HIV Vaccine Researchers Search for Holy Grail of Broadly Neutralizing Antibodies
Presenter: Lynn Morris, PhD, Head, HIV Virology, National Institute for Communicable Diseases, (NICD), Research Professor, Director Antibody Immunity Research Unit, University of the Witwatersrand, Johannesburg, South Africa
A summary of HIV Vaccines and Immunotherapy: Quo Vadis? presented July 19, 2021, at the 11th International AIDS Society (IAS) Conference on HIV Science.
Inducing broadly neutralizing antibodies (bNAbs) is considered the holy grail for a preventive HIV vaccine. But four decades into the HIV epidemic, researchers are still searching.
“We are not able to get on top of transmission of AIDS because we don’t have a vaccine,” said Lynn Morris, PhD, Head, HIV Virology, National Institute for Communicable Diseases, Johannesburg, South Africa at a session entitled HIV Vaccines and Immunotherapy: Quo Vadis?
Currently, there are 32 COVID-19 candidate treatments undergoing efficacy testing and 8 vaccines have been approved for use. “In stark contrast, after 20 years of HIV vaccine research, there are 7 efficacy trials and no approved vaccines,” said Morris.
Why has it been so much easier to make a vaccine against COVID-19 than HIV? HIV is a much tougher, moving target as it is a chronic infection that integrates into the DNA, and few people with HIV develop bNAbs after many years. Also, HIV has multiple epitopes on the envelope glycoprotein, Morris noted.
Recently, there has been a spate of activity in HIV vaccine trials. The RV144 vaccine showed moderate efficacy in 2009, which led to the HIV Vaccine Trials Network (HVTN) 702 trial in 2019 to build on the success of RV144. “Disappointingly, that vaccine failed to show efficacy. We have one trial in efficacy testing, HVTN705/706, which is designed to elicit non-neutralizing antibodies, and we await the results in 2022 or 2023,” said Morris.
The Antibody Mediated Prevention (AMP) trial used the bNAb VRC01 that targets the CD4 binding site on the HIV envelope, showing that broadly neutralizing antibodies can work on HIV. In this trial, recently reported in the New England Journal of Medicine, 4600 high-risk male patients from the Americas and female patients in Africa received infusions of VRC01 every 2 months for a total of 10 infusions for 2 years. “In real-time, we were monitoring the breakthrough viruses for VRC01 sensitivity and also measuring the serum levels of VRC01 measured by ELIZA and neutralization,” said Morris.
Overall, the trial did not show efficacy, however, when researchers looked at viruses based on prespecified sensitivity to VRC01, they did see a signal. In viruses considered sensitive to VRC01, the efficacy was 75%. There was no efficacy in intermediately sensitive viruses or those considered resistant.
The researchers also looked at individual 80% inhibitory concentration (IC80) levels, the amount of VRC01 that it takes to inhibit the virus. The control group with naturally circulating viruses showed a wide range of sensitivities of viruses to VRC01. In the two active arms, viruses were blocked by VRC01. “If we take the median from the two active arms, the viruses had a 2.4-fold higher IC80 than viruses from the placebo cases. In other words, they really were more resistant,” said Morris.
Unpublished data from the AMP study provide another critical piece of information about the levels of VRC01 needed to protect against HIV infection. Researchers measured the levels of VRC01 over time and did predictive modeling to map the pharmacokinetics. “With increasing concentrations of IC80 we saw increased efficacy. An efficacy of 90% will require a serum dilution of 1:200,” said Morris.
She added that fewer than 30% of circulating strains were sensitive to VRC01 in the AMP trial. “We need more potent antibodies and combinations to increase efficacy. Protection will likely require high levels of serum antibodies,” said Morris. “AMP validated our in vitro assays and non-human primate models. We now have a biomarker. This signal will allow us to test better bNAbs.”
A robust pipeline of bNAbs that target different sites will be tested for HIV prevention. Tests of multi-specific antibodies show a triple bNAb combination should yield high levels of efficacy over 4 to 6 months, Morris said.
Disclosures
Lynn Morris, PhD, reported nothing to disclose.
References
Corey L, Gilbert PB, Juraska M, et al for the HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N Engl J Med 2021; 384:1003–1014. DOI: 10.1056/NEJMoa2031738
Corey L, Gray GE. Preventing acquisition of HIV is the only path to an AIDS-free generation. Proc Natl Acad Sci U S A. 2017; 114(15):3798–3800. DOI: 10.1073/pnas.1703236114
Karuna ST, Corey L. Broadly neutralizing antibodies for HIV prevention. Annu Rev Med 2020; 71:329–346. doi: 10.1146/annurev-med-110118-045506.
National Institute of Allergy and Infectious Diseases. Experimental HIV vaccine regimen ineffective in preventing HIV. Accessed July 19, 2021. https://www.niaid.nih.gov/news-events/experimental-hiv-vaccine-regimen-ineffective-preventing-hiv