Pandemic H5N1 Influenza Vaccine development: An Update

Hana M El Sahly; Wendy A Keitel


Expert Rev Vaccines. 2008;7(2):241-247. 

In This Article

Development of H5N1 Vaccines

So far, attempts to develop H5N1 vaccines have met multiple challenges. Traditional influenza vaccine development requires growing the influenza strain in embryonated eggs. However, in addition to the hazard of affecting the environment and personnel, infection of eggs with HPAI strains resulted in the rapid death of the embryos and hence, adequate viral titers could not be reached. Scientists initially attempted to circumvent this problem by using low-pathogenicity strains as surrogates. A low-pathogenicity strain for the currently circulating H5N1 strains has not been identified. Removal of the polybasic amino acid of the hemagglutinin (HA) cleavage site that is responsible for the virulence of the HPAI, followed by reassortment with an A/PR8/34 backbone permitted growth of the virus in eggs.[20,21,22] This latter approach, known as reverse genetics, has resulted in viral titers compatible with vaccine production, albeit at lower titers than interpandemic strains. Alternative vaccine production methods have been explored, including baculovirus-expressed recombinant-HA vaccines, live-attenuated influenza vaccines (LAIV), whole virus vaccines and adenovirus-vectored H5 vaccines.[23,24,25,26,27,28] Adenovirus-vectored vaccines are currently in the preclinical developmental stages, with no data on safety and immunogenicity in humans yet. Another approach to design influenza vaccines involves creating constructs aimed at eliciting immune responses against the conserved influenza proteins M2 and/or nucleoprotein, hence minimizing the impact of the strain drift.[29,30] Animal data are promising, and human clinical trials are underway.

The sensitivity of the hemagglutinin inhibition assays (HAI), the standard antibody assay used to measure influenza vaccine responses depends, in part, on the substrate used. The widely used chicken or turkey red blood cells are less sensitive than horse red blood cells at detecting antibody responses against H5N1 strains.[31,32] Moreover, studies have shown that there is a wide intra- and interlaboratory variability in the reproducibility of the HAI and viral neutralization assays. The variability was more pronounced for the viral neutralization assay than the HAI, with different laboratories using different protocols and methods of detection of neutralization. The use of a uniform serum standard has been shown to improve the reproducibility of both assays in at least two studies, but the use of the standard is not applied currently. In the case of H5N1 viruses, antigenic drift and the fact that the strain that may cause the pandemic is unknown, add complexity to the issue by making the choice of a standard largely speculative.[33,34] The lack of standardization of the immunogenicity assays makes comparisons between different vaccine clinical trials difficult. The available guidelines proposed for testing influenza vaccine immunogenicity have been developed based on experience and data from interpandemic influenza studies, and caution needs to be applied when extrapolating these to pandemic influenza.[35,36]

There are several additional hurdles that need to be overcome:

  • There is a need for global cooperation between various governmental and nongovernmental institutions to advance the development of the vaccine, since avian influenza has affected various regions of the world disproportionately;

  • Influenza A H5N1 strains continue to undergo antigenic drift and expand in diversity, making predictions of the strain that will cause a pandemic more difficult;

  • There is need for biosafety level-3 containment laboratory to manipulate the virulent H5N1 strains;

  • If and when a vaccine is deemed safe and immunogenic for public use, the cost of production, deployment to high-risk areas, access to vaccine in resource-poor countries and p-rioritization of resources will become major issues.


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