Long-term booster schedules with AS03A-adjuvanted heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults

Abstract

BackgroundThe pandemic potential of avian influenza A/H5N1 should not be overlooked, and the continued development of vaccines against these highly pathogenic viruses is a public health priority.MethodsThis open-label extension booster study followed a Phase III study of 1206 adults who had received two 3.75 μg doses of primary AS03A-adjuvanted or non-adjuvanted H5N1 split-virus vaccine (A/Vietnam/1194/2004; clade 1) (NCT00449670). The aim of the extension study was to evaluate different timings for heterologous AS03A-adjuvanted booster vaccination (A/Indonesia/5/2005; clade 2.1) given at Month 6, 12, or 36 post-primary vaccination. Immunogenicity was assessed 21 days after each booster vaccination and the persistence of immune responses against the primary vaccine strain (A/Vietnam) and the booster strain (A/Indonesia) was evaluated up to Month 48 post-primary vaccination. Reactogenicity and safety were also assessed.ResultsAfter booster vaccination given at Month 6, HI antibody responses to primary vaccine, and booster vaccine strains were markedly higher with one dose of AS03A-H5N1 booster vaccine in the AS03A-adjuvanted primary vaccine group compared with two doses of booster vaccine in the non-adjuvanted primary vaccine group. HI antibody responses were robust against the primary and booster vaccine strains 21 days after boosting at Month 12 or 36. At Month 48, in subjects boosted at Month 6, 12, or 36, HI antibody titers of ≥1:40 against the booster strain persisted in 39.2%, 61.2%, and 95.6% of subjects, respectively. Neutralizing antibody responses and cell-mediated immune responses also showed that AS03A-H5N1 heterologous booster vaccination elicited robust immune responses within 21 days of boosting at Month 6, 12, or 36 post-primary vaccination. The booster vaccine was well tolerated, and no safety concerns were raised.ConclusionsIn Asian adults primed with two doses of AS03A-adjuvanted H5N1 pandemic influenza vaccine, strong cross-clade anamnestic antibody responses were observed after one dose of AS03A-H5N1 heterologous booster vaccine given at Month 6, 12, or 36 after priming, suggesting that AS03A-adjuvanted H5N1 vaccines may provide highly flexible prime–boost schedules. Although immunogenicity decreased with time, vaccinated populations could potentially be protected for up to three years after vaccination, which is likely to far exceed the peak of the a pandemic.

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults

“…In addition, recent studies seem to suggest that a robust immune response to the HA head and stalk domains, as measured with enzyme-linked immunosorbent assay, may be induced even in the absence of HI and MN response [27], so the clinical relevance of the decline in antibody titers is not clear. The observed kinetics of the immune response in adjuvanted groups in our study is similar to that elicited by other influenza vaccines, in particular the adjuvanted H5N1 vaccines [28], for which a strong anamnestic response was elicited by a heterologous booster dose, up to 3 years after priming [29, 30]. …”

Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial

“…In support of this theory, Gillard et al . have previously shown that a 2-dose prime regimen with 3.75mcg of split-virus H5N1 vaccine (A/Vietnam/1194/2004) without adjuvants led to cross-reactive seroprotection following a second 2-dose boost regimen with a heterologous 3.75mcg split-virus unadjuvanted H5N1 vaccine (A/Indonesia/5/2005) administered 6 months later [88]. Accordingly, the monocyte and neutrophil time trend responses that we observed to accompany early upregulation of MHC class-II responses in those cell types in the SV-AS03 group were also increased slightly at day 28 in the unadjuvanted vaccine group ( Fig 4 ).…”

Reactogenicity and safety of AS03B-adjuvanted H5N1 influenza vaccine in children: an open-label, one-way, crossover trial

“…In the previous open-label pediatric study of Dresden-manufactured H5N1 vaccine, 2 doses (1.9 μg HA) of AS03 B -H5N1 vaccine (n = 51) was associated with an overall rate of injection site pain of 60.8% in children aged 3-5 years and 86.3% in children aged 6-9 years [8]. Our study of Québec-manufactured AS03 B -H5N1 vaccine (1.9 μg HA) included children with a broader age range than that in the previous study and showed that the incidence of solicited injection site pain in vaccine recipients overall was 67.2% in Year 1 and 72.1% in Year 2 [14].…”

“…In a Phase III study of AS03 Aadjuvanted H5N1 (AS03 A -H5N1) pandemic influenza vaccination in populations in Taiwan, Thailand, Singapore, and Hong Kong, the vaccine was found to be immunogenic and well tolerated [7]. A 4-year follow-up study showed that the vaccine was immunogenic and cross-reactive when given according to various prime-boost schedules, which is key to providing adequate and rapid vaccine coverage in the event of the emergence and rapid spread of a pandemic strain [8].…”