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Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1
Source: 10-OCT-2008 Intellasia | Content
10 Oct, 2008 - 7:00:00 AM
Antigenically distinct avian influenza A (H5N1) viruses are widely dispersed.1 Clade 1 H5N1 viruses previously predominated in Indochina. Indonesian, Eurasian, and African viruses are clustered in a clade 2 group, with antigenically distinct sublineages. Clade 0 viruses caused influenza outbreaks in Hong Kong in 1997 but have not been isolated since then. To reduce shortfalls in vaccine supply at the onset of the next pandemic, advance stockpiling of vaccine has been suggested. Because of antigenic evolution of H5N1, current vaccines may be suboptimally matched to the actual pandemic virus. Proactive priming may induce immune memory, allowing low-dose vaccination to induce rapid cross-protection when needed.
We report on an open-label study conducted from June through August 2007 at Leicester Royal Infirmary, Leicester, United Kingdom. Two 7.5-µg doses of MF59-adjuvanted, surface-antigen vaccine against clade 1 A/Vietnam/1194/2005 (NIBRG-14) (Novartis) were administered by intramuscular injection 21 days apart to subjects who had been vaccinated (primed) with clade 0 H5 vaccine at least 6 years earlier. All primed subjects had received two doses of either MF59-adjuvanted or nonadjuvanted (plain) A/duck/Singapore/97 (H5N3) vaccine containing 7.5 to 30 µg of hemagglutinin in studies conducted between 1999 and 2001.2,3,4 Some subjects had also received a booster dose 16 months after primary immunisation.3 Antibody responses were detected with the use of neutralising and hemagglutination-inhibition assays performed at the UK Health Protection Agency, with homologous clade 1 NIBRG-14 and heterologous clade 2.2 NIBRG-23 vaccine reference strains and by hemagglutination-inhibition assay at the Centres for Disease Control and Prevention with wild-type A/Vietnam/1194/2005 (clade 1), A/Indonesia/5/2005 (clade 2.1), A/Anhui/1/2005 (clade 2.3), and A/Turkey/15/2006 (clade 2.2) viruses.
Twenty-four subjects had received two or three doses of either plain or MF59-adjuvanted H5N3 vaccine, with subjects equally divided between the two groups. Thirty subjects were unprimed. Vaccines had acceptable side-effect profiles, and no serious vaccine-related adverse events were recorded. Serum samples were obtained immediately before each of the two doses of vaccine was administered (on days 0 and 21) and on days 7, 14, and 42 after vaccination.
On each post-vaccination day, and with each assay, geometric mean titers of antibodies to NIBRG-14 and NIBRG-23 were significantly higher among the primed subjects than among the unprimed subjects (P0.001 for all comparisons, except on day 42 for NIBRG-14 on hemagglutination-inhibition assay). From day 14 onward, and for each assay, titers of antibodies to both viruses were significantly higher in the MF59-primed group than in the plain-primed group (P0.05 for all comparisons). The highest titers were observed on day 14 in the MF59-primed group, with geometric mean titers of antibodies to NIBRG-14 and NIBRG-23 of 1:378 and 1:347, respectively, on hemagglutination-inhibition assay and of 1:1754 and 1:2128, respectively, on neutralising assay. No relation between the post-vaccination titer and the number of previous doses of H5N3 vaccine or their antigen content was observed. By day 7, at least 80% of MF59-primed subjects had titers of at least 1:40 for all wild-type viruses tested on hemagglutination-inhibition assay.
Modeling of pandemic spread shows that the maximum reduction in viral transmission is achieved by the induction of a response within 2 weeks after the outbreak of the pandemic.5 Because two doses of the vaccine are required, rapid vaccine deployment will be challenging. Our findings indicate that priming subjects with H5 antigen induces a rapidly mobilised, long-lasting immune memory after the administration of low-dose, antigenically distinct vaccine. Given the protective titers detected by day 7, the effect of MF59 adjuvant is striking. Consideration could be given to a proactive vaccine-priming strategy, particularly among those at high risk for pandemic influenza such as health care workers, so that cross-clade antibodies could be rapidly generated after single vaccination or after exposure to the pandemic virus.
Iain Stephenson, M.A., F.R.C.P.
Karl G. Nicholson, F.R.C.Path., F.R.C.P.
University Hospitals Leicester
Leicester LE1 5WW, United Kingdom
iain.stephenson@uhl-tr.nhs.uk
Katja Hoschler, Ph.D.
Maria C. Zambon, Ph.D.
Health Protection Agency
Colindale NW9 5HT, United Kingdom
Kathy Hancock, Ph.D.
Joshua DeVos, M.P.H.
Jacqueline M. Katz, Ph.D.
Centres for Disease Control and Prevention
Atlanta, GA 30333
Michaela Praus
Angelika Banzhoff, M.D.
Novartis Vaccine
35041 Marburg, Germany
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