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

Abstract and Introduction

The spread and evolution of highly pathogenic influenza A/H5N1 viruses in birds worldwide, and the associated human fatalities, have raised concern about an imminent influenza pandemic. Studies evaluating the safety and immunogenicity of traditional (egg-grown, subvirion and whole virus) vaccines and alternative vaccine approaches (recombinant, live-attenuated and adjuvanted vaccines) have been performed. Results show that, using unadjuvanted subvirion vaccines, at least two vaccine doses containing high dosages of influenza virus hemagglutinin are needed to elicit a titer of antibody that has been associated with protection in vaccinated subjects. High antigen-dosage requirements may be reduced and immunogenicity improved with the use of whole virus vaccines or adjuvants, such as MF59 and GlaxoSmithKline proprietary adjuvant. There is a suggestion that prepandemic priming against drifted H5N1 variants is possible; however, additional data are needed. Newer approaches using live-attenuated, DNA vaccines and conserved epitopes are currently under development.

Pandemics of influenza have been ravaging societies for at least as long as human history has been recorded. The medical, social and economic impact of influenza pandemics is exemplified by the 1918 "Spanish flu", which was caused by the H1N1 strain of influenza A and resulted in the estimated death of 500,000 individuals in the USA, and 50 million people worldwide.[1,2] The Spanish flu pandemic was exceptionally lethal (crude death rate of 218.4 per 100,000 people) and unusual in causing high mortality rates in healthy young adults, not just in infected individuals at extremes of age.[3] This is often described as the "W-shaped" mortality curve of the Spanish flu, compared with the usual "U-shaped" mortality curve of other pandemics. Two other pandemics ensued: the "Asian flu" of 1957, caused by the H2N2 strain of influenza A and the "Hong Kong flu" of 1968, caused by the H3N2 strain of influenza A. While the human H1N1 strain is thought to be an avian strain adapted to humans, the H3N2 and H2N2 pandemic strains arose from reassortment of avian strains with the human-adapted H1N1 virus; both pandemics resulted in appreciably lower mortality rates than the Spanish flu.[4,5,6,7,8]

Almost four decades after the last pandemic, the WHO declared that the emergence and persistence of the H5N1 strain of influenza A in birds is a public-health threat and published early response strategies to contain the pandemic.[52] There are various characteristics of the epidemiology of H5N1 influenza that j-ustify this concern:

  • Highly pathogenic avian influenza (HPAI) H5N1 strain of various sublineages is now endemic in many avian species, especially in Southeast Asia, thus raising the likelihood of reassortment with human strains and a repeat of the pandemic scenarios of 1957 and 1968;

  • Human populations are immunologically naive to the H5N1 strain;

  • Mortality of H5N1 infections in humans has exceeded 50%, a mortality worse than that associated with the "Spanish flu";

  • Thus far, the different genotypes of H5N1 have demonstrated the ability to infect humans through transmission from poultry, albeit without efficient human to human transmission.[9,10,11,12,13,14,52]

In the last 10 years, other species of avian influenza have resulted in human disease, such as H7N7 and H9N2, but neither has been as widely disseminated as H5N1 in avian species, nor caused as many recognized fatalities in humans.[15,16] While the rule about influenza pandemics is that they are unpredictable, the aforementioned facts necessitate advance preparation for containment and prevention of a potential H5N1 pandemic. This review will focus on the development of vaccines against influenza A/H5N1 strains.

Reducing the impact of the potential pandemic would entail pharmaceutical and nonpharmaceutical interventions. Non-pharmaceutical interventions aim mainly to delay the spread of the virus in the community, allowing time for pharmaceutical interventions, such as vaccines, to improve the readiness of the community. Nonpharmaceutical interventions include limiting international travel, isolation and treatment of ill individuals, monitoring and possible quarantine of exposed individuals and the cancellation of mass gatherings.[17,18] Pharmaceutical approaches include vaccines and antiviral medications. Stockpiling of antivirals has been suggested as an option, but this approach is fraught with budgetary restrictions (especially in developing countries) and concerns about the misuse and development of drug resistance. Furthermore, because pandemics usually come in waves, it is unrealistic to expect that stockpiled antivirals would be available in high enough quantities to contain and/or prevent disease in a large number of susceptible individuals for a protracted period of time. A more feasible approach to reducing the pandemic impact would require the development of safe and effective vaccines against H5N1, and developing strategies for implementation of rapid, large-scale vaccine administration campaigns. According to mathematical modeling by Ferguson et al., mass vaccination with a vaccine of modest efficacy (50% reduction in probability of becoming a case) may significantly reduce the impact of the pandemic in a society if deployed early.[19]


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