HIV-1-neutralizing antibody induced by simian adenovirus- and poxvirus MVA-vectored BG505 native-like envelope trimers.

Silvia Capucci,Jonathan Dodd,Nicola Borthwick,Torben Schiffner,David Montefiori,Celia C Labranche,Tomáš Hanke,John P Moore,Edmund G Wee,Quentin Sattentau,Hansi Dean,Albert Cupo,Per J Klasse,Rogier W Sanders,Shibo Jiang

doi:10.1371/journal.pone.0181886

Abstract

Rabbits and monkeys immunized with HIV type 1 (HIV-1) native-like BG505 SOSIP.664 (BG505s) glycoprotein trimers are known to induce antibodies that can neutralize the autologous tier-2 virus. Here, we assessed the induction of HIV-1 trimer binding and neutralizing antibody (nAb) titres when BG505s trimers were also delivered by non-replicating simian (chimpanzee) adenovirus and non-replicating poxvirus modified vaccinia virus Ankara (MVA) vaccine vectors. First, we showed that approximately two-thirds and one-third of the trimers secreted from the ChAdOx1.BG505s (C) and MVA.BG505s (M) vaccine-infected cells, respectively, were cleaved and in a native-like conformation. Rabbits were immunized intramuscularly with these vaccine vectors and in some cases boosted with ISCOMATRIX™–adjuvanted BG505s protein trimer (P), using CCC, MMM, PPP, CPP, MPP and CMP vaccine regimens. We found that the peak trimer-binding antibody and tier-1A and autologous tier-2 nAb responses induced by the CC, CM, PPP, CPP, MPP and CMP regimens were comparable, although only PPP induced autologous tier-2 nAbs in all the immunized animals. Three animals developed weak heterologous tier-2 nAbs. These results demonstrate that ChAdOx1 and MVA vectors are useful delivery modalities for not only T-cell, but also antibody vaccine development.

Highlights

Vaccines remain the best solution to ending of the HIV type 1 (HIV-1)/AIDS epidemic
A 2G12-reactive protein band of relative molecular mass of ~600 kDa that corresponds to an envelope glycoprotein (Env) trimer was detectable in the supernatants of cells infected with the ChAdOx1.BG505 SOSIP.664 (BG505s) virus at multiplicity of infection (MOI) >100 (Fig 1A), but we were unable to detect any Env protein expression by Western blot at any MOI and at any time point in the modified vaccinia virus Ankara (MVA)
We constructed novel vaccines vectored by chimpanzee adenovirus ChAdOx1 (C) and MVA (M) that express BG505 SOSIP.664 (BG505s) Env proteins and assessed systematically their immunogenicity in homologous and heterologous vaccine regimens that included ISCOMATRIXTM-adjuvanted trimer proteins (P)

Summary

Introduction

Vaccines remain the best solution to ending of the HIV-1/AIDS epidemic. Ideally, a vaccine would induce protective levels of broadly neutralizing antibodies (bnAbs) against multiple HIV-1 variants [1, 2]. BnAbs emerge in 20–30% of HIV-1-infected individuals after two or more years of infection, and multiple lineages have been isolated [1, 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19] In these individuals, bnAbs do not provide clinical benefit because they are slow to mature and once they appear, the viruses can still escape [20,21,22]. For active immunization by Env-based vaccines, the key obstacle is the need to induce bnAbs against tier-2 viruses, which dominate human transmission and are relatively neutralization-insensitive. Increasing understanding of the Env structure and its glycan shield, and the ability to follow virus and antibody co-evolution during infection and evolutionary convergence of bnAb specificities among some patients [31, 32] are cumulative, if gradual, steps towards the induction of bnAbs

Methods

Results

Conclusion