SOSIP-NP/mRNA combination for novel preventive and therapeutic HIV-1 vaccine regimens

ABSTRACT The ultimate goal of the proposed studies is to contribute to ending the HIV/AIDS epidemic. It has been four decades since the start of the HIV/AIDS epidemic and a protective vaccine or functional cure has been elusive. In 2020, there was an estimated 37.6 million people living with HIV. Despite highly active anti-retroviral

therapies, hundreds of thousands of people still die from AIDS-related diseases and millions of new infections continue to emerge. Thus, finding a way to end this pandemic remains a global priority. The overall goal of the Consortium for Innovative HIV/AIDS Vaccine and Cure Research (CIAVCR) is to develop an effective combined immunotherapeutic regimen for HIV-1 prevention and cure using the non-

human primate (NHP) model that has a direct path to the clinic for use in humans. There are two FOCI proposed in the CIAVCR: In FOCUS 1, our overall goal is to demonstrate the correlates and mechanisms of protection for a protective vaccine, and the role of vaccine-induced immune responses in selecting and limiting

the latent reservoir. The benefits of using novel mRNA constructs to deliver immunogens that can elicit both humoral and cellular responses will be evaluated. In FOCUS 2, our overall goal is to determine the role of vaccine-induced immune responses to 1) control HIV-1 infection by reducing the size or eliminating HIV-1

reservoirs, and/or 2) delay plasma virus load rebound. The protective vaccines studied in FOCUS 1 will be tested to define the mechanisms of vaccine-induced B and T cell responses in clearing HIV-1 reservoirs. Additionally, novel therapies will be combined with the vaccines to augment clearance of HIV-1 reservoirs.

In both FOCUS 1 and 2, analysis of the breakthrough and latent reservoir Env sequences will inform the design of new vaccine boosts for an improved protective vaccine regimen that can also limit rebound viruses. The NHP-SHIV Centralized Research Resource (CRR) will support the NHP studies in FOCUS 1 and

2 to investigate the effectiveness of vaccine-induced polyfunctional responses and novel immunotherapies in clearing HIV-1 reservoirs. These studies will use innovative barcoded-SHIVs to determine the effect of vaccine-induced responses on eliminating the viral reservoirs, and to evaluate the quantity and quality of

viruses that are reactivated by latency reversing agents (LRAs) following treatment interruption. The Management and Operations Support Unit (MOS) will coordinate the scientific and administrative activities of this CIAVCR Program to ensure that the FOCI and NHP-SHIV CRR function cohesively. By the end of this grant, we expect to have designed a combined preventive and therapeutic approach to

effectively protect from infection and eliminate viral reservoirs—a strategy for effectively impacting the HIV/AIDS pandemic.