Development of cold-adapted recombinant live, attenuated influenza A vaccines in the U.S.A. and U.S.S.R.

Abstract

Influenza remains a major public health problem in many countries. Periodic epidemics disrupt economic and social activities within entire communities, impose sudden large demands on available medical facilities, and can cause excess mortality, particularly in the elderly or those with certain chronic illnesses [5,7,21]. Vaccination can provide significant protection against infection and illness during natural epidemics, but this protection is usually considered to be of limited duration, particularly due to the changes in antigenic specificity of influenza virus surface glycoproteins (hemagglutinin (HA) and neuraminidase (NA)) which continually occur [58]. This problem affects the two methods that exist for influenza vaccination. Inactivated (killed) vaccines must be constantly updated to include newer strains, which in any event often induce maximum antibody responses not to themselves but to previously prevalent strains, as expounded in the 'Doctrine of Original Antigenic Sin' [48,62]. Live, attenuated virus vaccines might be expected to produce a more long-lasting protection than inactivated vaccines on the assumption that they would mimic natural infection which, for unknown reasons, probably protects longer than inactivated vaccines [15]. However, live vaccines must be infectious, attenuated, induce protective immunity and be genetically stable, a combination of properties that might not be obtained in a short space of time with each important new strain (antigenic variant) as it appears. The ability to recombine influenza viruses by mixed infections during which the segmented RNA genome can reassort [52] raised the prospect that once a suitable attenuated vaccine strain of influenza A was prepared, this property could be transferred to a new strain with contemporary HA and NA antigens [8,35,37]. Provided only that these glycoproteins did not contribute significantly to other (non-antigen dependent)