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Development of Vaccines Against Influenza H5

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  • Development of Vaccines Against Influenza H5

    The Lancet Infectious Diseases 2006; 6:458-460
    Development of vaccines against influenza H5 Iain Stephenson a, Ian Gust b c, Yuri Pervikov d and Marie Paule Kieny d

    During 2006, highly pathogenic avian influenza A (H5N1) has extended its geographic range, with outbreaks occurring in poultry and migratory birds in Europe and Africa.1 Genomic and antigenic analyses of H5N1 viruses isolated since 2004 reveal at least two distinct sublineages with different geographic distributions.2 Clade 1 H5N1 viruses circulate in China and the Indochina peninsula, whereas isolates from Indonesia and some neighbouring countries are clustered in a divergent clade 2 group. Recent human H5N1 infections have been with viruses of both sublineages.1 Manufacturers in nine countries are developing candidate vaccines, and several prepared from influenza A/Vietnam/2004 (H5N1) (clade 1 virus) have entered, or completed, clinical trials.
    On May 4?5, 2006, WHO convened the second of a series of meetings3 to evaluate data from current vaccine studies, review the research agenda, and plan future activities to accelerate development of these vaccines. Here, we present a summary of discussions.
    The diversity of circulating H5N1 viruses suggests that the reference strains currently available might not optimally match an emerging pandemic virus. WHO has a crucial role in coordinating surveillance of H5N1 viruses and identifying reference strains suitable for provision to manufacturers. However, there are still barriers to the rapid distribution of reference viruses that need to be tackled. Some of them relate to intellectual property rights and differing national regulations on genetically modified organisms.
    To generate reference viruses for provision to vaccine manufacturers, highly pathogenic H5N1 viruses are manipulated by reverse genetics to remove the polybasic aminoacid sequence responsible for virulence, and reassorted with viruses that have previously grown well in eggs, an important characteristic for vaccine production.4 However, most manufacturers report that yields of antigen from reverse genetics-derived H5N1 viruses are 30?40% of the average of seasonal influenza viruses, reducing the quantity of antigen available for vaccine formulation. There is an urgent need to improve the yield of reverse genetics-derived H5N1 viruses in eggs (figure), which necessitates an improved understanding of the molecular basis of influenza virus replicative capacity.

    Click to enlarge image

    Figure. The yield of reverse genetic-derived H5N1 virus in eggs needs to be improved James King-Holmes/Science Photo Library

    Several clinical trials to evaluate candidate subvirion H5N1 vaccines are underway, mainly in healthy adults. In the USA, a dose-ranging study of non-adjuvanted subvirion influenza A/Vietnam/1203/04 (H5N1) vaccine was done in healthy adults.5 Although vaccine was well tolerated, only two doses each containing 90 μg haemagglutinin induced levels of antibody acceptable for licensing. Post-hoc analysis suggests that substantially higher responses occurred in recipients under 40 years of age. In a concurrent study, intradermal administration of two doses of vaccine containing 3 μg and 9 μg haemagglutinin was poorly immunogenic.
    Within the constraints of the current global manufacturing capacity for influenza vaccines, efforts to increase supply in the short-term and medium-term focus on new formulations that require less antigen per dose (?antigen-sparing? strategy). In Australia, 400 healthy adults received two doses of aluminium phosphate-adjuvanted or unadjuvanted subvirion influenza A/Vietnam/1194/04 (H5N1) vaccine. After two doses of unadjuvanted vaccine containing 7?5 μg or 15 μg haemagglutinin, 18% and 34% of recipients developed neutralising antibody, respectively. Addition of alum induced modest increases in immunogenicity, with 34% and 41% of recipients seroconverting, respectively. In France, two doses of an aluminium hydroxide-adjuvanted subvirion influenza A/Vietnam/1194/04 (H5N1) vaccine was immunogenic at 30 μg dose, inducing seroconversion by neutralising antibody in 41% of recipients.6 There was no adjuvant effect at doses of 7?5 μg or 15 μg haemagglutinin. Additional antigen-sparing strategies are urgently needed to increase pandemic vaccine global supply.
    Whole-virus vaccines are being considered in pandemic vaccine planning, since such vaccines have been demonstrated to be more immunogenic in unprimed human beings.7 Animal studies of adjuvanted whole-virus reverse genetics-derived H5N1 vaccines demonstrate protection against lethal challenge with homologous and antigenically distinct H5N1 viruses.8,9 Encouraging results were reported from Hungary in a study of aluminium phosphate-adjuvanted whole-virus vaccine prepared from reverse genetics-derived influenza A/Vietnam/1194/04 (H5N1). A single dose, containing 6 μg antigen, induced seroconversions in 68% of 146 recipients, as measured by haemagglutinin-inhibition tests with chicken erythrocytes. Alum-adjuvanted whole-virus vaccine studies are underway in China and Japan. However, if whole-virus vaccines are confirmed to be more immunogenic than subvirion vaccines, this will pose challenges to manufacturers and regulators, since it will require substantial changes to existing licensed production processes. Importantly, reactogenicity will need to be assessed carefully.
    The antigenic diversity of circulating H5N1 viruses means that vaccines prepared (and possibly stockpiled) from reference strains generated in 2004 could be suboptimally matched to a future pandemic virus. Proper adjuvantation could help to alleviate that problem. In a clinical trial of MF59-adjuvanted subunit influenza A/Duck/Singapore/97 (H5N3) vaccine, a third vaccine dose induced immune responses that were broadly cross-reactive to a range of H5N1 antigenic variants, suggesting that a priming strategy might be useful against a future H5N1 pandemic.10 Additional studies are required to evaluate the merits of priming populations in advance of a pandemic.
    Live attenuated influenza vaccines, which are licensed for prevention of seasonal influenza, are highly efficacious, and seem to induce a broader immune response than antigenically matched inactivated split-virus vaccines. A single dose of cold-adapted H5N1 vaccine demonstrated protective efficacy against lethal challenge with homologous and antigenically distinct H5N1 variants in the mouse model. In addition, the growth characteristics of reverse genetics-derived influenza A/Vietnam/2004 (H5N1) live attenuated virus are favourable for bulk vaccine production. Candidate live attenuated H5N1 vaccines are planned to enter clinical evaluation in 2006.
    To allow comparative analysis of studies, priority should be given to the generation of international standards for assessing serological responses to H5N1 antigens. The lack of established correlates of immunity in animals and human beings poses challenges to developing consistent immunological endpoints for clinical trials and appropriate criteria for vaccine licensing. Moreover, the relevance of currently accepted standards of seroconversion for seasonal vaccines needs to be revisited for their relevance to pandemic vaccines.
    Appropriately powered and controlled clinical studies of antigen-sparing and adjuvanted vaccine formulations in children, healthy adults, and elderly people remains an important international health priority and they cannot be carried out without government support. Although substantial investment in vaccine manufacturing capacity and infrastructure is occurring, this will be insufficient to meet the expected worldwide demand for vaccines in case of an influenza pandemic. WHO will continue to provide leadership to optimise immunisation strategies for pandemic influenza, and will review additional data when it becomes available early in 2007.

    <!--start simple-tail=-->References

    1. WHO. Avian influenza
    (accessed June 22, 2006).
    2. WHO Global Influenza Program Surveillance Network. Evolution of avian influenza viruses in Asia. Emerg Infect Dis 2005; 11: 1515-1521. MEDLINE
    3. Stephenson I, Gust I, Kieny MP, Pervikov Y. Development and evaluation of pandemic influenza vaccines. Lancet Infect Dis 2006; 6: 71-72. Full Text | PDF (41 KB) | MEDLINE | CrossRef
    4. Webby RJ, Perez DR, Coleman JS, et al. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet 2004; 363: 1009-1103.
    5. Treanor JJ, Campbell JD, Zangwill KM, Rowe T, Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006; 354: 1345-1351.
    6. Bresson JL, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006; 367: 1657-1664. Abstract | Full Text | PDF (123 KB) | CrossRef
    7. Stephenson I, Nicholson KG, Wood JM, Zambon MC, Katz JM. Confronting the avian influenza threat: vaccine development for a potential pandemic. Lancet Infect Dis 2004; 4: 499-509. Abstract | Full Text | PDF (572 KB) | MEDLINE | CrossRef
    8. Lipatov AS, Webby RJ, Govorkova EA, Krauss S, Webster RG. Efficacy of H5 influenza vaccines produced by reverse genetics in a lethal mouse model. J Infect Dis 2005; 191: 1216-1220. MEDLINE | CrossRef
    9. Hoffmann E, Lipatov AS, Webby RJ, Govorkova EA, Webster RG. Role of haemagglutinin amino acids in the immunogenicity and protection of influenza virus vaccines. Proc Natl Acad Sci USA 2005; 102: 12915-12920.
    10. Stephenson I, Bugarini R, Nicholson KG, et al. Cross-reactivity to highly pathogenic avian influenza viruses after vaccination with MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005; 191: 1210-1215. MEDLINE | CrossRef
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    <!--end simple-tail-->Affiliations

    a. Infectious Diseases Unit, University Hospitals Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
    b. WHO Collaborating Centre for Influenza, Reference and Research Melbourne
    c. Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    d. Initiative for Vaccine Research, WHO, Geneva, Switzerland

  • #2

    Figure. The yield of reverse genetic-derived H5N1 virus in eggs needs to be improved