Prepandemic Influenza Vaccine H5N1 (Split Virion, Inactivated, Adjuvanted) [Prepandrix™]

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Abstract
Although rare, influenza pandemics are a recurrent event, and influenza A/H5N1 is generally considered to be the most likely causative agent of the next pandemic. Vaccines are widely considered to be the first line of defense for protecting populations in advance of an influenza pandemic. Because it is not known beforehand which strain of influenza A/H5N1 virus could give rise to a pandemic, prepandemic vaccines that impart broad cross-reactive immunogenicity are required. In addition, low doses of H5 hemagglutinin are preferable in order to make antigen supplies go further towards meeting global demands for prepandemic vaccines. Prepandemic influenza vaccine H5N1 [Prepandrix™; AS03-H5N1 vaccine] is a split virion, inactivated vaccine containing H5 hemagglutinin antigen adjuvanted with a novel 10% oil-in-water emulsion-based adjuvant system (AS03). It is approved in the EU for use as an active immunization against H5N1 subtype influenza A virus (influenza A/H5N1 virus) in adults aged 18–60 years. The recommended dosage in this population is two doses of 0.5 mL containing 3.75 µg of H5 hemagglutinin, administered ≥21 days apart. Adjuvantation of H5N1 vaccine with AS03 allows for a reduction in the H5 hemagglutinin dose required to elicit an adequate immune response, and administration of two doses of the adjuvanted vaccine met all criteria for the licensure of influenza vaccines set out in European Committee for Proprietary Medicinal Products (CPMP) and US FDA documents. In two clinical trials, two doses of AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin induced an immune response in healthy volunteers aged 18–60 years against the homologous, clade 1 vaccine strain, A/Vietnam/1194/2004, and the heterologous, drifted, clade 2 nonvaccine strains, A/Anhui/1/2005, A/Indonesia/5/2005, and A/turkey/Turkey/1/2005. This cross-clade response persisted for ≥6 months following administration of the first vaccine dose in the majority of vaccine recipients. In addition, AS03-H5N1 vaccine protected against lethal challenge with A/Vietnam/1194/2004 or A/Indonesia/5/2005 in animal studies. The vaccine was generally well tolerated and adverse events were transient and predominantly of mild to moderate severity. AS03-H5N1 vaccine has demonstrated antigen dose-sparing properties and cross-clade reactive immunity in clinical trials and challenge studies in animal models. As a result, stockpiling AS03-H5N1 vaccine has the potential to protect populations against a pandemic caused by an influenza A/H5N1 virus and may represent an important measure in pandemic preparedness. AS03-H5N1 vaccine containing an H5 hemagglutinin dose of 3.75 µg elicited a satisfactory immune response against the homologous, clade 1, vaccine strain A/Vietnam/1194/2004 in a randomized, observer-blind, parallel-group, dose-finding trial and a phase III, lot-to-lot consistency trial in adult volunteers aged 18–60 years. In the dose-finding study, volunteers received AS03-H5N1 (n = 200) or nonadjuvanted-H5N1 (n = 200) vaccine containing 3.75, 7.5, 15.0, or 30.0 µg of H5 hemagglutinin. An H5-hemagglutinin dose-response effect was observed for antihemagglutinin antibody and neutralizing antibody titers over the dose range studied. All CPMP and FDA acceptance criteria for the licensure of influenza vaccines were met following two doses of AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin administered 21 days apart. This allowed for antigen dose sparing when compared with nonadjuvanted-H5N1 vaccine, which only met two of three CPMP criteria after two doses of vaccine containing 30 µg of H5 hemagglutinin. Based on the results of the dose-finding study, the phase III, lot-to-lot consistency study focused solely on the immunogenicity of AS03-H5N1 (n = 961) and nonadjuvanted-H5N1 (n = 245) vaccine containing 3.75 µg of H5 hemagglutinin. Where endpoints were reported, CPMP criteria were met with AS03-H5N1, but not nonadjuvanted-H5N1 vaccine, in the consistency study. Not only did AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin elicit an adequate immune response against the clade 1 vaccine strain A/Vietnam/1194/2004, but it also induced cross-clade immunity against the heterologous, drifted, clade 2 strains A/Anhui/1/2005 (subclade 2.3), A/Indonesia/5/2005 (subclade 2.1), and A/turkey/Turkey/1/2005 (subclade 2.2). In the dose-finding study, the neutralizing antibody serocon-version rate against these clade 2 strains following the second vaccine dose was 75%, 77%, and 85% for A/Anhui/1/2005, A/Indonesia/5/2005, and A/turkey/Turkey/1/2005, respectively; in the consistency study, the neutralizing antibody seroconversion rate was 91.4% for A/Indonesia/5/2005. In terms of neutralizing antibody seroconversion rates, 60–70% of recipients had retained a cross-neutralizing response against A/Anhui/1/2005 and A/turkey/Turkey/1/2005 and 40% had retained a cross-neutralizing response against A/Indonesia/5/2005 at 6 months after administration of the first vaccine dose. Because the efficacy of AS03-H5N1 vaccine cannot ethically be studied in the target population prior to the onset of a pandemic, animal studies are required; ferrets are widely considered to be the best proxy for humans in the study of influenza A/H5N1 vaccines. In two such studies, ferrets receiving AS03-H5N1 vaccine containing 0.6–15.0 µg of H5 hemagglutinin or either a control vaccine containing AS03 alone, phosphate-buffered saline, or nonadjuvanted-H5N1 vaccine containing 15.0 µg of H5 hemagglutinin, were challenged with a lethal dose of the homologous clade 1, vaccine influenza A/H5N1 strain A/Vietnam/1194/2004 or the heterologous, drifted, clade 2, nonvaccine strain A/Indonesia/5/2005. Challenge with the vaccine strain resulted in an H5 hemagglutinin-dose-dependent immune response in ferrets receiving AS03-H5N1 vaccine, with all ferrets receiving the 15 µg dose surviving the challenge. The majority of AS03-H5N1 vaccine-receiving ferrets (≥65%) had a low viral load (2 50% tissue culture infective dose/g or mL) in lung tissue and on pharyngeal swabs. In addition, 74% and 61% of ferrets that were challenged with the clade 2, nonvaccine strain, A/Indonesia/5/ 2005, and received AS03-H5N1 vaccine, demonstrated a serologic response against the vaccine and nonvaccine viral strains. The majority (≥67%) of these ferrets had a low level of virus replication in lung tissue and on pharyngeal swabs, had a low rate of viral shedding, and survived until the end of the challenge period. This was in contrast to the control ferrets, none of which developed a serologic response, and all of which had a high level of virus replication and shedding, and either died or were euthanized because they were moribund during the challenge period. In addition, even in those ferrets receiving AS03-H5N1 vaccine that did not show a serologic response, the lung viral loads were generally lower than those seen with control animals. AS03-H5N1 vaccine containing 3.75, 7.5, 15.0, or 30.0 µg of H5 hemagglutinin administered as two doses 21 days apart was generally well tolerated in healthy adults aged 18–60 years. Regardless of H5 hemagglutinin dose, injection site pain was the most frequently reported solicited local adverse event associated with AS03-H5N1 vaccine in a dose-finding study in healthy adults aged 18–60 years, and in a phase III active comparator trial in healthy adults aged ≥18 years. In these studies, the incidence of pain was significantly higher in those who received AS03-H5N1 vaccine than in those who received nonadjuvanted-H5N1 or seasonal influenza vaccine/placebo. Other frequently reported solicited local adverse events associated with AS03-H5N1 vaccine included injection site redness, induration, swelling, and less commonly, ecchymosis. Fatigue, myalgia, and headache were the most frequently occurring solicited general adverse events associated with AS03-H5N1 vaccine. The majority of local and general adverse events were of mild to moderate severity; in addition, most local adverse events had resolved or decreased in intensity within 48 hours. Unsolicited adverse events, including grade 3 unsolicited adverse events, were reported with similar frequency in AS03-H5N1 vaccine recipients and seasonal influenza vaccine/placebo recipients. Lymph-node related adverse events were uncommon (≤3.5%), and those that were thought to be vaccine-related and of grade 3 severity had fully resolved within 2–4 days.

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