Abstract
With the HIV-1 epidemic in southern Africa still rising, a prophylactic vaccine against the region’s most prolific subtype (subtype C) would be a significant step forward. In this paper we report on the effect of 2 different adjuvants, AddaVax and AlhydroGel, formulated with HIV-1 subtype C gp140, on the development of binding and neutralising antibody titres in rabbits. AddaVax is a squalene-based oil-in-water nano-emulsion (similar to MF59) which can enhance both cellular and humoral immune responses, whilst AlhydroGel (aluminium hydroxide gel) mainly drives a Th2 response. The gp140 gene tested was derived from the superinfecting virus (SU) from participant CAP256 in the CAPRISA 002 Acute infection cohort. The furin cleavage site of the Env protein was replaced with a flexible linker and an I559P mutation introduced. Lectin affinity purified soluble Env protein was mainly trimeric as judged by molecular weight using BN-PAGE and contained intact broadly neutralising epitopes for the V3-glycan supersite (monoclonal antibodies PGT128 and PGT135), the CD4 binding site (VRC01) and the V2-glycan (PG9) but not for the trimer-specific monoclonal antibodies PG16, PGT145 and CAP256-VRC26_08. When this soluble Env protein was tested in rabbits, AlhydroGel significantly enhanced soluble Env and V1V2 binding antibodies when compared to AddaVax. Finally, AlhydroGel resulted in significantly higher neutralization titres for a subtype C Tier 1A virus (MW965.26) and increased neutralization breadth to Tier 1A and 1B viruses. However, no autologous Tier 2 neutralisation was observed. These data suggest that adjuvant selection is critical for developing a successful vaccine and AlhydroGel should be further investigated. Additional purification of trimeric native-like CAP256 Env and/or priming with DNA or MVA might enhance the induction of neutralizing antibodies and possible Tier 2 HIV-1 neutralisation.
Highlights
Despite treatment and other interventions the HIV pandemic continues to grow, and a combination of prevention modalities needs to be implemented [1]
The structure of Env is important in vaccine studies [23]: the antigen in this study was stabilised by replacing the furin cleavage site with a flexible glycine-rich linker [37, 38], and a I559P mutation [36]
The purified CAP256 superinfecting virus (SU) gp140 preparation contained trimeric species, based on molecular weight, as confirmed by BN-PAGE gel and western blot analyses, and several broadly neutralizing antibody epitopes were detected with monoclonal antibodies for CAP256 SU gp140-flexible linker sequence (FL)-IP-His
Summary
Despite treatment and other interventions the HIV pandemic continues to grow, and a combination of prevention modalities needs to be implemented [1]. In the non-human primate (NHP) model passive immunisation with neutralising antibodies has been shown to protect from SHIV challenge [7,8,9]. It is desirable for HIV vaccines to elicit a robust antibody response including neutralising antibodies [10]. The pathways to obtaining neutralising antibody responses appear to differ from those that elicit binding antibodies, as high titre binding antibodies do not correlate with neutralising antibody titres [11]. Neutralising antibody responses are associated with high levels of CD4+ T follicular helper cells (Tfh) and low levels of T regulatory cells (Treg) in the germinal centres [11, 12]
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