Human Vaccines & Immunotherapeutics

ISSN: 2164-5515 (Print) 2164-554X (Online) Journal homepage: http://www.tandfonline.com/loi/khvi20

Influenza vaccination in children primed with ® MF59 -adjuvanted or non-adjuvanted seasonal influenza vaccine Timo Vesikari, Aino Forstén, Ashwani Arora, Theodore Tsai & Ralf Clemens To cite this article: Timo Vesikari, Aino Forstén, Ashwani Arora, Theodore Tsai & Ralf Clemens ®

(2015) Influenza vaccination in children primed with MF59 -adjuvanted or non-adjuvanted seasonal influenza vaccine, Human Vaccines & Immunotherapeutics, 11:8, 2102-2112, DOI: 10.1080/21645515.2015.1044167 To link to this article: http://dx.doi.org/10.1080/21645515.2015.1044167

View supplementary material

Accepted online: 19 Jun 2015.

Submit your article to this journal

Article views: 44

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=khvi20 Download by: [Universite Laval]

Date: 15 October 2015, At: 05:23

RESEARCH PAPER Human Vaccines & Immunotherapeutics 11:8, 2102--2112; August 2015; © 2015 Taylor and Francis Group, LLC

Influenza vaccination in children primed with Ò MF59 -adjuvanted or non-adjuvanted seasonal influenza vaccine Timo Vesikari1, Aino Forst en1, Ashwani Arora2,*, Theodore Tsai2, and Ralf Clemens2 1

University of Tampere Medical School; Tampere, Finland; 2Novartis Vaccines and Diagnostics Inc.; Cambridge, MA USA

Keywords: adjuvant, influenza, MF59, pediatric, revaccination, seasonal vaccine

Downloaded by [Universite Laval] at 05:23 15 October 2015

Abbreviations: AE, adverse event; aTIV, MF59-adjuvanted trivalent inactivated influenza vaccine; CBER, Center for Biologics Evaluation & Research; CHMP, European Committee for Medicinal Products for Human Use; FAS, full analyses set; HI, hemagglutination inhibition; CI, confidence interval; LAIV, live-attenuated influenza vaccine; GMR, geometric mean ratio; GMT, geometric mean titer; HI, hemagglutination inhibition; TIV, trivalent inactivated influenza vaccine; SAE, serious adverse event; SD, standard deviation

Routine annual influenza immunization is increasingly recommended in young children. We compared the safety and immunogenicity of vaccination with trivalent inactivated influenza vaccine (TIV) versus MF59-adjuvanted TIV (aTIV) in children who received 2 half or full doses of aTIV or TIV, or non-influenza control vaccine, in an efficacy trial conducted 2 years earlier. 197 healthy children aged 30–96 months were randomized to receive vaccination with aTIV or TIV in 2010. To evaluate responses to the first follow-up seasonal vaccination after priming we excluded children who received influenza vaccine(s) in the 2009 pandemic year leaving 40 children vaccinated with aTIV, 26 children with TIV and 10 children with aTIV after a control vaccine in the parent study. Hemagglutination inhibiting antibodies were assayed on Days 1, 22 and 181. aTIV vaccination produced 6.9 to 8.0-fold higher antibody responses than the reference TIV-TIV regimen against A/H3N2 and B strains, which remained higher 6 months following vaccination. The response to the B/Victoria lineage antigen in the second year’s vaccine (the first vaccine contained a B/Yamagata lineage antigen) demonstrated that aTIV primed for an adequate response after a single dose on Day 22 (GMTs 160, 95 to antigens in the 2 lineages, respectively), whereas TIV did not (GMTs 38, 20). Vaccination with aTIV produced slightly higher but acceptable local and systemic reactogenicity compared to TIV-TIV and TIV-aTIV mixed regimens. Within the limitations of a small study, the strong immune responses support the use of aTIV for vaccination in young children.

Introduction Routine annual influenza immunization of children is recommended in the USA and Finland where nearly half of children who are hospitalized for influenza were previously healthy, without recognized risk factors.1-5 Similarly, 40% of fatal influenza cases in children occur in previously healthy children.6 These characteristics of pediatric influenza support the universal use of influenza vaccine in children at an early age with annual revaccinations. Although the medical need for routine influenza immunization in children is clear, available vaccines have limitations; trivalent inactivated influenza vaccines (TIV) have less than optimal efficacy and live-attenuated influenza vaccine (LAIV) has restrictions for children under 24 months years of age because of safety concerns.7–9 While TIV may be »40–60% efficacious in children under 6 years old, there is no clear evidence for efficacy in the youngest age group, 6–23 month-olds.8,9 LAIV has been shown to be more efficacious than TIV in 2–7 year-olds, but

cannot be used in children under 5 years of age who have a history of wheezing, and not at all in children under 24 months of age.7,10 The use of adjuvants such as MF59 can significantly enhance the immune response in previously unvaccinated children, with protective antibodies levels being achieved earlier and lasting longer than with non-adjuvanted TIV.11,12 MF59 also stimulates a broader immune response that may provide for increased efficacy Ò against heterovariant strains.13-15 MF59 (Novartis Vaccines) was the first oil-in-water emulsion adjuvant included in a licensed vaccine, the adjuvanted seasonal TIV (aTIV) indicated for older Ò adults (Fluad Novartis Vaccines).16,17 We previously demonstrated in a head to head trial in vaccinena€ıve 6–71 month old children (conducted principally in the 2007–2008 season) that aTIV had 86% efficacy in preventing laboratory-confirmed influenza while confirming in the same trial the modest efficacy of TIV, at 42%.11 This phase 3b extension study was conducted to assess the safety and immunogenicity of Ò vaccination with aTIV vs. TIV (Agrippal , Novartis Vaccines) in

*Correspondence to: Ashwani Arora; Email: [email protected] Submitted: 11/07/2014; Revised: 04/03/2015; Accepted: 04/19/2015 http://dx.doi.org/10.1080/21645515.2015.1044167

2102

Human Vaccines & Immunotherapeutics

Volume 11 Issue 8

Downloaded by [Universite Laval] at 05:23 15 October 2015

children from the previous efficacy trial, now at 30– 96 months of age.11 The 2009 H1N1 pandemic prevented us from evaluating the vaccination response in the season immediately following the efficacy trial. All subjects who received either seasonal or monovalent pandemic vaccine in 2009 were excluded in this study analysis, in order to more clearly demonstrate the immune response of re-vaccination in the first follow-up seasonal vaccination after priming. The vaccine strains in 2010–2011 [A/ California/7/2009 (H1N1), A/ Perth/16/2009 (H3N2) and B/Brisbane/ 60/2008 (Victoria)] were antigenically distinct from those in the priming vaccine in 2008–2009 [A/Brisbane/59/2007 (H1N1), A/Brisbane/10/2007 (H3N2), and B/Florida/4/2006 (Yamagata)], providing us with the opportunity to examine prime to boost responses in young children following a change in B antigens, from B/Yamagata lineage to B/Victoria lineage strain.

Results Subjects Fewer subjects were enrolled in the extension study than the originally planned 1970 subjects, due to parental concerns in

Finland with narcolepsy associated with an AS03-adjuvanted H1N1 vaccine that was used in several European countries including Finland during the 2009 H1N1 influenza pandemic.18 In total, 197 subjects were enrolled and were categorized into 2 age cohorts, 6 -< 36 months (n D 29) and 36 -< 96 months (n D 168). The younger age group was too small to draw conclusions on the immune response so the age cohorts were combined and results were grouped by vaccine received. Of the 197 subjects that were enrolled and randomized to receive aTIV (n D 135) and TIV (n D 62), 188 completed the study. Reasons for premature withdrawal were withdrawal of consent (N D 4) and loss to follow-up (N D 5) (Fig. 1). To more clearly demonstrate the immune responses to vaccination in follow-up seasonal vaccination after priming, all subjects who received influenza vaccine in 2009, seasonal or monovalent pandemic, were excluded from the immunogenicity and safety analyses presented in this report. Ultimately, 40 children revaccinated with aTIV, 26 children revaccinated with TIV, and 10 control children receiving influenza vaccine for the first time (and were administered aTIV) were included in the analyses for this study (Fig. 1). The baseline demographic characteristics of the enrolled subjects by priming and subsequent vaccines are presented in

Figure 1. Study flow.

www.tandfonline.com

Human Vaccines & Immunotherapeutics

2103

Table 1. Study population demographics by priming vaccine in the original efficacy study and vaccination with aTIV or TIV Priming Vaccine Revaccination Vaccine Age, mean § SD, months Male (%) Race (%) Caucasian Hispanic Other Weight § SD weight, kg Height § SD height, cm Met Study Criteria (%)

aTIV (n D 29)

TIV (n D 37)

Control (n D 10)

aTIV (nD17) 58.2§22.6 53

TIV (nD12) 62.6§21.1 50

aTIV (nD23) 64.8§21.3 52

TIV (nD14) 67.4§16.7 14

aTIV (nD10) 64.6§18.7 30

100 0 0 19.8 § 5.9 109.5 § 14.7 100

100

96 4

90

20.5 § 4.9 111.7§12.9 100

19.8 § 4.3 112.0 § 13.1 100

86 7 1 20.1 § 3.2 114.3 § 10.4 100

10 21.7 § 4.6 115.4 § 12.7 100

Downloaded by [Universite Laval] at 05:23 15 October 2015

TIV: trivalent inactivated influenza vaccines, aTIV: MF59 adjuvanted TIV, SD: standard deviation. Children vaccinated with non-influenza control during parent study only received aTIV in the extension study.

Table 1. Vaccine groups were comparable with respect to age, body size characteristics, and the majority of study subjects were Caucasian. There was a higher proportion of girls in the children

primed with TIV and revaccinated with TIV and those who previously received the control non-influenza vaccines and were vaccinated with aTIV.

Figure 2. Homologous antibody responses in children 30-< 96 months old vaccinated with aTIV or TIV, by priming vaccine. Dashed lines indicates Committee for Medicinal products for Human Use (CHMP) criterion; the percentage of subjects achieving seroprotection (HI antibody titer 40) should be >70%, the percentage of subjects achieving seroconversion should be 40% and geometric mean ratio should be >2.5. None of the subjects were vaccinated with seasonal or pandemic vaccine in 2009. Children vaccinated with non-influenza control during parent study only received aTIV in the extension study.

2104

Human Vaccines & Immunotherapeutics

Volume 11 Issue 8

Downloaded by [Universite Laval] at 05:23 15 October 2015

Immunogenicity analyses Evaluation of immunogenicity criteria according to European Committee for Medicinal Products for Human Use (CHMP) criteria is presented in Figure 2. Subjects who were primed with aTIV and TIV and vaccinated with aTIV in the extension study met all 3 CHMP criteria for seroprotection (>70%), seroconversion (>40%) and geometric mean ratio (GMR) (>2.5) against the 3 homologous strains with persistence up to 6 months following vaccination. Subjects who were primed with TIV and vaccinated with aTIV or TIV in the extension study met all 3 CHMP criteria against A/California/7/2009 (A/H1N1) and A/ Perth/16/2009 (A/H3N2) and 2 out of 3 criteria (vaccination aTIV) and 1 out of 3 criteria (vaccination TIV) against B/Brisbane/60/2008 (Victoria). Children who were previously vaccinated with non-influenza control vaccine and vaccinated with aTIV met all CHMP criteria except for seroprotection against B/ Brisbane/60/2008 (Victoria) at Day 22. When using Center for Biologics Evaluation & Research (CBER) criteria, only the subjects who were primed with aTIV and revaccinated with aTIV

met both CBER criteria for seroconversion and seroprotection at Day 22 (Fig. 2). Percentages of subjects achieving a more stringent cut-off criterion hemagglutination inhibition (HI) titer 110 are presented in Figure 3. In children primed with aTIV, HI titers 110 at Day 22 were achieved in 94% (A/H1N1), 100% (A/ H3N2) and 69% (B/Brisbane/60/2008) after vaccination with aTIV and 75% (A/H1N1), 100% (A/H3N2) and 58% (B/ Brisbane/60/2008) following vaccination with TIV. In TIVprimed children, the proportion achieving HI titres of 110 were 91%, 100% and 22% (vaccination aTIV) and 100%, 71% and 0% (vaccination TIV) against A/H1N1, A/H3N2 and B strains, respectively. In children previously vaccinated with non-influenza control and vaccinated with aTIV, 89% achieved a titer 110 to A/H1N1, 100% to H3N2 and 33% to B/Brisbane/60/2008 (Victoria lineage). Day 181 HI titers 110 were achieved in 24–100% and 8–100% in children after vaccination with aTIV and TIV, respectively (Fig. 3).

Figure 3. Percentages of subjects with HI antibody titers 110 in children 30-< 96 months old vaccinated with aTIV or TIV, by priming vaccine. None of the subject was vaccinated with seasonal or pandemic vaccine in 2009. Children vaccinated with non-influenza control during parent study only received aTIV in the extension study.

www.tandfonline.com

Human Vaccines & Immunotherapeutics

2105

Antibody responses by subtype

Downloaded by [Universite Laval] at 05:23 15 October 2015

H1N1 Although subjects who received the 2009 pandemic vaccine were excluded from this analysis, baseline titers in all 3 groups suggested that pandemic exposure had occurred relatively uniformly in all groups, with geometric mean titers (GMTs) in the range of 33 to 59. All groups responded well to their first vaccination against A/California/07/2009 (H1N1) irrespective of having received adjuvanted, non-adjuvanted or no previous influenza vaccine in the earlier study, with 12.6 to 27.9 fold increases in response to aTIV and 9.7 to 24.2 fold increases in response to TIV. Six months later, higher titers, in the range of 1.3 to 1.4 fold higher, were maintained in the aTIV- compared to TIV-vaccinated children (Table 2). H3N2 Baseline antibody titers were 2.3 to 5.8 fold higher in children who had previously received aTIV compared to children who had been vaccinated originally with TIV. However, better persistence of the antibody-induced response in the aTIVprimed group cannot be inferred because control children who had not previously received influenza vaccine had evidence of baseline H3N2 antibodies at even higher levels, presumably deriving from natural infection. Children primed with aTIV and those who had received control vaccines (and who had evidence of natural infection) responded to aTIV with a 10.4 to 14.3 fold rise to a GMT of~2200 at Day 22. Children who had been primed with TIV and then boosted with aTIV exhibited a 17.7 fold rise, though to a lower absolute GMT of 1205 as their baseline titer after TIV priming was lower. The other mixed regimen of aTIV followed by TIV produced an intermediate rise of 4.5 fold to a GMT of 678, while successive TIV vaccinations produced the lowest GMT of 328, albeit as a result of a

13.1 fold rise. aTIV vaccinated children maintained a 2.7 fold higher GMT compared to TIV vaccinated children at 6 months. The GMT of the aTIV-aTIV group (925) was 7.7 fold higher than the TIV-TIV group (120) at that point (Table 2).

B Baseline titers to the Victoria lineage B/Brisbane/60/2008 strain were uniformly low in all groups, including those who had been primed with 2 vaccine doses in 2008–2009, as that formulation contained a B/Yamagata lineage strain. The children who had been primed with TIV and were revaccinated with TIV mounted a suboptimal response against the B/Victoria lineage antigen from GMT 5 (pre-vaccination) to GMT 20 (Day 22 post-vaccination) and GMT 17 (Day 181 post-vaccination). In contrast, aTIV-primed children responded with at least 10-fold rises to the B/Victoria lineage antigen, achieving GMTs of 160 and 95 on Day 22, whether they were revaccinated with adjuvanted or non-adjuvanted vaccine, respectively, with persistence of higher GMTs (135 and 94) up to 6 months following vaccination. The six month GMT of the aTIV-aTIV group was almost 8-fold higher than that of the TIV-TIV group. The responses of the TIV-primed children were intermediate and reached a low level of

Influenza vaccination in children primed with MF59-adjuvanted or non-adjuvanted seasonal influenza vaccine.

Routine annual influenza immunization is increasingly recommended in young children. We compared the safety and immunogenicity of vaccination with tri...
1MB Sizes 0 Downloads 6 Views