Abstract
Given that continuing antigenic shift and drift of influenza A viruses result in the escape from previous vaccine-induced immune protection, a universal influenza vaccine has been actively sought. However, there were very few vaccines capable of eliciting cross-group ant-influenza immunity. Here, we designed two novel composite immunogens containing highly conserved T-cell epitopes of six influenza A virus internal antigens, and expressed them in DNA, recombinant adenovirus-based (AdC68) and recombinant vaccinia vectors, respectively, to formulate three vaccine forms. The introduction of the two immunogens via a DNA priming and viral vectored vaccine boosting modality afforded cross-group protection from both PR8 and H7N9 influenza virus challenges in mice. Both respiratory residential and systemic T cells contributed to the protective efficacy. Intranasal but not intramuscular administration of AdC68 based vaccine was capable of raising both T cell subpopulations to confer a full protection from lethal PR8 and H7N9 challenges, and blocking the lymphatic egress of T cells during challenges attenuated the protection. Thus, by targeting highly conserved internal viral epitopes to efficiently generate both respiratory and systemic memory T cells, the sequential vaccination strategy reported here represented a new promising candidate for the development of T-cell based universal influenza vaccines.
Highlights
Influenza A virus (IAV) has continued to be a major threat to human health (Horimoto and Kawaoka, 2005; Gostin et al, 2014)
As the first step to develop new cross-protective IAV vaccine, we sought to identify new immunogens that have a broad coverage of conserved CD8+ T cell epitopes of IAV antigens
To be more efficient in immunogen design, we only included partial sequences of PA, PB1, and PB2 enriched with CD8+ T cell epitopes as predicted by online tools (Singh and Raghava, 2003; Moutaftsi et al, 2006)
Summary
Influenza A virus (IAV) has continued to be a major threat to human health (Horimoto and Kawaoka, 2005; Gostin et al, 2014). The licensed influenza vaccines, the majority of which act by inducing antibody against the viral hemagglutinin surface protein, only induce strain-specific immunity and could not provide efficient protection against mismatched epidemic and pandemic. Unlike the surface viral proteins which evolve fast in response to the pressure of human neutralizing antibodies, the internal IAV structural proteins, as exampled by matrix protein (Fan et al, 2004; Valkenburg et al, 2014), nuclear protein (Lamere et al, 2011; Pica and Palese, 2013), and polymerase protein (Cox and Dewhurst, 2015; Uddback et al, 2016) are more conserved and the derived conserved epitopes have shown potential to induce broadspectrum cellular responses and provide cross-protection (Jaiswal et al, 2013). It’s worth mentioning that tissue-resident memory CD8 T cells have been reported to be indispensable for cross-protection against different strains of influenza virus (Brown and Kelso, 2009)
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