Computationally Selected Multivalent HIV-1 Subtype C Vaccine Protects Against Heterologous SHIV Challenge

Area of Science:

• Vaccinology
• Immunology
• Virology

Background:

• The RV144 trial demonstrated partial efficacy for an HIV-1 vaccine, with antibodies targeting the V2 region of the envelope being crucial.
• Subsequent trials like HVTN702 in southern Africa failed, possibly due to higher subtype C viral diversity compared to the CRF01_AE subtype in Thailand.

Purpose of the Study:

• To investigate if an ALVAC prime with computationally selected gp120 boost immunogens, maximizing coverage of subtype C virus V1V2 diversity, enhances protection in non-human primates (NHPs) against a heterologous subtype C SHIV challenge.
• To compare this novel approach to traditional vaccine regimens.

Main Methods:

• Non-human primates were immunized with an ALVAC prime and various subtype C gp120 boosts, including computationally designed ones.
• NHPs were challenged with a heterologous subtype C SHIV (Simian-Human Immunodeficiency Virus).
• Immunogenicity was assessed, focusing on gp120 and V1V2 binding antibodies, Fc-mediated responses, and neutralization. Correlates of protection were identified using Cox proportional hazard analysis and systems serology.

Main Results:

• An ALVAC prime with Trivalent subtype C gp120 boosts provided statistically significant protection against repeated SHIV challenges compared to controls.
• Different gp120 boosts induced comparable high levels of V1V2-binding antibodies and strong Fc-mediated responses, but low neutralization.
• Antibody-dependent cellular cytotoxicity (ADCC) against the challenge envelope was identified as a correlate of protection.

Conclusions:

• Computationally designed vaccines maximizing subtype C V1V2 coverage successfully protected NHPs from a heterologous Tier-2 subtype C SHIV challenge.
• This strategy offers a promising avenue for developing effective HIV vaccines, particularly in regions with high subtype C prevalence.