Abstract
An effective universal vaccine for influenza will likely need to induce virus-specific T-cells, which are the major mediator of heterosubtypic cross-protection between different subtypes of influenza A virus. In this study we characterise the cell-mediated immune response in ferrets during heterosubtypic protection induced by low-dose H1N1 virus infection against an H3N2 virus challenge, given 4 weeks later. Although the ferrets were not protected against the infection by H3N2 virus, the duration of virus shedding was shortened, and clinical disease was markedly reduced. No cross-reactive neutralizing antibodies were detected, but cross-reactive interferon-gamma-secreting T cells were detected in the circulation prior to H3N2 challenge. These T-cells peaked at 11 days post-H1N1 infection, and were strongly induced in blood and in lung following H3N2 infection. The rapid induction of interferon-gamma-secreting cells in ferrets previously infected with H1N1 virus, but not in naïve ferrets, suggests induction of memory T-cells. These results are in accord with the observations that pre-existing cross-reactive T-cells correlate with protection in humans and have implications for outbreak modelling and universal vaccine design.
Highlights
Influenza viruses are responsible for an estimated 3 to 5 million cases of severe illness and up to 650,000 deaths annually[1]
The data presented here demonstrate that infection with a low dose of H1N1 virus 28 days prior to infection with H3N2 virus leads to significant partial protection against disease, and reduced duration of virus shedding
This same low-dose infection with H1N1 led to complete protection against disease and virus shedding following a homologous H1N1 challenge. This complete protection was accompanied by high serum haemagglutination-inhibition assay (HAI) and neutralization titres against H1N1 virus prior to the second challenge
Summary
Influenza viruses are responsible for an estimated 3 to 5 million cases of severe illness and up to 650,000 deaths annually[1]. The inactivated vaccine provides strain-specific immunity mediated primarily by neutralizing antibodies, and would not elicit protection in the case of a new pandemic virus. It has long been known that prior infection with one subtype can lead to at least some protection against a different subtype in the ferret model, which is considered the “gold standard” for pre-clinical studies with human influenza A virus[7,8,9]. Studies of cellular immune responses in ferrets have been hampered by the lack of ferret-specific reagents and protocols, compared to the mouse model. We investigated the immune responses involved in cross-protection between H1N1 and H3N2 viruses in the ferret model, using our low-dose challenge model which more closely mimics natural influenza infections than the high infectious doses often used to challenge ferrets[21]. The H1 and H3 proteins are only distantly related phylogenetically, being representatives of HA groups 1 and 2, respectively[22], minimising the possibility of cross-protective antibody responses
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