Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates.

Merika T Koday,Shulin Qin,Adriana Forero,James T Fuller,Deborah Heydenburg Fuller,Amy L Hartman,Todd A Reinhart,Debra L Bratt,Robert Murnane,Juliet Morrison,Jolie A Leonard,Karen Duus,Michael G Katze,Ilhem Messaoudi,Michael Koday,Paul Munson,Kelly Stefano-Cole

doi:10.1371/journal.pone.0189780

Abstract

Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. We investigated immunogenicity and protective efficacy of a multi-antigen (MA) universal influenza DNA vaccine consisting of HA, M2, and NP antigens in cynomolgus macaques. Following challenge with a heterologous pandemic H1N1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. The MA DNA vaccine induced robust serum and mucosal antibody responses but these high antibody titers were not broadly neutralizing. In contrast, the vaccine induced broadly-reactive NP specific T cell responses that cross-reacted with the challenge virus and inversely correlated with lower viral loads and inflammation. These results demonstrate that a MA DNA vaccine that induces strong cross-reactive T cell responses can, independent of neutralizing antibody, mediate significant cross-protection in a nonhuman primate model and further supports development as an effective approach to induce broad protection against circulating and emerging influenza strains.

Highlights

Influenza is a serious public health issue, and new vaccines are needed to better combat seasonal and pandemic strains
Neutralizing antibodies mediate effective protection against influenza, and it is generally expected that a successful universal influenza vaccine that protects against both seasonal antigenic drift and emerging influenza pandemics will likely need to induce both broadly neutralizing antibody to blunt initial viral replication and cross-reactive CD8+ T cell responses to help clear the cells that become infected
DNA vaccines have been combined with other types of vaccines, such as live viral vectors or recombinant proteins in a prime-boost regimen that results in a synergistic induction of robust antibody that is higher than levels induced by either vaccine alone [42, 43, 65]

Summary

Introduction

Influenza is a serious public health issue, and new vaccines are needed to better combat seasonal and pandemic strains. The currently licensed live-attenuated and inactivated vaccines induce strong HA-specific antibody and afford significant protection against matched circulating influenza strains they require annual reformulations to keep pace with antigenic drift in HA, and a completely new vaccine is needed in the event of an antigenic shift [1, 2]. Recent efforts have focused on the development of a new generation of influenza vaccines that could provide broad spectrum, “universal” protection against a wider range of influenza variants including strains with pandemic potential. DNA vaccines induce both antibody and T cell responses, and both arms of immunity contribute to cross-protection against different influenza variants [7, 8]. Many studies have shown that DNA vaccines are highly effective in the induction of CD8+ T cell responses that can play a critical role in rapid clearance of influenza virus, limiting pathogenesis [9,10,11,12] as well as CD4+ T cell responses that play a key role in maintaining CD8+ T cell memory and providing help for B cells that mediate rapid antibody production [13, 14]

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