of Disease 2 into Cuba in 1981.21 Since then, the other two DENVs have
been imported from SE Asia establishing hyper-endemicity in
Early in the 20th century, investigators studying dengue fever
the American tropics.
outbreaks successfully transmitted infection from person to per-
son through the bite of Aedes aegypti mosquitoes.1 The epidemi-
ology and clinical descriptions of this disease made it possible
to identify outbreaks of dengue fever from historical records. A
Why the Disease Is Important
well-characterized outbreak of “break-bone fever” occurred in Since World War II, the four DENVs have spread throughout
late summer of 1780 on the Philadelphia waterfront.2 Benjamin tropical and many subtropical areas to achieve pandemic
Rush fully described the classical signs and symptoms of den- status with recent annual aggregate estimates of 58–96 mil-
gue fever. Importantly, he recognized the postillness depression, lion overt disease occurrences annually22 (Fig. 19.1). Of these,
unique to dengue. Remarkably, in 1779, David Bylon “stads about 10.5 million were hospitalized. The most recent (2019)
cirurgyn” of Batavia (Jakarta) described another epidemic febrile global burden estimates (95% uncertainty interval) are 56.9
exanthema. This had an acute onset with joint involvement (37.1–101) million cases, 36,199 (9200–44,500) deaths, and
leading to persisting pain and swelling.3,4 The febrile period was 2.38 (0.83–3.27) disability-adjusted life-years (DALYs).23–26
shorter than that of break-bone fever. These features identify the Of these, perhaps 1–2 million persons are hospitalized with
1779 outbreak as chikungunya. For many years the Java out- severe illnesses, including DHF and DSS, and 0.1–5% die.24–26
break was cited as the classic description of dengue fever.5 Estimated costs are illustrated by a 2018 study in Indone-
A dengue zoonosis was recognized in Philippine monkeys sia with each nonfatal case in hospitals costing $ 316, each
in 1931.6 This was formally identified by Rudnick who recov- ambulatory case $22, each nonmedically attended case
ered dengue viruses (DENVs)-1, -2, and -4 in Malaysia from $7.50, with an overall average of $50 per case of dengue.27
wild-caught monkeys.7,8 It is likely that the four DENVs evolved Costs of nonfatal episodes were borne by the patient’s house-
from an ancestral virus that circulated in nonhuman primates hold (37%), social contributors (relatives and friends, 20%),
on mainland Asia that was subsequently fragmented into the national health insurance (25%), and other sources (govern-
Indonesian archipelago and the Philippines by the rise of ocean ment, charity, and private insurance, 18%). Including fatal
levels during the current interglacial period.9,10 This separation cases, the average cost per episode was $90.41. Indonesia had
permitted the evolution of viruses whose envelope proteins an estimated 7.535 million dengue episodes in 2017, with a
differed sufficiently to escape cross-neutralization—hence the national aggregate cost of $681.26 million. The study found
four virus types. One of these, DENV-2, was introduced into this cost was 73% higher than previously estimated. Dengue
Africa where it re-established a diverse zoonosis in nonhuman exacts a high socioeconomic toll on inhabitants of 128 tropical
primates.11 countries.
Aedes aegypti, a vector mosquito of enormous consequence An eight-country survey found costs for both outpatient
to human health, may have been introduced into Africa from and inpatient dengue illnesses to be substantial, ranging from
Indian Ocean islands 85,000 years ago.12 There it evolved 8 to 56 days of gross domestic product (GDP) per capita.28 The
to two subspecies, Ae aegypti formosus and Ae aegypti aegypti, global annual economic burden of dengue is $8.9 (3.7–19.7)
respectively, sylvatic and domestic vectors. The spread during billion.22 This cost exceeds that of other major infectious dis-
historical times of A. aegypti aegypti from Africa throughout eases with comparable data such as cholera, rotavirus, gastro-
the world created an ecologic niche that supported the urban enteritis, Chagas, and canine rabies.22 While underestimation
transmission of yellow fever, Zika, chikungunya, and the of passive surveillance system creates substantial uncertainty,
DENVs.13,14 Genetic studies of Aedes aegypti populations sug- the global burden of dengue is substantial.29,30 The worldwide
gest that the species was imported during the colonial era from DALYs due to dengue grew from 822,800 in 1990 to 2,920,000
Africa to the Western Hemisphere and from there to Asia.15,16 in 2017, contradicting the global shift in disease burden from
Analysis of the few existing zoonotic DENV strains suggests communicable to noncommunicable diseases.31,32 Dengue
that the four sylvatic virus types were independently imported exacts a burden on productivity. A 2016 study in India esti-
into the urban cycle within the past 1000 years.10 From eco- mated 53,210,706 cases and 22,527 deaths, resulting in $5.71
logical evidence this likely occurred in tropical Asia following billion in economic costs.33 In a recent review of 20 stud-
the introduction of Ae aegypti. ies, productivity costs varied between U.S.$6.7–1445.9 and
Prior to World War II, localized dengue outbreaks were rec- U.S.$3.8–1332 for hospitalized and outpatient nonfatal epi-
ognized by their clinical and epidemiological features. Some sodes, respectively.34 The productivity cost associated with fatal
were dramatic. A classical outbreak of dengue hemorrhagic dengue episodes varied between U.S.$12,035 and $1,453,237,
fever/dengue shock syndrome (DHF/DSS) was reported in variations reflecting the wide range of countries and socioeco-
northern Queensland, Australia in 1897, and another in Ath- nomic populations affected. Finally, dengue symptoms often
ens in 1928, with one million cases and a thousand deaths.17,18 persist resulting in chronic disability and consequently exact a
A pan-Pacific dengue fever outbreak of DENV-1 occurred dur- severe impact on quality of life.35–37
ing World War II.19 With infections supported by postwar In addition, visitors to dengue-endemic countries are
population growth, urbanization, and air travel, epidemic infected. In 2007, 141 million persons traveled to dengue-
dengue hemorrhagic fever/dengue shock syndrome (DHF/ affected areas in Asia.38 The risk of travel-acquired dengue
DSS) emerged into recognition in the Philippines in 1956 depends on destination, season, duration of travel and activi-
and Thailand in 1958.20 DENVs inexorably spread globally. ties during travel. Seroconversion rates reported in returning
DENV-1 of SE Asian origin was introduced into the Western travelers vary between <1% and >20%.39
275
Descargado para Alonso Humberto Bolbaran Castillo ([email protected]) en University of Chile de ClinicalKey.es por Elsevier en mayo 06,
2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
276 SECTION II Licenced Vaccines and Vaccines in Development
Evidence consensus
Complete (absence)
Good
. ,,.
• ·:~,~ ~\ .
Moderate
•
Poor
Indeterminable
Poor
Moderate
Good
Complete (presence)
Fig. 19.1 National and subnational consensus on complete absence (green) through complete presence (red) of human dengue cases.
Blue dots are past reported cases or outbreaks. (From Brady OJ, Gething PW, Bhatt S, et al: Refining the global spatial limits of dengue virus
transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012;6:e1760.)
DISEASE, VIRUS, EPIDEMIOLOGY, AND high concentrations and may activate toll-receptor 4 (TLR4),
directly damage endothelial cells, contribute to the damage of
PATHOGENESIS liver cells, activate complement, and stimulate the release of
Clinical Description cytokines.47–51 All of these are the observed features of DVPS.
Infection with DENV-1 (five genotypes), DENV-2 (six geno-

types), DENV-3 (five genotypes), or DENV-4 (four genotypes) Complications
may be asymptomatic, result in a mild febrile illness, dengue The most important but avoidable complication of DVPS is
fever (DF), or severe illness including DHF/DSS.40,41 Dengue the failure to promptly resuscitate with adequate fluid and,
fever is a self-limited febrile illness, with an average incuba- when required, protein solution. The next most important
tion period of 5 days, characterized by acute onset of fever complication is the continued administration of fluid after
and, variously, headache, myalgia/arthralgia, inappetence, the vascular leak has healed. This may rapidly result in hyper-
prostration, gastrointestinal symptoms, and rash. The contin- volemia leading to heart failure and pulmonary edema. Each
uum from DF to severe dengue is differentiated by the onset of these complications contribute to fatal outcomes in DENV
of the dengue vascular permeability syndrome (DVPS), which infections. For treatment guidelines, clinicians should consult
may rapidly appear around the time of defervescence, when the WHO Technical Guide for the Diagnosis, Treatment and
virus-infected cells are being immunologically eliminated Prevention of Dengue.52
(Table 19.1). Dengue vascular permeability syndrome, the cen-
tral component of DHF/DSS, is well described. Hemorrhage,
mild or severe, occurs with both DF and DHF/DSS. Vascular
Virology
permeability is of short duration that spontaneously and rap- DENV-1–4 are single stranded positive RNA members of the
idly self-heals.42–45 Proper management requires careful moni- Flavivirus group in the virus family Flaviviridae. The flavivirus
toring of clinical status obtaining multiple measurements of genome consists of approximately 11,000 base pairs, which
hematocrit and platelets.46 Evidence from recent in vitro stud- translate into three structural and seven nonstructural proteins
ies and a relevant animal model shows that nonstructural pro- (see “Chimeric virus vaccines,” later). The four distinct DENVs
tein 1 (NS1) released from all DENV-infected cells circulates at all evolved from a common sylvatic ancestor, with separate
introductions into the urban cycle of transmission—humans
to Aedes mosquitoes to humans which has limited virus evolu-
tion compared to other RNA viruses needing to accommodate
two hosts.9,53 The basic virology of the four DENVs is similar
TABLE 19.1 The Dengue Vascular Permeability Syndrome86 to that of yellow fever (see Chapter 64) and Japanese encepha-
DVPS, a syndrome that occurs late in the course of an acute dengue litis (see Chapter 35). The structural arrangement of DENV
illness (on or near defervescence) consisting of: surface proteins controls how antibodies neutralize viruses.
• Thrombocytopenia (<100,000/mm3). Dengue virus is an enveloped, positive-strand RNA spherical
• Altered hemostasis: most commonly prolonged bleeding time, viral particle with a diameter of approximately 500 A. RNA,
elevated aPTT (activated partial thromboplastin time) and reduced when complexed with capsid proteins, forms the inside of the
fibrinogen levels. virus particle. It is surrounded by a lipid bilayer membrane.
• Activated complement, by classical and alternative pathways. The viral envelope contains two integral membrane proteins
• Elevated liver transaminase enzyme levels usually accompanied by designated envelope (E) and premembrane (prM). E protein
enlarged liver. binds to cellular receptors and mediates fusion of viral and cel-
• Hypoproteinemia and vascular permeability with clinically significant
lular membranes during viral entry into cells and is the main
loss of fluid and small macromolecules (e.g., albumin) into interstitial
spaces, commonly serosal cavities.
target of neutralizing antibodies. Anchored on the outside of
the membrane are the M and E proteins. The M protein is a
Dengue Vaccines 277
small protein that is hidden under the E protein but that proj- not detectable by immunoassays, may retain endothelial tox-
ects to the surface in its immature state. Each virus particle has icity, in vivo. Progress in understanding dengue pathogenesis 19
180 monomers of E that are organized into 90 tightly packed is hindered by the absence of an aggressive research agenda.
dimers that lie flat on the surface of the viral membrane. Specific antiviral medications are not available, but sup-
Each E protein monomer has three domains: DI, DII, and portive intensive care and careful fluid management is life-sav-
DIII.54–57 The hinge that connects DI to DII is used to flex DII ing.79 The single available preventive measure, comprehensive
in the low pH environment of the endosome, leading to the mosquito control, has not been effective. Increases in ambient
exposure of its fusion loop.56,57 DIII is thought to be involved temperatures increase vectoral capacity.80,81
in receptor binding. Individual subunits of E protein consist of
three β-barrel domains designated domains I (EDI), II (EDII),
and III (EDIII), with the native protein forming a head-to-tail Epidemiology
homodimer. The hydrophobic viral fusion peptide is located Infection of humans follows the bite of an infected Aedes
at the tip of domain II and is shielded by domain III of the mosquito (primarily Aedes aegypti, and to a lesser extent Aedes
adjacent subunit. Domain III appears to be responsible for albopictus or Aedes polynesiensis). Ae aegypti eggs are laid indi-
binding to cellular receptors as several mutations that affect vidually by the female mosquito on the walls of both artifi-
receptor binding are located in this domain.58 cial and natural water containers. Eggs resist desiccation for
weeks to months and hatch when submerged in water. Larvae
and pupae prefer clean water in many different types of artifi-
Pathogenesis as It Relates to Prevention cial containers: water storage containers (tanks, jars, cisterns,
Classical DHF/DSS accompanies first DENV infections in pots), ornamental containers (flower holders, ant traps, shrine
5–11-month-old infants born to dengue-immune mothers.59 objects), and discarded items (rubber tires, plastic contain-
Altogether 90+% of cases accompany second (occasionally ers, bottles). The species also occasionally uses natural larval
third) heterotypic DENV infections in individuals older than habitats, such a bromeliads and tree holes. Containers located
1 year.43,60,61 These two epidemiologic settings have in com- outside dwellings can be filled with rainwater and are produc-
mon a single immune factor—IgG1 DENV antibodies. Numer- tive during the rainy season. Indoor or sheltered containers
ous studies show that at subneutralizing concentrations DENV may produce pupae throughout the year. When extensive use
antibodies enhance DENV infections in Fc-receptor-bearing is made of outdoor larval habitats the prevalence of larvae
cells, a process referred to as antibody-dependent enhance- and adults are often subject to marked seasonal variation. The
ment (ADE).62,63 In humans, peak viremia titers measured duration of the larval stages is 7–9 days at 25°C and that of the
early in secondary DENV infections were positively correlated pupal stage is 2–3 days at the same temperature.
with the subsequent occurrence of DHF/DSS.64 DHF/DSS is The ecology of adult Ae aegypti in a domestic urban envi-
rare, seen in only 2–4% of second DENV infections.65 ronment is characterized by strong anthropophilia and diur-
The discovery that DVPS is a toxicosis, mediated by NS1 nal feeding usually with two peaks, one in mid-morning and
a protein with endotoxin-like properties, has fundamentally another in late afternoon. It seems likely that most females
changed the dengue pathogenesis landscape.47–51,66 For 60 can feed twice or even three times during a single gonotro-
years, competing camps promoted many alternative hypoth- phic cycle.82–84 The preferred resting sites of adults are sheltered
eses of the pathogenesis of severe dengue: intrinsic viral viru- dark spaces inside houses. The average life span for females is
lence, autoimmunity, direct DENV infection of endothelial 8–15 days and that for males about 3–6 days. Geographic dis-
cells, “original antigenic sin” and second-infection pathogenic persal of adults is usually limited, averaging about 30–50 m a
immune responses (“cytokine storm”).67–73 These hypotheses day for females, which means that a female rarely visits more
centered on explaining DHF/DSS due to second heterotypic than two or three houses during her lifetime. In some locales,
DENV infections but, ignored or made no attempt to explain such as Puerto Rico, female flight distance may be related to
DVPS during a first infection in infants born to dengue- the availability of oviposition sites (breeding sites) and so
immune mothers. NS1 toxicosis provides a unitary pathogene- might be much longer. Passive dispersal of eggs and larvae is
sis hypothesis. Antibodies, actively or passively acquired form common, including trains, boats, and aircraft. Because of the
immune-complexes with circulating virus, infect Fc-R-bearing weak spontaneous dispersal of the species and its easy passive
cells leading to increased production of DENV NS1. dispersal, the International Sanitary Regulations require that
Comprehensive pathology studies on 13 fatal DSS cases the area within 400 m of international ports and airports be
found splenic and lymph node macrophages were produc- kept free of Ae aegypti.
tively infected.74 Endothelial cells were not infected. There Two main factors regulate Ae aegypti populations: climate
was evidence of nonreplicative DENV infection of hepatocytes and the availability of breeding sites. Population changes may
and widespread staining of parenchymal cells by DENV NS or may not correlate with weather. Daily, seasonal, and inter-
1 and complement subunits.74,75 While there is a correlation annual variability in temperature, atmospheric moisture, and
between DVPS and peak NS1 blood levels measured soon after rainfall all influence mosquitoes in a variety of ways. From an
onset of fever, when measured during the period of severe vas- epidemiological perspective, the increased number of inter-
cular permeability NS1 blood concentrations may be rather rupted feeding per replete feeds that is the consequence of
low. During the late acute stage, anamnestic antibodies nearly 2° or 3° warmer temperatures is equivalent to a doubling of
obliterate viremias and RNAemias. Formal attempts to cor- the density of Ae aegypti. Under circumstances where a major-
relate NS1 blood levels with vascular permeability are prob- ity of breeding sites are indoors, warm temperature and high
ably only possible during primary DENV infections. In the moisture contribute to increased adult survival together with
literature almost all studies on NS1 blood levels and vascular the effect of warmer temperatures on shortening the extrin-
permeability have been performed during secondary DENV sic incubation period contribute to the occurrence of dengue
infections. The few studies on infants with severe primary den- outbreaks during the hot, rainy season of Southeast Asia. In
gue found relatively low viremias compared with peak values countries with seasonal variation, DENV transmission is high-
in secondary infections.76–78 Consecutive daily measurements est during warm or rainy seasons. In the true tropics, such as
were not made. Damage to endothelial cells may be a thresh- Singapore, DENV transmission is year-round, but, impacted
old phenomenon and related to duration of exposure to NS1. by seasonal variations in nearby countries whose populations
It is also possible that circulating NS1 antibody complexes, either work in or may visit Singapore.
Immunity in Dengue ACTIVE IMMUNIZATION

Immune responses of humans to DENV infections are both History of Vaccine Development
simple and complex. A first DENV infection produces lifelong
protection to homotypic virus reinfection. Interactive immu- The complexity of dengue pathogenesis and dengue virology
nity by the different DENV infections is complex and poorly has deferred the achievement of safe and efficacious dengue
understood. A first infection with any DENV conveys early but vaccines for more than four decades.95 Each DENV type causes
waning cross-protection against a second heterotypic DENV disease and death, and in many dengue-endemic areas, there
infection. For a period of roughly 2 years this results in the is concomitant cocirculation of multiple types, mandating
important benefit of protecting against or reducing the sever- vaccines that protect against all four DENVs. Following natu-
ity of secondary infection DVPS.85 Unfortunately, as the gap ral infection of humans with DENV-1 a short-duration cross-
between first and second DENV infections widens, the rate and protection against infection with DENV-2 was observed.19 It is
severity of secondary DENV infection DVPS rises.86 It is this now well established that heterotypic protective immunity fol-
attribute of dengue immunity that endangers the outcomes of lowing infection with any first DENV reduces the risk of severe
imperfect dengue vaccines. Sequential infections with any two disease with a second heterotypic DENV infection for a period
DENVs produce strong and durable protection against severe of 2 years.85,96 As the interval between first and second DENV
disease accompanying a third DENV infection.43,87 We neither infections lengthens, so does the risk of severe disease. Immu-
have reliable markers of protection nor a comprehensive under- nologically primed individuals may be at risk of enhanced
standing of the mechanisms of dengue immunity, protective disease for a lifetime as evidenced by DHF/DSS accompany-
or immunopathogenic. A belief, long held, unsubstantiated ing secondary DENV-2 or DENV-3 infections 20 years after
by evidence, is that antibodies are the sole or a major mecha- DENV-1.97,98 The mechanism of early heterotypic protection
nism of life-long protective immunity. There is no question is not established. Studies on DENV-immune humans and
that in the right concentrations and composition, antibodies experimental studies using mouse models of severe disease
are protective. For example, antibodies passively transferred suggest a role for T cells.99,100 But antibodies also contribute to
from women with two or more previous DENV infections pro- protection.101
tect their infants from DENV infection and disease. But, in a Several flaviviral live-attenuated vaccines (LAV) have proved
matter of months, these same antibodies degrade to efficiently safe and durably efficacious, 17D yellow fever and SA 14-14-2
enhance dengue disease.88 Insights into mechanisms of pro- Japanese encephalitis vaccine.102–105 Live-attenuated viral vac-
tection were improved when it was recognized that antibody cines replicate in recipients, presumably present all viral anti-
interactions with three dimensional virion structures were cru- gens in a manner analogous to that of wild virus infections,
cial to neutralization of homotypic DENVs.89 eliciting antibody and T-cell responses. In dengue endemic
All candidate tetravalent DENV vaccines rely on the tetra- countries many adults experiencing 3–4 DENV sequential
valent protection demonstrated in monkeys given four live infections are demonstrably protected against severe dengue
DENVs as a single dose. Protection was evidenced by tetrava- disease.
lent neutralizing antibodies plus solid protection to challenge
with each of the four wild-type DENVs.90 “Solid protection”
was defined as the absence of viremia - and
- anamnestic hemag-
Initial Approaches That Were Abandoned
glutination-inhibition (HI) or neutralizing antibody responses. Dengue vaccine development began in 1929 by inactivat-
ing virus in blood or mosquitoes with phenol, formalin, or
Diagnosis bile.6,106 During World War II, passaging DENV-1 serially in
suckling mouse brain produced a live-attenuated virus (LAV)
Specific etiology is established by detecting the agent or viral pro- vaccine.107,108 DENV-2 was similarly attenuated.109 These early
tein in blood or by documenting a specific antibody response live virus vaccines were abandoned because of concerns about
after infection. Etiology during the acute phase can be determined the safety of inoculating mouse tissues into humans.110
by isolating virus in any of several host systems or detecting cir-
culating DENV RNA. The standard method is the detection of
NS1 by ELISA or immunoassay while it circulates in the blood in Current Approaches
the acute and early convalescent phases.77,91–93 In addition, there
are many commercial tests on the market that identify antibody Since the 1970s, numerous dengue vaccine constructs have
responses to DENV infection. The first to be marketed detected entered preclinical and clinical development. Seven vaccine
IgM and IgG antibodies using the enzyme-linked immunosor- constructs reached Phase 1, three of which attained Phase 3
bent assay (ELISA).52,94 Clinically, the tests of choice now are the clinical testing (Table 19.2).95,111–123
rapid immunoassays. These tests identify acute or recent primary Dog Kidney Passaged Vaccines. Once it was found that
DENV infections when DENV IgM is detected in sera collected DENVs could be recovered directly in tissue culture, most can-
5 days or more after onset of fever. A secondary DENV infection didate vaccines have been tissue culture-based.124 In 1971, rec-
is tentatively established when the etiological agent is recovered ognizing the high burden imposed by the 20th-century dengue
in an individual with circulating IgG antibodies during the acute pandemic, the U.S. Armed Forces Epidemiology Board initi-
or early convalescent stage. Formal diagnosis requires evidence ated a cooperative scientific effort to develop vaccines against
that antibodies measured derive from a prior DENV and not DENV types 1–4. This generated the discovery that serial pas-
another flavivirus infection. In the United States, the Food and sage of all four DENVs in primary dog kidney cells (PDK)
Drug Administration (FDA) regulates the marketing of commer- reproducibly selected for attenuation of viruses that retained
cial tests to detect dengue. immunogenicity for humans.125,126 Live-attenuated candi-
date tetravalent dengue vaccines at the University of Hawaii
Treatment and Prevention With Antimicrobials to Mahidol University and the Walter Reed Army Institute of
Research (WRAIR) evolved from this discovery.126,127
or Antivirals Attenuation of DENV was carried out by serial passage in
There are no antivirals available to treat or prevent DENV PDK cells at the University of Hawaii and Mahidol University
infections/disease. in Bangkok. Virus strains DENV-1 16007, DENV-2 16681, and
Dengue Vaccines 279
TABLE 19.2 Dengue Fever Vaccines in Clinical Testing

19
Type of Vaccine Dengue Virus Genes/Proteins (N) Testing Stage, Developers
Live-attenuated virus (traditional) (10) Phase 2: tetravalent (Mahidol/Aventis WRAIR/GSK Biologicals)

Live-attenuated virus (molecular) (10) Phase 3: tetravalent (Butantan, U.S. National Institutes of Health, LATV)
DENV 2/4 chimera plus mutagenized Butantan-DV
DENV 1, 3, 4 Phase 2: tetravalent (Panacea Biotec, LATV) Dengue Tetravalent Vaccine
Yellow fever chimera (7) Completed Phase 3: licensed, Dengvaxia (Sanofi Pasteur)
Chimera, DENV 1- 4/YF 17 D
Dengue chimera (10) Attenuated DENV 2 Completed Phase 3: tetravalent Takeda TAK 003
(7) DENV-2/1, 2/3 2/4 chimeras
Purified inactivated (3) Phase 1: tetravalent (GSK, Fiocruz, WRAIR)
Recombinant subunit <1 Phase 1: tetravalent (Merck Inc.)
DENV-4 1036 were passaged 15–50 times in primary dog kid- find a balance between acceptable levels of reactogenicity and
ney (PDK) cells.128 Candidate vaccines were tested at Phase 1 obtaining high rates of tetravalent neutralizing antibodies in
in Thailand in flavivirus-susceptible adult Thai volunteers.129 humans. Manufacturing complexities and the desire to find a
DENV-1 PDK13, DENV-2 PDK53, and DENV-4 PDK48 dem- vaccine with a shorter time to protection led to the abandon-
onstrated acceptable reactogenicity and immunogenicity.130–132 ment of the project. An important outcome of these efforts
All 10 U.S. Army soldiers inoculated with DENV-2 PDK 53 was finding live DENVs that could be used as challenge viruses
developed neutralizing antibodies in the absence of dengue- to test protection of vaccinated subjects.150,151
like symptoms.133 DENV-3 16562 did not replicate in PDK
cells and was attenuated by 48 passages in primary African DNA Vaccines. Workers at the Naval Medical Research Center
green monkey kidney (AGMK) cells and 3 final passages in evaluated two eukaryotic plasmid expression vectors (pkC-
fetal rhesus lung cells (FRhL).129 The four monovalent candi- MVint-Polyli and pVR1012; Vical, Inc., San Diego, CA) express-
dates after a single dose of 103.7–104.4 plaque-forming units ing the PrM protein and 92% of the E protein for DENV-1
(pfu), tested separately, elicited neutralizing antibody sero- and DENV-2 virus (see Table 19.2). These constructs induced
conversions in 3/5, 5/5, 5/5, and 5/5 American volunteers, neutralizing antibody in mice,152 and they were subsequently
respectively.134 Bivalent and trivalent formulations using improved by adding immunostimulatory CpG motifs, and the
DENV-1, -2, and -4 vaccine candidates elicited balanced full-length E gene with PrM.152–155 In early studies, a DENV-1
seroconversions.135 The tetravalent vaccine was designed to DNA vaccine protected a portion of challenged monkeys from
induce primary-type immune responses to each of the four viremia for varying lengths of time.156 With the recognition
DENVs simultaneously as had been demonstrated in suscep- that dendritic cells are the percutaneous portal for dengue
tible rhesus monkeys.90,136 virus replication,157 efforts were taken to target DNA vaccines
In 1993, attenuated DENVs were shipped to Aventis to these cells.158
Pasteur for commercial production.129 Concerned about In a Phase 1 clinical trial, a DENV-1 DNA vaccine was
the safety of primary AGMK cells, the manufacturer chose administered intramuscularly to 22 flavivirus-negative volun-
FRhL to produce the DENV 3 GMK 30 component. This tet- teers, half of whom received high and low dosages, respec-
ravalent vaccine entered Phase 1 testing in 1995. Problems tively, in a three-dose series (at day 0, and at 1 and 5 months).
were recognized immediately. During Phase 1 and Phase 2, At the completion of this series, none of the low-dosage recip-
the vaccine was moderately reactogenic, failed to raise neu- ients and only 5 of 11 high-dosage recipients developed neu-
tralizing antibodies against DENV 1, 2, and 4 viruses, and tralizing antibodies. In addition, all volunteers immunized
exhibited a dominant DENV 3 viremia.134,137–141 It was con- with high-dose monovalent DENV-1 DNA vaccine developed
cluded that DENV-3 GMK 35 FRhL 3 had reverted toward T-cell responses as measured by interferon gamma ELISPOT
wild-type virus with attributes that suppressed the growth assay.159
of PDK-attenuated DENVs. An effort was made by Aventis To enhance neutralizing antibody responses, a tetrava-
to find a satisfactorily attenuated strain of DENV 3 GMK 30 lent dengue DNA vaccine was formulated in a lipid-based
FRhL 3 by plaque purification.142 A virus with small plaque adjuvant, Vaxfectin, and evaluated in a nonhuman primate
morphology, temperature sensitive, with reduced infectivity model. The vaccine was administered by intramuscular injec-
for vector mosquitoes and reduced viremia in monkeys was tions using the Biojector 2000 needle-free delivery device.
grown in Vero cells and given at a low dose (10−2 pfu) to 15 The results showed a significant increase in neutralizing anti-
Hong Kong medical students. This produced nonhospital- body responses to DENV-1, DENV-3, and DENV-4 in animals
ized dengue fever in all, graded as “severe” in 13. This ended immunized with the formulated tetravalent vaccine compared
the effort by Aventis for commercial production of the PDK/ to animals given the unformulated dengue DNA vaccine. The
GMK-passaged dengue vaccine. use of Vaxfectin also resulted in significantly greater protec-
The WRAIR developed and tested a large number of tion against live DENV-2 challenge.160 A subsequent Phase 1
monovalent and tetravalent live-attenuated DENVs. In col- clinical trial of the formulated tetravalent dengue DNA vac-
laboration with GlaxoSmithKline Vaccines (GSK), DENV-1–4 cine delivered by needle injection showed that the vaccine
serially passaged in PDK cells were prepared as vaccines in was safe but generated minimal tetravalent antidengue anti-
FRhL. Some of the resultant candidate vaccines were evaluated body responses.161 Robust IFNgamma T-cell responses were
in Phase 2 tests in adults and children, both susceptibles and observed, as was seen in the Phase 1 trial of the monovalent
partial dengue immunes.143–149 The group found it difficult to DENV-1 DNA vaccine.
To enhance dengue DNA vaccine immune responses, Wil- vaccinated rhesus monkeys had breakthrough viremias or
liams et al. explored different methods of delivery.162 Investi- RNAemias. Nearly all had anamnestic antibody responses and
gators compared electroporation and needle-free jet injection elevated levels of AST and distinctive cytokine response pat-
given by either the intramuscular or intradermal route. Utiliz- terns IL-10, IL-18, IFN-gamma, IL-12, and liver enzymes.174
ing high (5 mg) and low (1 mg) doses of tetravalent dengue This is the first demonstration of dengue vaccine challenge
DNA vaccine, the highest neutralizing antibody and IFN- virus enhanced abnormal host physiological responses in an
gamma T-cells responses were achieved with the high dose experimental animal model. Detection of subclinical ADE in a
administered by intradermal electroporation. When chal- vaccinated monkey model resulted in termination of the PIV
lenged 1 year postimmunization with live DENV-1, animals development program.
in this group also exhibited significantly fewer mean days of
viremia (1.5 days) postchallenge compared to control unvac-
cinated animals (6.5 days) as determined by RT-PCR. The only Vaccines Completing Phase 3 Clinical Evaluation
other group showing significant protection was the low dose
intradermal electroporation group. Further evaluation of tet- TAK-003. Produced by Takeda Pharmaceutical Company, TAK
ravalent dengue DNA vaccines by electroporation in a Phase 1 003 is a two-dose vaccine given 3 months apart consisting of
clinical trial is under consideration. the prM and E protein genes of DENV-1, -3, and -4 inserted
Incorporating dengue DNA vaccines into a heterologous into a DENV-2 genetic backbone.175,176 This is the same DENV
prime-boost approach was explored for inducing protec- 2 PDK-attenuated DENV 2 strain used in the Mahidol/Aventis
tive antidengue immune responses. Using a rhesus monkey Pasteur vaccine. In January 2018, Takeda announced the com-
model, Simmons et al. showed that, compared to priming pletion of its Phase 3 trial conducted in eight dengue endemic
with DENV-2 DNA vaccine and boosting with two doses of countries in Southeast Asia and Latin America among 20,071
DENV-2 protein, the highest neutralizing antibodies were children 4–16 years of age randomized 2:1 to vaccine or pla-
achieved with three doses of a DENV-2 DNA combined with cebo.177 At 12 months after the second dose, the efficacy of
either a recombinant DENV-2 E protein or purified inacti- preventing dengue among 12,696 vaccinated children, sero-
vated DENV-2 virus.163 However, the best protection against negatives, and seropositives, was 80.2% (95% CI: 73.3–85.3).
live DENV-2 challenge was observed in animals receiving three There were 61 cases (0.5%) of virologically confirmed dengue
doses of purified inactivated virus.164 A more recent study com- in the vaccine group and 149 (2.4%) in the placebo group.
pared priming with either a tetravalent dengue DNA vaccine In the seronegative population of 3531 vaccinated children,
or tetravalent purified inactivated dengue vaccine (PIV) and 20 (0.6%) had virologically confirmed dengue contrasted with
boosting with a tetravalent live-attenuated vaccine (LAV) in 39 among 1726 seronegative controls (2.3%), an efficacy of
the same rhesus monkey model.158 74.9 % (CI: 57.0–85.4). Of 12,696 vaccinated children only
In an effort to simplify the tetravalent dengue DNA vac- five were hospitalized versus 53 among 6314 in the placebo
cine consisting of four separate DNA vaccine plasmids, DNA group. Vaccine efficacy against hospitalization, regardless of
shuffling technology was utilized to generate a single plasmid immune status, was 95.4%. Among seronegatives, two vac-
containing a chimeric tetravalent prME gene that expresses cinated children were hospitalized with severe dengue or
proteins from all four dengue serotypes. The chimeric plas- DHF compared with five among controls. Vaccine efficacy was
mid was created by shuffling the envelope genes from the 97.7% against DENV-2 disease, 73.7 % against DENV-1, and
four dengue viruses. Selected shuffled DNA was transfected 62.6% against DENV-3. There were too few DENV-4 cases to
into human cells, subjected to flow cytometry, and reacted enable efficacy calculations. Notably, DENV-4 antibody titers
with type-specific dengue antibodies. Antibody markers per- and seropositivity persistence were lowest out to 48 months
mitted rapid screening of libraries and identification of novel and 36 months using an older formulation (before a DENV-2
expressed chimeric antigens. A panel of chimeric clones reduction) in Phase 2 studies in dengue-endemic areas driven
expressing C-terminal truncated antigens that combined enve- by lower initial immune responses to DEN-4 in baseline
lope and prM epitopes from all four DENV types when inoc- seronegatives.178,179
ulated in mice and monkeys successfully raised neutralizing Over 27 months of observation the cumulative efficacy for
antibodies. Monkeys resisted challenge with DENV-1 but not all dengue cases, baseline seronegatives and seropostives, was
DENV-2.165,166 Further clinical testing is pending.167 72.7% (95% CI: 67.1–77.3).180 Because TAK-003 efficacy varies
by serotype, the observed changes in serotype dominance in
Inactivated Whole Virus Vaccines. Comprehensive efforts vaccine study sites may contribute to year-to-year efficacy dif-
were undertaken to develop and test candidate purified for- ferences. During the second year, dengue efficacy declined to
malin inactivated dengue vaccines (PIV). The results illustrate 56.2% (95% CI: 42.3–66.8) with the largest decline to 24.5%
the risks of the partial protection phenomenon. At WRAIR, (−34.2 to 57.5) in 4–5-year-old children, with efficacies of
monovalent or tetravalent formalin-inactivated DENV vac- 60.6% (43.8–72.4) in 6–11-year-olds and 71.2% (41.0–85.9)
cines were prepared with or without adjuvants, inoculated in the 12–16-year age groups. Prevention of hospitalization by
in rhesus monkeys and challenged with wild-type DENVs at vaccine remained high at 89.2% (96% CI: 82.4–93.3). Dur-
varying intervals. All PIVs raised significant levels of neutral- ing 27 months, among children vaccinated as seronegatives,
izing antibodies, but usually low levels of challenge viremias prevention of dengue was 67.0% (95% CI: 53.6–76.5). There
or RNAemias were detected.168–170 Because challenge viremia were five vaccinated children, ages 4–5 years, hospitalized with
levels were thought to be below the level that would cause breakthrough dengue infections in year 2 compared with just
disease in humans and antibody responses were fairly robust, one in year 1. While not significant, a trend of increasing inci-
these vaccines were advanced to Phase 1 in susceptibles and dence of breakthrough dengue disease in vaccinated children
partially dengue-immunes.171–173 WRAIR awarded an exclusive may be a warning.
license to GSK and the Oswaldo Cruz Foundation (FioCruz)
for producing and testing a commercial candidate tetravalent
PIV formulation (DPIV). Adjuvanted with AlOH or a GSK
proprietary Adjuvant System (AS), a short-interval challenge
Vaccines in Phase 3 Clinical Trials
concluded that immunized rhesus monkeys were protected.168 Live-Attenuated Tetravalent Dengue Vaccine (LATV-
When a larger group of animals were immunized and chal- 003/005). For nearly 20 years, workers at the National Insti-
lenged at 8 months with wild-type DENV-1–4, a number of tute of Allergy and Infectious Diseases (NIAID) and the Johns
Dengue Vaccines 281
Hopkins Bloomberg School of Public Health have continuously DENV-4, 1228 that have been tested in extensive preclinical
designed and tested dengue vaccine candidates. DENV-1 and -4 and Phases 1 and 2 trials in flavivirus susceptible and immune 19
were attenuated by removing 30 nucleotides (Δ30) from the individuals. Vero cells serve as the substrate for vaccine virus
nontranslated region (NTR) of the DENV genome. A DENV-2 production. These earlier data are described in the sixth and
vaccine was constructed as a chimera with DENV-4 Δ30 and the seventh editions of this book.
DENV-3 Δ30/31vaccine strain and by deleting additional NTR A three-dose chimeric yellow fever tetravalent dengue vac-
nucleotides.113 A crucial component of this development pro- cine was evaluated in multipart Phases 2b and 3 efficacy trials
gram was that all monovalent vaccine candidates were tested involving 35,000 children in 10 dengue-endemic countries.
for immunogenicity and attenuation in seronegative human Among trials started in 2011, efficacy results were mixed.141,209
volunteers. Innovatively, a second vaccine dose was used as a Pooled efficacy rates for symptomatic dengue 25 months after
test of protection.181–184 A single dose of LATV has solidly pro- complete immunization were 60.3% for all participants, 65.6%
tected seronegative human volunteers for short and long peri- for those 9–16 years of age and 44.6% for those younger than
ods by challenge with nonparental wild-type-like DENV-2 Δ30 9 years of age. Vaccine protection against hospitalization was
(Tonga 74) or DENV-3 Δ30 (Sleman 78). (Durbin, A., personal better at 72.6% for children of all ages, 80.75% for children 9
communication, December 28, 2020). After a single dose of years and older and 55.8% for those under 9 years. Eighteen
vaccine was given to 20 susceptible volunteers, challenge at 6 children were hospitalized for severe dengue among the 22,177
months with DENV-2 Δ30 (Tonga 74) resulted in no viremia, (0.08%) who were vaccinated compared with six among 11,089
dengue rash, or anamnestic antibody response.185 That LATV (0.05%) controls. A high rate of hospitalization among vacci-
protection is likely to be of long duration is supported by solid nated 2–5-year-olds was observed. Among the 2029 children
immunity against a booster dose of live-attenuated vaccine 5 years or younger who received vaccine, 20 were hospitalized
given 12 months after initial dose.186 for dengue, a rate significantly higher (0.99%) than controls
These results are complemented by data showing that a 2/1005 (0.2%), a relative risk of 4.95, P = 0.03. This was attrib-
single dose of LATV raises monospecific DENV-1–4 neutraliz- uted to novel, unstudied pathogenic mechanisms such as young
ing antibodies that are conformationally similar to those after age, a temporal “clustering” of vaccine-related cases occurring
human infections with wild-type DENVs and found to corre- in young children due to the large numbers given vaccine over
late with protection.187–189 Moreover, CD4+ and CD8+ T cell a short period, or to the immunological immaturity of recipi-
responses to LATV closely resemble those raised after infections ents.209,210 These data led the manufacturer and WHO advisory
with wild-type DENVs.190–192 There is growing evidence that groups to recommend vaccine be given to children 9 years of
human T cell responses directed at epitopes on nonstructural age and older and directed to populations in settings, national
proteins contribute importantly to homotypic and heterotypic and regional, with a dengue seroprevalence of 70% or grea
DENV protective immunity.193–195 Finally, LATV contains genes ter.209,211,212 To provide guidance for the deployment of vaccine,
for three of the four DENV NS1 proteins. There is evidence WHO described sampling and statistical methods for measur-
from experimental animal models that DENV NS1 used as a ing population-based DENV seroprevalence.213,214
vaccine antigen protected against lethal DENV challenge.196 Experts not affiliated with clinical trials suggested post-
LATV has been licensed independently to Butantan, a vac- vaccination clinical responses exhibited hallmarks of vaccine
cine manufacturer in Sao Paulo, Brazil, Panacea Biotec Ltd, New ADE and recommended that efficacy should be separately cal-
Delhi, India and to Merck. Vaccine manufactured by Butantan culated for individuals vaccinated when seronegative or sero-
(Butantan-DV) is in the fourth year of Phase 3 clinical testing. positive.215 The manufacturer implemented this suggestion.
An interim analysis found no significant early adverse events and Because fewer than 12% of Phase 3 children had blood col-
high rates of tetravalent DENV neutralizing antibody seroconver- lected prior to vaccination, efficacy and safety calculations were
sions in seronegatives.197 The accrual of efficacy data has been based on inferred serostatus from blood taken 12 months after
slowed by an inadvertent event, the Zika pandemic of 2016-16 the initial dose.216 These data resulted in a revision of estimates
in South America which was associated with an 80% reduction of vaccine efficacy and safety. There was a decline in vaccine
in reported dengue cases.198 Release of Phase 3 results from Brazil efficacy against symptomatic dengue to 34%, compared with
are expected in 2022. Panacea has completed a phase 2 safety 60.3% at 2 years, with a relative risk of 0.66. The cumulative
and immunogenicity analysis for its version of LATV, Tetravalent 5-year incidence of hospitalization was 1.37% among vaccin-
Dengue Vaccine (TDV) with satisfactory results.198a Phase 3 test- ees and 2.0% among controls. Among hospitalized children
ing plans have not been released. Plans for the development and of all ages, 76 receiving vaccine had severe dengue (0.37%)
release of vaccine by Merck have not been announced. compared with 49 among controls (0.45%), a vaccine efficacy
of 25% and relative risk of 1.33.
Vaccine-enhanced hospitalizations were documented for
2–8-year-old seronegative children. Among 1820 vaccinated
Licensed Vaccine children, 131 were hospitalized compared with 33 among 1010
Dengvaxia: Yellow Fever Dengue Chimeras. Insertion of controls (chi-square with Yates = 15.86, P = 0.000068, rela-
flavivirus preM and E genes into the cDNA backbone of yel- tive risk = 2.2). Of these, 25 had severe dengue adverse events
low fever (YF) 17D was pioneered at the St. Louis University compared with four in the placebo group (chi-square with
Health Sciences Center.199,200 Using this technology, DENV Yates = 5.0944, P = 0.024, relative risk = 2.8). In 9–16-year-
chimeras were developed by Acambis, Inc., and licensed for olds, among 3300 vaccinated seronegatives and 1710 controls,
manufacture to Sanofi Pasteur.201,134 It was expected that these 12 vaccinated children were hospitalized with severe dengue
vaccines would benefit from the high fidelity of YF 17D poly- versus 1 in the controls (chi-square = 2.9443, P = 0.086182,
merase.202 Studies to date suggest that chimeric structure of N.S.). Absence of statistical power can be attributed to small
DENV and West Nile viruses provides attenuation.199,201,203–205 numbers. Using Phase 3 data, in the Philippines, where
In contrast, when wild-type prM- E genes of JE, tick-borne, 880,464 9-year-old children were vaccinated in 2016, among
and St Louis encephalitis viruses were inserted into YF 17D an estimated 132,070 seronegatives, during the next 4 years
they retained encephalitic properties requiring alterations in there would be 2241 hospitalizations and 480 cases of severe
prM-E genes to achieve attenuation.199,203,206–208 Sanofi Pasteur dengue expected.217 Serious consequences would be expected
produced chimeras of yellow fever virus and PrM-E genes from as the case fatality rate among Philippine children hospital-
DENV-1, PUO-359; DENV-2, PUO-218; DENV-3, PaH881; and ized for dengue is approximately 5% (Tables 19.3 and 19.4).
TABLE 19.3 Hospitalizations, Severe Dengue Cases and Relative Risk in 2–8 and 9–16-Year-Olds Who Were Given Vaccine or Placebo 5 Years
Earlier216
Hospitalizations Severe
Cases/10% Sample Cases/10% Sample
Categories 2–8 Years 9–16 Years 2–8 Years 9–16 Years
Vacc 137.4/192.8 64.2/375.1 30.1/192.8 14.8/375.1
Sero Neg Placebo 37.2/100.6 25.3/207.2 5/100.6 3.6/207.2
RR 1.95 1.41 3.31 2.44
Vacc 96.3/313/2 58.8/1502.9 23.9/313.2 11.2/1502.9
Sero Pos Placebo 89.8/156.4 137.7/729.8 20/156.4 33.4/729.8
RR 0.50 0.21 0.58 0.16
Numerator data, derived by multiple imputation method, are total symptomatic patients hospitalized or severe dengue. Denominator data are children
in the 10% serological sample.
TABLE 19.4 Hospitalizations and Relative Risk in Three Age Groups of Children, Ages 4–16 Years, Given TAK 003 or Placebo 2 Years Earlier
Hospitalizations Severe
Cases/Total Cases/Total
Categories 4–5 Years 6–11 Years 12–16 Years 4–5 Years 6–11 Years 12–16 Years
Vacc 3/662 4/2200 0/669 1/662 1/2200 1/669
Sero Neg Placebo 3/337 18/1065 3/324 1/337 0 0
RR 0.51 0.11 0.16
Vacc 3/957 3/4808 3/3402 0 1/4808 0
Sero Pos Placebo 4/464 30/2423 17/1700 1/464 5/2423 4/1700
RR 0.36 0.05 0.088
Severe cases are shown without RR calculations (Medina et al., 2021).180
Constituents Including Antibiotics, Dosage and Route: IM, SC, Oral

Preservatives, Adjuvants, Etc. Dengvaxia is reconstituted from lyophilized power in single-
After reconstitution, each 0.5-mL dose of DENGVAXIA con- dose vials using a saline diluent and administered subcutane-
tains 4.5–6.0 log10 CCID50 of each of the chimeric yellow ously as a 0.5 mL dose three times at months 0, 6, and 12.
fever dengue (CYD) virus serotypes 1, 2, 3, and 4. Each 0.5-mL
dose is formulated to contain 2 mg sodium chloride and the
following ingredients as stabilizers: 0.56 mg essential amino Vaccine Stability at Room Temperature,
acids (including L-phenylalanine), 0.2 mg nonessential amino Refrigerator
acids, 2.5 mg L-arginine hydrochloride, 18.75 mg sucrose, Dengvaxia has a shelf life of 3 years and should be stored at
13.75 mg D-trehalose dihydrate, 9.38 mg D-sorbitol, 0.18 mg 2–8°C without freezing, protected from light. Once reconsti-
trometamol, and 0.63 mg urea. The vaccine does not contain tuted, the vaccine should be administered immediately but can
a preservative. be stored at 2–8°C for up to 30 minutes [ref = U.S. Prescriber
Information and EMA Summary of Product Characteristics].
Process of Vaccine Manufacture
DNA technology was used to construct the four CYD viruses in IMMUNOGENICITY OF VACCINE
Dengvaxia replacing the prM and E proteins in the YF 17D204
vaccine virus genome with those encoding the homologous Viremia—Describe How Measured
sequences of the DENV-1, -2, -3, and -4, respectively. Each Vaccine viremia can occur 7–14 days after vaccination with a
CYD virus is grown separately in Vero cells under serum-free duration of <7 days.
conditions, harvested from the supernatant, and purified by
membrane chromatography and ultrafiltration. The purified
and concentrated harvest of each CYD virus is diluted in sta- Antibody Responses—How Measured
bilizer solution to produce the four monovalent components
Early studies to understand how antibodies neutralize or
with final bulk a mixture of the four drug substances. The final
enhance DENV infection were performed using mouse mono-
drug product is sterilized by filtration, filled into vials, and
clonal antibodies (mAbs). Many of these mice had been immu-
freeze-dried.
nized with E proteins. Neutralizing mouse mAbs have been
mapped to all three EDs. The strongest serotype-specific neu-
tralizing antibodies bind to domain III. Two partially overlap-
Producers and Trade Names ping epitopes on EDIII designated the lateral ridge and A strand
Dengvaxia (Dengue Tetravalent Vaccine, Live) is manufactured are the main targets of mouse mAbs that neutralize DENV. The
and distributed by Sanofi Pasteur Inc., Swiftwater, PA, USA. lateral ridge epitope interacts with serotype-specific strongly
Dengue Vaccines 283
neutralizing antibodies. Mouse mAbs that bind to the A strand of modelers.226–233 The regulatory and ethical issues associated
epitope cross react with more than one serotype of DENV and with the known occurrence of severe hospitalized dengue in 19
are designated dengue subcomplex neutralizing mAbs. It is also vaccinated seronegatives experiencing their first DENV infec-
becoming clear that the hypothetical structure of the mature tion have not been formally addressed. Without consensus
flavivirus particle generated by cryoelectron microscopy and on the safe use of Dengvaxia or approved serological screen-
molecular fitting does not always predict epitope exposure. ing test(s) these models do not contribute usefully to vaccine
Binding of some E-reactive antibodies depends on the dynamic deployment.
movement of protein molecules (“breathing”) in the virion
particle leading to transient exposure of hidden epitopes.218,219
Recently, studies on DENV antibodies have shifted to those EXCRETION OF VACCINE VIRUS, IF ANY
raised by DENV infection of humans. Technological devel-
opments now enable the rapid generation of human mAbs. Risk of Spread to Contacts
Polyclonal human monotypic dengue-immune sera contain A widely accepted criterion for live DENV vaccines is demon-
mostly weakly neutralizing cross-reactive and enhancing anti- strated low ability to be transmitted by Ae aegypti.
bodies.89,220 DIII antibodies, although highly neutralizing, are
only present in human sera at low levels. Only a small fraction
of antibodies is serotype specific and highly neutralizing and DURATION OF IMMUNITY AND PROTECTION,
these recognize a quaternary structure on the intact virion.89,221 INCLUDING DESCRIPTION OF REINFECTION IF ANY
A similar DENV-1 mAb has been studied by cryoelectron
microscopy.222 Presumably, live-attenuated tetravalent DENV Dengvaxia induced neutralizing antibodies waned to low lev-
vaccines should raise neutralizing antibodies directed at each els in seronegative adults 5 years after receiving a full course
of the four type-specific quaternary structures. This has been of vaccine.
confirmed to be the case for the attenuated DENV-1 developed
by the National Institutes of Health (NIH).187
DENGUE HUMAN INFECTION MODEL (DHIM)
Cellular Responses It is essential that DENV vaccines achieve solid protective
immunity against each of the four viruses following the
Cellular responses to monovalent or tetravalent vaccines in administration of combination vaccines. Recently, vaccine-
seronegative subjects have usually been measured by stimulat- associated ADE was observed in a macaque DENV challenge
ing CD 8+ or CD 4+ T cells with viral antigens. model.174 The vaccine tested had been formalin-inactivated.
It is not known if this model can be extended to test for sen-
Correlates of Protection sitization to ADE by live-attenuated vaccines. In the same
study, viremia following a freeze–thaw cycle for serum con-
As discussed below, the Sanofi Pasteur Phase 2b and Phase 3 taining neutralizing antibody was lower than for challenge
clinical trials have demonstrated that vaccine-induced neutral- of naïve animals though RNAemia was not affected; this
izing antibodies measured in epithelial cell monolayers are not must be considered for challenge models. The absence of
correlates of protection against DENV infection and disease. validated immune protection correlates in humans together
However, when the infection experience of humans has been with an imprecise understanding of protective immunity
a single wild-type DENV, homotypic neutralizing antibodies have crippled dengue vaccine development. Early tests of
are a protection correlate as demonstrated in challenge experi- candidate vaccine protective immunity in humans would be
ments conducted by Sabin.19,223 Following an initial wild-type useful. To that end, the NIH group has used monovalent-
DENV infection in humans, the development of heterospecific attenuated DENV-2 and -3 as challenge viruses (described
neutralizing antibodies correlates with protection against devel- above). Historically, there has been a huge experience of
oping severe disease during a heterotypic DENV infection.224 experimental infections of humans with wild-type DENVs
While these predictive correlates may extend to live-attenuated beginning in the early 1900s with no adverse outcomes repo
viruses, as discussed below, full protection may require infec- rted.6,19,107,108,234–237,239–241
tion by a complete dengue virus, not a chimera, as protective A single dose of LATV solidly protected seronegative
T-cell immunity may depend on presentation of DENV nonhuman volunteers for short and long periods to challenge
structural antigens.99,195,225 Of interest, administration of the with nonparental wild-type-like DENV-2 Δ30 (Tonga 74) or
monovalent or tetravalent NIH vaccine elicits type-specific and DENV-3 Δ30 (Sleman 78). After a single dose of vaccine was
more broadly reactive human T-cell responses.190,192 given to 20 susceptible volunteers, challenge at 6 months with
DENV-2 Δ30 (Tonga 74) resulted in no viremia, dengue rash,
In Special Groups (Premature Infants, or anamnestic antibody response.185 A similar outcome was
Immunosuppressed) achieved among 20 seronegative adults given a single dose of
LATV and at 6 months challenged with DENV-3. (Durbin, A.,
Dengvaxia is not recommended for infants or immunosup- personal communication, December 28, 2020). In view of this
pressed individuals. experience, a group of investigators at the Walter Reed Army
Institute of Research initiated trials to reestablish a DHIM
EFFICACY AND EFFECTIVENESS using partially attenuated DENV to test vaccine-induced pro-
tective immunity.150,151 Human safety studies on DENV can-
For the Individual Vaccinee didates are in progress at SUNY Upstate School of Medicine,
Efficacy data from Phase 3 have been described above while Syracuse, New York as well as at the University of Maryland
vaccine safety issues are discussed below. with a goal of optimizing the dose that induces a mild den-
gue like illness. At SUNY Upstate Medical University to date,
21 volunteers have been infected with DENV-1 LVHC strain
For the Community 45AZ5 and 6 volunteers with DENV-3 (Endy, T. P., personal
Estimating effectiveness of giving Dengvaxia to communities communication), demonstrating reproducible viremia with
based on epidemiological variables has attracted the attention viral loads equivalent to wild-type infection and a clinical
illness consistent with mild dengue fever.242 Studies are ongo- vaccinating partially immune humans is good news, but it is
ing at the University of Maryland where this strain of DENV-1 troubling that CYD vaccines do not present DENV NS1 anti-
is being used to assess the performance of a new dengue vac- gens to the immune system. As described above, new evidence
cine in clinical development. No serious adverse events were strongly suggests that NS1 is a viral toxin and the direct cause
noted. The DHIM using these attenuated viruses is safe, result- of the DVPS.47,50
ing in clinical illness consistent with wild-type dengue infec-
tions. In addition to simplifying, accelerating, and reducing
costs of dengue vaccine development, the human challenge
INDICATIONS FOR VACCINE—WHO AND WHY
model should help achieve a better understanding of clinical, Licensed for individuals age 9 years and older with evidence of
pathophysiological and immunological correlates of disease a prior dengue infection.
responses, evaluate anti-DENV drugs and study vector-human
interactions. A crucial benefit of DHIM challenge tests of
candidate vaccines is the identification of reactogenic and/or
CONTRAINDICATIONS AND PRECAUTIONS
nonprotective vaccines early in the development process.243,244 Dengvaxia should not be given to pregnant women or to sero-
negatives of any age.
SAFETY (ADVERSE EVENTS)
Two safety issues have been identified for live-attenuated
PUBLIC HEALTH CONSIDERATIONS
dengue vaccines: (a) preexisting dengue or nondengue fla- There are no meaningful published data on the public health
vivirus antibodies in the vaccinated person may increase outcomes of large-scale administration of Dengvaxia. The
the reactogenicity of the attenuated vaccine virus, and (b) potential adverse outcomes and possible deaths in seronega-
in the event of primary or secondary vaccine failure or wan- tive 9-year-old Philippine children have received comment,
ing neutralizing antibody, enhanced infection and disease but organized Phase 4 studies of postvaccination outcomes
may accompany breakthrough wild-type DENV infections. have not been undertaken at sufficient scale.217,254
With respect to the first issue, no dengue-like symptoms
accompanied administration of vaccine to seropositive chil-
dren.245,246 However, months after vaccination an increased
FUTURE VACCINES (BRIEF)
relative risk of hospitalizations of vaccinated children, ages In addition to the candidate vaccines described here, many
2–5 years, was observed. A WHO advisory committee labeled other recombinant DENV vaccines have been produced, some
this a “safety signal,” while soon, others found vaccine to be reaching Phase 1.
a causal association.217,247–249
CYD dengue vaccine was designed to raise type specific
antibodies to structural antigens for each of the four dengue-
Subunit Vaccines
like viruses in seronegatives and group-reactive antibodies Much of this approach entailed mapping DENV T- and B-cell
in seropositives. In addition, it was expected that successive epitopes on linear structural and nonstructural proteins.192,253,255
doses regardless of initial immune status would raise dengue It was assumed that a combination of epitopes could provide
group reactive cross protective neutralizing antibodies. CYD a safe effective vaccine at moderate cost.256 Structural and non-
rarely raised type-specific neutralizing antibodies as defined structural DENV proteins can be produced in large quantities
by the de Silva group to any of the four DENV either in sus- in many expression systems including Escherichia coli,257,258
ceptibles or partial immunes (immune to a single wild-type baculovirus in Spodoptera frugiperda insect cells,259–261 yeast,262
DENV).89,250,251 Whatever the mix of immune responses that vaccinia virus,263–265 and Drosophila cells.266,267 A Phase 1 clini-
follows administration of one or more doses of CYD, these cal trial demonstrated that both the 10 μg and 50 μg formula-
have failed to prevent symptomatic primary DENV infections. tions of DEN1-80E with 1.25 mg of elemental aluminum were
There is an urgent need to solve this problem at a fundamental immunogenic when administered in a three-injection series
level.215 (0, 1, 2 months) to healthy, flavivirus-naïve adults. The vaccine
In addition, based on data from children 5 years of age formulations induced DENV-1 neutralizing antibodies in the
or younger, one or more doses of CYD vaccine produced an majority of subjects. Titers in most subjects were modest and
immune response that followed by a wild-type DENV infection waned over time.268 A tetravalent vaccine consisting of 80% E
resulted in hospitalization due to increased vascular permea- proteins of each of the four dengue viruses was tested for pro-
bility. In retrospect, this outcome could have been anticipated tection in rhesus monkeys. Formulations at low (3, 3, 3, 6 μg
in preclinical testing. All four monotypic CYD viruses should of DEN1-80E, DEN2-80E, DEN3-80E, and DEN4-80E, respec-
have been inoculated into susceptible monkeys who were then tively), medium (10, 10, 10, 20 μg), and high (50, 50, 50, 100
to be challenged at an interval no earlier than 6 months with μg) doses were comparably immunogenic, inducing high titer,
homotypic wild-type virus. This challenge regime should have balanced neutralizing antibodies against all four DENV. Upon
been repeated in susceptible humans who were to be chal- challenge with the four wild-type DENV, all animals in the
lenged with partially attenuated DENVs (see “Dengue Human low and medium dose groups were protected against viremia
Infection Model” later).252 In the Sanofi vaccine clinical trials, while two animals in the high-dose group exhibited break-
vaccination of seropositives provided moderate to good pro- through viremia.269
tection against severe DENV disease. Presumably, this reflects Cuban investigators have produced candidate dengue vac-
a booster immunological effect. cines using recombinant proteins. DENV-3 DIII protein fused
There are several unestablished explanations for the poor with a P64k Neisseria meningitidis carrier protein, adminis-
vaccine protection in seronegatives compared with seroposi- tered with Freund’s complete adjuvant, protected nonhuman
tives. First, CYD vaccines do not present DENV nonstruc- primates after challenge.270 However, only partial protection
tural proteins to the immune system. This is likely to result was obtained using aluminum hydroxide as the adjuvant,
in suboptimal protective CD8+ T cell responses. In humans, and this required use of the Neisseria serogroup A polysac-
nonstructural DENV antigens may contribute importantly to charide.271 The authors have also expressed a domain III
T-cell protection against DENV-2 infections and disease.192,253 capsid chimeric protein of the four DENV in Escherichia coli
The observed protection against severe disease obtained by and are testing this construct as a vaccine.272 Tetra DIIIC, a
Ooogue Vaccines 285
subunit vaccine candidate based on fusion proteins derived Replication-Defective Vaccines

from structural proteins from all four DENY serotypes was
tested in rhesus macaques primed with one or two doses o f Capsid-Gene Deletion
Tetra DIIIC and then boosted with TV005, the NIAID lATV.
Several flavivirus vaccines have been made by deleting the cap-
This combination was accompanied by a tetravalent neutral-
sid gene (C) and propagating the virus in cells that express
izing antibody response and successfully prevented break-
high levels of C. 275 Such a virus undergoes only a single cycle
through viremia. 273 The two evaluated prime-boost regimes
of infection in vaccinated hosts. A DENV-2 RepliVAX was pro-
were equivalent to a single administration ofTV005 in terms
duced by replacing the prM/E genes o f RepliVAX West Nile
of the development o f virus-binding and neutralizing anti-
virus with the same genes o f DEN .176
bodies as well as the protection against viral challenge. This
approach was investigated under the mistaken notion that
TV005 produced significant clinical adnrse responses in sus-
ceptible human subjects.
Synthetic Peptides
Synthetic peptides containing B- and T-cell epitopes are
immunogenic in mice, and combinations of peptides h a n
Nucleic Acid-Based Vaccines been tested as subunit vaccines. 277• Antibodies directed to
278
DNA vaccines consist of a plasmid (or plasmids) contain- synthetic peptides h a n been detected in sera from patients
ing DENY genes reproduced to high copy number in bacteria convalescing from dengue infections. 236• •279•2so Peptides 2 37
such as E. coli. The plasmid contains a eukaryotic promoter are unlikely to raise antibodies that will completely protect
and termination sequence to drive transcription in the vac- against DENY infection as they may provide fewer of the con-
cine recipient. The transcribed RNA is translated to produce formational epitopes required.
proteins to be processed and presented to the immune system
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2024. Para uso personal ex.clusivameole. No se permiten otros usos sin aulorizaci6n. Copyrigbl ©2024. Elsevier fuc. Todos los de:redws resenrados.
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Inmunidad Vacunas Dengue

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19 Dengue Vaccines

Scott B. Halstead, David W. Vaughn

INTRODUCTION Hemisphere in 1977, and was quickly followed by an out-

Infection with DENV-1 (five genotypes), DENV-2 (six geno-

Immunity in Dengue ACTIVE IMMUNIZATION

TABLE 19.2 Dengue Fever Vaccines in Clinical Testing

Live-attenuated virus (traditional) (10) Phase 2: tetravalent (Mahidol/Aventis WRAIR/GSK Biologicals)

Severe cases are shown without RR calculations (Medina et al., 2021).180

Constituents Including Antibiotics, Dosage and Route: IM, SC, Oral

subunit vaccine candidate based on fusion proteins derived Replication-Defective Vaccines

REFERENCES 30. Shepard DS, Undurraga EA, Betancourt-Cravioto M, et al.

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