In the nearly 40 years since the discovery of HIV (human immunodeficiency virus), scientists have made major advances in developing antiretroviral therapy (ART) medicines to treat HIV infections. However, it remains critical that a safe and broadly effective vaccine be developed if we hope to get HIV transmission under control.
Attempts to generate a vaccine using traditional vaccine development approaches have so far failed to produce sufficiently protective immune responses. Recent evidence has suggested that virus-like particles (VLPs)—non-infectious particles that resemble the virus but have none of its genetic material—may enhance immune responses. A small study in monkeys found that an mRNA vaccine designed to induce VLPs containing membrane-anchored HIV-1 envelope (Env) proteins elicited antibodies capable of neutralizing a large number of HIV-1 variants and reduced the risk of infection by an HIV-like virus in vaccinated monkeys.
- Bill and Melinda Gates Foundation*
- BIOQUAL, Inc.
- Collaboration for AIDS Vaccine Discovery (CAVD)
- National Institute of Allergy and Infectious Diseases (NIAID) (subaward)
- University of Montreal Health Center (CHUM) (subaward)
*Provided financial support
Preclinical Trial Seeks to Expand and Confirm Earlier HIV Vaccine Study Results
This preclinical trial will administer a series of mRNAs encoded to generate VLPs possessing modified Env proteins (normally) located on the envelope of the HIV-1 virus. The Env proteins are the foreign molecules that stimulate an immune system response. The sequential approach will target a rare subset of naïve, or first-generation, B cells—the white blood cells responsible for producing antibodies—signaling them to proliferate and generate diversity in the subsequent generations. The goal is to guide the genetic and functional maturation of select lineages of B cells by preferentially targeting daughter cells better able to bind to regions of interest on the Env protein. The end result is B cells capable of producing antibodies that tightly bind and neutralize a wide variety of HIV-1 and provide protection from future infection. If successful, this innovative approach could be used to identify optimized sequence design and streamline an HIV vaccine and administration schedule for use in future human clinical trials.
- Contribute to the development of a protective HIV-1 vaccine
- Validate findings from a previous preclinical study in monkeys
- Establish proof-of-concept for a sequential vaccine approach using mRNA
- Optimize the VLP antigenicity
- Optimize the design of the Env antigens
Results and Accomplishments
The project launched during 2020 with multiple partners, including University of Montreal Health Center (CHUM) and NIAID. Preclinical studies to support future clinical trials are now underway.
Zhang, P., Narayanan, E., Liu, Q. et al. A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques. Nat Med 27, 2234–2245 (2021). https://doi.org/10.1038/s41591-021-01574-5