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A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children
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Review
A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children Jorgen Stassijns, Kaatje Bollaerts, Marc Baay, Thomas Verstraeten ∗ P-95, Epidemiology and Pharmacovigilance Consulting and Services, Koning Leopold III Laan 1, 3001 Heverlee, Belgium
a r t i c l e
i n f o
Article history: Received 16 September 2015 Received in revised form 8 December 2015 Accepted 10 December 2015 Available online xxx Keywords: Vaccine Adjuvants Safety Children
a b s t r a c t Introduction: New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children. Methods: We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted. Results: Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75–0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases. Conclusions: Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction A number of new adjuvants have been developed to improve the efficacy of vaccines as well as for dose sparing. The new adjuvants that are licensed or in advanced clinical development and that are used in children are AS01, AS02, AS03 and MF59. The GlaxoSmithKline (GSK)-developed Adjuvant Systems (AS) are based on a combination of immuno-stimulants in different adjuvant formulations: AS01 contains 3-O-desacyl-4 -monophosphoryl lipid A (MPL) and the saponin QS-21 and is a liposome-based formulation; AS02 also contains MPL and QS-21 and is an oil-in-water emulsionbased formulation. AS03 is composed of ␣-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. The Novartisdeveloped MF59® adjuvant is a squalene-based oil-in-water based adjuvant [1–3] (Table 1).
The experience with the pandemic influenza vaccines as well as the development of a new malaria vaccine have shown that new adjuvants may be particular beneficial for children. A few reviews have been carried out for individual adjuvant systems [4–11], but a comprehensive systematic review and meta-analysis of the safety of all newly pediatric adjuvanted vaccines has not yet been done. In this study we systematically review the current evidence on the safety of the newly adjuvanted vaccines in children and perform meta-analyses using data from published clinical trials. In particular we perform meta-analyses for serious adverse events (SAEs), local and general solicited AEs, unsolicited AEs and AEs of special interest by group of adjuvants. 2. Methods 2.1. Data sources
∗ Corresponding author. Tel.: +32 474 534868. E-mail address: [email protected] (T. Verstraeten).
We searched Medline (1990 to April 2015), ClinicalTrials.gov and the Cochrane Library for clinical trials including any of the new
http://dx.doi.org/10.1016/j.vaccine.2015.12.024 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
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2 Table 1 Overview characteristics new adjuvants included in review. Adjuvant
Components
Formulation
Vaccine(s)
Licensed
Manufacturer
AS01
Monophosphoryl lipid A (MPL) + saponin QS-21 Monophosphoryl lipid A (MPL) + saponin QS-21 ␣-Tocopherol, squalene and polysorbate 80
Liposome-based
RTS,S malaria vaccine
No
GlaxoSmithKline
Oil-in-water emulsion
RTS,S malaria vaccine
No
GlaxoSmithKline
Oil-in-water emulsion
Yes (Pandemrix® )
GlaxoSmithKline
Squalene
Oil-in-water emulsion
Influenza A (H1N1) virus (swine flu) H5N1 influenza (avian flu) Pandemic influenza A/California/7/2009(H1N1) Seasonal influenza
Yes (Arepanrix® ) Yes (Focetria® , Celtura® , Fluad® )
Novartis
AS02 AS03
MF59
adjuvant systems. Bibliographies of the publications selected for the review and systematic reviews were hand searched for additional relevant trials.
of heterogeneity [13]. The analyses were based on the number of individuals who experienced the event at least once. For trials with more than one treatment/control group, we used the data for the combined treatment/control groups.
2.2. Study selection 3. Results Eligibility criteria for studies to be included in the meta-analysis were as follows: (1) randomized controlled trial (RCT); (2) study on the safety of vaccines using the adjuvant systems AS01, AS02, AS03, or MF59; (3) performed on infants or children and (4) reporting the safety of both the adjuvanted group and a control group. AS04, the new adjuvant used in some vaccines such as the bivalent HPV vaccine Cervarix, has not been used for children under the age of 9. Therefore we have not included AS04 in this review. A literature search was performed in PubMed for the adjuvantsystems with the following search terms: (“AS01” [All Fields] OR “AS02” [All Fields] OR “AS03” [All Fields] OR “MF59” [All Fields]) AND “vaccine” [All Fields] AND (“child” [All Fields] OR “children” [All Fields] OR “infant” [All Fields] OR “infants” [All Fields] OR “adolescent” [All Fields]). 2.3. Outcomes Safety outcomes from Phases I, II and III clinical trials were categorized as: 1) serious adverse events (SAEs); 2) solicited local and general adverse events; 3) unsolicited adverse events and 4) adverse events of special interest. The length of follow-up depended on the category of AE: SAEs were monitored for the whole duration of the trial, solicited AEs up to 1 week, and unsolicited AEs up to 60 days after each dose. For SAEs and solicited AEs unsolicited adverse events, which are collected and reported consistently across all studies, we performed meta-analyses across all adjuvant systems and by groups of adjuvant systems. For the unsolicited AEs and AEs of special interest, we only analyzed the studies by adjuvant group. Given their similar composition and paucity of data on AS02, we grouped AS01 and AS02 for this review. In our analysis, the safety data of the newly-adjuvanted study groups are pooled across different antigens; the safety data for control groups are pooled across adjuvanted and non-adjuvanted cohorts, including different antigens. 2.4. Statistical analysis We conducted meta-analyses using restricted maximum likelihood. The results are reported as relative risks (RR) with 95% confidence intervals (CI). We quantified the between-trial heterogeneity using the I2 statistic, which is to be interpreted as the proportion of total variation in the estimates of treatment effect that is due to heterogeneity between studies [12]. Low, moderate and high levels of heterogeneity correspond to I2 values of 25%, 50% and 75% respectively. In addition, we computed the Q-statistic, for which p-values <0.05 indicate a significant amount
3.1. Selected trials Using the search terms described, we identified 291 publications for the different adjuvants (70 for AS01/AS02, 100 for AS03 and 127 for MF59, with 6 papers referring to both AS03 and MF59). Screening the reference lists of the papers selected for full review resulted in one additional study on AS03, and 10 additional studies on AS01/AS02. After application of the selection criteria a total of 14 [14–30], 4 [31–35], and 11 [36–47] trials were retained for the meta-analysis of AS01/AS02, AS03 and MF59 adjuvants (Table 2), with some trials being reported in multiple publications. Fur a full description of the selection process we refer to the PRISMA flow diagram (Fig. 1, cfr Moher [48]). A total of 41,700 children between 6 weeks and 10 years were included in the meta-analysis: 25,056 received an adjuvanted vaccine and 16,644 a control vaccine. Out of these, 12,207, 5057 and 7792 were exposed to at least one dose of the AS01/AS02, AS03 or MF59-adjuvanted vaccine, compared to 6457, 2757 and 7430 children receiving a control vaccine in the AS01/AS02, AS03 and MF59 trials. Trials including the AS01 and AS02 adjuvant systems have thus far been conducted only in Sub-Saharan Africa, whereas the AS03 and MF59 trials have been carried out among Asian, European and American children. Children in control groups were exposed to different antigens such as rabies, meningococcus C, hepatitis B (HB), 7-valent pneumococcal conjugate (PCV7) or Haemophilus Influenzae Type B (Hib) (Table 2). 3.2. Serious Adverse Events The rate of SAEs reported in the different trials ranged between 1.2 and 33.5% for the AS01/AS02-adjuvanted vaccines, 0.0–8.0% for the AS03 and 0.0–10.4% for the MF59-adjuvanted vaccines (Supplementary Table). SAEs were not reported more frequently among children who received the newly adjuvanted vaccines compared to control groups. The pooled relative risks (RR) were 0.86 (95%CI 0.74–1.01), 1.49 (95%CI 0.50–4.44) and 0.74 (95%CI 0.57–0.97) among the AS01/AS02, AS03 and MF59-adjuvanted groups respectively. The overall pooled RR was 0.85 (95%CI 0.75–0.96) (Fig. 2). In the multi-centric Phase III trial, assessing the safety of the RTS,S/AS01 malaria vaccine (in which ‘R’ stands for the central repeat region of the Plasmodium falciparum ‘circumsporozoite protein (CSP); ‘T’ for the T-cell epitopes of the CSP, ‘S’ for the hepatitis B surface antigen, and ‘S’ for a free protein), SAEs occurred with similar frequency between RTS,S/AS01 and control groups in
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Phase
Year
Country
Study population
Macete et al. [14] Bojang et al. [15] Aide et al. [16] Aponte et al.; Sacarlal et al. [17,18] Lusingu et al. [19] Abdulla et al. [20] Agnandji et al. [21] Owusu-Agyei et al. [22] RTS,S/S Clin Trial Partnership [23–25] Thera et al. [26] Withers et al. [27] Thera et al. [28] Ogutu et al. [29] Idoko et al. [30] Waddington et al. [31] Langley et al. [32] Diez-Domingo et al. [33,34] Nolan et al. [35] Johnson et al. [36] Block et al. [37] Nassim et al. [38] Arguedas et al. [39] Knuf et al. [40,41]
1 1 1/2B 2B
2002 2001–02 2005–07 2003–07
Mozambique The Gambia Mozambique Mozambique
1–4 years 1–5 years, 6–11 years 10–18 weeks 1–4 years
2B 2B 2 2 3
2007 2006–08 2007–09 2006–08 2009–11
Kenya/Tanzania Tanzania Ghana/Gabon/Tanzania Ghana Multicentric (11 sites)
5–17 months 8–16 weeks 6–10 weeks 5–17 months 6
1 1B 2B 2B 2 2 2 2
2006 2003 2007–08 2005 2010–12 2009 2009 2007–08
Mali Kenya Mali Kenya Gambia UK Canada Spain
1–6 years 12–47 months 1–6 years 12–47 months Infants 6 months–4 years, 5–12 years 6 months–8 years 3–5 years, 6–9 years
3 1 2/3 2/3 3 3
2010–11 2013 2009–10 2009–10 2009 2009–11
Multicentric USA USA/Mexico USA Costa Rica Multicentric
Della Cioppa et al. [42] Vesikari et al. [43] Solares et al. [44] Zedda et al. [45] Vesikari et al. [46] Nolan et al. [47]
1B 2 2 2 3 3
2008–09 2006–07 2008 2011 2007–09 2011–12
Finland/Belgium Finland Guatemala Belgium Germany, Finland Multicentric
6 months–10 years ≥3 years 6–<36 months 3–<9 years 3–8 years, 9–17 years 6–11 months, 12–35 months, 3–8 years, 9–17 years 6–<36 months 6–<36 months 6–<36 months, 36–<60 months 6–<36 months 6–36 months, 36–72 months 6–<72 months
Nr. Subjects
Adjuvant
Vaccine
Control
AS02 AS02 AS02 AS02
Malaria RTS/S Malaria RTS/S Malaria RTS/S Malaria RTS/S
HB Rabies HB HB, PCV7, Hib
AS01 AS02 AS01 AS01/AS02 AS01
Malaria RTS/S Malaria RTS/S Malaria RTS/S Malaria RTS/S Malaria RTS/S
Rabies HB EPI Rabies Meningitis, Rabies
100 135 400 400 300 943 322 405
AS02 AS02 AS02 AS02 AS01 AS03 AS03 AS03
Malaria FMP2.1 Malaria FMP1 Malaria FMP2.1 Malaria FMP1 TB M72 Pandemic influenza Pandemic influenza Pandemic influenza
Rabies Rabies Rabies Rabies Meningitis, EPI Non-adj vaccine Non-adj vaccine Seasonal TIV
6145 627 654 1357 392 561
AS03 MF59 MF59 MF59 MF59 MF59
Pandemic influenza H3N2 Pandemic influenza Pandemic influenza Pandemic influenza Pandemic influenza
Placebo, non-adj vaccine Non-adj vaccine 15 g Non-adj vaccine 7.5/15 g Non-adj vaccine 7.5/15 g Non-adj vaccine 15/30 g Non-adj vaccine 15 g
480 281 360 84 4707 6078
MF59 MF59 MF59 MF59 MF59 MF59
Seasonal influenza Seasonal influenza Seasonal influenza Seasonal influenza Seasonal influenza Seasonal influenza
Non-adj vaccine 7.5/15 g TIV TIV 22.5/45 g TIV 7.5 g TIV and non-influenza TIV 1, TIV 2
60 225 214 2022 894 340 511 540 15460
HB, Hepatitis B; PCV7, pneumococcal conjugate 7-valent; Hib, Haemophilus Influenzae Type B; EPI, expanded program on immunisation; TIV, trivalent influenza.
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Table 2 Clinical trials included in the meta-analysis on the safety of newly adjuvanted vaccines.
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Idenficaon
4
Records idenfied through database searching (n = 291)
Addional records idenfied from reference lists (n = 11)
Eligibility
Screening
Records aer duplicates removed (n = 302)
Records screened (n = 302)
Full-text arcles assessed for eligibility (n = 71)
Records excluded (n = 231)
Full-text arcles excluded (n = 28)
Included
Studies included in qualitave synthesis (n = 43)
Studies included in quantave synthesis (meta-analysis) (n = 29)
Fig. 1. PRISMA flow diagram. From: Moher D., et al. (2009). PLoS Med 6(6): e1000097.
children 6–12 weeks old (AS01: 22.0%, 95%CI 22.8–23.3; control: 23.1%, 95%CI 21.3–24.9), whereas the 5–17 months age group reported significantly less SAEs in the RTS,S/AS01 compared to the control group, even after exclusion of malaria (17.6% (95%CI 16.6–18.6) versus 21.2% (95%CI 19.7–22.7)) [25]. Pooled analysis of data from Phase II trials reported significantly lower rates of SAEs in recipients of RTS,S/AS01 & AS02 compared to control (21.4% versus 28.0%, RR 0.77 (0.69–0.87), p < 0.001) [6]. After exclusion of the malaria events, the proportion of SAEs in the RTS,S/AS group was still lower than in the control group (14.9% versus 17.7%, RR 0.81 (0.69–0.95), p = 0.008) [6]. No related SAEs were reported in the AS03 trials. In the MF59 trials, three SAEs possibly related to vaccination occurred in the adjuvanted group: a case of mild allergic shock in an 8-month old child, a case of seizure in a 37-month old child [46] and one febrile convulsion [47]. Fatal AEs after administration of RTS,S/AS01 & AS02-adjuvanted vaccines were similar (Phase III) or less frequent (Phase II) as compared to controls and none was considered related to vaccination [6,23–25]. Three fatal events were reported in AS03 Phase III trials, none was considered vaccine related [35]. Eight deaths occurred in the multi-centric MF59 trial, one of which in the adjuvanted group, considered unrelated to vaccination [47].
3.3. Solicited Adverse Events For most of the solicited AEs the reactogenicity of the newly adjuvanted vaccines was significantly higher than for the control vaccines: AS01/AS02-adjuvanted vaccines cause significantly more drowsiness, irritability and loss of appetite. The AS03-adjuvanted vaccines generate significantly more local pain, swelling, fever and
irritability. The RR for local pain, redness, fever, irritability and loss of appetite are significantly higher for the MF59-adjuvanted vaccines as compared to the control vaccines (Table 3). Across the different adjuvants, local pain was reported as one the most frequent solicited AE, with rates between 8.0 and 91.4% (AS01/AS02), 31.7–84.6% (AS03) and 1.0–59.0% (MF59) (Supplementary Table). Grade 3 pain was reported infrequently in Phase III trials: 0.1–0.3% for AS01 [23,24] and below 1% for MF59adjuvanted vaccines [47]. For AS03-adjuvanted vaccines, rates of grade 3 pain were between 4.3% [47] and 12.4% [49]. Fever is an AE of particular concern because of the possible association with febrile seizures. The incidence across trials ranged between 1.0 and 42.4% (AS01/AS02), 11.0–23.8% (AS03) and 4.0–19.0% (MF59) (Supplementary Table). The incidence of Grade 3 temperature (>39◦ ) in Phase III Trials was low: 2.5% of the RTS/AS01 children 5–17 months of age, compared to 1.1% of the control group [23] and <1% among infants 6–12 weeks of age [24], 1.9–5.4% for AS03 [35,49] and ≤1% for MF59-adjuvanted vaccines [40,47].
3.4. Unsolicited Adverse Events Across the different trials the rate of unsolicited AEs ranged between 47.2 and 99.5% for AS01/AS02, 36.3–65.0% for AS03 and 49.0–55.0% for MF59-adjuvanted vaccines (Supplementary Table). The proportion of children reporting at least one unsolicited AE was similar among children who received the newly adjuvanted vaccines compared to control groups. The relative risks were 1.00 (95%CI 0.99–1.02), 1.00 (95%CI 0.97–1.04) and 0.94 (95%CI 0.59–1.51) among the AS01/AS02, AS03 and MF59 adjuvanted groups respectively. The overall RR was 1.00 (95%CI 0.99–1.02) (Fig. 3).
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Study
Vaccinated n N
Control n N
7 201 15 200 75 2 5 199 90 4 90 2 30 2 57 170 70 341 35 107 1012 235 51 447 115 495 10307 2067
99 4 200 8 25 2 201 1 45 3 40 2 30 2 170 62 36 171 107 34 1010 326 88 447 45 7 5153 1179
5
Relative Risk [95% CI]
AS01−AS02 Idoko 2014 (30) Ogutu 2009 (29) Thera 2010 (26) Thera 2011 (28) Withers 2006 (27) Bojang 2005 (15) Macete 2007 (14) Abdulla 2013 (20) Agnandji 2010 (21) Aide 2010 (16) Aponte 2007: Sacarlal 2009 (17−18) Lusingu 2010 (19) Owusu−Agyei 2009 (22) RTS.S 2014 (25)
0.86 [ 0.26 , 2.88 ] 1.87 [ 0.81 , 4.32 ] 0.33 [ 0.05 , 2.24 ] 5.05 [ 0.60 , 42.84 ] 0.67 [ 0.16 , 2.85 ] 0.44 [ 0.06 , 3.04 ] 1.00 [ 0.15 , 6.64 ] 0.92 [ 0.69 , 1.23 ] 0.98 [ 0.68 , 1.39 ] 1.03 [ 0.70 , 1.52 ] 0.72 [ 0.62 , 0.83 ] 0.58 [ 0.42 , 0.80 ] 1.49 [ 0.74 , 3.01 ] 0.88 [ 0.82 , 0.93 ]
Overall (Heterogeneity: Q = 23.5 p−value = 0.04 ; I2 = 53 %)
0.86 [ 0.74 , 1.01 ]
AS03 Diez−Domingo 2010:2015 (33−34) Langley 2012 (32) Nolan 2014 (35)
297 195 4168
4 5 142
102 127 2049
3.11 [ 0.17 , 57.28 ] 7.18 [ 0.40 , 128.80 ] 1.03 [ 0.77 , 1.36 ]
0 0 68
Overall (Heterogeneity: Q = 2.3 p−value = 0.32 ; I2 = 26 %)
1.49 [ 0.50 , 4.44 ]
MF59 Della Cioppa 2011 (42) Solares 2014 (44) Vesikari 2009 (43) Arguedas 2011 (39) Block 2012 (37) Knuf 2014: 2015 (40−41) Nassim 2012 (38) Nolan 2014 (47) Vesikari 2011 (46)
284 180 130 46 329 293 843 3125 1941
5 1 2 0 6 25 16 125 122
119 180 139 123 325 37 505 2953 2766
0.70 [ 0.17 , 2.88 ] 1.00 [ 0.06 , 15.86 ] 0.36 [ 0.07 , 1.73 ] 2.64 [ 0.05 , 131.06 ] 0.37 [ 0.15 , 0.93 ] 1.58 [ 0.39 , 6.40 ] 1.20 [ 0.52 , 2.78 ] 0.89 [ 0.70 , 1.13 ] 0.62 [ 0.51 , 0.76 ]
3 1 6 0 16 2 8 133 279
Overall (Heterogeneity: Q = 10.7 p−value = 0.22 ; I2 = 33 %)
0.74 [ 0.57 , 0.97 ] 0.85 [ 0.75 , 0.96 ]
Overall (Heterogeneity: Q = 43 p−value = 0.01 ; I2 = 50 %)
0.02
0.14
1.00
7.39
54.60
403.43
Relative Risk Fig. 2. Forest plot of relative risks of serious adverse events by adjuvant group and overall.
In RTS,S/AS01 and control groups, most frequent AEs were upper respiratory tract infections (URTI), malaria, pneumonia and gastroenteritis. Less than 3% of the URTI were assessed as grade 3 in intensity and none were considered to be related to vaccination [6]. In the Phase 3 AS03-trial, grade 3 AEs and AEs possibly related to vaccination were between 0.5–1.2% and 2.5–2.9% [35]. In the Phase 3 MF59-adjuvanted vaccine trials, the type of unsolicited AEs corresponded to what is expected in a pediatric population. Upper respiratory infections were the most frequent AEs (9–32% of participants) [46,47].
During Phase 2 Trials febrile convulsions occurred in similar proportions in the RTS,S/AS01 & AS02 and control groups <7 days after vaccination or during the whole follow up period (RR 0.73; 95%CI 0.44–1.22) [6]. Rates of febrile convulsions were not reported in AS03-and MF59-trials. Nassim [38] and Nolan [47] each found one case of a febrile convulsion possibly related to vaccination. Vesikari reported 5 febrile convulsions in the adjuvanted group, 5 in the nonadjuvanted group and 4 in the control group, but further details were not provided [46]. 3.6. Meningitis
3.5. Convulsions Across the AS01/AS02-trials the rate of convulsions was between 0.5 and 3.5% (Supplementary Table). Our meta-analysis showed that the occurrence of convulsions was similar between adjuvanted and control vaccines: the RR was 0.96 (95%CI 0.8–1.15) for AS01/AS02, 1.14 (95%CI 0.42–3.14) for AS03 and 1.69 (95%CI 0.6–4.81) for MF59-adjuvanted vaccines. The overall RR was 1.00 (95%CI 0.84–1.19).
A higher rate of meningitis was reported for the AS01adjuvanted vaccine: during Phase III Trials meningitis occurred more frequently in the RTS,S/AS01 study group as compared to control groups. After 18 months follow-up the incidence of meningitis was 2–3/1000 in the adjuvanted groups and 0–1/1000 in the control groups. Seventeen cases were reported among children 5–17 months: 16 cases/5949 children in the RTS,S/AS01 group and 1 case/2974 children in the control group (RR 8.0 (95%CI, 1.1–60.3)).
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–
3.1 (0.68) 0%
1.5 (0.91) 0%
–
1.09 [1;1.18]
1.09 [1.01;1.17]
–
Block, Knuf, Vesikari, Solares, Zedda, Vesikari
Block, Knuf, Vesikari, Solares, Zedda, Vesikari
Among infants 6–12 weeks 12 cases were reported: 9 cases/4358 infants in the RTS,S/AS01 group and 3 cases/2179 in the control group (RR 1.5 (95%CI, 0.41–5.55)). According to the authors, none of the meningitis cases were temporally related to vaccination [25]. AS03- and MF59-adjuvant trials did not provide information on the occurrence of cases of meningitis. 3.7. Potential immune-mediated diseases Cases of potential immune-mediated diseases (pIMD), such as alopecia areata, glomerulonephritis and idiopathic thrombocytopenic purpura, were observed across different study groups in the Phase III AS03 trial, ranging from 0.05–0.15% in the adjuvanted to 0.20% in the control group [35]. No information was provided on the rate of pIMD in the other AS03-trials [49,50], AS01/AS02 or MF59-adjuvanted vaccine trials. 3.8. New onset of chronic diseases
–
–
Two MF59-trials documented the occurrence of new chronic diseases such as attention deficit disorder, hypersensitivity and allergic dermatitis [38,40,41]. The events were evenly distributed across study groups and none were considered to be vaccinerelated [38]. –
14.8 (0.01) 73% 1.41 [1.16;1.72] 4.2 (0.12) 0%
24.7 (<0.01) 76% 1.5 [0.98;2.3] 2.2 (0.14) 54%
10.8 (0.09) 0% 1.31 [1.12;1.53] 1.7 (0.19) 41%
61.9 (<0.01) 84% 1.42 [1.17;1.72]
Block, Arguedas, Knuf, Vesikari, Solares, Zedda, Vesikari Block, Arguedas, Knuf, Vesikari, Solares, Zedda, Vesikari Block, Arguedas, Knuf, Vesikari, Solares, Zedda, Vesikari Block, Knuf, Vesikari, Solares, Zedda, Vesikari 3.9 (0.05) 75%
Q (p-value) I2 RR [95%CI] Studies Q (p-value) I2
MF59
6
1.13 [0.96;1.34] Loss of appetite
Irritability
Drowsiness
Fever
4.1. Summary of evidence SAEs, fatalities, unsolicited AEs and convulsions do not occur more frequently in newly adjuvanted compared to control vaccines. Although newly adjuvanted vaccines are more reactogenic than control vaccines, a consistent pattern across adjuvants could not be demonstrated. Pain is among the most prevalent AEs, but often mild and of short duration. Our results are consistent with previous analyses and reviews which focused on the safety of specific adjuvants [3,5–11,51]. A pooled analysis of safety data from Phase II RTS,S/AS01 & AS02 malaria candidate vaccine trials reported a significantly decreased rate of SAEs. After exclusion of malaria, the percentage of participants reporting any SAE was still significantly lower in the RTS,S/AS group [6]. We also observed a significantly reduced rate of SAEs across all newly adjuvanted vaccines. However, when malaria cases were excluded in our meta-analysis, the decrease became nonsignificant (RR 0.87, 95%CI 0.75–1.00). We did not evaluate the safety of newly adjuvanted vaccines depending on the dose, the amount of antigen or adjuvant. A review on the safety of the pandemic influenza MF59 and AS03-adjuvanted vaccines reported that higher amounts of antigen/adjuvant, and a second dose were associated with a higher reactogenicity, but this was not consistent across trials [7]. 4.2. Limitations Significant results are depicted in bold.
Waddington 16.1 (0.01) 58% 1.25 [1.04;1.5]
1.44 [1.23;1.68] Waddington 44.1 (<0.01) 92% 1.47 [1.11;1.94]
– 10.7 (0.1) 48% 1.25 [1.07;1.46]
1.85 [1.6;2.14]
Waddington, Diez-Domingo, Nolan – 327.6 (<0.01) 98% 1.45 [0.85;2.47]
1.99 [1.3;3.04] Waddington, Diez-Domingo 73.7 (<0.01) 93% Swelling
Macete, Bojang, Aide, Abdulla, Lusingu, Adjandji, RTS a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b
1.24 [0.82;1.88]
1.24 [0.91;1.67] Waddington, Diez-Domingo 1.7 (0.2) 40% Redness
1 [0.79;1.26]
1.67 [1.25;2.24] Waddington, Diez-Domingo 91.5 (<0.01) 98% 1.24 [0.96;1.59]
Studies
Macete, Bojang, Aide, Abdulla, Lusingu, Adjandji, RTS a & b RTS,S a & b Pain
AS01/AS02 Adverse event
Table 3 Results meta-analyses Solicited Adverse Events.
Q (p-value) I2
AS03
RR [95%CI] Studies
RR [95%CI]
4. Discussion
Apart from the SAEs and unsolicited AEs, the definitions of solicited AEs, AEs of special interest, the type and grading of AEs are not always standardized. We therefore analyzed these events by adjuvant type. As the same adjuvant types are produced by single manufacturers, there is a better consistency at this level. The follow-up period is mostly less than a week for solicited AEs, but the length of follow-up for SAEs (usually the whole duration of the trial, and hence varying from several months to up to 2 years) and unsolicited AEs (varying between 28 and 62 days in different trials) varies substantially across trials. Comparison of AEs between the trials should therefore be done with caution.
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Vaccinated Study
7
Control Relative Risk [95% CI]
N
n
N
n
Abdulla 2013 (20)
170
137
170
141
0.97 [ 0.88 , 1.07 ]
Agnandji 2010 (21)
340
321
171
164
0.98 [ 0.95 , 1.02 ]
Idoko 2014 (30)
199
94
98
48
0.96 [ 0.75 , 1.24 ]
Lusingu 2010 (19)
447
348
447
330
1.05 [ 0.98 , 1.14 ]
AS01−AS02
Macete 2007 (14)
30
27
30
28
0.96 [ 0.83 , 1.12 ]
Ogutu 2009 (29)
200
197
200
197
1.00 [ 0.98 , 1.02 ]
Owusu−Agyei 2009 (22)
315
245
45
27
1.30 [ 1.01 , 1.66 ]
Thera 2011 (28)
199
198
201
195
1.03 [ 1.00 , 1.05 ]
Withers 2006 (27)
90
78
45
40
0.98 [ 0.86 , 1.11 ]
RTS.S 2012 (24)
1462
1161
738
600
0.98 [ 0.94 , 1.02 ]
RTS.S 2014 (25)
1479
1273
721
626
0.99 [ 0.96 , 1.03 ]
Overall (Heterogeneity: Q = 12.4 , p−v alue = 0.26 ; I2 = 14 %)
1.00 [ 0.99 , 1.02 ]
AS03 Diez−Domingo 2010: 2015 (33−34)
297
27
102
6
1.55 [ 0.66 , 3.64 ]
Nolan 2014 (35)
8192
4179
4098
2085
1.00 [ 0.97 , 1.04 ]
Overall (Heterogeneity: Q = 1 , p−value = 0.32 ; I2 = 0 %)
1.00 [ 0.97 , 1.04 ]
MF59 Zedda 2015 (45)
41
18
0.94 [ 0.59 , 1.51 ]
20
43
1.00 [ 0.99 , 1.02 ]
Overall (Heterogeneity: Q = 13.4 , p−v alue = 0.42 ; I2 = 6 %)
0.37
0.61
1.00
1.65
2.72
4.48
Relative Risk Fig. 3. Forest plot of relative risks of unsolicited adverse events by adjuvant group and overall.
Some categories of AEs – certain types of solicited AEs, unsolicited AEs or AEs of special interest in particular – are not systematically reported and therefore the number of studies reporting a certain AE that could be included in the meta-analysis was low. Overall, the number of subjects exposed to the different adjuvanted vaccines is relatively small, and might be insufficient to detect the risk of rare events. The study population was different for the adjuvant-systems: the AS01/AS02-adjuvanted trials have been carried-out in SubSaharan Africa only, whereas the AS03 and MF59-adjuvanted trails were done in European, Asian and American contexts. It is not clear how this might have influenced safety results. The control vaccines consisted of adjuvanted vaccines (such as the aluminum containing hepatitis B or 7-valent pneumococcal conjugate vaccines) or non-adjuvanted vaccines (rabies, seasonal influenza or meningitis C vaccines) and varied both between and within the adjuvant groups. As some of these vaccines may have a higher reactogenicity profile or even be associated with differing SAE rates, this needs to be taken into account when interpreting results.
None of the trials assessed the newly adjuvants alone versus a placebo, but always the adjuvant in combination with an antigen, often new as well. The AS01-adjuvant has been used only with the RTS,S-antigen in children, the AS03 adjuvant mostly with the pandemic influenza vaccine and MF59 adjuvant with the seasonal influenza vaccine mostly. Further experience with new adjuvant and antigen combinations will provide further reassurance that our findings can be extrapolated across all combinations. A number of Good Clinical Practice concerns have been raised for the pivotal Phase III MF59 Trial carried out in Finland and Germany included in this review [46,52]. A sensitivity analysis in which this large trial was excluded from the analysis did not affect the conclusions of our analyses. A significant higher rate of meningitis was observed for the RTS,S/AS01-adjuvanted vaccine. The authors could not find an obvious explanation for the association: a temporal relationship was lacking, the biological plausibility was low and a causal relationship could not be confirmed nor excluded [25]. The recently published final results, including the safety data of the booster vaccine, have confirmed the significant imbalance in the incidence of meningitis
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in the 5–17 months age group, but not among the infants. Postregistration studies are planned to establish the significance of the finding [53]. Only clinical trials were included in this review, which limits the assessment to the safety in healthy children. It remains unknown whether the results can be generalized to other, more vulnerable populations. Post-marketing surveillance revealed a number of signals for AS03-adjuvanted vaccines, including febrile seizures and seizures in epilepsy. An increased risk of narcolepsy in children under 18 years of age has also been reported, and assessments are ongoing to confirm the causal mechanism [54–57]. Post-marketing analysis showed that reporting rates of AEs for the pandemic MF59-adjuvanted vaccine were about 20% higher than for the seasonal vaccine, but consistent with the safety profile found during clinical trials [58]. Available but limited observations did not show an increased risk of narcolepsy with MF59-adjuvanted pandemic vaccines [59]. The AS01/AS02 and MF59-adjuvanted seasonal influenza vaccine have not been licensed in children, therefore post-marketing surveillance data are not available. 4.3. Conclusions This meta-analysis – the first one carried-out for all newly adjuvanted vaccines in children – showed no overall increase in SAEs, fatalities, or unsolicited AEs following the administration of newly adjuvanted vaccines. Higher rates for some local or general AEs were observed for all newly adjuvanted vaccines, but were mostly mild and transient. The most consistently increased solicited AE is pain at injection site. A number of safety signals observed in clinical trials such as meningitis are still under evaluation. Authors’ contributions TV and JS conceived and designed the study, JS and MB performed the literature review, KB performed the meta-analyses, JS drafted the manuscript, all authors revised it, and approved the final version to be submitted. Conflict of interest statement TV and KB have received consulting fees from GSK and Novartis, unrelated to this review. The other authors declare no conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2015.12. 024. References [1] Garcon N, Van Mechelen M. Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Rev Vaccines 2011;10(4):471–86. [2] Alving CR, Rao M, Steers NJ, Matyas GR, Mayorov AV. Liposomes containing lipid A: an effective, safe, generic adjuvant system for synthetic vaccines. Expert Rev Vaccines 2012;11(6):733–44. [3] Fox CB, Haensler J. An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants. Expert Rev Vaccines 2013;12(7):747–58. [4] World Health Organization. Pandemic influenza A (H1N1) 2009 virus vaccine – conclusions and recommendations from the october 2009 meeting of the immunization Strategic Advisory Group of experts. Wkly Epidemiol Rec 2009;84(49):505–16. [5] Pellegrini M, Nicolay U, Lindert K, Groth N, Della Cioppa G. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine 2009;27(49):6959–65. [6] Vekemans J, Guerra Y, Lievens M, Benns S, Lapierre D, Leach A, et al. Pooled analysis of safety data from pediatric Phase II RTS,S/AS malaria candidate vaccine trials. Hum Vaccines 2011;7(12):1309–16.
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Review
A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children Jorgen Stassijns, Kaatje Bollaerts, Marc Baay, Thomas Verstraeten ∗ P-95, Epidemiology and Pharmacovigilance Consulting and Services, Koning Leopold III Laan 1, 3001 Heverlee, Belgium
a r t i c l e
i n f o
Article history: Received 16 September 2015 Received in revised form 8 December 2015 Accepted 10 December 2015 Available online xxx Keywords: Vaccine Adjuvants Safety Children
a b s t r a c t Introduction: New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children. Methods: We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted. Results: Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75–0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases. Conclusions: Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction A number of new adjuvants have been developed to improve the efficacy of vaccines as well as for dose sparing. The new adjuvants that are licensed or in advanced clinical development and that are used in children are AS01, AS02, AS03 and MF59. The GlaxoSmithKline (GSK)-developed Adjuvant Systems (AS) are based on a combination of immuno-stimulants in different adjuvant formulations: AS01 contains 3-O-desacyl-4 -monophosphoryl lipid A (MPL) and the saponin QS-21 and is a liposome-based formulation; AS02 also contains MPL and QS-21 and is an oil-in-water emulsionbased formulation. AS03 is composed of ␣-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. The Novartisdeveloped MF59® adjuvant is a squalene-based oil-in-water based adjuvant [1–3] (Table 1).
The experience with the pandemic influenza vaccines as well as the development of a new malaria vaccine have shown that new adjuvants may be particular beneficial for children. A few reviews have been carried out for individual adjuvant systems [4–11], but a comprehensive systematic review and meta-analysis of the safety of all newly pediatric adjuvanted vaccines has not yet been done. In this study we systematically review the current evidence on the safety of the newly adjuvanted vaccines in children and perform meta-analyses using data from published clinical trials. In particular we perform meta-analyses for serious adverse events (SAEs), local and general solicited AEs, unsolicited AEs and AEs of special interest by group of adjuvants. 2. Methods 2.1. Data sources
∗ Corresponding author. Tel.: +32 474 534868. E-mail address: [email protected] (T. Verstraeten).
We searched Medline (1990 to April 2015), ClinicalTrials.gov and the Cochrane Library for clinical trials including any of the new
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2 Table 1 Overview characteristics new adjuvants included in review. Adjuvant
Components
Formulation
Vaccine(s)
Licensed
Manufacturer
AS01
Monophosphoryl lipid A (MPL) + saponin QS-21 Monophosphoryl lipid A (MPL) + saponin QS-21 ␣-Tocopherol, squalene and polysorbate 80
Liposome-based
RTS,S malaria vaccine
No
GlaxoSmithKline
Oil-in-water emulsion
RTS,S malaria vaccine
No
GlaxoSmithKline
Oil-in-water emulsion
Yes (Pandemrix® )
GlaxoSmithKline
Squalene
Oil-in-water emulsion
Influenza A (H1N1) virus (swine flu) H5N1 influenza (avian flu) Pandemic influenza A/California/7/2009(H1N1) Seasonal influenza
Yes (Arepanrix® ) Yes (Focetria® , Celtura® , Fluad® )
Novartis
AS02 AS03
MF59
adjuvant systems. Bibliographies of the publications selected for the review and systematic reviews were hand searched for additional relevant trials.
of heterogeneity [13]. The analyses were based on the number of individuals who experienced the event at least once. For trials with more than one treatment/control group, we used the data for the combined treatment/control groups.
2.2. Study selection 3. Results Eligibility criteria for studies to be included in the meta-analysis were as follows: (1) randomized controlled trial (RCT); (2) study on the safety of vaccines using the adjuvant systems AS01, AS02, AS03, or MF59; (3) performed on infants or children and (4) reporting the safety of both the adjuvanted group and a control group. AS04, the new adjuvant used in some vaccines such as the bivalent HPV vaccine Cervarix, has not been used for children under the age of 9. Therefore we have not included AS04 in this review. A literature search was performed in PubMed for the adjuvantsystems with the following search terms: (“AS01” [All Fields] OR “AS02” [All Fields] OR “AS03” [All Fields] OR “MF59” [All Fields]) AND “vaccine” [All Fields] AND (“child” [All Fields] OR “children” [All Fields] OR “infant” [All Fields] OR “infants” [All Fields] OR “adolescent” [All Fields]). 2.3. Outcomes Safety outcomes from Phases I, II and III clinical trials were categorized as: 1) serious adverse events (SAEs); 2) solicited local and general adverse events; 3) unsolicited adverse events and 4) adverse events of special interest. The length of follow-up depended on the category of AE: SAEs were monitored for the whole duration of the trial, solicited AEs up to 1 week, and unsolicited AEs up to 60 days after each dose. For SAEs and solicited AEs unsolicited adverse events, which are collected and reported consistently across all studies, we performed meta-analyses across all adjuvant systems and by groups of adjuvant systems. For the unsolicited AEs and AEs of special interest, we only analyzed the studies by adjuvant group. Given their similar composition and paucity of data on AS02, we grouped AS01 and AS02 for this review. In our analysis, the safety data of the newly-adjuvanted study groups are pooled across different antigens; the safety data for control groups are pooled across adjuvanted and non-adjuvanted cohorts, including different antigens. 2.4. Statistical analysis We conducted meta-analyses using restricted maximum likelihood. The results are reported as relative risks (RR) with 95% confidence intervals (CI). We quantified the between-trial heterogeneity using the I2 statistic, which is to be interpreted as the proportion of total variation in the estimates of treatment effect that is due to heterogeneity between studies [12]. Low, moderate and high levels of heterogeneity correspond to I2 values of 25%, 50% and 75% respectively. In addition, we computed the Q-statistic, for which p-values <0.05 indicate a significant amount
3.1. Selected trials Using the search terms described, we identified 291 publications for the different adjuvants (70 for AS01/AS02, 100 for AS03 and 127 for MF59, with 6 papers referring to both AS03 and MF59). Screening the reference lists of the papers selected for full review resulted in one additional study on AS03, and 10 additional studies on AS01/AS02. After application of the selection criteria a total of 14 [14–30], 4 [31–35], and 11 [36–47] trials were retained for the meta-analysis of AS01/AS02, AS03 and MF59 adjuvants (Table 2), with some trials being reported in multiple publications. Fur a full description of the selection process we refer to the PRISMA flow diagram (Fig. 1, cfr Moher [48]). A total of 41,700 children between 6 weeks and 10 years were included in the meta-analysis: 25,056 received an adjuvanted vaccine and 16,644 a control vaccine. Out of these, 12,207, 5057 and 7792 were exposed to at least one dose of the AS01/AS02, AS03 or MF59-adjuvanted vaccine, compared to 6457, 2757 and 7430 children receiving a control vaccine in the AS01/AS02, AS03 and MF59 trials. Trials including the AS01 and AS02 adjuvant systems have thus far been conducted only in Sub-Saharan Africa, whereas the AS03 and MF59 trials have been carried out among Asian, European and American children. Children in control groups were exposed to different antigens such as rabies, meningococcus C, hepatitis B (HB), 7-valent pneumococcal conjugate (PCV7) or Haemophilus Influenzae Type B (Hib) (Table 2). 3.2. Serious Adverse Events The rate of SAEs reported in the different trials ranged between 1.2 and 33.5% for the AS01/AS02-adjuvanted vaccines, 0.0–8.0% for the AS03 and 0.0–10.4% for the MF59-adjuvanted vaccines (Supplementary Table). SAEs were not reported more frequently among children who received the newly adjuvanted vaccines compared to control groups. The pooled relative risks (RR) were 0.86 (95%CI 0.74–1.01), 1.49 (95%CI 0.50–4.44) and 0.74 (95%CI 0.57–0.97) among the AS01/AS02, AS03 and MF59-adjuvanted groups respectively. The overall pooled RR was 0.85 (95%CI 0.75–0.96) (Fig. 2). In the multi-centric Phase III trial, assessing the safety of the RTS,S/AS01 malaria vaccine (in which ‘R’ stands for the central repeat region of the Plasmodium falciparum ‘circumsporozoite protein (CSP); ‘T’ for the T-cell epitopes of the CSP, ‘S’ for the hepatitis B surface antigen, and ‘S’ for a free protein), SAEs occurred with similar frequency between RTS,S/AS01 and control groups in
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Phase
Year
Country
Study population
Macete et al. [14] Bojang et al. [15] Aide et al. [16] Aponte et al.; Sacarlal et al. [17,18] Lusingu et al. [19] Abdulla et al. [20] Agnandji et al. [21] Owusu-Agyei et al. [22] RTS,S/S Clin Trial Partnership [23–25] Thera et al. [26] Withers et al. [27] Thera et al. [28] Ogutu et al. [29] Idoko et al. [30] Waddington et al. [31] Langley et al. [32] Diez-Domingo et al. [33,34] Nolan et al. [35] Johnson et al. [36] Block et al. [37] Nassim et al. [38] Arguedas et al. [39] Knuf et al. [40,41]
1 1 1/2B 2B
2002 2001–02 2005–07 2003–07
Mozambique The Gambia Mozambique Mozambique
1–4 years 1–5 years, 6–11 years 10–18 weeks 1–4 years
2B 2B 2 2 3
2007 2006–08 2007–09 2006–08 2009–11
Kenya/Tanzania Tanzania Ghana/Gabon/Tanzania Ghana Multicentric (11 sites)
5–17 months 8–16 weeks 6–10 weeks 5–17 months 6
1 1B 2B 2B 2 2 2 2
2006 2003 2007–08 2005 2010–12 2009 2009 2007–08
Mali Kenya Mali Kenya Gambia UK Canada Spain
1–6 years 12–47 months 1–6 years 12–47 months Infants 6 months–4 years, 5–12 years 6 months–8 years 3–5 years, 6–9 years
3 1 2/3 2/3 3 3
2010–11 2013 2009–10 2009–10 2009 2009–11
Multicentric USA USA/Mexico USA Costa Rica Multicentric
Della Cioppa et al. [42] Vesikari et al. [43] Solares et al. [44] Zedda et al. [45] Vesikari et al. [46] Nolan et al. [47]
1B 2 2 2 3 3
2008–09 2006–07 2008 2011 2007–09 2011–12
Finland/Belgium Finland Guatemala Belgium Germany, Finland Multicentric
6 months–10 years ≥3 years 6–<36 months 3–<9 years 3–8 years, 9–17 years 6–11 months, 12–35 months, 3–8 years, 9–17 years 6–<36 months 6–<36 months 6–<36 months, 36–<60 months 6–<36 months 6–36 months, 36–72 months 6–<72 months
Nr. Subjects
Adjuvant
Vaccine
Control
AS02 AS02 AS02 AS02
Malaria RTS/S Malaria RTS/S Malaria RTS/S Malaria RTS/S
HB Rabies HB HB, PCV7, Hib
AS01 AS02 AS01 AS01/AS02 AS01
Malaria RTS/S Malaria RTS/S Malaria RTS/S Malaria RTS/S Malaria RTS/S
Rabies HB EPI Rabies Meningitis, Rabies
100 135 400 400 300 943 322 405
AS02 AS02 AS02 AS02 AS01 AS03 AS03 AS03
Malaria FMP2.1 Malaria FMP1 Malaria FMP2.1 Malaria FMP1 TB M72 Pandemic influenza Pandemic influenza Pandemic influenza
Rabies Rabies Rabies Rabies Meningitis, EPI Non-adj vaccine Non-adj vaccine Seasonal TIV
6145 627 654 1357 392 561
AS03 MF59 MF59 MF59 MF59 MF59
Pandemic influenza H3N2 Pandemic influenza Pandemic influenza Pandemic influenza Pandemic influenza
Placebo, non-adj vaccine Non-adj vaccine 15 g Non-adj vaccine 7.5/15 g Non-adj vaccine 7.5/15 g Non-adj vaccine 15/30 g Non-adj vaccine 15 g
480 281 360 84 4707 6078
MF59 MF59 MF59 MF59 MF59 MF59
Seasonal influenza Seasonal influenza Seasonal influenza Seasonal influenza Seasonal influenza Seasonal influenza
Non-adj vaccine 7.5/15 g TIV TIV 22.5/45 g TIV 7.5 g TIV and non-influenza TIV 1, TIV 2
60 225 214 2022 894 340 511 540 15460
HB, Hepatitis B; PCV7, pneumococcal conjugate 7-valent; Hib, Haemophilus Influenzae Type B; EPI, expanded program on immunisation; TIV, trivalent influenza.
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Table 2 Clinical trials included in the meta-analysis on the safety of newly adjuvanted vaccines.
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Idenficaon
4
Records idenfied through database searching (n = 291)
Addional records idenfied from reference lists (n = 11)
Eligibility
Screening
Records aer duplicates removed (n = 302)
Records screened (n = 302)
Full-text arcles assessed for eligibility (n = 71)
Records excluded (n = 231)
Full-text arcles excluded (n = 28)
Included
Studies included in qualitave synthesis (n = 43)
Studies included in quantave synthesis (meta-analysis) (n = 29)
Fig. 1. PRISMA flow diagram. From: Moher D., et al. (2009). PLoS Med 6(6): e1000097.
children 6–12 weeks old (AS01: 22.0%, 95%CI 22.8–23.3; control: 23.1%, 95%CI 21.3–24.9), whereas the 5–17 months age group reported significantly less SAEs in the RTS,S/AS01 compared to the control group, even after exclusion of malaria (17.6% (95%CI 16.6–18.6) versus 21.2% (95%CI 19.7–22.7)) [25]. Pooled analysis of data from Phase II trials reported significantly lower rates of SAEs in recipients of RTS,S/AS01 & AS02 compared to control (21.4% versus 28.0%, RR 0.77 (0.69–0.87), p < 0.001) [6]. After exclusion of the malaria events, the proportion of SAEs in the RTS,S/AS group was still lower than in the control group (14.9% versus 17.7%, RR 0.81 (0.69–0.95), p = 0.008) [6]. No related SAEs were reported in the AS03 trials. In the MF59 trials, three SAEs possibly related to vaccination occurred in the adjuvanted group: a case of mild allergic shock in an 8-month old child, a case of seizure in a 37-month old child [46] and one febrile convulsion [47]. Fatal AEs after administration of RTS,S/AS01 & AS02-adjuvanted vaccines were similar (Phase III) or less frequent (Phase II) as compared to controls and none was considered related to vaccination [6,23–25]. Three fatal events were reported in AS03 Phase III trials, none was considered vaccine related [35]. Eight deaths occurred in the multi-centric MF59 trial, one of which in the adjuvanted group, considered unrelated to vaccination [47].
3.3. Solicited Adverse Events For most of the solicited AEs the reactogenicity of the newly adjuvanted vaccines was significantly higher than for the control vaccines: AS01/AS02-adjuvanted vaccines cause significantly more drowsiness, irritability and loss of appetite. The AS03-adjuvanted vaccines generate significantly more local pain, swelling, fever and
irritability. The RR for local pain, redness, fever, irritability and loss of appetite are significantly higher for the MF59-adjuvanted vaccines as compared to the control vaccines (Table 3). Across the different adjuvants, local pain was reported as one the most frequent solicited AE, with rates between 8.0 and 91.4% (AS01/AS02), 31.7–84.6% (AS03) and 1.0–59.0% (MF59) (Supplementary Table). Grade 3 pain was reported infrequently in Phase III trials: 0.1–0.3% for AS01 [23,24] and below 1% for MF59adjuvanted vaccines [47]. For AS03-adjuvanted vaccines, rates of grade 3 pain were between 4.3% [47] and 12.4% [49]. Fever is an AE of particular concern because of the possible association with febrile seizures. The incidence across trials ranged between 1.0 and 42.4% (AS01/AS02), 11.0–23.8% (AS03) and 4.0–19.0% (MF59) (Supplementary Table). The incidence of Grade 3 temperature (>39◦ ) in Phase III Trials was low: 2.5% of the RTS/AS01 children 5–17 months of age, compared to 1.1% of the control group [23] and <1% among infants 6–12 weeks of age [24], 1.9–5.4% for AS03 [35,49] and ≤1% for MF59-adjuvanted vaccines [40,47].
3.4. Unsolicited Adverse Events Across the different trials the rate of unsolicited AEs ranged between 47.2 and 99.5% for AS01/AS02, 36.3–65.0% for AS03 and 49.0–55.0% for MF59-adjuvanted vaccines (Supplementary Table). The proportion of children reporting at least one unsolicited AE was similar among children who received the newly adjuvanted vaccines compared to control groups. The relative risks were 1.00 (95%CI 0.99–1.02), 1.00 (95%CI 0.97–1.04) and 0.94 (95%CI 0.59–1.51) among the AS01/AS02, AS03 and MF59 adjuvanted groups respectively. The overall RR was 1.00 (95%CI 0.99–1.02) (Fig. 3).
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Study
Vaccinated n N
Control n N
7 201 15 200 75 2 5 199 90 4 90 2 30 2 57 170 70 341 35 107 1012 235 51 447 115 495 10307 2067
99 4 200 8 25 2 201 1 45 3 40 2 30 2 170 62 36 171 107 34 1010 326 88 447 45 7 5153 1179
5
Relative Risk [95% CI]
AS01−AS02 Idoko 2014 (30) Ogutu 2009 (29) Thera 2010 (26) Thera 2011 (28) Withers 2006 (27) Bojang 2005 (15) Macete 2007 (14) Abdulla 2013 (20) Agnandji 2010 (21) Aide 2010 (16) Aponte 2007: Sacarlal 2009 (17−18) Lusingu 2010 (19) Owusu−Agyei 2009 (22) RTS.S 2014 (25)
0.86 [ 0.26 , 2.88 ] 1.87 [ 0.81 , 4.32 ] 0.33 [ 0.05 , 2.24 ] 5.05 [ 0.60 , 42.84 ] 0.67 [ 0.16 , 2.85 ] 0.44 [ 0.06 , 3.04 ] 1.00 [ 0.15 , 6.64 ] 0.92 [ 0.69 , 1.23 ] 0.98 [ 0.68 , 1.39 ] 1.03 [ 0.70 , 1.52 ] 0.72 [ 0.62 , 0.83 ] 0.58 [ 0.42 , 0.80 ] 1.49 [ 0.74 , 3.01 ] 0.88 [ 0.82 , 0.93 ]
Overall (Heterogeneity: Q = 23.5 p−value = 0.04 ; I2 = 53 %)
0.86 [ 0.74 , 1.01 ]
AS03 Diez−Domingo 2010:2015 (33−34) Langley 2012 (32) Nolan 2014 (35)
297 195 4168
4 5 142
102 127 2049
3.11 [ 0.17 , 57.28 ] 7.18 [ 0.40 , 128.80 ] 1.03 [ 0.77 , 1.36 ]
0 0 68
Overall (Heterogeneity: Q = 2.3 p−value = 0.32 ; I2 = 26 %)
1.49 [ 0.50 , 4.44 ]
MF59 Della Cioppa 2011 (42) Solares 2014 (44) Vesikari 2009 (43) Arguedas 2011 (39) Block 2012 (37) Knuf 2014: 2015 (40−41) Nassim 2012 (38) Nolan 2014 (47) Vesikari 2011 (46)
284 180 130 46 329 293 843 3125 1941
5 1 2 0 6 25 16 125 122
119 180 139 123 325 37 505 2953 2766
0.70 [ 0.17 , 2.88 ] 1.00 [ 0.06 , 15.86 ] 0.36 [ 0.07 , 1.73 ] 2.64 [ 0.05 , 131.06 ] 0.37 [ 0.15 , 0.93 ] 1.58 [ 0.39 , 6.40 ] 1.20 [ 0.52 , 2.78 ] 0.89 [ 0.70 , 1.13 ] 0.62 [ 0.51 , 0.76 ]
3 1 6 0 16 2 8 133 279
Overall (Heterogeneity: Q = 10.7 p−value = 0.22 ; I2 = 33 %)
0.74 [ 0.57 , 0.97 ] 0.85 [ 0.75 , 0.96 ]
Overall (Heterogeneity: Q = 43 p−value = 0.01 ; I2 = 50 %)
0.02
0.14
1.00
7.39
54.60
403.43
Relative Risk Fig. 2. Forest plot of relative risks of serious adverse events by adjuvant group and overall.
In RTS,S/AS01 and control groups, most frequent AEs were upper respiratory tract infections (URTI), malaria, pneumonia and gastroenteritis. Less than 3% of the URTI were assessed as grade 3 in intensity and none were considered to be related to vaccination [6]. In the Phase 3 AS03-trial, grade 3 AEs and AEs possibly related to vaccination were between 0.5–1.2% and 2.5–2.9% [35]. In the Phase 3 MF59-adjuvanted vaccine trials, the type of unsolicited AEs corresponded to what is expected in a pediatric population. Upper respiratory infections were the most frequent AEs (9–32% of participants) [46,47].
During Phase 2 Trials febrile convulsions occurred in similar proportions in the RTS,S/AS01 & AS02 and control groups <7 days after vaccination or during the whole follow up period (RR 0.73; 95%CI 0.44–1.22) [6]. Rates of febrile convulsions were not reported in AS03-and MF59-trials. Nassim [38] and Nolan [47] each found one case of a febrile convulsion possibly related to vaccination. Vesikari reported 5 febrile convulsions in the adjuvanted group, 5 in the nonadjuvanted group and 4 in the control group, but further details were not provided [46]. 3.6. Meningitis
3.5. Convulsions Across the AS01/AS02-trials the rate of convulsions was between 0.5 and 3.5% (Supplementary Table). Our meta-analysis showed that the occurrence of convulsions was similar between adjuvanted and control vaccines: the RR was 0.96 (95%CI 0.8–1.15) for AS01/AS02, 1.14 (95%CI 0.42–3.14) for AS03 and 1.69 (95%CI 0.6–4.81) for MF59-adjuvanted vaccines. The overall RR was 1.00 (95%CI 0.84–1.19).
A higher rate of meningitis was reported for the AS01adjuvanted vaccine: during Phase III Trials meningitis occurred more frequently in the RTS,S/AS01 study group as compared to control groups. After 18 months follow-up the incidence of meningitis was 2–3/1000 in the adjuvanted groups and 0–1/1000 in the control groups. Seventeen cases were reported among children 5–17 months: 16 cases/5949 children in the RTS,S/AS01 group and 1 case/2974 children in the control group (RR 8.0 (95%CI, 1.1–60.3)).
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–
3.1 (0.68) 0%
1.5 (0.91) 0%
–
1.09 [1;1.18]
1.09 [1.01;1.17]
–
Block, Knuf, Vesikari, Solares, Zedda, Vesikari
Block, Knuf, Vesikari, Solares, Zedda, Vesikari
Among infants 6–12 weeks 12 cases were reported: 9 cases/4358 infants in the RTS,S/AS01 group and 3 cases/2179 in the control group (RR 1.5 (95%CI, 0.41–5.55)). According to the authors, none of the meningitis cases were temporally related to vaccination [25]. AS03- and MF59-adjuvant trials did not provide information on the occurrence of cases of meningitis. 3.7. Potential immune-mediated diseases Cases of potential immune-mediated diseases (pIMD), such as alopecia areata, glomerulonephritis and idiopathic thrombocytopenic purpura, were observed across different study groups in the Phase III AS03 trial, ranging from 0.05–0.15% in the adjuvanted to 0.20% in the control group [35]. No information was provided on the rate of pIMD in the other AS03-trials [49,50], AS01/AS02 or MF59-adjuvanted vaccine trials. 3.8. New onset of chronic diseases
–
–
Two MF59-trials documented the occurrence of new chronic diseases such as attention deficit disorder, hypersensitivity and allergic dermatitis [38,40,41]. The events were evenly distributed across study groups and none were considered to be vaccinerelated [38]. –
14.8 (0.01) 73% 1.41 [1.16;1.72] 4.2 (0.12) 0%
24.7 (<0.01) 76% 1.5 [0.98;2.3] 2.2 (0.14) 54%
10.8 (0.09) 0% 1.31 [1.12;1.53] 1.7 (0.19) 41%
61.9 (<0.01) 84% 1.42 [1.17;1.72]
Block, Arguedas, Knuf, Vesikari, Solares, Zedda, Vesikari Block, Arguedas, Knuf, Vesikari, Solares, Zedda, Vesikari Block, Arguedas, Knuf, Vesikari, Solares, Zedda, Vesikari Block, Knuf, Vesikari, Solares, Zedda, Vesikari 3.9 (0.05) 75%
Q (p-value) I2 RR [95%CI] Studies Q (p-value) I2
MF59
6
1.13 [0.96;1.34] Loss of appetite
Irritability
Drowsiness
Fever
4.1. Summary of evidence SAEs, fatalities, unsolicited AEs and convulsions do not occur more frequently in newly adjuvanted compared to control vaccines. Although newly adjuvanted vaccines are more reactogenic than control vaccines, a consistent pattern across adjuvants could not be demonstrated. Pain is among the most prevalent AEs, but often mild and of short duration. Our results are consistent with previous analyses and reviews which focused on the safety of specific adjuvants [3,5–11,51]. A pooled analysis of safety data from Phase II RTS,S/AS01 & AS02 malaria candidate vaccine trials reported a significantly decreased rate of SAEs. After exclusion of malaria, the percentage of participants reporting any SAE was still significantly lower in the RTS,S/AS group [6]. We also observed a significantly reduced rate of SAEs across all newly adjuvanted vaccines. However, when malaria cases were excluded in our meta-analysis, the decrease became nonsignificant (RR 0.87, 95%CI 0.75–1.00). We did not evaluate the safety of newly adjuvanted vaccines depending on the dose, the amount of antigen or adjuvant. A review on the safety of the pandemic influenza MF59 and AS03-adjuvanted vaccines reported that higher amounts of antigen/adjuvant, and a second dose were associated with a higher reactogenicity, but this was not consistent across trials [7]. 4.2. Limitations Significant results are depicted in bold.
Waddington 16.1 (0.01) 58% 1.25 [1.04;1.5]
1.44 [1.23;1.68] Waddington 44.1 (<0.01) 92% 1.47 [1.11;1.94]
– 10.7 (0.1) 48% 1.25 [1.07;1.46]
1.85 [1.6;2.14]
Waddington, Diez-Domingo, Nolan – 327.6 (<0.01) 98% 1.45 [0.85;2.47]
1.99 [1.3;3.04] Waddington, Diez-Domingo 73.7 (<0.01) 93% Swelling
Macete, Bojang, Aide, Abdulla, Lusingu, Adjandji, RTS a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b Macete, Aide, Abdulla, Lusingu, Adjandji, RTS,S a & b
1.24 [0.82;1.88]
1.24 [0.91;1.67] Waddington, Diez-Domingo 1.7 (0.2) 40% Redness
1 [0.79;1.26]
1.67 [1.25;2.24] Waddington, Diez-Domingo 91.5 (<0.01) 98% 1.24 [0.96;1.59]
Studies
Macete, Bojang, Aide, Abdulla, Lusingu, Adjandji, RTS a & b RTS,S a & b Pain
AS01/AS02 Adverse event
Table 3 Results meta-analyses Solicited Adverse Events.
Q (p-value) I2
AS03
RR [95%CI] Studies
RR [95%CI]
4. Discussion
Apart from the SAEs and unsolicited AEs, the definitions of solicited AEs, AEs of special interest, the type and grading of AEs are not always standardized. We therefore analyzed these events by adjuvant type. As the same adjuvant types are produced by single manufacturers, there is a better consistency at this level. The follow-up period is mostly less than a week for solicited AEs, but the length of follow-up for SAEs (usually the whole duration of the trial, and hence varying from several months to up to 2 years) and unsolicited AEs (varying between 28 and 62 days in different trials) varies substantially across trials. Comparison of AEs between the trials should therefore be done with caution.
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Vaccinated Study
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Control Relative Risk [95% CI]
N
n
N
n
Abdulla 2013 (20)
170
137
170
141
0.97 [ 0.88 , 1.07 ]
Agnandji 2010 (21)
340
321
171
164
0.98 [ 0.95 , 1.02 ]
Idoko 2014 (30)
199
94
98
48
0.96 [ 0.75 , 1.24 ]
Lusingu 2010 (19)
447
348
447
330
1.05 [ 0.98 , 1.14 ]
AS01−AS02
Macete 2007 (14)
30
27
30
28
0.96 [ 0.83 , 1.12 ]
Ogutu 2009 (29)
200
197
200
197
1.00 [ 0.98 , 1.02 ]
Owusu−Agyei 2009 (22)
315
245
45
27
1.30 [ 1.01 , 1.66 ]
Thera 2011 (28)
199
198
201
195
1.03 [ 1.00 , 1.05 ]
Withers 2006 (27)
90
78
45
40
0.98 [ 0.86 , 1.11 ]
RTS.S 2012 (24)
1462
1161
738
600
0.98 [ 0.94 , 1.02 ]
RTS.S 2014 (25)
1479
1273
721
626
0.99 [ 0.96 , 1.03 ]
Overall (Heterogeneity: Q = 12.4 , p−v alue = 0.26 ; I2 = 14 %)
1.00 [ 0.99 , 1.02 ]
AS03 Diez−Domingo 2010: 2015 (33−34)
297
27
102
6
1.55 [ 0.66 , 3.64 ]
Nolan 2014 (35)
8192
4179
4098
2085
1.00 [ 0.97 , 1.04 ]
Overall (Heterogeneity: Q = 1 , p−value = 0.32 ; I2 = 0 %)
1.00 [ 0.97 , 1.04 ]
MF59 Zedda 2015 (45)
41
18
0.94 [ 0.59 , 1.51 ]
20
43
1.00 [ 0.99 , 1.02 ]
Overall (Heterogeneity: Q = 13.4 , p−v alue = 0.42 ; I2 = 6 %)
0.37
0.61
1.00
1.65
2.72
4.48
Relative Risk Fig. 3. Forest plot of relative risks of unsolicited adverse events by adjuvant group and overall.
Some categories of AEs – certain types of solicited AEs, unsolicited AEs or AEs of special interest in particular – are not systematically reported and therefore the number of studies reporting a certain AE that could be included in the meta-analysis was low. Overall, the number of subjects exposed to the different adjuvanted vaccines is relatively small, and might be insufficient to detect the risk of rare events. The study population was different for the adjuvant-systems: the AS01/AS02-adjuvanted trials have been carried-out in SubSaharan Africa only, whereas the AS03 and MF59-adjuvanted trails were done in European, Asian and American contexts. It is not clear how this might have influenced safety results. The control vaccines consisted of adjuvanted vaccines (such as the aluminum containing hepatitis B or 7-valent pneumococcal conjugate vaccines) or non-adjuvanted vaccines (rabies, seasonal influenza or meningitis C vaccines) and varied both between and within the adjuvant groups. As some of these vaccines may have a higher reactogenicity profile or even be associated with differing SAE rates, this needs to be taken into account when interpreting results.
None of the trials assessed the newly adjuvants alone versus a placebo, but always the adjuvant in combination with an antigen, often new as well. The AS01-adjuvant has been used only with the RTS,S-antigen in children, the AS03 adjuvant mostly with the pandemic influenza vaccine and MF59 adjuvant with the seasonal influenza vaccine mostly. Further experience with new adjuvant and antigen combinations will provide further reassurance that our findings can be extrapolated across all combinations. A number of Good Clinical Practice concerns have been raised for the pivotal Phase III MF59 Trial carried out in Finland and Germany included in this review [46,52]. A sensitivity analysis in which this large trial was excluded from the analysis did not affect the conclusions of our analyses. A significant higher rate of meningitis was observed for the RTS,S/AS01-adjuvanted vaccine. The authors could not find an obvious explanation for the association: a temporal relationship was lacking, the biological plausibility was low and a causal relationship could not be confirmed nor excluded [25]. The recently published final results, including the safety data of the booster vaccine, have confirmed the significant imbalance in the incidence of meningitis
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in the 5–17 months age group, but not among the infants. Postregistration studies are planned to establish the significance of the finding [53]. Only clinical trials were included in this review, which limits the assessment to the safety in healthy children. It remains unknown whether the results can be generalized to other, more vulnerable populations. Post-marketing surveillance revealed a number of signals for AS03-adjuvanted vaccines, including febrile seizures and seizures in epilepsy. An increased risk of narcolepsy in children under 18 years of age has also been reported, and assessments are ongoing to confirm the causal mechanism [54–57]. Post-marketing analysis showed that reporting rates of AEs for the pandemic MF59-adjuvanted vaccine were about 20% higher than for the seasonal vaccine, but consistent with the safety profile found during clinical trials [58]. Available but limited observations did not show an increased risk of narcolepsy with MF59-adjuvanted pandemic vaccines [59]. The AS01/AS02 and MF59-adjuvanted seasonal influenza vaccine have not been licensed in children, therefore post-marketing surveillance data are not available. 4.3. Conclusions This meta-analysis – the first one carried-out for all newly adjuvanted vaccines in children – showed no overall increase in SAEs, fatalities, or unsolicited AEs following the administration of newly adjuvanted vaccines. Higher rates for some local or general AEs were observed for all newly adjuvanted vaccines, but were mostly mild and transient. The most consistently increased solicited AE is pain at injection site. A number of safety signals observed in clinical trials such as meningitis are still under evaluation. Authors’ contributions TV and JS conceived and designed the study, JS and MB performed the literature review, KB performed the meta-analyses, JS drafted the manuscript, all authors revised it, and approved the final version to be submitted. Conflict of interest statement TV and KB have received consulting fees from GSK and Novartis, unrelated to this review. The other authors declare no conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2015.12. 024. References [1] Garcon N, Van Mechelen M. Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Rev Vaccines 2011;10(4):471–86. [2] Alving CR, Rao M, Steers NJ, Matyas GR, Mayorov AV. Liposomes containing lipid A: an effective, safe, generic adjuvant system for synthetic vaccines. Expert Rev Vaccines 2012;11(6):733–44. [3] Fox CB, Haensler J. An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants. Expert Rev Vaccines 2013;12(7):747–58. [4] World Health Organization. Pandemic influenza A (H1N1) 2009 virus vaccine – conclusions and recommendations from the october 2009 meeting of the immunization Strategic Advisory Group of experts. Wkly Epidemiol Rec 2009;84(49):505–16. [5] Pellegrini M, Nicolay U, Lindert K, Groth N, Della Cioppa G. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine 2009;27(49):6959–65. [6] Vekemans J, Guerra Y, Lievens M, Benns S, Lapierre D, Leach A, et al. Pooled analysis of safety data from pediatric Phase II RTS,S/AS malaria candidate vaccine trials. Hum Vaccines 2011;7(12):1309–16.
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Please cite this article in press as: Stassijns J, et al. A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.12.024