Abstract
Current split influenza virus vaccines that induce strain-specific neutralising antibodies provide some degree of protection against influenza infection but there is a clear need to improve their effectiveness. The constant antigenic drift of influenza viruses means that vaccines are often not an exact match to the circulating strain and so levels of relevant antibodies may not be sufficiently high to afford protection. In the situation where the emergent influenza virus is completely novel, as is the case with pandemic strains, existing vaccines may provide no benefit. In this study we tested the concept of a combination vaccine consisting of sub-optimal doses of split influenza virus vaccine mixed with a cross-protective T-cell inducing lipopeptide containing the TLR2 ligand Pam2Cys. Mice immunised with combination vaccines showed superior levels of lung viral clearance after challenge compared to either split virus or lipopeptide alone, mediated through activation of enhanced humoral and/or additional cellular responses. The mechanism of action of these vaccines was dependent on the route of administration, with intranasal administration being superior to subcutaneous and intramuscular routes, potentially through the induction of memory CD8+ T cells in the lungs. This immunisation strategy not only provides a mechanism for minimising the dose of split virus antigen but also, through the induction of cross-protective CD8+ T cells, proves a breadth of immunity to provide potential benefit upon encounter with serologically diverse influenza isolates.
Highlights
The World Health Organization has estimated that seasonal influenza is responsible for about 3–5 million cases of severe illness worldwide and about 250,000–500,000 deaths annually
We have previously shown that a effective way of inducing memory CD8+ T cell responses is by use of an epitope-based lipopeptide vaccine in which the lipid, dipalmitoyl-S-glyceryl-cysteine (Pam2Cys), is covalently attached to influenza-specific CD4+ T cell and CD8+ T cell epitopes [12, 18, 19]
This study provides proof of principle for augmentation of viral clearing responses upon co-delivery of a T cell-inducing component with the split influenza virus vaccine
Summary
The World Health Organization has estimated that seasonal influenza is responsible for about 3–5 million cases of severe illness worldwide and about 250,000–500,000 deaths annually. Achieving broadly crossreactive immunity depends on invoking alternate types of immune effectors to the highly specific neutralizing antibody induced by inactivated vaccines. To this end, much attention has been focused on generating cross-reactive antibody immunity to conserved regions of IAV proteins such as the extracellular domain of M2 [3,4,5,6] or the HA stalk [7,8,9,10]. CD8+ T cells have been linked to effective immunity in humans against an emergent pandemic virus, and in the absence of specific antibody, correlate inversely with the duration of viral shedding [15] and with protection against symptomatic infection [16]. Recent clinical trials involving vaccination with the influenza nucleoprotein and matrix protein expressed from a pox-virus vector followed by challenge with infectious virus have recapitulated these effects [17]
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