Carine Claeys

AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial

BACKGROUND We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. METHODS We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65-74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. FINDINGS We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12-1·43] of 21 573 vs 310 [1·44%, 1·29-1·61] of 21 482; relative efficacy 12·11%, 95% CI -3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91-1·18] vs 270 [1·26, 1·11-1·41]; relative efficacy 17·53%, 95% CI 1·55-30·92) and influenza A H3N2 (170 [0·79, 0·67-0·92] vs 205 [0·95, 0·83-1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68-35·49). INTERPRETATION AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. FUNDING GlaxoSmithKline Biologicals SA.

A Randomized Trial of Candidate Inactivated Quadrivalent Influenza Vaccine versus Trivalent Influenza Vaccines in Children Aged 3–17 Years

Background. Two antigenically distinct influenza B lineages have cocirculated since 2001, yet trivalent influenza vaccines (TIVs) contain 1 influenza B antigen, meaning lineage mismatch with the vaccine is frequent. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages vs TIV in healthy children aged 3–17 years. Methods. Children were randomized 1:1:1 to receive QIV or 1 of 2 TIVs (either B/Victoria or B/Yamagata lineage; N = 2738). Hemagglutination-inhibition assays were performed 28 days after 1 or 2 doses in primed and unprimed children, respectively. Immunological noninferiority of QIV vs TIV against shared strains, and superiority against alternate-lineage B strains was based on geometric mean titers (GMTs) and seroconversion rates. Reactogenicity and safety were also assessed (Clinicaltrials.gov NCT01196988). Results. Noninferiority against shared strains and superiority against alternate-lineage B strains was demonstrated for QIV vs TIV. QIV was highly immunogenic; seroconversion rates were 91.4%, 72.3%, 70.0%, and 72.5% against A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, respectively. Reactogenicity and safety of QIV was consistent with TIV. Conclusions. QIV vs TIV showed superior immunogenicity for the additional B strain without interfering with immune responses to shared strains. QIV may offer improved protection against influenza B in children compared with current trivalent vaccines.

Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine: a phase III, randomized trial in adults aged ≥18 years

BackgroundTwo antigenically distinct influenza B lineages have co-circulated since the 1980s, yet inactivated trivalent influenza vaccines (TIVs) include strains of influenza A/H1N1, A/H3N2, and only one influenza B from either the Victoria or Yamagata lineage. This means that exposure to B-lineage viruses mismatched to the TIV is frequent, reducing vaccine protection. Formulations including both influenza B lineages could improve protection against circulating influenza B viruses. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in adults in stable health.MethodsA total of 4659 adults were randomized 5:5:5:5:3 to receive one dose of QIV (one of three lots) or a TIV containing either a B/Victoria or B/Yamagata strain. Hemagglutination-inhibition assays were performed pre-vaccination and 21-days after vaccination. Lot-to-lot consistency of QIV was assessed based on geometric mean titers (GMT). For QIV versus TIV, non-inferiority against the three shared strains was demonstrated if the 95% confidence interval (CI) upper limit for the GMT ratio was ≤1.5 and for the seroconversion difference was ≤10.0%; superiority of QIV versus TIV for the alternate B lineage was demonstrated if the 95% CI lower limit for the GMT ratio was > 1.0 and for the seroconversion difference was > 0%. Reactogenicity and safety profile of each vaccine were assessed. Clinicaltrials.gov: NCT01204671.ResultsConsistent immunogenicity was demonstrated for the three QIV lots. QIV was non-inferior to TIV for the shared vaccine strains, and was superior for the added alternate-lineage B strains. QIV elicited robust immune responses against all four vaccine strains; the seroconversion rates were 77.5% (A/H1N1), 71.5% (A/H3N2), 58.1% (B/Victoria), and 61.7% (B/Yamagata). The reactogenicity and safety profile of QIV was consistent with TIV.ConclusionsQIV provided superior immunogenicity for the additional B strain compared with TIV, without interfering with antibody responses to the three shared antigens. The additional antigen did not appear to alter the safety profile of QIV compared with TIV. This suggests that the candidate QIV is a viable alternative to TIV for use in adults, and could potentially improve protection against influenza B.Trial registrationClinical Trials.gov: NCT01204671/114269

Immunogenicity and safety of inactivated quadrivalent and trivalent influenza vaccines in children 18-47 months of age.

Background: Because inactivated trivalent influenza vaccines (TIVs) contain 1 influenza B strain, whereas 2 lineages may co-circulate, B lineage mismatch is frequent. We assessed an inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in young children. Methods: Children aged 18−47 months who had received 2 doses of TIV in a study during the previous season (primed cohort, n = 192) were randomized 1:1 to receive 1 dose of TIV or QIV, and a further 407 children (unprimed cohort) were randomized 1:1 to receive 2 doses of TIV or QIV 28 days apart. Immunogenicity was assessed by hemagglutination-inhibition (HI) prevaccination and 28 days after each vaccination. Immunogenic non-inferiority QIV versus TIV for shared strains, and superiority against the alternate-lineage B strain were based on HI geometric mean titers (pooled analyses of primed and half of unprimed cohort with Day 56 immunogenicity assessment). Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period, respectively (NCT00985790). Results: Non-inferiority for shared strains and superiority for the alternate-lineage B strain unique to QIV was demonstrated for QIV versus TIV. QIV was immunogenic against all 4 vaccine strains and 87.0%, 88.6%, 69.8% and 97.9% of children had postvaccination titers of ≥1:40 against A/H1N1, A/H3N2, B/Victoria and B/Yamagata, respectively. Reactogenicity and safety of QIV was consistent with TIV. Conclusions: QIV provided superior immunogenicity for the alternate-lineage B strain compared with TIV without interfering with immune responses to shared strains. Further studies are warranted to assess QIVs in children and to establish the clinical benefits of QIV versus TIV.

A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control

ABSTRACT The contribution of influenza B to the seasonal influenza burden varies from year-to-year. Although 2 antigenically distinct influenza B virus lineages have co-circulated since 2001, trivalent influenza vaccines (TIVs) contain antigens from only one influenza B virus. B-mismatch or co-circulation of both B lineages results in increased morbidity and mortality attributable to the B lineage absent from the vaccine. Quadrivalent vaccines (QIVs) contain both influenza B lineages. We reviewed currently licensed QIVs and their value by focusing on the preventable disease burden. Modeling studies support that QIVs are expected to prevent more influenza cases, hospitalisations and deaths than TIVs, although estimates of the case numbers prevented vary according to local specificities. The value of QIVs is demonstrated by their capacity to broaden the immune response and reduce the likelihood of a B-mismatched season. Some health authorities have preferentially recommended QIVs over TIVs in their influenza prevention programmes.

Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine Coadministered With Seasonal Influenza Vaccine in Adults Aged 50 Years or Older

When the adjuvanted HZ subunit vaccine candidate was coadministered with a quadrivalent seasonal influenza vaccine, no interference in the immune responses were observed, and no safety concerns were identified.

Immunogenicity of AS03-adjuvanted and non-adjuvanted trivalent inactivated influenza vaccines in elderly adults: A Phase 3, randomized trial and post-hoc correlate of protection analysis

ABSTRACT In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.

N-09: Immunogénicité et tolérance d’un vaccin antigrippal quadrivalent inactivé chez l’adulte : étude randomisée contrôlée

Contexte : Les vaccins trivalents antigrippaux saisonniers (TIV) contiennent une seule souche B alors que 2 lignages B (Victoria B/V et Yamagata B/Y) antigeniquement distincts circulent depuis les annees 80. L’addition du 2 nd lignage B dans un vaccin quadrivalent antigrippal (QIV) pourrait ameliorer la protection. Materiels et methodes Cette etude de phase III en aveugle partiel randomisee controlee multicentrique (NCT01204671) a evalue un QIV vs 2 TIV inactives (TIV1 B/V, TIV2 B/Y) chez le sujet adulte. Les titres en anticorps HI ont ete mesures avant et J21 post-vaccination dans un sous-groupe. La superiorite du QIV etait demontree pour la souche B additionnelle si la limite inferieure de l’IC95 % etait > 1 pour le ratio des moyennes geometriques des titres/MGT QIV/TIV et > 0 % pour la difference des taux de seroconversion/SCR QIV-TIV. La non-inferiorite du QIV pour les souches communes etait demontree si la limite superieure de l’IC95 % etait ≤1,5 pour le ratio des MGT TIV/QIV et ≤10 % pour la difference des SCR TIV-QIV. La tolerance a ete aussi evaluee. Resultats 4 656 sujets ont ete vaccines. La superiorite pour la souche additionnelle B et la non-inferiorite pour les souches communes du QIV vs TIV1 et TIV2 ont ete demontrees. Les EI sollicites et non sollicites ont ete rapportes avec une frequence similaire dans les 3 groupes. Aucun EIG n’a ete considere par les investigateurs comme lie au vaccin. Conclusion Le vaccin QIV presente une immunogenicite superieure pour la souche B additionnelle sans impact negatif sur les autres souches et sans affecter le profil de tolerance. Financement GSK Biologicals SA Extrait traduit-abstract presente au congres IVW 2012-EspagneKieninger D et al BMC Infect Dis 2013;13:343.