High-Dose Quadrivalent Influenza Vaccine for Prevention of Cardiovascular and Respiratory Hospitalizations in Older Adults.

BACKGROUND: We assessed the relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) in preventing respiratory or cardiovascular hospitalizations in older adults. METHODS: FinFluHD was a phase 3b/4 modified double-blind, randomized pragmatic trial. Enrolment of 121,000 adults ≥65 years was planned over three influenza seasons (October to December 2019-2021). Participants received a single injection of QIV-HD or QIV-SD. The primary endpoint was first occurrence of an unscheduled acute respiratory or cardiovascular hospitalization (ICD-10 primary discharge J/I codes), from ≥14 days post-vaccination until May 31. The study was terminated after one season due to COVID-19; follow-up data for 2019-2020 are presented. RESULTS: 33,093 participants were vaccinated (QIV-HD, n = 16,549; QIV-SD, n = 16,544); 529 respiratory or cardiovascular hospitalizations (QIV-HD, n = 257; QIV-SD, n = 272) were recorded. The rVE of QIV-HD versus QIV-SD to prevent respiratory/cardiovascular hospitalizations was 5.5% (95% CI, -12.4 to 20.7). When prevention of respiratory and cardiovascular hospitalizations were considered separately, rVE estimates of QIV-HD versus QIV-SD were 5.4% (95% CI, -28.0 to 30.1) and 7.1% (95% CI, -15.0 to 25.0), respectively. Serious adverse reactions were <0.01% in both groups. CONCLUSIONS: Despite insufficient statistical power due to the impact of COVID-19, rVE point estimates demonstrated a trend toward a benefit of QIV-HD over QIV-SD. QIV-HD was associated with lower respiratory or cardiovascular hospitalization rates than QIV-SD, with a comparable safety profile. Adequately powered studies conducted over multiple influenza seasons are needed to determine statistical significance of QIV-HD compared with QIV-SD against preventing respiratory and cardiovascular hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04137887.

Reply to letter to editor by Hadigal et al. regarding the immunogenicity and safety trial of high-dose influenza vaccine in adults aged ≥60 years.

Hadigal et al. argued the recommendation of high-dose influenza vaccine over standard-dose formulation is not supported by comparisons of numbers-needed-to-vaccinate (NNV) nor aligned with the WHO mandate of improving vaccine coverage. However, the authors' NNV calculation was inaccurate. A preferential recommendation for vaccines preventing influenza/complications can increase coverage. Furthermore, the impact of vaccination is a function of efficacy/effectiveness and the vaccine-preventable fraction of disease burden; therefore Hadigal et al. should interpret the absolute risk reduction by vaccination within the context of overall disease burden. To address the threat of COVID-19 pandemic, authorities should implement concomitant influenza/COVID-19 vaccination to reduce the burden of cocirculation of influenza and SARS- CoV- 2 viruses and increase the coverage of proven influenza vaccines as per WHO mandate.

Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: a randomized Phase III trial.

A quadrivalent high-dose inactivated influenza vaccine (IIV4-HD) is licensed for adults ≥65 y of age based on immunogenicity and efficacy studies. However, IIV4-HD has not been evaluated in adults aged 60-64 y. This study compared immunogenicity and safety of IIV4-HD with a standard-dose quadrivalent influenza vaccine (IIV4-SD) in adults aged ≥60 y. This Phase III, randomized, modified double-blind, active-controlled study enrolled 1,528 participants aged ≥60 y, randomized 1:1 to a single injection of IIV4-HD or IIV4-SD. Hemagglutination inhibition (HAI) geometric mean titers (GMTs) were measured at baseline and D 28 and seroconversion assessed. Safety was described for 180 d after vaccination. The primary immunogenicity objective was superiority of IIV4-HD versus IIV4-SD, for all four influenza strains 28 d post vaccination in participants aged 60-64 and ≥65 y. IIV4-HD induced a superior immune response versus IIV4-SD in terms of GMTs in participants aged 60-64 y and those aged ≥65 y for all four influenza strains. IIV4-HD induced higher GMTs in those aged 60-64 y than those aged ≥65 y. Seroconversion rates were higher for IIV4-HD versus IIV4-SD in each age-group for all influenza strains. Both vaccines were well tolerated in participants ≥60 y of age, with no safety concerns identified. More solicited reactions were reported with IIV4-HD than with IIV4-SD. IIV4-HD provided superior immunogenicity versus IIV4-SD and was well tolerated in adults aged ≥60 y. IIV4-HD is assumed to offer improved protection against influenza compared with IIV4-SD in adults aged ≥60 y, as was previously assessed for adults aged ≥65 y.

Effectiveness of the quadrivalent high-dose influenza vaccine for prevention of cardiovascular and respiratory events in people aged 65 years and above: Rationale and design of a real-world pragmatic randomized clinical trial.

BACKGROUND: Influenza has been an acknowledged cause of respiratory disease for decades. However, considerable related, and often unappreciated, disease burden stems from cardiovascular complications, exacerbations of underlying medical conditions and secondary respiratory complications, with the highest burden in the elderly. This novel study combines the gold standard method of a randomized controlled trial with real-world data collection through national registries, to assess the relative effectiveness of high-dose (QIV-HD) vs standard-dose quadrivalent influenza vaccine (QIV-SD) in preventing cardio-respiratory hospitalizations in a large cohort of adults aged ≥65 years. METHODS AND RESULTS: This trial (NCT04137887) is a Phase III/IV, modified double-blinded, randomized, registry-based trial, conducted by the Finnish Institute for Health and Welfare (THL). Participants (n>120 000) are being enrolled over multiple influenza seasons and randomized (1:1) to receive QIV-HD or QIV-SD. Participant follow-up is based on data collection up to 11 months post-vaccination using Finnish national health registries. The primary objective is to demonstrate the relative superior effectiveness of QIV-HD over QIV-SD in preventing cardio-respiratory hospitalizations up to 6 months post-vaccination. Safety will be assessed using automated online tools throughout the study, with causality assessed using statistical and probabilistic methods; serious adverse reactions and adverse events of special interest will be investigated individually. CONCLUSION: This large, real-world, randomized study will provide valuable insight into the contribution of influenza in causing severe cardio-respiratory events, and the role of vaccination with QIV-HD in reducing these outcomes compared to the current standard of care. FUNDING: Sanofi Pasteur.

Immunogenicity and safety of a multi-dose quadrivalent inactivated influenza vaccine in individuals aged 6 months to 17 years: a randomized phase III trial.

Annual vaccination is the most effective way to prevent seasonal influenza. Influenza vaccines in multi-dose vial (MDV) formats can facilitate timely vaccination of large populations by reducing per-dose costs and cold storage requirements compared to single-dose pre-filled syringe (PFS) formats. MDV vaccines require thiomersal or another preservative to prevent microbial contamination. We conducted a randomized, open-label trial in 302 healthy subjects aged 6 months to 17 years to evaluate the immunogenicity and safety of a quadrivalent influenza vaccine (QIV) in a thiomersal-containing MDV format compared to the licensed thiomersal-free PFS format. Subjects were randomly assigned in a 1:1 ratio to receive the MDV (n = 153) or PFS (n = 149) format. Post-vaccination hemagglutination inhibition titers for all four vaccine strains were ≥4.9-fold higher than baseline titers with no difference in magnitude between the MDV and PFS groups. Seroconversion rates per strain were also comparable between the two groups. There were no differences in reactogenicity or safety between the two vaccine formats. These results showed that the MDV format of QIV was as safe and immunogenic as the PFS format in infants, children, and adolescents. These findings support the use of MDV QIV as a resource-saving alternative for seasonal influenza vaccination.

Epidemiology and burden of influenza in healthy children aged 6 to 35 months: analysis of data from the placebo arm of a phase III efficacy trial.

BACKGROUND: Despite World Health Organization recommendations, in many countries young children are not targeted for influenza vaccination. To help inform influenza vaccination policy, we examined the occurrence and burden of influenza in healthy children aged 6 to 35 months using data from a recent phase III placebo-controlled influenza vaccine trial conducted in countries in the Northern and Southern Hemispheres. METHODS: This was an analysis of data from participants included in the placebo arm of a phase III clinical trial in healthy children aged 6 to 35 months (EudraCT no. 2013-001231-51). Included children had never been vaccinated for influenza and were observed for one influenza season. Outcome measures included the occurrence of influenza-like illness (ILI), laboratory-confirmed influenza, virus types/subtypes, severe symptoms and complications of confirmed influenza, and healthcare use associated with confirmed influenza. RESULTS: Data from 2210 participants were analysed. ILI was reported for 811 participants (36.7%). Of these, 255 participants (31.4%) had 263 virologically confirmed episodes of influenza. The overall influenza attack rate was 11.5%. The most common influenza virus detected was A(H3N2) (40.7%), followed by B/Yamagata (23.6%), A(H1N1) (18.6%), and B/Victoria (8.0%). Grade 3 fever was reported in 24.3% of confirmed episodes, acute lower respiratory infection in 8.7%, acute otitis media in 6.1%, and pneumonia in 1.9%. In most influenza episodes (93.2%), antipyretics, analgesics, or non-steroidal anti-inflammatory drugs were taken. Antibiotics were prescribed for 41.4% of influenza episodes. More than half of the influenza episodes (57.0%) resulted in outpatient visits. Influenza resulted in overnight hospitalisation in 1.1% of episodes. CONCLUSIONS: Influenza is associated with a significant burden of disease in healthy children. This analysis also revealed that antibiotics continue to be frequently used for young children with influenza. TRIAL REGISTRATION: EudraCT no. 2013-001231-51 .

Impact of a quadrivalent inactivated influenza vaccine on influenza-associated complications and health care use in children aged 6 to 35 months: Analysis of data from a phase III trial in the Northern and Southern Hemispheres.

BACKGROUND: A multi-season phase III trial conducted in the Northern and Southern Hemispheres demonstrated the efficacy of a quadrivalent split-virion inactivated influenza vaccine (IIV4) in children 6-35 months of age. METHODS: Data collected during the phase III trial were analysed to examine the vaccine efficacy (VE) of IIV4 in preventing laboratory-confirmed influenza in age subgroups and to determine the relative risk for IIV4 vs. placebo for severe outcomes, healthcare use, and parental absenteeism from work associated with laboratory-confirmed influenza. RESULTS: VE (95% confidence interval [CI]) to prevent laboratory-confirmed influenza due to any A or B strain was 54.76% (40.24-66.03%) for participants aged 6-23 months and 46.91% (23.57-63.53%) for participants aged 24-35 months. VE (95% CI) to prevent laboratory-confirmed influenza due to vaccine-similar strains was 74.51% (53.55-86.91%) for participants aged 6-23 months and 59.78% (19.11-81.25%) for participants aged 24-35 months. Compared to placebo, IIV4 reduced the risk (95% CI) by 31.28% (8.96-89.34%) for acute otitis media, 21.76% (6.46-58.51%) for acute lower respiratory infection, 40.80% (29.62-55.59%) for healthcare medical visits, 29.71% (11.66-67.23%) for parent absenteeism from work, and 39.20% (26.89-56.24%) for antibiotic use. CONCLUSION: In children aged 6-35 months, vaccination with IIV4 reduces severe outcomes of influenza as well as the associated burden for their parents and the healthcare system. In addition, vaccination with IIV4 is effective at preventing against influenza in children aged 6-23 and 24-35 months. TRIAL REGISTRATION: EudraCT no. 2013-001231-51.

Efficacy, immunogenicity, and safety of a quadrivalent inactivated influenza vaccine in children aged 6-35 months: A multi-season randomised placebo-controlled trial in the Northern and Southern Hemispheres.

BACKGROUND: A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6-35 months. METHODS: This was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6-35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains. RESULTS: The study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36-61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07-81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo. CONCLUSIONS: IIV4 was safe and effective for protecting children aged 6-35 months against influenza illness caused by vaccine-similar or any circulating strains. CLINICAL TRIAL REGISTRATION: EudraCT no. 2013-001231-51.

Safety, immunogenicity, and lot-to-lot consistency of a split-virion quadrivalent influenza vaccine in younger and older adults: A phase III randomized, double-blind clinical trial.

Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014-2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18-60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

Quadrivalent inactivated influenza vaccine (VaxigripTetra™).

INTRODUCTION: VaxigripTetra™ (IIV4; Sanofi Pasteur) is a quadrivalent split-virion influenza vaccine approved in Europe in 2016 for individuals ≥ 3 years of age. IIV4 builds on the well-established record of the trivalent split-virion influenza vaccine (Vaxigrip®). Areas covered: This literature review summarizes the rationale for developing quadrivalent influenza vaccines and discusses the phase III clinical trial results supporting the immunogenicity, safety, and tolerability of IIV4. Expert commentary: IIV4 is immunogenic and well tolerated. Adding a second B strain to the trivalent split-virion influenza vaccine provides a superior immune response for the additional strain but does not reduce the immune response for the three other strains or negatively affect the safety profile. By offering broader protection against co-circulating influenza B lineages, IIV4 has the potential to further reduce influenza-related morbidity and mortality beyond that achieved with trivalent vaccines.

Antibody Persistence and Booster Responses to Split-Virion H5N1 Avian Influenza Vaccine in Young and Elderly Adults.

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 µg of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 µg alum-adjuvanted vaccine or 7.5 µg dose vaccine were lower than 21-days after the primary course and waned further with time. Re-immunization with the clade 2, 30 µg alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody cross-reactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available. TRIAL REGISTRATION: ClinicalTrials.gov NCT00415129.

Safety and immunogenicity of an intramuscular quadrivalent influenza vaccine in children 3 to 8 y of age: A phase III randomized controlled study.

A quadrivalent, inactivated, split-virion influenza vaccine containing a strain from both B lineages (IIV4) has been developed, but its safety and immunogenicity in young children has not been described. This was a phase III, randomized, double-blind, active-controlled, multi-center study to examine the immunogenicity and safety of IIV4 in children 3-8 y of age (EudraCT no. 2011-005374-33). Participants were randomized 5:1:1 to receive the 2013/2014 Northern Hemisphere formulation of IIV4, an investigational trivalent comparator (IIV3) containing the B/Victoria lineage strain, or the licensed Northern Hemisphere IIV3 containing the B/Yamagata lineage strain. Participants who had not previously received a full influenza vaccination schedule received 2 doses of vaccine 28 d apart; all others received a single dose. 1242 children were included. For all 4 strains, IIV4 induced geometric mean haemagglutination inhibition titres non-inferior to those induced by the IIV3 comparators. For both B strains, geometric mean antibody titres induced by IIV4 were superior to those induced by the IIV3 with the alternative lineage strain. Similar proportions of participants vaccinated with IIV4 and IIV3 reported solicited injection-site reactions, solicited systemic reactions, and vaccine-related adverse events. A single vaccine-related serious adverse event, thrombocytopenia, was reported 9 d after vaccination with IIV4 and resolved without sequelae. In conclusion, in children aged 3-8 y who received one dose or 2 doses 28 d apart, IIV4 had an acceptable safety profile, was as immunogenic as IIV3 for the shared strains, and had superior immunogenicity for the additional B strain.

Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial.

BACKGROUND: Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains and one strain from each B lineage (Yamagata and Victoria) may offer broader protection against seasonal influenza than inactivated trivalent influenza vaccine (IIV3), containing a single B strain. This study examined the safety, immunogenicity, and lot consistency of an IIV4 candidate. METHODS: This phase III, randomized, controlled, multicenter trial in children/adolescents (9 through 17 years) and adults (18 through 60 years) was conducted in Australia and in the Philippines in 2012. The study was double-blind for IIV4 lots and open-label for IIV4 vs IIV3. Children/adolescents were randomized 2:2:2:1 and adults 10:10:10:1 to receive one of three lots of IIV4 or licensed IIV3. Safety data were collected for up to 6 months post-vaccination. Hemagglutination inhibition and seroneutralization antibody titers were assessed pre-vaccination and 21 days post-vaccination. RESULTS: 1648 adults and 329 children/adolescents received IIV4, and 56 adults and 55 children/adolescents received IIV3. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for IIV3 and IIV4 recipients in both age groups. Injection-site pain, headache, malaise, and myalgia were the most frequently reported solicited reactions, most of which were mild and resolved within 3 days. No vaccine-related serious adverse events or deaths were reported. Post-vaccination antibody responses, seroconversion rates, and seroprotection rates for the 3 strains common to both vaccines were comparable for IIV3 and IIV4 in both age groups. Antibody responses to IIV4 were equivalent among vaccine lots and comparable between age groups for each of the 4 strains. IIV4 met all European Medicines Agency immunogenicity criteria for adults for all 4 strains. CONCLUSIONS: In both age groups, IIV4 was well tolerated and caused no safety concerns, induced robust antibody responses to all 4 influenza strains, and met all EMA immunogenicity criteria for adults. CLINICAL TRIAL REGISTRY NUMBER: NCT01481454.

Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults.

BACKGROUND AND AIMS: Although two antigenically distinct B strain lineages of influenza have co-circulated globally since the mid-1980s, trivalent influenza vaccines (TIVs) contain only one, resulting in frequent mismatches. This study examined the safety and immunogenicity of an inactivated quadrivalent influenza vaccine (QIV) candidate. METHODS: This was a phase III, randomized, active-controlled, multicenter trial in adults during the 2011/2012 influenza season. Enrollment was stratified to include equal numbers of subjects 18-60 and >60 years of age. Subjects were randomized 5:1:1 to be vaccinated with the QIV, the licensed TIV, or an investigational TIV containing the alternate B strain lineage. Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination. RESULTS: 1116 subjects were vaccinated with QIV, 226 with the licensed TIV, and 223 with the investigational TIV. For all four vaccine strains, antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains. For both B strains, post-vaccination antibody responses to the QIV were superior to the responses to the TIVs lacking the corresponding B strain. The QIV met all European Medicines Agency criteria for all four vaccine strains. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for the QIV and pooled TIV groups. The most commonly reported solicited reactions were injection-site pain, headache, and myalgia, and most solicited reactions were mild or moderate and appeared and resolved within 3 days of vaccination. No treatment-related serious adverse events or deaths were reported. CONCLUSIONS: The inactivated QIV was well tolerated without any safety concerns. For all four vaccine strains, antibody responses to the QIV were superior to the responses to TIV for the unmatched strains and non-inferior for the matched strains. QIV could therefore help address an unmet need due to mismatched B strains in previous influenza vaccines. CLINICAL TRIAL REGISTRY NUMBER: EudraCT: 2011-001976-21.

Assessment of squalene adjuvanted and non-adjuvanted vaccines against pandemic H1N1 influenza in children 6 months to 17 years of age.

Vaccines were urgently needed in 2009 against A/H1N1 pandemic influenza. Based on the H5N1 experience, it was originally thought that 2 doses of an adjuvanted vaccine were needed for adequate immunogenicity. We tested H1N1 vaccines with or without AF03, a squalene-based adjuvant, in children.   Two randomized, open-label, trials were conducted. Participants 3-17 y received two injections of 3.8 µg or 7.5 µg hemagglutinin (HA) with adjuvant or 15 µg HA without adjuvant. Participants aged 6-35 mo received two injections of 1.9 µg or 3.8 µg HA with full or half dose adjuvant or 7.5 µg HA without adjuvant. All subjects 3 to 17 y reached seroprotection (hemagglutination inhibition (HI) titer ≥ 40) after the first dose of the adjuvanted vaccine, and 94% and 98% in the 3-8 and 9-17 y groups respectively with the non-adjuvanted vaccine. In children aged 6-35 mo responses were modest after one dose, but after two doses virtually all children were seroprotected regardless of HA or adjuvant dose. In this age group, antibody titers were 5 to 7 times higher after adjuvanted than non-adjuvanted vaccine. The higher responses with the adjuvanted vaccine were also reflected as better antibody persistence. There was no clustering of adverse events that would be suggestive of a safety signal. While a single injection was sufficient in subjects from 3 y, in children aged 6-35 mo two injections of this A/H1N1 pandemic influenza vaccine were required. Formulation of this vaccine with adjuvant provided a significant advantage for immunogenicity in the latter age group.

Similar immunogenicity of the A/H1N1 2009 pandemic influenza strain when used as a monovalent or a trivalent vaccine.

BACKGROUND: The WHO recommended including the A (H1N1) 2009 pandemic strain in the influenza vaccines for use in the 2010-2011 northern hemisphere (NH) influenza season. The immunogenicity and safety of the trivalent split inactivated vaccine (Vaxigrip®) NH 2010-2011 formulation was compared to that observed for the corresponding non-adjuvanted monovalent A (H1N1) pandemic vaccine (Panenza®), when tested in similar populations of adult and elderly volunteers. METHODS: The monovalent vaccine was evaluated in two clinical trials, conducted respectively in both adult and elderly subjects and in a population of adults. The trivalent vaccine was evaluated in a clinical study that enrolled both adult and elderly subjects. Antibody titers were measured in serum samples drawn at day 0 (before vaccination) and 21 days after one vaccine injection using the same hemagglutination inhibition (HI) assay method. The occurrence of adverse events was reported up to 21 days after vaccination. RESULTS: Before immunization in the three studies, most of the volunteers had antibody titers below seroprotective levels against the pandemic A(H1N1) 2009 virus. After vaccination, in each trial and in each age group, high seroprotection rates, GMT ratios and seroconversion rates were observed. Seroprotection rates after administration of the monovalent vaccine reached 93% and 98% in the adult groups, and 83.7% in the elderly group. After administration of the trivalent vaccine, seroprotection rates of 92.2% and 81.3% were obtained respectively in the adult and the elderly groups. No related serious adverse events and no safety signals were detected either with the monovalent or trivalent vaccine. CONCLUSION: Comparable immunogenicity profiles were observed in three clinical trials of the pandemic A(H1N1) 2009 strain when formulated either as a monovalent or as a component of a seasonal trivalent vaccine.

Heterosubtype neutralizing responses to influenza A (H5N1) viruses are mediated by antibodies to virus haemagglutinin.

BACKGROUND: It is increasingly clear that influenza A infection induces cross-subtype neutralizing antibodies that may potentially confer protection against zoonotic infections. It is unclear whether this is mediated by antibodies to the neuraminidase (NA) or haemagglutinin (HA). We use pseudoviral particles (H5pp) coated with H5 haemagglutinin but not N1 neuraminidase to address this question. In this study, we investigate whether cross-neutralizing antibodies in persons unexposed to H5N1 is reactive to the H5 haemagglutinin. METHODOLOGY/PRINCIPAL FINDINGS: We measured H5-neutralization antibody titers pre- and post-vaccination using the H5N1 micro-neutralization test (MN) and H5pp tests in subjects given seasonal vaccines and in selected sera from European elderly volunteers in a H5N1 vaccine trial who had detectable pre-vaccination H5N1 MN antibody titers. We found detectable (titer > or = 20) H5N1 neutralizing antibodies in a minority of pre-seasonal vaccine sera and evidence of a serological response to H5N1 in others after seasonal influenza vaccination. There was excellent correlation in the antibody titers between the H5N1 MN and H5pp tests. Similar correlations were found between MN and H5pp in the pre-vaccine sera from the cohort of H5N1 vaccine trial recipients. CONCLUSIONS/SIGNIFICANCE: Heterosubtype neutralizing antibody to H5N1 in healthy volunteers unexposed to H5N1 is mediated by cross-reaction to the H5 haemagglutinin.

Humoral and cellular immune responses to split-virion H5N1 influenza vaccine in young and elderly adults.

We evaluated the humoral and cellular immunogenicity of adjuvanted and non-adjuvanted H5N1 influenza vaccine in two groups of 300 adults: aged 18-60 and >60 years in a randomized, open-label, uncontrolled phase 2 trial. Participants received two injections (D0, D21) of 7.5 microg hemagglutinin without adjuvant or 30 microg with aluminum hydroxide adjuvant. Antibody responses and cytokine secretion were assessed before and after vaccination. Excluding the 6/300 non-elderly and 47/300 elderly participants with pre-existing antibodies, geometric mean titers (dil(-1)) on D42 were higher with 30 microg+Ad and were comparable between age groups. Participants with pre-existing antibodies responded strongly to the first vaccination (GMTs in the range 147-228 on D21). Vaccination increased both Th1 and Th2 T-cell responses. The predominantly Th1 profile observed before vaccination was unaffected by vaccination. H5N1 influenza vaccine is no less immunogenic in elderly adults than in younger adults and, due to a higher proportion non-naïve elderly, immunogenicity was higher in this latter group.

Safety, humoral and cell mediated immune responses to two formulations of an inactivated, split-virion influenza A/H5N1 vaccine in children.

BACKGROUND: Highly pathogenic influenza A/H5N1 has caused outbreaks in wild birds and poultry in Asia, Africa and Europe. It has also infected people, especially children, causing severe illness and death. Although the virus shows limited ability to transmit between humans, A/H5N1 represents a potential source of the next influenza pandemic. This study assesses the safety and immunogenicity of aluminium hydroxide adjuvanted (Al) and non adjuvanted influenza A/Vietnam/1194/2004 NIBRG-14 (H5N1) vaccine in children. METHODS AND FINDINGS: In a Phase II, open, randomised, multicentre trial 180 children aged 6 months to 17 years received two injections, 21 days apart, of vaccine containing either: 30 microg haemagglutinin (HA) with adjuvant (30 microg+Al) or 7.5 microg HA without adjuvant. An additional 60 children aged 6-35 months received two "half dose" injections (ie 15 microg+Al or 3.8 microg). Safety was followed for 21 days after vaccination. Antibody responses were assessed 21 days after each injection and cellular immune responses were explored. Vaccination appeared well tolerated in all age groups. The 30 microg+Al formulation was more immunogenic than 7.5 microg in all age groups: in these two groups 79% and 46% had haemagglutinination inhibition antibody titres > or =32 (1/dil). Among 6-35 month-olds, the full doses were more immunogenic than their half dose equivalents. Vaccination induced a predominantly Th2 response against H5 HA. CONCLUSIONS: This influenza A(H5N1) vaccine was well tolerated and immunogenic in children and infants, with Al adjuvant providing a clear immunogenic advantage. These results demonstrate that an H5N1 Al-adjuvanted vaccine, previously shown to be immunogenic and safe in adults, can also be used in children, the group most at risk for pandemic influenza.