Abstract
Influenza A virus is a respiratory pathogen which causes both seasonal epidemics and occasional pandemics; infection continues to be a significant cause of mortality worldwide. Current influenza vaccines principally stimulate humoral immune responses that are largely directed towards the variant surface antigens of influenza. Vaccination can result in an effective, albeit strain-specific antibody response and there is a need for vaccines that can provide superior, long-lasting immunity to influenza. Vaccination approaches targeting conserved viral antigens have the potential to provide broadly cross-reactive, heterosubtypic immunity to diverse influenza viruses. However, the field lacks consensus on the correlates of protection for cellular immunity in reducing severe influenza infection, transmission or disease outcome. Furthermore, unlike serological methods such as the standardized haemagglutination inhibition assay, there remains a large degree of variation in both the types of assays and method of reporting cellular outputs. T-cell directed immunity has long been known to play a role in ameliorating the severity and/or duration of influenza infection, but the precise phenotype, magnitude and longevity of the requisite protective response is unclear. In order to progress the development of universal influenza vaccines, it is critical to standardize assays across sites to facilitate direct comparisons between clinical trials.
Highlights
Influenza-associated morbidity disproportionately affects the younger child and older adult, with influenza-concomitant deaths occurring excessively in adults over the age of 65
Wilkinson and authors reported that baseline T-cell responses to influenza as determined by ELISPOT were below 1000 spot forming units (SFU)/106 peripheral blood mononuclear cells (PBMCs) when cells were stimulated with 18mer peptides overlapping by 10, spanning the full proteome of H1N1 (A/Brisbane/59/2004), H3N2 surface proteins (A/New York/388/2005) or H3N2 internal proteins (A/New York 232/2004), rather than just NP+matrix protein-1 (M1) as in our vaccine studies [42]
It is evident that standardization of all aspects of cellular assays will be required in order to advance our understanding of the T-cell mediated correlates of protection in influenza infection
Summary
Influenza-associated morbidity disproportionately affects the younger child and older adult, with influenza-concomitant deaths occurring excessively in adults over the age of 65. Neutralizing antibody responses to influenza viruses are largely directed towards the virus surface glycoproteins haemagglutinin (HA) and neuraminidase (NA). Reassortment combinations of the 18 HA or 11 NA proteins can result in a large number of influenza subtypes (e.g., H5N1 or H1N1), some of which can result in the emergence of mammalian-adapted influenza strains for which there is little or non-existing prior immunity in the human population. The ongoing evolution of influenza viruses by antigenic shift and drift can allow evasion of these pre-existing, protective neutralizing antibody (NAb) responses. This remains a significant challenge for the development of broadly cross-protective NAb responses to influenza and limits pandemic preparedness
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