Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges.

Samir K Lakhashe,Joshua A Weiner,Sheetal Sawant,Sylvain Fleury,Chris Gast,Kyle S Morrison,Hemant K Vyas,Guido Ferrari,Vicky Roy,Galit Alter,David C Montefiori,Georgia D Tomaras,Dinesh Hariraju,Mario Amacker,Nicole L Yates,Ruth M Ruprecht,Margaret E Ackerman

doi:10.3389/fimmu.2022.788619

Abstract

A virosomal vaccine inducing systemic/mucosal anti-HIV-1 gp41 IgG/IgA had previously protected Chinese-origin rhesus macaques (RMs) against vaginal SHIVSF162P3 challenges. Here, we assessed its efficacy in Indian-origin RMs by intramuscular priming/intranasal boosting (n=12/group). Group K received virosome-P1-peptide alone (harboring the Membrane Proximal External Region), Group L combined virosome-rgp41 plus virosome-P1, and Group M placebo virosomes. Vaccination induced plasma binding but no neutralizing antibodies. Five weeks after boosting, all RMs were challenged intravaginally with low-dose SHIVSF162P3 until persistent systemic infection developed. After SHIV challenge #7, six controls were persistently infected versus only one Group L animal (vaccine efficacy 87%; P=0.0319); Group K was not protected. After a 50% SHIV dose increase starting with challenge #8, protection in Group L was lost. Plasmas/sera were analyzed for IgG phenotypes and effector functions; the former revealed that protection in Group L was significantly associated with increased binding to FcγR2/3(A/B) across several time-points, as were some IgG measurements. Vaginal washes contained low-level anti-gp41 IgGs and IgAs, representing a 1-to-5-fold excess over the SHIV inoculum’s gp41 content, possibly explaining loss of protection after the increase in challenge-virus dose. Virosomal gp41-vaccine efficacy was confirmed during the initial seven SHIV challenges in Indian-origin RMs when the SHIV inoculum had at least 100-fold more HIV RNA than acutely infected men’s semen. Vaccine protection by virosome-induced IgG and IgA parallels the cooperation between systemically administered IgG1 and mucosally applied dimeric IgA2 monoclonal antibodies that as single-agents provided no/low protection – but when combined, prevented mucosal SHIV transmission in all passively immunized RMs.

Highlights

The first cases of unexplained acquired immunodeficiency syndrome in young individuals, later termed AIDS, were described approximately 40 years ago, and the causative agent, HIV-1, was discovered in 1983 [1]
Two scientists leading the NHP study were aware that Group M rhesus macaques (RMs) were controls; veterinary staff directly involved in the animal experiments did not know the status of any of the three groups during the ensuing SHIV challenges
Regular viremia levels were assessed immediately to decide whether SHIV challenges should continue for any given RM; the experimental design called for stopping challenges once an RM reached vRNA levels ≥104 copies/ml

Summary

Introduction

The first cases of unexplained acquired immunodeficiency syndrome in young individuals, later termed AIDS, were described approximately 40 years ago, and the causative agent, HIV-1, was discovered in 1983 [1]. Since the beginning of the AIDS pandemic, HIV has infected ~75.7 million individuals and caused 32.7 million deaths (UNAIDS). 90% of all new HIV infections are the result of mucosal exposures, including sexual and perinatal transmission events. During HIV sexual transmission, the genital and rectal tissues are the main virus entry points where primary infection foci are established, from which the virus spreads into the intestinal tract and other host organs. A newly infected individual harbors one predominant strain initially, the so-called transmitted founder virus. This is the case even if the source person harbors a multitude of HIV quasi-species

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