Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis

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Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis Manish M. Patel ⇑, William Davis, Lauren Beacham, Sarah Spencer, Angela P. Campbell, Kathryn Lafond, Melissa Rolfes, Min Z. Levine, Eduardo Azziz-Baumgartner, Mark G. Thompson, Alicia M. Fry Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

a r t i c l e

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Article history: Received 26 June 2019 Received in revised form 11 September 2019 Accepted 18 October 2019 Available online xxxx Keywords: Influenza Inactivated influenza vaccine Adjuvants Children Immunogenicity

a b s t r a c t Background: Identifying optimal priming strategies for children <2 years could substantially improve the public health benefits of influenza vaccines. Adjuvanted seasonal influenza vaccines were designed to promote a better immune response among young vaccine-naïve children. Methods: We systematically reviewed randomized trials to assess hemagglutination inhibition (HAI) antibody response to MF59-adjuvanted inactivated influenza vaccine (aIIV) versus nonadjuvanted IIV among children. We estimated pooled ratios of post-vaccination HAI geometric mean titer (GMT) for aIIV versus IIV and confidence intervals (CIs) using the pooled variances derived from reported CIs. Results: Mean age was 28 months (range, 6–72 months). Children received vaccines with either 7.5 lg (6–35 months) or 15 lg (36 months) hemagglutinin of each strain depending on age. Seven of eight trials administered trivalent vaccines and one used quadrivalent vaccine. Pooled post-vaccination GMT ratios against the three influenza vaccine strains were 2.5–3.5 fold higher after 2-dose-aIIV versus 2dose-IIV among children 6–72 months, and point estimates were higher among children 6–35 months compared with older children. When comparing 1-dose-aIIV to 2-dose-IIV doses, pooled GMT ratios were not significantly different against A/H1N1 (1.0; 95% CI: 0.5–1.8; p = 0.90) and A/H3N2 viruses (1.0; 95% CI: 0.7–1.5; p = 0.81) and were significantly lower against B viruses (0.6; 95% CI: 0.4–0.8; p < 0.001) for both age groups. Notably, GMT ratios for vaccine-mismatched heterologous viruses after 2-dose-aIIV compared with 2-dose-IIV were higher against A/H1N1 (2.0; 95% CI: 1.1–3.4), A/H3N2 (2.9; 95% CI: 1.9–4.2), and B-lineage viruses (2.1; 95% CI: 1.8–2.6). Conclusions: Two doses of adjuvanted IIV consistently induced better humoral immune responses against Type A and B influenza viruses compared with nonadjuvanted IIVs in young children, particularly among those 6–35 months. One adjuvanted IIV dose had a similar response to two nonadjuvanted IIV doses against Type A influenza viruses. Longer-term benefits from imprinting and cell-mediated immunity, including trials of clinical efficacy, are gaps that warrant investigation. Published by Elsevier Ltd.

1. Background Children are at high risk for influenza associated morbidity and mortality worldwide and are suspected to be one of the primary drivers of influenza transmission [1–5]. Higher risk of disease and complications are common in young children <2 years [6,7], possibly resulting from a combination of factors such as underdeveloped immune systems [8], waning maternally-derived antibodies [9,10], few prior infections [7,11,12], higher transmission rates [13], extrapulmonary manifestations of infection [14,15], ⇑ Corresponding author at: Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS H24-7, Atlanta, GA 30329, USA. E-mail address: [email protected] (M.M. Patel).

and possibly ongoing alveolarization and changing physiology of lungs during childhood [16,17]. Vaccinating children against influenza is a priority for mitigating the high risk of disease in children 6 months through 5 years [18–20], though infants <6 months are at the highest risk of influenza-related complications [14]. Because studies of nonadjuvanted inactivated influenza vaccines (IIVs) suggest that vaccination at an early age requires two doses in order to provide optimal protection [21–31], the United States Advisory Committee on Immunization Practices (ACIP) recommends that previously unvaccinated children aged 6 months to 8 years receive two priming doses of influenza vaccine, including doses received in non-consecutive seasons [19]. The World Health Organization has adopted similar recommendations for countries initiating or expanding programs for seasonal influenza vaccination. For many

https://doi.org/10.1016/j.vaccine.2019.10.053 0264-410X/Published by Elsevier Ltd.

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

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children living in countries with vaccination programs that target young children, vaccine viruses are likely to be their first exposure to influenza viruses. The immune system’s prime or first exposure to influenza imparts an ‘‘imprint” or establishes a pattern of immune response to subsequent exposures [32–34]. Thus, the possibility also exists that priming children through vaccination may not only protect children from influenza illness in the short-term but may also potentially provide longer-term protection, through immune imprinting, against homologous and some heterologous viruses in subsequent years. Therefore, identifying optimal interventions for priming the immune response could substantially improve the public health benefits of influenza vaccines globally. Studies have suggested that live attenuated influenza vaccine (LAIV) and adjuvanted vaccines may rapidly induce strong and long-lasting memory T- and B-cell responses, thus expanding the breadth of immunity to drifted viruses and providing immunity mimicking natural infection [35–40]. Some evidence also indicates that a second booster dose may not be necessary for vaccine naïve children receiving LAIV as their first vaccine [22,41], however this may be specific to protection against A/H3N2 and not A/H1N1 or B viruses [42,43]. Moreover, LAIV is only licensed for children 2 years and older and many children in the United States will already have received their first vaccine dose before the age of 2 years. In recent years, studies of a subunit IIV containing MF59, an oilin-water emulsion adjuvant, have demonstrated safety, immunogenicity, and efficacy in children [44–54]. MF59 contains squalene oil, a biodegradable and biocompatible adjuvant that was first approved for human use among older adults in 1997. Trivalent MF59 adjuvanted IIV (aIIV; Fluad, Sequirus) is licensed for use in the United States among adults 65 years, but is not currently licensed for use in children or other age groups [19]. Adjuvanted trivalent IIV is licensed for use among children 6–23 months in Canada but is recommended along with other unadjuvanted trivalent IIVs only if quadrivalent IIV is unavailable [55]. A recent RCT has evaluated a quadrivalent aIIV in children 6 months–5 years [53], but to our knowledge, no country has licensed or is using adjuvanted quadrivalent IIV in children. To explore potential benefits of adjuvanted influenza vaccines, we conducted a systematic review of randomized clinical trials to compare humoral immune response results as measured by hemagglutination inhibition (HAI) titers after aIIV compared with nonadjuvanted IIV in young children. Our primary objectives were to summarize the evidence comparing influenza subtype and lineage-specific HAI antibody immune responses to two doses of aIIV compared with two doses of IIV in young children. Secondary objectives included assessing HAI responses to one dose of aIIV compared with two doses of IIV, possible differences in HAI responses to homologous vaccine viruses by age, examining the HAI effects to heterologous viruses that were antigenically distinct from the vaccine viruses, and describing the duration of elevated antibody titers. 2. Methods We followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for this systematic review and registered the protocol in the International Prospective Register of Systematic Reviews (PROSPERO CRD42019127152). 2.1. Search methods We systematically searched MEDLINE, EMBASE, CINAHL, Scopus, and the Cochrane Library Center Register of Controlled Trials

to identify articles published between 1 January 1997 (the year when adjuvanted vaccine, FluadÒ (Seqirus) was first licensed in elderly) and 28 February 2019 [Supplement: Additional search methods]. The search used combinations of key terms including: (MF59 OR squalene OR Fluad OR ‘‘MF-59”) AND influenza AND (child* OR infants) NOT (exp/animals NOT exp/humans). We also evaluated reference lists of eligible articles to identify additional published studies. No language limits were applied. One reviewer (SS) screened title and abstracts of all articles for potential inclusion. Two reviewers (SS and WD) assessed all papers determined to be potentially eligible for inclusion. 2.2. Study selection We included randomized controlled trials of studies that assessed immunogenicity of aIIV compared with a comparator nonadjuvanted IIV among children 8 years. We excluded animal studies, studies exclusively of persons aged 9 years and older, studies restricted to special populations (e.g., immunosuppressed patients), duplicate reports, interim reports superseded by a final report, extension studies of repeat vaccination in a subsequent season after initial priming, and dose-response studies. 2.3. Data extraction Two independent reviewers (MP and WD) extracted data from selected articles on eligibility criteria, study characteristics, age, timing of blood draw, pre and post-vaccination HAI antibody geometric mean titers (GMTs), and additional measures of immunogenicity (Supplement: Data extraction and management). Reviewers were not blinded to study authors, affiliations, or journal name. 2.3.1. Study quality assessment Two authors (MP and WD) assessed risk of bias in randomized trials using the seven recommend domains in the Cochrane Risk of Bias Tool (Supplement: Risk of bias) [56]. We recorded each domain as low, high, or unclear risk of bias, with specific emphasis on identifying factors that could potentially affect immunogenicity outcomes. We also documented the laboratory immunoassays used to measure the HAI antibody response in each clinical trial (Supplement Table 1). 2.3.2. Data analysis Following the approach taken by Ng et al. [57], our primary comparisons of interest were ratios of post-vaccination GMTs after two doses of aIIV versus two doses of IIV and after one dose of aIIV versus two doses of IIV, by influenza virus subtype and lineage. When reported, we also assessed HAI response to heterologous influenza viruses, duration of immune response after vaccination, and HAI response stratified by age at vaccination. We estimated ratios of post-vaccination GMTs and confidence intervals (CIs) for aIIV compared with IIV. When these were not reported, log2 ratios of GMTs were estimated as log2 postvaccination GMTs after aIIV divided by log2 post vaccination GMT after IIV. Variances for both vaccines were estimated from reported confidence intervals assuming a t-distribution and critical value of 1.96. We then calculated a pooled variance and confidence interval for the ratio of post-vaccination GMTs using the pooled variance equation [58]. Pooled estimates of ratios of post-vaccination GMTs after aIIV versus IIV and 95% confidence intervals were computed using a mixed linear model on aggregate study endpoints with inverse variance weighting to minimize the variance of the weighted

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

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average. The model used log2 of the post-vaccination GMTs as independent effects and study as a random effect. The I2 statistic was used to assess heterogeneity in outcomes between studies and deemed to be low if <25% and high if >75% [59]. We assessed for effect modification of ratios of post-vaccination GMTs by age, considering p-value < 0.15 as statistically significant which is in line with guidance for interpreting interactions between two dichotomous variables when effect size is expected to be moderate to high [60,61]. We conducted a sensitivity analysis by excluding trials that had domains identified by the Cochrane Risk of Bias Tool with high risk of bias in any of the seven domains that could potentially affect immunogenicity outcomes. Statistical analysis was conducted using R software version 3.4.1.

3. Results We identified 26 full-text peer-reviewed articles (Supplement Fig. 1). From these, we identified eight studies that provided data for one or more immunogenicity outcomes of interest. We excluded three trials of aIIV immunogenicity in children either because they were extension studies of trials already included [45,49] or were designed to evaluate dosing of adjuvant content [47]. Other reasons for exclusion included age >8 years (n = 3), evaluation of monovalent IIV (n = 4), lack of a serologic outcome (n = 2), or restriction of study to special populations (n = 6). Based on the risk of bias assessment, we identified high bias for three domains (performance, attrition, and other) in one study, where bias in the ‘‘other” domain was due to published reports that their immunogenicity outcomes may have been biased due to violations of Good Clinical Practice and use of a comparator IIV that was immunologically inferior to other available IIVs [48,62,63]. Results from this one study were excluded in sensitivity analyses. Three other studies reported bias in one domain (reporting), but these were not deemed to affect immunogenicity outcomes (Supplement Figs. 2, 3).

3.1. Study demographics We identified eight studies conducted in multiple locations between 2006 and 2015 that assessed immune response to aIIV versus a comparator IIV (Table 1). Study size ranged widely within the aIIV (total N = 2858; range 25–1362) and the IIV groups (total N = 2918; range 30–1307). Age of all enrolled children ranged from 6 to 72 months, with six studies providing HAI antibody results by two age subgroups. The youngest group of children aged 6–35 months includes results from studies reporting results for children either age 6–23 (n = 2) or 6–35 (n = 4) months. The other age group starts at either 24 or 36 months and goes up to ages 60 or 72 months (hereafter referred to as > 24–36 months). The mean age for aIIV and IIV groups was 28 months and all trials restricted enrollment to healthy children. Trivalent aIIV and IIV were administered in seven studies while one recent study used quadrivalent vaccines. All studies used 7.5 lg HA per strain among children aged 6–35 months (i.e., half dose or 0.25 mL) and 15 lg HA per strain (i.e., 0.5 mL dose) among children aged > 36 months for both aIIV and IIV. HAI antibody titers were measured in all studies as the primary endpoint of immunogenicity evaluation. The vast majority of the enrolled children were vaccine naïve (i.e., no prior influenza vaccination by parental report), constituting > 90% in 6 of 8 studies and > 50% in the other two studies (Supplement: Study characteristics) [44,46,48,50–52].

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3.2. Heterogeneity in antibody response In all of the primary analyses comparing 1 and 2-dose aIIV to 2dose IIV, we observed a high degree of heterogeneity (I2 > 75%; P < 0.001) for ratios of post-vaccination GMTs (Figs. 1–3) for A and B viruses. 3.3. Antibody response after two doses of aIIV or IIV Among seven studies that reported post-vaccination GMTs after two doses of aIIV and two doses of IIV in children 6–72 months, pooled ratios after aIIV were higher for A/H1N1 (2.8; 95% CI: 1.8–4.4), A/H3N2 (2.5; 95% CI: 1.7–3.81), and B vaccine viruses (3.5; 95% CI: 2.8–4.5) (Fig. 1). These results were similar when we conducted a sensitivity analysis in which we excluded one study with biases potentially impacting HAI antibody responses (Fig. 2) [48]. The magnitude of antibody response by other measures (seroconversion, seroprotection, and mean fold rise) was also consistently greater after 2-dose-aIIV than after 2-dose-IIV against all three influenza vaccine viruses in all eight studies identified (Table 2). Seven of eight trials reported both post-vaccination GMTs and seroconversion and each of these trials individually met FDA criteria for non-inferiority (Supplement: Data Extraction and Management) of 2-dose-aIIV compared with 2-dose-IIV for all three vaccine viruses (Fig. 1; Table 2). One small study reported mean fold rise in GMTs post-vaccination compared to pre-vaccination but did not report actual HAI titers post-vaccination. Thus we were unable to estimate ratio of post-vaccination GMTs for aIIV compared with IIV [51]. 3.4. Antibody response after one dose of aIIV versus two doses of IIV One dose of aIIV provided an antibody response that was comparable to two doses of IIV against A viruses but not B viruses among six studies that measured these HAI antibody response in children 6–72 months. The pooled ratio of post-vaccination GMTs for 1-dose-aIIV compared to 2-dose-IIV were not significantly different against A/H1N1 (1.0; 95% CI: 0.5–1.8; P = 0.90) and A/ H3N2 viruses (1.0; 95% CI: 0.7–1.5; P = 0.81), but were significantly lower against B viruses (0.6; 95% CI: 0.4–0.8; P < 0.001)) (Fig. 3). These results were similar when we excluded one study with potential biases (Supplemental Fig. 4). When comparing seroprotection and seroconversion after 1-dose-aIIV compared with 2dose-IIV, they were also generally similar against A/H1N1 and A/ H3N2, but were lower against B virus (Supplement Table 2). Of note, absolute GMTs against B virus were substantially lower than A/H1N1 and A/H3N2 after both aIIV and IIV. 3.5. Antibody response after one dose of aIIV versus one dose of IIV Among six studies, pooled ratio of post-vaccination-GMT after 1-dose-aIIV compared with 1-dose-IIV was higher for A/H1N1 (3.3; 95% CI: 1.9–5.6), A/H3N2 (2.6; 95% CI: 1.8–3.8), and B viruses (1.8; 95% CI: 1.5–2.1) in children 6–72 months (Supplement Fig. 5). The pooled ratios were similar when we excluded one study with potential biases (Supplemental Fig. 6). The magnitude of antibody response by other measures after 1-dose-aIIV trended higher compared with 1-dose-IIV against A/H1N1, A/H3N2, and B lineage viruses (Supplement Table 3). 3.6. Antibody response against heterologous viruses after two doses of aIIV or IIV Seven of 8 studies tested HAI response against at least one virus that study authors reported to be antigenically distinct from the

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

118 122 316 820 30 93 1307 112 2006–2007 2008 2008–2009 2011–2012 2011 2013 2013–2015 2014–2015 Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]8 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53]9 Cruz 2018 [54]

HI denotes hemagglutinin; ug denote micrograms; aIIV denotes MF59 adjuvanted inactivated influenza vacccine; IIV denotes unadjuvanted IIV; WHO denotes World Health Organization; Tri denotes trivalent; Quad denotes quadrivalent; ND denotes not done or group not included in study. 1 Season when the immunogenicity study was done (some studies had broader enrollment periods for efficacy which are not shown). 2 Sanofi Pasteur (split virion). 3 GSK (split virion). 4 Novartis (subunit vaccine). 5 Eight sites in Argentina, five in Australia, two in Chile, 12 in The Philippines, and five in South Africa. 6 Nine countries (Finland, USA, Canada, Italy, Poland, Spain, Philippines, Thailand, Taiwan). 7 Precise data not reported; assumption is majority based on exclusion criteria. 8 Two IIV comparator groups; IIV results are an average of the two comparator IIV groups. 9 Includes naïve (2 doses) and non-naïve (1 dose); for analysis, restricted to only naïve (2 doses) so age range may be different in analysis tables.

ND 2 ND 2 ND ND 1 1 2 2 2 2 2 2 2 2

Northern Northern Northern Southern Northern Northern Northern Northern Non-naïve Naïve

100 majority7 100 94–99 100 100 67 54 IIV

– 15 15 15 – 15 15 15 – 15 15 15 – 15 15 15

aIIV IIV

7.5 7.5 7.5 7.5 7.5 15 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

aIIV IIV

Tri Tri Tri Tri Tri Tri Both Tri Tri Tri Tri Tri Tri Tri Quad Tri

aIIV

Vaxigrip2 Fluzone2 Influsplit3 Agriflu4& Fluzone2 Aggripal4 Vaxigrip2 Fluzone2 Fluzone2 IIV

104 120 319 715 25 99 1362 114

Season1

N

aIIV

Location

Finland Guatemala Finland Multiple5 Belgium Senegal Multiple6 Mexico

Age range

6m-36m 6m-60m 6m-72m 6m-72m 6m-36m 6m-72m 6m-60m 6m-72m

21 22 32 37 20 27 36 30

Mean age (mos)

Comparator vaccine

# of antigens (Tri, Quad, Both)

HA content (ug, <36 mos age)

HA content (ug,>36 mos age)

% Vaccine naïve

# priming doses

WHO vaccine formulation

(2006–2007] (2007–2008) (2008–2009) (2011) (2010–2011) (2012–2013) (2013–2014 & 2014–2015) (2014–2015)

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Reference (#)

Table 1 Study descriptors for immunogenicity clinical trials comparing adjuvanted inactivated influenza vaccines (IIVs) with nonajuvanted IIVs among children (ordered by season when study was conducted).

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vaccine virus (Table 3). Antibody titers in children 6–72 months were consistently greater against these heterologous viruses after 2-dose-aIIV compared with 2-dose-IIV, with pooled ratios of post-vaccination GMTs 2.0- to 2.9-fold higher against A/H1N1 (2.0; 95% CI: 1.1–3.4), A/H3N2 (2.9; 95% CI: 1.9–4.2), and B lineage viruses (2.1; 95% CI: 1.8–2.6). 3.7. Duration of immune response after two doses of aIIV or IIV The difference in HAI antibody titers after 2-dose-aIIV compared with 2-dose-IIV persisted at 6 months. In two studies that assessed immune response at 180 days after receipt of the second dose of vaccine, ratios of post-vaccination GMTs comparing 2dose-aIIV to 2-dose-IIV remained significantly higher in both studies against A/H1N1 (GMT ratios = 2.7 and 4.3), A/H3N2 (GMT ratios = 1.8 and 3.1), and B lineage viruses (GMT ratios = 2.1 and 2.5) (Supplement Table 4). 3.8. Antibody response by age at vaccination (after two doses of aIIV or IIV) We explored whether age had an effect of HAI antibody titers and observed higher pooled ratios among children vaccinated before 36 months (Table 4). Pooled ratios of post-vaccination GMTs among recipients of 2-dose-aIIV compared with recipients of 2-dose-IIV were 3.5 to 3.9 fold higher against the three influenza vaccine strains among children vaccinated at 6–36 months for both A viruses [A/H1N1 (3.9; 95% CI: 1.9–8.1), A/H3N2 (3.5; 95% CI: 1.8–6.8), and B vaccine viruses (3.8; 95% CI: 2.3–6.2)] (Table 4; Supplement Table 5). In contrast, among children vaccinated at >24–36 months, the pooled ratios were also significantly >1 but the magnitude of the effects were only 1.6 to 2.1-fold higher [A/H1N1 (2.1; 95% CI: 1.5–3.0), A/H3N2 (1.6; 95% CI: 1.1–2.4), B vaccine viruses (1.9; 95% CI: 1.5–2.6)]. The enhanced HAI antibody response in younger versus older children was statistically significant for A/H1N1 (P = 0.14), A/H3N2 (P = 0.06), and B viruses (P = 0.02). Pooled mean fold rise in HAI antibody titers from baseline were also higher after 2-dose-aIIV compared with 2-dose-IIV for both age groups (Supplement Table 6). Interestingly, the mean fold rise in titers from baseline after IIV in younger and older children was similar for A viruses, but the mean fold rise after aIIV was lower among older versus younger children. The point estimates remained higher in the younger children when we excluded one study with potential biases (Supplement Table 7). In this sensitivity analysis, the ratios of post-vaccination titers after aIIV were higher than IIV (2.5–3.3 fold higher) among children 6–35 months than those > 24–36 months (1.4–1.8 fold higher). The enhanced HAI antibody response in younger versus older children remained statistically significant for A/H1N1 (P = 0.14), A/H3N2 (P = 0.01), and B viruses (P = 0.02). 4. Discussion Our systematic review identified several lines of evidence that an adjuvanted seasonal influenza vaccine may promote improved HAI antibody immune responses in children, most of whom were vaccine naïve. The humoral antibody responses after equivalent number of doses (2 vs 2 and 1 vs 1) were consistently better for adjuvanted than nonadjuvanted vaccines in children 6–72 months. The antibody response to 2-doses of adjuvanted IIV compared with 2 doses of unadjuvanted IIV was better at 6 months after vaccination and also against heterologous viruses that were antigenically different from vaccine viruses [38,40]. These results suggest that adjuvanted vaccines may induce an enhanced antibody response

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

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Fig. 1. Ratios of geometric mean hemagglutinin inhibition (HAI) antibody titers after two doses adjuvanted compared with two doses nonadjuvanted inactivated influenza vaccines among children 6 months to 72 months.1 GMT ratio denotes ratio of post-vaccination geometric mean HAI titers after 2-dose-adjuvanted IIV versus 2-dose-IIV; RE denotes random effects; reference numbers for each study are provided in Table 1. 1: Zedda et al PIDJ 2015 [51] was excluded because the paper reported mean fold rise in GMTs post-vaccination compared to baseline but did not report actual HAI titers post-vaccination. Thus, we were unable to estimate ratio of post-vaccination GMTs for aIIV compared with IIV.

in young children in terms of duration and breadth that is more comparable to natural infection, than nonadjuvanted vaccines. The enhanced antibody response in young children 6–35 months compared with older children in our review was also consistent with the higher relative efficacy of quadrivalent adjuvanted IIV compared with nonadjuvanted IIV among younger children (31%) versus older children ( 15%) in a recently published clinical trial [53]. Thus, adjuvanted vaccines may be advantageous in young children by offering improved protection to this high risk group in the immediate season and possibly longer term advantages in protection against future infections if indeed the immune response is more like imprinting from natural infection. The potential risks and benefits of the use of an adjuvanted vaccine as a first vaccine in young children requires consideration. From the safety perspective, a meta-analysis of clinical trials of MF59-adjvanted vaccines in a total of ~7800 children <10 years, including six studies that involved ~4900 children 6–24 months,

did not identify any increase in serious or unsolicited adverse events, or any increase in fatalities [64]. Children receiving MF59 adjuvanted vaccines had higher rates of mild-moderate and transient solicited adverse events indicative of reactogenicity (local pain, redness, fever, irritability, and loss of appetite). Based on these reassuring safety and immunogenicity data, trivalent MF59 adjuvanted IIV has been licensed for use among children 6–23 months in Canada, though no data exist on routine use of the vaccine in pediatric populations [55,65]. To our knowledge, no other country at this time has licensed or is using aIIV in children and no post-marketing data have been published from use of this vaccine in children. In terms of potential benefits, the broadened immune response to adjuvanted vaccines may more closely mimic natural infection and have benefits years after vaccination [51,66–68]. However, clinical trials have not assessed whether immune responses would continue to offer protection years after priming. We observed

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

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Fig. 2. Sensitivity analysis for ratios of hemagglutinin inhibition (HAI) antibody titers after two doses adjuvanted IIV compared with two doses of nonadjuvanted IIV among children 6 months to 72 months, excluding one trial1 with potential bias that may have affected HAI titers. HAI denotes hemagglutinin inhibition antibodies; IIV denotes inactivated influenza vacccine; IIV denotes nonadjuvanted IIV; GMT ratio denotes ratio of post-vaccination geometric mean HAI titers after 2-dose-adjuvanted IIV versus 2dose-IIV; RE denotes random effects; reference numbers for each study are provided in Table 1. 1: Excludes Vesikari 2011 [48] because of potential concerns raised by EMA about Good Clinical Practice violations and potential use of comparator vaccine with inferior immune responses to other nonadjuvanted IIVs [62,63].

consistently higher humoral responses after adjuvanted IIV compared with nonadjuvanted IIV in all trials and relative benefits were highest in children 6–35 months. Interestingly, the mean fold rise in GMTs from baseline for influenza A viruses were lower after 2 doses of adjuvanted IIV in older children compared to younger children. In contrast, the mean fold rise in GMTs was similar after IIV, which could support the notion that higher relative benefits of adjuvanted vaccines in younger children reflects a better response to adjuvants rather than an inferior response to unadjuvanted IIV. Because risk of severe influenza is high in young children and vaccination might be their first exposure to influenza viruses, if the immunologic benefits translate to clinical efficacy, adjuvanted vaccines might be an attractive option in this age group. However, adjuvanted vaccines may not offer a clear advantage in older children, because of the availability of other vaccine types (eg, LAIV, cell-based IIV) and lesser relative benefits of adjuvnated vaccine in older versus younger children. While adjuvanted IIV improved antibody immune response, higher HAI titers may not correlate with clinical protection especially among children where higher titers are needed to achieve

protection compared with adults [69]. Two of the studies included in our analysis also assessed vaccine efficacy. An initial trial conducted during 2006–2007 demonstrated superior relative vaccine efficacy among children 6–72 months vaccinated with adjuvanted vaccine compared with unadjuvated vaccine in Finland and Germany [48]. However, a subsequent multi-country efficacy study among children 6–60 months from 11 countries, predominantly from Thailand, Philippines, and the US, demonstrated no overall increase in efficacy [53]. Post-hoc analysis that restricted the analysis to younger children demonstrated higher relative efficacy, including reducing influenza risk between the first and second dose of adjuvanted vaccine. The higher antibody responses in our analysis among younger children were consistent with these efficacy data. To effectively control influenza infections in children, the logistics of vaccine delivery needs to be considered, especially the practicalities of getting children vaccinated with two doses in their first influenza season. The notable finding of significantly better HAI antibody response to one dose of adjuvanted vaccine versus one dose of standard vaccine against all three influenza vaccine viruses

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

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7

Fig. 3. Ratios of geometric mean hemagglutinin inhibition (HAI) antibody titers after one dose adjuvanted compared with two doses nonadjuvanted inactivated influenza vaccines among children 6 months to 72 months. GMT ratio denotes ratio of post-vaccination geometric mean HAI titers after 1-dose-adjuvanted IIV versus 2-dose-IIV; RE denotes random effects; reference numbers for each study are provided in Table 1.

(1.8–3.3 fold increase) may be of public health interest because children may only receive one dose in routine practice despite policy recommendations for two doses. Experience with prime-boost pandemic vaccines also indicates that a priming dose of adjuvanted vaccines provides an expanded breadth of immune response even when priming is followed with a booster dose of nonadjuvanted IIV [70]. Thus, priming with adjuvanted seasonal IIV followed by a nonadjuvanted IIV in the same or even non-consecutive seasons may be a strategy that could be cost-effective and worth further exploration. Interestingly, two doses of standard IIV were required for children to achieve similar antibody response against A/H1N1 and A/H3N2 viruses compared to one dose of adjuvanted vaccine. However, this was not the case for B vaccine viruses where one dose of aIIV provided a lower antibody response than two doses of IIV. The timing of the blood draw between the 1-dose-aIIV (21 days post baseline) and the 2-dose-IIV group (50 days post baseline) was different and thus the lower antibody response to B viruses after 1 dose could be explained by the lesser duration of exposure to circulating viruses compared to the 2 dose group. The difference in HAI titers for B viruses could also possibly reflect a true effect whereby two doses of either nonadjuvanted or adjuvanted IIV may be necessary for mounting sufficient antibody response against B viruses. None of the studies were designed to assess the effect of one dose of vaccine, and thus all of these findings may be related to lack of power. Both adjuvanted and

nonadjuvanted groups received similar HA content and most vaccines were trivalent IIV, however children 6–35 months received aIIV and IIV with half the HA content. Quadrivalent nonadjuvanted IIVs with full HA content are now also licensed for children 6–35 months and could improve the lower antibody response to B-viruses [71]. Full dose quadrivalent adjuvanted IIVs are not currently available and have not been assessed in young children. Comparison of a half and a full dose of adjuvanted IIV with a full dose of unadjuvanted IIV, and a better understanding of 1 dose of aIIV versus 2 doses of IIV, could help to identify strategies for improving the efficacy of influenza vaccines in children. Recurrent influenza infections among individuals are common largely because influenza viruses evade immunity by ‘‘drifting” or acquiring mutations in the exposed epitopes of hemagglutinin surface glycoprotein [72]. In our review, adjuvanted vaccines provided higher HAI antibody immune response to heterologous influenza viruses in children, suggesting that protection from adjuvanted vaccines in children might be better against drifted viruses within the immediate or subsequent season. Some studies suggest that MF59 may enhance priming of adaptive immune responses and expand the breadth of immunity to drifted viruses [37,39]. Adjuvants may also qualitatively and quantitatively improve functional antibody responses to influenza [37,38]. MF59 has been demonstrated to increase antigen uptake, macrophage recruitment, B-cell migration to lymph nodes, and avidity of antibody binding

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

8

% Seroconversion2

HAI GMTs

A/H1N1 Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]1 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53] Cruz 2018 [54] A/H3N2 Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]1 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53] Cruz 2018 [54] B lineage4 Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]1 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53]5 Cruz 2018 [54]

aIIV

(95% CI)

195 1639 735 1507 322 1065 675 507 2134 762 1920 1032 1275 1280 105 198 109 488 460 225 76

IIV

% Seroprotection3

(95% CI)

aIIV

(95% CI)

IIV

(95% CI)

aIIV

(95% CI)

(159, 240) 92 (1361, 1975) 1397 (608, 888) 89 (1358, 1673) 555 Not reported (230, 450) 125 (916, 1239) 555 (536, 849) 166

(76, 111) (1161, 1682) (74, 108) (502, 614)

100 98 100 93 100 98 86 90

(97, (94, (99, (90, (86, (85, (83, (83,

86 98 59 81 73 89 80 75

(79, (93, (53, (79, (54, (74, (76, (66,

92) 99) 64) 84) 88) 97) 82) 83)

100 100 100 99 100 100

(97, (97, (99, (98, (86, (88,

(412, 623) 195 (1773, 2568) 1029 (634, 915) 95 (1799, 2050) 912 Not reported (750, 1430) 706 (1109, 1467) 720 (1077, 1521) 495

(160, 237) (856, 1238) (79, 115) (856, 971)

100 97 97 97 100 93 81 77

(97, 100) (92, 99) (95, 99) (95, 98) (86, 100) (79, 99) 78, 84) (68, 85)

99 90 63 91 100 96 79 67

(95, (83, (57, (89, (86, (83, (76, (57,

(88, 127) 20 (159, 248) 67 (97, 123) 22 (447, 532) 163 Not reported (361, 587) 197 (189, 268) 87 (61, 93) 16

(17, 24) (54, 84) (19, 25) (150, 177)

99 95 93 98 100 93 87 78

(95, (89, (89, (96, (86, (79, (85, (69,

33 75 38 86 100 73 65 22

(25, (67, (32, (83, (86, (55, (61, (15,

(88, 178) (476, 644) (132, 208)

(494, 1014) (626, 829) (417, 588)

(133, 294) (73, 104) (13, 20)

100) 100) 100) 94) 100) 100) 88) 95)

100) 98) 95) 99) 100) 98) 90) 85)

MFR compared to baseline (95% CI)

aIIV

(95% CI)

(79, (97, (54, (87, (78, (74,

33 108 76 58 41 29

(28, (82, (67, (51, (23, (22,

99

100) 86 100) 100 100) 59 100) 90 100) 93 100) 89 Not reported (95, 100) 88

(81, 94)

46

100) 95) 68) 93) 100) 99) 82) 76)

100 100 99 100 93 100

(97, (97, (97, (99, (78, (89,

(95, (97, (60, (99, (83, (87,

61 57 60 48 199 20

100

100) 99 100) 100 100) 65 100) 99 99) 97 100) 99 Not reported (97, 100) 97

(92, 99)

42) 83) 43) 88) 100) 87) 68) 31)

99 95 93 99 53 100

(95, (89, (89, (98, (34, (89,

(25, (67, (33, (86, (37, (78,

84

IIV

100) 33 98) 75 95) 38 100) 88 72) 57 100) 92 Not reported (76, 90) 32

IIV

(95% CI)

38) 14 144) 57 86) 9 67) 27 74) 10 38) 14 Not reported (34, 62) 11

(12, 17) (41, 80) (7.9, 10) (24, 31) (5.9, 17) (10, 18)

(18, 27) (21, 41) (6.9, 9.3) (21, 25) (24, 51) (10, 21)

21

(50, 75) 22 (41, 80) 29 (52, 59) 8.0 (43, 54) 23 (130, 303) 35 (13, 32) 15 Not reported (16, 28) 8.4

42) 83) 44) 90) 75) 98)

19 34 17 49 34 24

(16, (27, (15, (45, (22, (16,

(3.4, 4.6) (9.1, 14) (3.0, 3.6) (15, 18) (3.8, 8.3) (5, 15)

(24, 42)

10

92) 100) 65) 92) 99) 96)

100) 100) 71) 100) 100) 100)

23) 4.0 42) 11 19) 3.3 54) 17 52) 5.6 36) 9 Not reported (8.3, 13) 2.3

(8.1, 15)

(6.7, 11)

(1.8, 2.3)

HAI denotes hemagglutinin inhibition antibodies; aIIV denotes MF59 adjuvanted inactivated influenza vaccine; IIV denotes nonadjuvanted IIV; GMTs denote geometric mean titers; MFR denotes mean fold rise of GMTs after dose 2 compared to baseline GMT; NR denotes not reported. 1 Study used two nonadjuvanted IIVs; presented average of the two vaccines. 2 Seroconversion defined as a change in prevaccination HI titer of <1:10 to postvaccination HI titer 1:40 or 4-fold or greater increase in HI titer in a subject with a prevaccination titer 1:10. 3 Seroprotection defined as the proportion of subjects achieving an HI titer 1:40 postvaccination. 4 B-lineage was Yamagata or Victoria depending on the WHO recommended strain in the trivalent vaccine during the season when the study was conducted (Table 1). 5 Only study to have adjuvanted quadrivalent and nonadjuvanted quadrivalent in addition to nonadjuvanted trivalent IIV. For comparison with other vaccines, data in this table only depicts the trivalent B-lineage included in the vaccine.

M.M. Patel et al. / Vaccine xxx (xxxx) xxx

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

Table 2 Comparison of hemagglutinin inhibition (HAI) antibody responses after dose 2 for adjuvanted IIV vs nonadjuvanted IIV by influenza subtype and lineage.

9

M.M. Patel et al. / Vaccine xxx (xxxx) xxx

Table 3 Summary of hemagglutinin inhibition (HAI) antibody responses against viruses heterologous to vaccine viruses after 2 doses of adjuvanted IIV (inactivated influenza vaccine) versus nonadjuvanted IIV. N

A/H1N1 Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]1 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53]2 Pooled results (H1N1) A/H3N2 Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]1 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53]2 Pooled results (H3N2) B lineage Vesikari 2009 [44] Solares 2014 [46] Vesikari 2011 [48] Nolan 2014 [50]1 Zedda 2015 [51] Diallo 2018 [52] Vesikari 2018 [53]2 Pooled results (B)

Heterologous virus

aIIV

IIV

104 120 319 380

118 120 316 438

295

HAI GMTs aIIV

(95% CI)

Solomon Islands/3/2006 Brisbane/59/2007 Solomon Islands/3/2006 New Jersey/8/1976

55 399 228 51

291

Brisbane/59/2007

7.5

104 120 319 715 25

118 120 316 820–822 30

New York/55/2004 Brisbane/10/2007 Wisconsin/15/2009 Uruguay/716/2007 Uruguay/716/2007

106 466 518 184 19

292

290

HongKong/4801/2014

104 120 319 715 25 99 295

118 120 316 820–822 30 93 292

Jiangsu/10/2003 Florida/4/2006 Brisbane/60/2008 Malaysia/2506/2004 Malaysia/2506/2004 Brisbane/60/2008 Phuket/3073/2013

IIV

2-dose-aIIV vs. 2dose-IIV (95% CI)

GMR

(95% CI)

(41, 72) 26 (309, 515) 294 (182, 287) 41 (45, 58) 30 Not done Not done Not reported 6.5

(20, 34) (227, 379) (33, 51) (27, 35)

2.1 1.4 5.6 1.7

(1.6, (1.1, (4.5, (1.5,

Not reported

1.1 2.0

(1.1, 1.2) (1.1, 3.4)

(31, 53) (135, 246) (57, 87) (71, 89) (5.2–11)

2.6 2.6 7.4 2.3 2.5

(2.0, (1.9, (6.0, (2.1, (1.7,

577

(80, 141) 41 (345, 629) 182 (420, 639) 70 (165, 206) 80 (13–30) 7.6 Not done Not reported 298

Not reported

1.9 2.9

(1.6, 2.3) (1.9, 4.2)

11 57 12 99 41 43 146

(10, 12) (47, 68) (11, 13) (89, 111) (26–63) (28, 65) Not reported

(5.4, 6.8) (24, 34) (6.2, 7.2) (31, 39) (7.6–16) (18, 41) Not reported

1.8 2.0 1.8 2.8 3.7 1.6 2.2 2.1

(1.6, 2.0) (1.6, 2.4) (1.7, 1.9) (2.5, 3.2) (2.4, 5.8) (1.1, 2.4) (1.8, 2.6) (1.8, 2.6)

6.1 29 6.7 35 11 27 67

2.8) 1.8) 6.9) 1.9)

3.4) 3.5) 9.1) 2.6) 3.7)

HAI denotes hemagglutinin inhibition antibodies; aIIV denotes MF59 adjuvanted inactivated influenza vaccine; IIV denotes nonadjuvanted IIV; GMT denotes post-vaccination (50 days after baseline for dose 2) geometric mean HAI titers ; GMR denotes ratio of postvaccination GMTs after aIIV versus IIV. 3: Cruz et al. (54) did not conduct HAI testing against heterologous viruses and thus not included in this table. 1 Study used two nonadjuvanted IIVs with nearly equal sample size; presented average of the two vaccines. 2 Only study to have adjuvanted quadrivalent and nonadjuvanted quadrivalent in addition to nonadjuvanted trivalent IIV. For comparison with other vaccines, data in this table only depicts the trivalent B-lineage included in the vaccine.

to the hemagglutinin globular head of influenza viruses [37,73–75]. It should be noted that the clinical trials in our review only assessed HAI antibody responses and did not assess whether immune responses would continue to offer protection years after priming. These data should be interpreted in the context of several caveats. We focused on HAI data, and none of these studies assessed efficacy of one dose versus two doses of vaccine. Improved HAI antibody responses may not be predictive of clinical efficacy or effectiveness. While the differences in antibody responses were consistently in favor of adjuvanted vaccines, we also observed marked heterogeneity in titers across trials. This variation may reflect setting and seasonal differences or influenza virus exposure history. Possible differences in performance of antibody assays may also account for heterogeneity [76,77]. Influenza A/H3N2 viruses may be specifically affected because viruses during the recent influenza seasons had reduced ability to agglutinate red blood cells [78]. Modern A/H3N2 viruses may also be difficult to characterize by HAI related to neuraminidase-dependent agglutination thus requiring neuraminidase inhibition through the addition of oseltamivir carboxylate to the HAI assay protocols [78]. Further, ether treatment of influenza B antigen is often used for the detection of antibodies in human sera but may not have been used in these studies [79]. HI assays using antigens without ether treatment may suffer from lower sensitivity and lower detected titers. Only one study specified that the B viruses were not ethertreated [48]. Others did not report assay details thus making it difficult to assess the validity of these results. Nonetheless, we expect similarity in assay-related biases for adjuvanted and unadjuvanated groups and thus a lower likelihood that differences in

laboratory methods resulted in better pooled antibody responses after adjuvanted vaccine than nonadjuvanted vaccine. Trials also largely used trivalent vaccines with similar antigenic content and formulations for both adjuvanted and nonadjuvanted vaccines. Lastly, differences in the comparator vaccine may also have affected the results [62]. Oversight, design, and financial support for these trials was provided by the manufacturer of adjuvanted IIV. Reasons prompting study investigators to select specific comparator vaccines are unclear from the available literature. Nevertheless, a wide range of comparator vaccines were evaluated across the eight trials thus increasing the likelihood that the overall increased antibody response after aIIV was related to an enhanced effect of aIIV rather than a diminished response to IIV. Our sensitivity analysis based on excluding one study that was deemed to potentially bias the immunogenicity results did not affect our overall interpretation. The higher risk of severe illness from influenza infection and the opportunity for imprinting immune systems to provide broad and durable immune responses provides a compelling reason to identify optimal vaccination strategies in children, especially among those <2 years of age. Our review of the clinical trial immune response data for two types of vaccine products available for young children demonstrates the potential incremental benefit of adjuvanted vaccines compared to nonadjuvanted inactivated vaccines for priming children’s immune system against influenza infection. Two doses of adjuvanted influenza vaccine consistently induced better humoral immune responses against Type A and B influenza viruses compared with nonadjuvanted vaccines in young children. Identifying priming strategies in children <2 years that improve

Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

10

M.M. Patel et al. / Vaccine xxx (xxxx) xxx

Table 4 Comparison and pooled hemagglutinin inhibition (HAI) antibody responses after two doses of adjuvanted IIV (inactivated influenza vaccine) and nonadjuvanted IIV by age group1 and A subtype and B lineage. Age 6–24 months or 6–36 months Age range (mos)

N

Age > 24 or > 36 months

2-dose-aIIV vs. 2dose-IIV

aIIV

IIV

GMR

(95% CI)

6–24 6–24 6–36 6–36 6–36 6–36

266 595 97 166 61 71

387 567 97 165 60 70

4.5 2.3 1.2 14.7 2.6 8.0 3.9

(3.5, 5.7) (2.1, 2.6) (0.9, 1.4) (11.5, 18.7) (1.9, 3.6) (4.6, 14) (1.9, 8.1)

A/H3N2 Nolan 2014 [50] Vesikari 2018 [53] Solares 2014 [46] Vesikari 2011 [48] Diallo 2018 [52] Cruz 2018 [54] Pooled results (H3N2)

6–24 6–24 6–36 6–36 6–36 6–36

266 595 97 166 61 71

387 567 97 165 60 70

3.1 2.1 2.6 15.9 1.4 4.4 3.5

B lineage2 Nolan 2014 [50] Vesikari 2018 [53]3 Solares 2014 [46] Vesikari 2011 [48] Diallo 2018 [52] Cruz 2018 [54] Pooled results (B)

6–24 6–24 6–36 6–36 6–36 6–36

266 595 97 166 61 71

387 567 97 165 60 70

5.4 1.7 3.5 7.2 1.8 6.6 3.8

A/H1N1 Nolan 2014 [50] Vesikari 2018 [53] Solares 2014 [46] Vesikari 2011 [48] Diallo 2018 [52] Cruz 2018 [54] Pooled results (H1N1)

Age range (mos)

N

2-dose-aIIV vs. 2dose-IIV

aIIV

IIV

GMR

(95% CI)

24–72 24–60 36–60 36–72 36–72 36–72

270 327 23 166 38 43

135 299 23 165 33 22

2.4 1.4 1.2 4.2 2.5 1.8 2.1

(2.0, 2.8) (1.2, 1.5) (0.9, 1.6) (3.2, 5.4) (1.8, 3.6) (1.1, 2.8) (1.5, 3.0)

(2.7, 3.6) (1.2, 2.9) (2.1, 3.1) (13.3, 19.1) (1.0, 2.1) (2.8, 7.0) (1.8, 6.8)

24–72 24–60 36–60 36–72 36–72 36–72

270 327 23 166 38 43

135 299 23 165 33 22

1.6 1.3 0.8 3.7 1.6 1.3 1.6

(1.4, 1.8) (1.2, 1.5) (0.5, 1.3) (2.8, 4.9) (1.2, 2.2) (1.0, 1.8) (1.1, 2.4)

(4.6, 6.6) (1.4, 2.0) (2.8, 4.4) (6.3, 8.2) (1.2, 2.9) (4.2, 10.5) (2.3, 6.2)

24–72 24–60 36–60 36–72 36–72 36–72

270 327 23 166 38 43

135 299 23 165 33 22

1.7 1.6 1.1 3.4 1.7 2.8 1.9

(1.4, 1.9) (1.4, 1.8) (0.6, 2.0) (2.9, 4.0) (1.2, 2.3) (1.8, 4.7) (1.5, 2.6)

HAI denotes hemagglutinin inhibition antibodies; aIIV denotes MF59 adjuvanted inactivated influenza vaccine; IIV denotes nonadjuvanted IIV; GMT denotes post-vaccination (50 days after baseline for dose 2) geometric mean HAI titers; GMR denotes ratio of postvaccination GMTs after aIIV versus IIV. 1 Two studies either did not provide age stratification [Zedda et al PIDJ 2015 (Ref: 51)] or only enrolled children 6–36 months and did not stratify by age (Vesikari et al. 2009 (Ref: [44])]. 2 B-lineage was Yamagata or Victoria depending on the WHO recommended strain in the trivalent vaccine during the season when the study was conducted (Table 1). 3 Only study to have adjuvanted quadrivalent and nonadjuvanted quadrivalent in addition to nonadjuvanted trivalent IIV. For comparison with other vaccines, data in this table only depicts the trivalent B-lineage included in the vaccine.

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Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053

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Please cite this article as: M. M. Patel, W. Davis, L. Beacham et al., Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2019.10.053