Immunization with cross-conserved H1N1 influenza CD4⁺ T-cell epitopes lowers viral burden in HLA DR3 transgenic mice

Abstract

The emergence of the pandemic H1N1 strain of influenza in 2009 was associated with a unique w-shaped age-related susceptibility curve, with higher incidence of morbidity and mortality among young persons and lower incidence among older persons, also observed during the 1918 influenza pandemic. Pre-existing H1N1 antibodies were not cross-reactive with the prior seasonal vaccine, forcing influenza experts to scramble to develop a new vaccine specific for the pandemic virus. We hypothesized that response to T-cell epitopes that are cross-conserved between pandemic H1N1 and the 2008 seasonal influenza vaccine strains might have contributed to partial protection from clinical illness among older adults, despite the lack of cross-reactive humoral immunity. Using immunoinformatics tools, we previously identified hemagglutinin and neuraminidase epitopes that were highly conserved between seasonal and pandemic H1N1. Here, we validated predicted CD4⁺ T-cell epitopes for their ability to bind HLA and to stimulate interferon-γ production in peripheral blood mononuclear cells from a cohort of donors presenting with influenza-like illness during the 2009 pandemic and a separate cohort immunized with trivalent influenza vaccine in 2011. A limited-epitope heterologous DNA-prime/peptide-boost vaccine composed of these sequences stimulated immune responses and lowered lung viral loads in HLA DR3 transgenic mice challenged with pandemic 2009 H1N1 influenza. Cross-priming with conserved influenza T-cell epitopes such as these may be critically important to T cell-mediated protection against pandemic H1N1 in the absence of cross-protective antibodies.

Keywords: :

• T-cell epitope
• immunoinformatics
• influenza
• vaccine
• pandemic

10.4161/hv.26511

Disclosure of potential conflicts of interest

Two of the contributing authors, De Groot AS and Martin WD, are senior officers and majority shareholders at EpiVax, Inc., a privately owned biotechnology company located in Providence, RI. Leonard Moise is employed by and holds stock options in EpiVax. These authors acknowledge that there is a potential conflict of interest related to their relationship with EpiVax and attest that the work contained in this research report is free of any bias that might be associated with the commercial goals of the company.

Acknowledgments

We are grateful to Dr Donald Drake (VaxDesign) for providing PBMC samples. This work was supported by NIH grant R21AI090359 (ADG).