Viral & host immunomodulators in improved Fowlpox virus recombinant vector vaccines for use in poultry against highly pathogenic Avian Influenza H5N1

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Until 1997, avian influenza viruses, even the highly pathogenic strains (HPAI) that cause high mortality in chickens and turkeys, were thought to pose little direct threat to humans, needing first to mix genetic information (or recombine), thought most likely to occur in pigs, with influenza viruses already adapted to humans. This assessment changed when 18 people in direct contact with poultry in Hong Kong were directly infected with a virus, killing six. The virus carried the distinctive surface markers H5 and N1. The H5N1 virus has since spread widely throughout SE Asia, reaching Europe and Africa, and continues to infect humans infrequently (about 200 cases with a continued high mortality rate of 51%) as well as zoo animals and cats. It can clearly spread widely by infection of migratory birds and continues to evolve and diversify, threatening to develop into a human pandemic strain, either directly by mutation or by recombination. Measures are being taken to improve protection against emergence of a possible human pandemic virus (which may or may not retain the H5 and N1 markers) but it is recognised that control of the virus in poultry and birds is important to reducing the risk of the emergence of such a pandemic strain. Standard practise in the UK and EU in the event of focal outbreaks of HPAI is containment and slaughter. However, in the face of widespread HPAI (H5N2) in Mexico in the mid-1990's, vaccination was introduced and was partially successful, in so far as it eradicated HPAI, but it failed to eradicate low pathogenicity strains (LPAI). This campaign was a landmark in that as well as using conventional vaccines based on killed influenza viruses of the same or 'homologous' type as the epidemic strain, a genetically modified Fowlpox virus coding for the H5 part of the influenza virus was used for the first time as a so called 'recombinant vaccine'. In the face of the current H5N1 epidemic, several countries have introduced vaccination programmes. In China, three types of vaccine have been used: (i) conventional, mismatched or 'heterologous' (H5N2) killed influenza vaccine, (ii) a killed, LPAI derivative of H5N1, engineered into a safer backbone by genetic modification, and (iii) a recombinant Fowlpox virus expressing both H5 and N1. In France, as the recombinant Fowlpox virus and the genetically modified H5N1 have not been licensed, a conventional, heterologous, killed vaccine (the H5N2 used as a homologous vaccine in Mexico) has been used. With the speed of evolution of the H5N1 strain, the use of older versions of H5 in vaccines, especially that from the H5N2 strain used in Mexico, causes some concern. Current vaccines protect vaccinated birds but do not always prevent them become infected and a quarter of those infected birds become carriers. As vaccines becomes less effective due to evolution of the virus, there are fears that the vaccine's inability to stop bird-to-bird transmission will contribute to a vicious circle of increased virus variation. The conventional and recombinant Fowlpox virus vaccines induce good, protective antibody responses but are not so good at inducing the 'cellular responses' necessary to allow the body to clear itself of infected cells. Work in mice has shown that better cellular responses would be expected not against H5 and N1 but from the internal and non-structural proteins of influenza virus so we will make recombinant Fowlpox viruses based on these proteins as well as on H5 and N1. We may also need to adjust the balance of antibody versus cellular responses. This could be done by incorporating chicken immune regulators into the recombinant Fowlpox virus vaccines, and we will try this in the experimental situation. However we think it would be preferable to achieve this adjustment by changing some of the Fowlpox virus's own immune regulators; we already have demonstrated this approach can work against a different virus disease of poultry.