Parainfluenza Virus 5 Priming Followed by SIV/HIV Virus-Like-Particle Boosting Induces Potent and Durable Immune Responses in Nonhuman Primates.

Peng Xiao,Huiling Wei,Biao He,Krista Dienger-Stambaugh,Paul Spearman,Pooja Tiwari,Francois Villinger,Ashley C Beavis,Xuemin Chen,Shannon Phan,Karnail Singh,Nihar R Deb Adhikary

doi:10.3389/fimmu.2021.623996

Abstract

The search for a preventive vaccine against HIV infection remains an ongoing challenge, indicating the need for novel approaches. Parainfluenza virus 5 (PIV5) is a paramyxovirus replicating in the upper airways that is not associated with any animal or human pathology. In animal models, PIV5-vectored vaccines have shown protection against influenza, RSV, and other human pathogens. Here, we generated PIV5 vaccines expressing HIV envelope (Env) and SIV Gag and administered them intranasally to macaques, followed by boosting with virus-like particles (VLPs) containing trimeric HIV Env. Moreover, we compared the immune responses generated by PIV5-SHIV prime/VLPs boost regimen in naïve vs a control group in which pre-existing immunity to the PIV5 vector was established. We demonstrate for the first time that intranasal administration of PIV5-based HIV vaccines is safe, well-tolerated and immunogenic, and that boosting with adjuvanted trimeric Env VLPs enhances humoral and cellular immune responses. The PIV5 prime/VLPs boost regimen induced robust and durable systemic and mucosal Env-specific antibody titers with functional activities including ADCC and neutralization. This regimen also induced highly polyfunctional antigen-specific T cell responses. Importantly, we show that diminished responses due to PIV5 pre-existing immunity can be overcome in part with VLP protein boosts. Overall, these results establish that PIV5-based HIV vaccine candidates are promising and warrant further investigation including moving on to primate challenge studies.

Highlights

Combination antiretroviral therapy (ART) has markedly changed the clinical outlook for human immunodeficiency virus (HIV)-infected patients and represents a major advance in the fight against HIV/AIDS
We found that an HIV vaccine regimen employing an intranasal (IN) prime with recombinant Parainfluenza virus 5 (PIV5) vector followed by boosting with SHIV virus-like particles (VLPs) elicited robust and durable systemic responses, including polyfunctional T cell responses and antibodies mediating neutralization and ADCC
To generate PIV5-based HIV vaccine candidates, we inserted HIV-1 JRFL gp140 at the SH-HN junction to generate PIV5-HIVgp140 and inserted SIV Gag between HN and L in a PIV5 vector that included a deletion of the SH gene to produce PIV5DSH-SIVGag (Figure 2A)

Summary

Introduction

Combination antiretroviral therapy (ART) has markedly changed the clinical outlook for human immunodeficiency virus (HIV)-infected patients and represents a major advance in the fight against HIV/AIDS. Viral suppression from ART has been shown to reduce sexual transmission of HIV, leading to the concept of treatment as prevention as a proven intervention to slow the spread of the epidemic [1,2,3]. Despite this advance, there still are an estimated 1.7 million new HIV infections per year worldwide [4]. In the absence of well-established correlates of protection, desirable characteristics of an HIV vaccine include the induction of robust and long-lasting functional antibodies against Env and antigen-specific T cell polyfunctional responses for controlling viral replication in the event of infection [11, 12]. Vaccineelicited mucosal immune responses against HIV are less well explored but are desirable characteristics of vaccine candidates [13]

Methods

Results

Conclusion