Mucosal and systemic SIV-specific cytotoxic CD4+ T cell hierarchy in protection following intranasal/intramuscular recombinant pox-viral vaccination of pigtail macaques

Mayank Khanna,Charani Ranasinghe,Ronald J Jackson,Anthony D Kelleher,Zheyi Li,Thakshila H Amarasena,Stephen J Kent,Sheilajen Alcantara

doi:10.1038/s41598-019-41506-5

Abstract

A HIV vaccine that provides mucosal immunity is urgently needed. We evaluated an intranasal recombinant Fowlpox virus (rFPV) priming vaccine followed by intramuscular Modified Vaccinia Ankara (rMVA) booster vaccine, both expressing SIV antigens. The vaccination generated mucosal and systemic SIV-specific CD4+ T cell mediated immunity and was associated with partial protection against high-dose intrarectal SIVmac251 challenge in outbred pigtail macaques. Three of 12 vaccinees were completely protected and these animals elicited sustained Gag-specific poly-functional, cytotoxic mucosal CD4+ T cells, complemented by systemic poly-functional CD4+ and CD8+ T cell immunity. Humoral immune responses, albeit absent in completely protected macaques, were associated with partial control of viremia in animals with relatively weaker mucosal/systemic T cell responses. Co-expression of an IL-4R antagonist by the rFPV vaccine further enhanced the breadth and cytotoxicity/poly-functionality of mucosal vaccine-specific CD4+ T cells. Moreover, a single FPV-gag/pol/env prime was able to induce rapid anamnestic gp140 antibody response upon SIV encounter. Collectively, our data indicated that nasal vaccination was effective at inducing robust cervico-vaginal and rectal immunity, although cytotoxic CD4+ T cell mediated mucosal and systemic immunity correlated strongly with ‘complete protection’, the different degrees of protection observed was multi-factorial.

Highlights

Despite the availability of highly active antiretroviral therapy (ART), human immunodeficiency virus-1 (HIV-1) remains a significant global health burden with an estimated 36.7 million people infected to date and 1.8 million new infections in 20161
(rFPV) vaccine trial[11,12], the HVTN 505 phase IIb trial which utilised a recombinant DNA (rDNA) prime followed by a recombinant adenovirus 5 booster strategy[13], and the EV02 Phase I trial where a rDNA vaccine was followed by New York Vaccinia strain (NYVAC)[14]
An IL-4R antagonist adjuvanted (IL-4R antagonist) vaccine that transiently inhibited IL-4/IL-13 signalling via STAT6 pathway at the vaccination site[41], was shown to induce immune responses similar to that observed in HIV elite controllers[44,45,46]

Summary

Introduction

Despite the availability of highly active antiretroviral therapy (ART), human immunodeficiency virus-1 (HIV-1) remains a significant global health burden with an estimated 36.7 million people infected to date and 1.8 million new infections in 20161. Resulting in enhanced mucosal and systemic high avidity/poly-functional HIV-specific CD8+ T cells and robust long-lived HIV Gag-specific B-cell immunity[47] This strategy following a gp[140] Env protein booster in mice has been shown to induce effective Env-specific antibodies (Ranasinghe et al unpublished observations). Given these promising features, in the current study we evaluated the protective efficacy of IL-4R antagonist adjuvanted vaccine compared to unadjuvanted and empty vector controls, in an i.n. rFPV/i.m rMVA prime-booster modality followed by a high dose intra rectal SIVmac[251] challenge in pigtailed macaques

Methods

Findings

Conclusion