Recombinant HIV-1 vaccine candidates based on replication-defective flavivirus vector

Maryann Giel–Moloney ,Thierry Calandra ,Sanjay Phogat ,Kathryn E Foulds ,Gregory J Mize ,Andre Spies ,Mario Roederer ,Mariano Esteban ,Chelsey Bennett ,Michael Vaine ,Matthieu Perreau ,Benedikt Asbach ,Mark Parrington ,Harold Kleanthous ,Beatriz Perdiguero ,Nicole L Yates ,Guido Ferrari ,Thierry Roger ,David C Montefiori ,Bryan T Mayer ,Karen V Kibler ,Ralf Wagner ,Deborah Weiss ,Bertram L Jacobs ,Song Ding ,M Juliana Mcelrath ,Georgia D Tomaras ,Brendan Oakes ,Annette Ives ,Shu‐Fang Kao ,Giuseppe Pantaleo ,Raphaël Gottardo ,Jim Tartaglia ,К В Пугачев

doi:10.1038/s41598-019-56550-4

Abstract

Multiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

Highlights

Multiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV
The HIV-1 efficacy trial RV144 provided the first evidence that a HIV-1 vaccine is possible, where vaccination with ALVAC-HIV in combination with subunit, alum-adjuvanted gp[120] protein (AIDSVAX B/E) prevented HIV infection, with 60% and 31.2% efficacy documented at 12 months and 3.5 years, respectively[2]
The RV144 trial has been one of the most successful trials showing that a HIV vaccine is possible in preventing infection and efforts continue with improving the priming and boosting components for a vaccine

Summary

Introduction

The HIV-1 efficacy trial RV144 provided the first evidence that a HIV-1 vaccine is possible, where vaccination with ALVAC-HIV (vCP1521) in combination with subunit, alum-adjuvanted gp[120] protein (AIDSVAX B/E) prevented HIV infection, with 60% and 31.2% efficacy documented at 12 months and 3.5 years, respectively[2] This stimulated further exploration of new delivery systems and/or antigen designs and formulations for new, improved prime-boost regimens. RV-HIV candidates expressing clade C Gag or Env (gp120TM) were constructed and their vaccine potential evaluated in in vitro and in vivo models, including NHPs in prime-boost combinations with recombinant DNA or the attenuated poxvirus NYVAC candidates expressing the same HIV-1 antigens as RV-HIV, and administered with adjuvanted subunit HIV-1 Env protein described previously[11,12]. Our findings revealed the potential benefit of the combination of RV/NYVAC/ protein components as vaccination approach against HIV-1

Methods

Results

Conclusion