Vaccine 36 (2018) 4207–4214

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

A systematic review and meta-analysis on the safety of newly

adjuvanted vaccines among older adults q
Marc Baay, Kaatje Bollaerts, Thomas Verstraeten ⇑
P95, Epidemiology and Pharmacovigilance Consulting and Services, Leuven, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: New adjuvants have been developed to improve the efficacy of vaccines and for dose-
Received 16 March 2018 sparing capacity and may overcome immuno senescence in the elderly. We reviewed the safety of
Received in revised form 31 May 2018 newly-adjuvanted vaccines in older adults.
Accepted 1 June 2018
Methods: We searched Medline for clinical trials (CTs) including new adjuvant systems (AS01, AS02,
Available online 6 June 2018
AS03, or MF59), used in older adults, published between 01/1995 and 09/2017. Safety outcomes were:
serious adverse events (SAEs); solicited local and general AEs (reactogenicity); unsolicited AEs; and
Keywords:
potentially immune-mediated diseases (pIMDs). Standard random effects meta-analyses were conducted
Vaccine
Adjuvants
by type of safety event and adjuvant type, reporting Relative Risks (RR) with 95% confidence intervals
Safety (95% CI).
Older adults Results: We identified 1040 publications, from which we selected 7, 7, and 12 CTs on AS01/AS02, AS03
and MF59, respectively. 47,602 study participants received newly-adjuvanted vaccine and 44,521 control
vaccine, or placebo. Rates of SAEs (RR = 0.99, 95% CI = 0.96–1.02), deaths (RR = 0.99, 95% CI = 0.92–1.06)
and pIMDs (RR = 0.94, 95% CI = 0.79–1.1) were comparable in newly-adjuvanted and control groups.
Vaccine-related SAEs occurred in <1% of the subjects in both groups. The reactogenicity of AS01/AS02
and AS03 adjuvanted vaccines was higher compared to control vaccines, whereas MF59-adjuvanted vac-
cines resulted only in more pain. Grade 3 reactogenicity was reported infrequently, with fatigue (RR =
2.48, 95% CI = 1.69–3.64), headache (RR = 2.94, 95% CI = 1.24–6.95), and myalgia (RR = 2.68, 95% CI = 1.
86–3.80) occurring more frequently in newly-adjuvanted groups. Unsolicited AEs occurred slightly more
frequently in newly-adjuvanted groups (RR = 1.04, 95% CI = 1.00–1.08).
Conclusions: Our review suggests that, within the clinical trial setting, the use of new adjuvants in older
adults has not led to any safety concerns, with no increase in SAEs or fatalities. Higher rates for solicited
AEs were observed, especially for AS01/AS02 and AS03 adjuvanted vaccines, but AEs were mostly mild
and transient. Further evidence will need to come from the use of new adjuvants in the real-world set-
ting, where larger numbers can be studied to potentially detect rare reactions.
Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction nation of immuno-stimulants in different adjuvant formulations:

AS01 contains 3-O-desacyl-40 -monophosphoryl lipid A (MPL) and
Several new adjuvants have been developed to improve the effi- the saponin QS-21 and is a liposome-based formulation; AS02 also
cacy of vaccines and for dose sparing capacity. New adjuvants that contains MPL and QS-21 and is an oil-in-water emulsion-based for-
are licensed or in advanced clinical development are AS01, AS02, mulation. AS03 is composed of a-tocopherol, squalene and
AS03, AS04 and MF59. The Novartis-developed MF59Ò adjuvant polysorbate 80 in an oil-in-water emulsion. Finally, AS04 is a com-
is a squalene-based oil-in-water based adjuvant. The GlaxoSmithK- bination of aluminum hydroxide and MPL [1–3].
line (GSK)-developed Adjuvant Systems (AS) are based on a combi- These new adjuvants are increasingly being used across the
entire age range. MF59 was first approved in 1997 as part of the
trivalent influenza vaccine FLUAD. More recently, FLUAD was
q
Statement about prior postings and presentations: Neither this manuscript nor approved for use in adults over 65 in the US [4], and adults over
any similar paper is under consideration by any other scientific journal. Preliminary
data have been submitted for presentation at the ICPE 2018 conference in Prague.
75 in the UK [5]. The first AS-adjuvanted vaccine was Fendrix,
⇑ Corresponding author at: P95, Epidemiology and Pharmacovigilance Consulting which includes AS04 and was approved in Europe in 2005 for the
and Services, Koning Leopold III Laan 1, 3001 Leuven, Belgium. prevention of infections with hepatitis B virus in adolescents and
E-mail address: [email protected] (T. Verstraeten).

https://doi.org/10.1016/j.vaccine.2018.06.004
0264-410X/Ó 2018 Elsevier Ltd. All rights reserved.
4208 M. Baay et al. / Vaccine 36 (2018) 4207–4214

adults [6]. Cervarix, another AS04-adjuvanted vaccine, was Additional relevant trials described in the selected publications
approved in Europe in 2007 for the prevention of premalignant were also extracted.
anogenital lesions and cancers causally related to oncogenic HPV
types in people aged 9–14 (two doses), whereas those aged 15 2.2. Study selection
and above should receive three doses [7]. More recently, Mos-
quirix, a vaccine for the prevention of malaria which includes Eligibility criteria for studies to be included in the meta-analysis
AS01 and was originally developed in combination with AS02, were as follows: (1) randomized controlled trial (RCT); (2) study on
was approved in 2015 for use in children aged between 6 weeks the safety of vaccines using the adjuvant systems AS01, AS02,
and 17 months [8]. Finally, Shingrix, a vaccine which includes AS03, or MF59; (3) including older adults (i.e., reporting separately
AS01 as adjuvant, was approved in March 2018 in the European on those 50 years and older); and (4) reporting the safety of both
Union, for the prevention of Herpes Zoster and post-herpetic neu- the adjuvanted group and a control group.
ralgia, for adults aged 50 years and older [9]. The use of new adju- The bivalent human papillomavirus (HPV) vaccine Cervarix and
vants appears to be safe in children and young adults [10–12], the hepatitis B vaccine Fendrix, both containing AS04, have been
although the occurrence of meningitis after vaccination with Mos- studied in adults, but not in the elderly. Therefore, we have not
quirix is still under evaluation [13], and narcolepsy has been included AS04 in this review.
observed following the use of Pandemrix [14–16]. A literature search was performed in PubMed for the adjuvant-
The use of adjuvant in older adults may present different safety systems with the following search terms: (‘‘vaccines”[MeSH
challenges, however, compared to their use in younger adults or Terms] OR ‘‘vaccines”[All Fields] OR ‘‘vaccine”[All Fields]) AND
children. In the light of the expected increased use of adjuvants (‘‘adjuvants, immunologic”[Pharmacological Action] OR ‘‘adju-
in this age group, we decided to conduct a review of the combined vant”[All Fields] OR (‘‘adjuvants”[All Fields] AND ‘‘immunologic”
observations of the use of adjuvants in the older adult population. [All Fields])) AND ((‘‘aged”[MeSH Terms] OR ‘‘aged”[All Fields] OR
In this study, we systematically review the cumulative evidence ‘‘elderly”[All Fields]) OR geriatric[All Fields]) AND ‘‘Clinical Trial”
on the safety of the newly adjuvanted vaccines in older adults and [All Fields] AND ((‘‘1995/01/0100 [PDAT] : ”2017/09/1100 [PDAT])
perform meta-analyses using data from published clinical trials. In AND English[lang]).
particular, we perform meta-analyses for Serious Adverse Events
(SAEs), local and general solicited AEs, and unsolicited AEs, by 2.3. Outcomes
group of adjuvants and all adjuvants combined.
The following safety outcomes were investigated: (1) SAEs; (2)
solicited local and general AEs; (3) unsolicited AEs and (4) poten-
2. Methods tially immune-mediated diseases (pIMDs). SAEs were monitored
for the whole duration of the trial (ranging from 90 days to 42
2.1. Data sources months), solicited AEs mostly up to 1 week, and unsolicited AEs
generally 3–4 weeks after each dose. For SAEs, solicited AEs, and
We searched Medline (January 1st, 1995 to September 11th, unsolicited AEs, we performed meta-analyses by groups of adju-
2017) for clinical trials including any of the new adjuvant systems. vant systems and across all adjuvant systems. Given their similar

Table 1
Clinical trials included in the meta-analysis on the safety of newly adjuvanted vaccines.

Study [ref no.] Phase Year Country Study population NR. Subjects Adjuvant Vaccine Control
Leroux-Roels 2012 [8] 2 2007–2008 Belgium 50–70 135 AS01b HZ/su OKA/HZ/su+OKA
Chlibek 2013 [9] 2 2009–2010- CZ/ES/USA 60+ 410 AS01b/AS01E HZ/su NA-HZ/su placebo
Chlibek 2014 [10] 2 2007–2011 CZ/DE/NL/SE 60+ 715 AS01b HZ/su placebo
Lal 2015 [11] 3 2010–2014 World-wide 50+ 15,411 AS01b HZ/su placebo
Cunningham 2016 [12] 3 2010–2015 World-wide 70+ 14,816 AS01b HZ/su placebo
Leroux-Roels 2015 [13] 2 2004–2007 Belgium 65+ 150 AS02v PhtD Alum-PhtD/23PPV
Pauksens 2014 [14] 1 2008–2009 Sweden 65–85 167 AS02v PhtD/PCV8 Alum-PhtD/Alum-PCV8/23PPV
Rumke 2008 [15] 3 2006 Europe 60+ 538 AS03 H5N1 Seasonal TIV
Heijmans 2011 [16] 2 2006–2008 Italy/Belgium 61+ 437 AS03 H5N1 NA-H5N1
Gillard 2014 [17] 2 2006–2009 Italy/Belgium 60+ 345 AS03 H5N1 H5N1
Langley 2011 [18] 3 2008–2009 North America 65+ 1489 AS03 H5N1 placebo
McElhaney 2013 [19] 3 2008–2010 World-wide 65+ 43,695 AS03 Seasonal TIV Seasonal TIV
Ferguson 2012 [20] 2 2009–2010 USA/CA 61–90 681 AS03 H1N1 NA-H1Ni1
Yang 2013 [21] 3 2009–2011 USA/CA 65+ 961 AS03 H1N1 NA-H1N1
Minutello 1999 [22] 2 1992–1994 Italy 65+ 92 MF59 Seasonal TIV Seasonal TIV
De Donato 1999 [23] 1993–1995 Italy 64–87 211 MF59 Seasonal TIV Seasonal TIV
Gasparini 2001 [24] 3 1994–1995 Italy 65+ 308 MF59 Seasonal TIV Seasonal TIV
Squarcione 2003 [25] 4 1998–1999 Italy 65+ 2150 MF59 Seasonal TIV Seasonal TIV
Ruf 2004 [26] 3 2002–2003 Germany 60+ 827 MF59 Seasonal TIV Seasonal TIV
Li 2008 [27] 3 2006 China 60+ 600 MF59 Seasonal TIV Seasonal TIV
Della Cioppa 2012 [28] 2008–2009 PL/BE/DE 65+ 357 MF59 Seasonal TIV Seasonal TIV
Frey 2014 [29] 3 2010–2011 CO/PA/PHI/USA 65+ 7109 MF59 Seasonal TIV Seasonal TIV
Seo 2014 [30] 3 2011 Korea 65+ 224 MF59 Seasonal TIV Seasonal TIV
Scheifele 2013 [31] 4 2011–2012 Canada 65+ 608 MF59 Seasonal TIV Seasonal TIV
Song 2015 [32] 4 2013 Korea 65+ 224 MF59 Seasonal TIV PPV23
Song 2017 [33] 2014–2015 Korea 60+ 1149 MF59 Seasonal TIV PCV13

Countries: Be – Belgium; Ca – Canada; Co – Colombia; Cz – Czech Republic; De – Germany; Es – Spain; Nl – the Netherlands; Pa – Panama; Phi – Philippines; Pl – Poland; Se –
Sweden; USA – United States of America.
Vaccines: HZ/su – herpes zoster subunit; NA – non-adjuvanted; OKA – varicella vaccine; PCV – pneumococcal conjugate vaccine; PhtD - Streptococcus pneumoniae vaccine;
PPV – pneumococcal polysaccharide vaccine.
 M. Baay et al. / Vaccine 36 (2018) 4207–4214 4209

composition, we grouped AS01 and AS02 for this review. In our to I2 values of 25%, 50% and 75% respectively. In addition, we com-
analysis, the safety data of the newly adjuvanted study groups puted the Q-statistic, for which p-values < 0.05 indicate a signifi-
were pooled across different antigens; the safety data for control cant amount of heterogeneity [18]. The analyses were based on
groups were also pooled across different controls, including some- the number of individuals who experienced a given adverse event
times alum-adjuvanted and non-adjuvanted vaccines, sometimes at least once. In case of multiple doses, we considered the number
different antigens and sometimes placebo. of events per dose and not per subject. For trials with more than
one treatment/control group, we used the data for the combined
treatment/control groups.
2.4. Statistical analysis

Random effects meta-analyses using restricted maximum likeli- 3. Results

hood were conducted, with the results reported as Relative Risks
(RR) with 95% confidence intervals (95CI). Between-trial hetero- 3.1. Selected trials
geneity was quantified using the I2 statistic, which is to be inter-
preted as the proportion of total variation in the estimates of We identified 1025 publications on new adjuvants. Screening
treatment effect that is due to heterogeneity between studies the reference lists of the selected papers resulted in 15 additional
[17]. Low, moderate and high levels of heterogeneity correspond studies. Of these 1040 publications, 7 [19–25], 7 [26–32], and 12

Fig. 1. Prisma flow diagram.

4210 M. Baay et al. / Vaccine 36 (2018) 4207–4214

[33–44] trials were retained for extraction of data on AS01/AS02, similar in participants who received the newly adjuvanted vacci-
AS03 and MF59 adjuvants, respectively (Table 1). For a full descrip- nes and in control groups. Vaccine-related SAEs, if present at all,
tion of the selection process, we refer to the PRISMA flow diagram occurred in less than 1% of the subjects, and in both newly adju-
(Fig. 1, [45]). vanted and control groups [23,30,38].
A total of 92,123 men and women of 50 years and older were The meta-analyses showed that the relative risks of SAEs were
included in this review: 47,602 received a newly adjuvanted vac- very close to 1 (ranging between 0.97 and 1.00), for each of the
cine and 44,521 a control vaccine, or placebo. 15,816, 25,115 and adjuvant groups, as well as for the combined analysis, with very lit-
6671 were exposed to at least one dose of the AS01/AS02, AS03 tle heterogeneity between studies (p-values > 0.55, I2 = 0% in all
or MF59-adjuvanted vaccine, compared to 14,948, 23,465 and cases, Fig. 2). The overall RR for SAEs as measured across all adju-
6108 individuals in control groups in the AS01/AS02, AS03 and vant groups was 0.99 (95% CI = 0.98–1.02).
MF59 trials. Regardless of the adjuvant systems used, trials have Death rates varied widely across the different studies with rates
been carried out primarily among European, American and Asian ranging from 0.1% [29] to 7.4% of the subjects in one study [21].
older adults. Subjects in control groups were generally exposed The most frequent causes of death, if specified, were cancer or
to the same, but not newly adjuvanted, antigen as in the study heart failure. Furthermore, deaths were evenly distributed
arm, or received a placebo (Table 1). between study and control arms (RR = 0.99, 95% CI = 0.92–1.06).

3.2. Serious adverse events 3.3. Solicited adverse events

The rate of SAEs reported in the different trials ranged between The reactogenicity of the AS01/AS02 and AS03 adjuvanted vac-
0.0 and 28.8% for the AS01/AS02-adjuvanted vaccines, 0.3–18.6% cines was significantly higher than the reactogenicity of the control
for the AS03-adjuvanted vaccines and 0.0–7.1% for the MF59- vaccines: significantly more pain at the injection site, redness,
adjuvanted vaccines (Supplementary Table 1). Rates of SAEs were swelling, fever, myalgia, fatigue, and headache were reported with

Fig. 2. Forest plot of relative risks of serious adverse events by adjuvant group and overall, adjuvanted groups compared to the control group. Heterogeneity between studies:
The I2 statistic is the proportion of total variation in the estimates of treatment effect that is due to heterogeneity. Low, moderate and high levels of heterogeneity correspond
to I2 values of 25%, 50% and 75% respectively.
 M. Baay et al. / Vaccine 36 (2018) 4207–4214 4211

AS-adjuvanted vaccines. In contrast, solicited AEs did not appear to infrequently reported in MF59 studies. The proportion of older
occur significantly more frequently after MF59-adjuvanted vacci- adults reporting at least one unsolicited AE was slightly, but not
nes compared to controls, with the exception of pain (Fig. 3). This significantly, higher among those who received newly adjuvanted
was confirmed by meta-analysis, but significant heterogeneity vaccines compared to control groups. The most frequently reported
between studies was frequently shown. unsolicited events were back pain, chills, injection site pruritus,
Grade 3 events were reported infrequently but were more fre- upper respiratory tract infections and influenza-like symptoms
quent for redness and myalgia in subjects receiving AS01/AS02 for AS01/AS02; cough, nasopharyngitis, headache and oropharyn-
and for fatigue, fever, headache and myalgia in subjects receiving geal pain for AS03; and nasopharyngitis, infections and injection
AS03 adjuvanted vaccines, compared to controls (Supplementary site conditions for MF59.
Fig. 2). Gastrointestinal complaints were specifically reported for The Relative Risks were 1.06 (95% CI = 1.00–1.13), 1.09 (95% CI
the AS01/02 adjuvant, and were either not solicited, or not = 0.96–1.22) and 1.00 (95% CI = 0.90–1.12) among the AS01/AS02,
reported for the other adjuvants. AS03 and MF59 adjuvanted groups respectively, for unsolicited
Across the different adjuvants, local pain was reported as the AEs. The overall RR was 1.04 (95% CI = 1.00–1.08) (Fig. 4).
most frequent solicited AE, with rates between 45.7 and 91.1%
(AS01/AS02), 41.0–68.6% (AS03) and 0.7–64.8% (MF59) (Supple- 3.5. Potential immune-mediated diseases
mentary Table 1).
Cases of potentially immune-mediated diseases (pIMDs) were
3.4. Unsolicited adverse events reported in some of the larger studies with a rate between 1.0
and 1.3% for AS01/AS02 [22,23], and 0.1–0.7% for AS03 [30,31],
Rates of unsolicited AEs ranged between 18.0 and 43.5% for whereas pIMDs were not recorded in any MF59 study. pIMDs were
AS01/AS02, 2.9–41.8% for AS03 and 15.8–23.9% for MF59- evenly distributed between study and control arms (RR = 0.94, 95%
adjuvanted vaccines (Supplementary Table 1), although they were CI = 0.79–1.1). No difference in types of PIMDs were noted between

Fig. 3. Forest plot of relative risks of solicited adverse events by adjuvant group and overall, adjuvanted groups compared to the control group. Heterogeneity between
studies: The I2 statistic is the proportion of total variation in the estimates of treatment effect that is due to heterogeneity. Low, moderate and high levels of heterogeneity
correspond to I2 values of 25%, 50% and 75% respectively.
4212 M. Baay et al. / Vaccine 36 (2018) 4207–4214

Fig. 4. Forest plot of relative risks of unsolicited adverse events by adjuvant group and overall, adjuvanted groups compared to the control group. Heterogeneity between
studies: The I2 statistic is the proportion of total variation in the estimates of treatment effect that is due to heterogeneity. Low, moderate and high levels of heterogeneity
correspond to I2 values of 25%, 50% and 75% respectively.

the study groups, with polymyalgia rheumatica and rheumatoid adjuvanted vaccines are significantly more reactogenic than con-
arthritis being reported most frequently in both groups. trol vaccines. Furthermore, the data suggest that AS01/AS02 and
AS03 are more reactogenic than MF59, although the data are not
3.6. Other new adjuvants always consistent; one MF59 study showed a reactogenicity com-
parable to the other adjuvants [39]. Pain was the most prevalent
During our review of the literature, we retrieved eight reports solicited AE but was often mild and of short duration. Finally, unso-
on other new adjuvants, such as Toll-like receptor-based [46], licited AEs occur slightly more frequently in adjuvanted vaccines.
interleukin 12-based [47,48], liposome-based [49], ADVAX [50]
or Virosomal [37,51,52] adjuvants. However, these reports were
based on limited study populations, and did not extensively report 4.2. Limitations and strengths
on safety data.
Our study had some strengths: the large number of individuals
4. Discussion (>90,000) in the final analysis, and the consistent way of measuring
safety in the clinical trials, allowed us to perform pooled analyses
4.1. Summary of evidence with low heterogeneity in SAEs and unsolicited AEs, although there
was significant heterogeneity in solicited AEs. The inclusion of sev-
We found information on the clinical safety of newly adju- eral different adjuvant systems enabled us to draw general conclu-
vanted vaccines in more than 90 thousand adults aged 50 or more, sions on the use of adjuvants in older adults.
of whom 47 thousand were exposed to adjuvanted vaccines. Our Only clinical trials were included in this review, which limits
review suggests that SAEs and fatalities do not occur more fre- the assessment to the safety in (relatively) healthy older adults.
quently in newly adjuvanted compared to control vaccines. Newly It remains unknown whether the results can be generalized to
 M. Baay et al. / Vaccine 36 (2018) 4207–4214 4213

other, more vulnerable populations, as the prevalence of chronic Acknowledgements

diseases and multimorbidity is high in the elderly population [53].
Secondly, the length of follow-up differed between studies, with The authors are grateful to Aaron Mendelsohn for critical review of
studies as short as 90 days, and as long as 42 months. We were the manuscript.
unable to address these differences in the analysis, however, while
studies differed in duration, follow-up within studies was the same Conflict of interest
for the study arm and the control arm.
Thirdly, we did not evaluate the safety of newly adjuvanted vac- TV and KB have received consulting fees from GSK and Novartis,
cines depending on dose, amount of antigen or adjuvant. A review unrelated to this review. MB declares no conflict of interest.
on the safety of the pandemic influenza MF59 and AS03-
adjuvanted vaccines in children and adolescents reported that
Authors’ contributions
higher amounts of antigen/adjuvant, and a second dose were asso-
ciated with a higher reactogenicity, but this was not consistent
TV and MB conceived and designed the study, MB performed
across trials [54]. To our knowledge, no similar reviews have been
the literature review, KB performed the meta-analyses, MB drafted
published in older persons.
the manuscript, all authors revised it, and approved the final ver-
As in any meta-analysis, there was a risk of publication bias if
sion to be submitted.
studies with unfavorable safety results for the adjuvanted vaccines
fail to get published. To assess this risk, we searched clinicaltri-
als.gov for completed studies with one of the new adjuvants, Appendix A. Supplementary material
regardless of antigen or age of the study population, using the
NCT registration number to look for publications in PubMed. Supplementary data associated with this article can be found, in
Between 2003 and 2017, 141 studies were registered. Studies with the online version, at https://doi.org/10.1016/j.vaccine.2018.06.
published results had a median lag time between study registra- 004.
tion and publication date of 3 years (range 0–8 years). Of the stud-
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