Background
The development of a protective vaccine remains one of the top priorities for the control of the HIV/AIDS pandemic on a global scale. Due to its versatility and ability to drive endogenous protein production, mRNA is emerging as a promising platform for an HIV vaccine. We previously reported that a virus-like particle (VLP)-forming HIV-1 env-gag mRNA vaccine elicited heterologous tier-2 neutralizing antibodies and protection from heterologous tier-2 SHIV (AD8) in rhesus macaques (Nat. Med. 27:2234, 2021). Here, we report further optimization of this vaccine platform.
Methods
In two separate studies, juvenile rhesus macaques were immunized repeatedly over the course of 12 months with mRNA expressing different HIV-1 Envs in combination with Gag and GagPol to produce mature VLPs. Immunized animals were longitudinally studied for trimer-binding and neutralizing antibodies, virus-specific T-cell responses and other immune parameters. After immunization, the animals were challenged with weekly low-dose intra-rectal inoculations of SHIV-AD8. Infection was monitored by plasma viremia using TaqMan PCR.
Results
We further optimized our mRNA vaccine platform by addition of the viral protease (using full-length gag-pol transcript) to produce mature VLPs, and by priming with the germline (gl)-engaging Env 426c-DG3, which in the VLP/mRNA formulation showed exceptional potency in VRC01-gl knock-in mice. In two pre-clinical studies in macaques, sequential immunization with VLP/mRNA formulations expressing Envs from 3 clades (A,B,C) reproducibly elicited heterologous tier-2 neutralizing antibodies, along with strong Env- and Gag-specific CD4+ T-cell responses, including T-follicular helper cells, while CD8+ T-cell responses were less pronounced. Inclusion of the protease induced better protection from SHIV-AD8 compared to Env+Gag alone. Protection correlates included heterologous tier-2 neutralizing antibodies, as well as Env-specific antibodies present in mucosal secretions.
Conclusions
A VLP-forming mRNA vaccine supplemented with the viral protease and utilizing an optimized priming immunogen was effective in inducing broad-spectrum neutralization and protection in a relevant nonhuman primate model. A Phase-I clinical protocol (HVTN 310) is under development to evaluate the safety and immunogenicity of the VLP-forming mRNA vaccine in healthy human volunteers.
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