In the early days of HIV science, experts believed that the human immune system was largely incapable of creating naturally occurring antibodies that could neutralize HIV. Flash forward a few decades, and a growing collection of promising research is making a case that these broadly neutralizing antibodies, or bNAbs, may be the key to the next revolution in HIV treatment and prevention.
The first bNAbs were isolated in the 1990s from the serum of people living with HIV. Although studies attempting to use these early bNAbs in HIV treatment showed mediocre results, new technologies paved the way for a later generation of bNAbs with greater potency and breadth. Today there is a steady stream of preclinical and clinical studies of a range of bNAbs, both for treatment and prevention. The latest evidence for that progress was a hot topic at the biennial HIV Research for Prevention (HIVR4P) conference, which took place virtually this year in late January and early February.
Initial Results From Groundbreaking AMP Studies
Perhaps the most eagerly awaited bNAb data presented at HIVR4P was a late-breaker presentation on the initial results from the Antibody-Mediated Prevention (AMP) Studies. Launched in 2016, these two phase-2b trials were designed to evaluate a bNAb called VRC01 for HIV pre-exposure prophylaxis (PrEP) and were the first-ever efficacy trials of an HIV antibody.
One trial (called HVTN 704/HPTN 085) enrolled 2,699 HIV-negative cisgender men and transgender people who have sex with men or transgender partners in Brazil, Peru, Switzerland, and the United States, where HIV clade B is dominant. The other trial (called HVTN 703/HPTN 081) enrolled 1,924 HIV-negative cisgender women in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe, where HIV clade C is dominant. Together, the two studies included more than 4,600 participants.
Overall, VRC01 was safe and tolerable but did not significantly reduce HIV acquisition, according to study results presented by Lawrence Corey, M.D., of the Fred Hutchinson Cancer Research Center in Seattle. There was, however, a lower HIV incidence for in vitro VRC01-sensitive (IC80 <1 µg/mL) isolates in those who received VRC01 compared to those who received placebo. The AMP findings suggest that a combination approach will probably be needed to achieve effective antibody-mediated HIV prevention.
Additional Research Related to the AMP Studies and VRC01
In another HIVR4P presentation, researchers conducted a genetic analysis of HIV obtained from participants in both AMP trials who became HIV positive while receiving PrEP with VRC01. The findings were presented by Carolyn Williamson, Ph.D., of the University of Cape Town.
Williamson and colleagues used an innovative technology called single-molecule, real-time (SMRT) sequencing to analyze viral quasispecies and neutralization sensitivity of HIV breakthrough infections. This analysis allowed them to determine how genetic characteristics of the HIV env gene impact the prevention efficacy of VRC01.
Williamson et al identified minor founders (HIV types responsible for infection) not detected using conventional genetic sequencing methods. In addition, they found evidence of infection with viruses of mixed neutralization phenotypes, and in some cases, low frequency resistance mutations that were likely due to selection pressure exerted by VRC01. These insights into the limitations of VRC01 monotherapy will help guide future bNAb prevention studies, Williamson said.
A separate HIVR4P presentation assessed the neutralization sensitivity of breakthrough viruses from the southern African VRC01 AMP trial (HVTN 703/HPTN 081). Presented by Nonhlanhla N. Mkhize, Ph.D., of South Africa’s National Institute for Communicable Diseases, the study used env sequences of breakthrough infections from 30 women in the AMP trial to produce transmitted/founder (T/F) pseudotyped viruses. The researchers then tested these sequences against 14 bNAbs targeting the CD4bs (n=4), V3-glycan (n=3), V2-apex (n=3), gp120-gp41 interface (n=2), and the MPER (n=2) in the TZM-bl neutralization assay. Using the resulting neutralization data, they modeled the efficacy of various bNAb combinations.
Mkhize and colleagues found that all breakthrough viruses were of the tier 2 phenotype, which is typical of T/F viruses. They found that the VRC07-523LS neutralized 91% of viruses, representing the best coverage by a single bNAb. Combinations of two to four bNAbs increased the number of viruses neutralized, with a four-bNAb combination neutralizing 100% of viruses. The best-in-class three-bNAb combination provided 97% coverage.
These data confirm the takeaway message from the main AMP studies, Mkhize said: Combination bNAbs will need to be used in passive immunization trials to improve coverage of clade C viruses.
Effective bNAb Regimens Will Most Likely Come in Combinations
The likely necessity of a combination bNAb regimen was reinforced by a number of other HIVR4P presentations that highlighted the emerging role of this approach both for antiretroviral therapy (ART) and for PrEP. “Nearly three decades ago, we learned that three HIV drugs were better than one,” said Andrew Mujugira, MBChB, of Makerere University in Kampala, Uganda, who co-chaired a roundtable session on Jan. 27 that addressed the progress of antibody infusion strategies form the pipeline to the clinic. “Similarly, triple broadly neutralizing antibody combinations are likely to be more effective in preventing HIV acquisition than single antibodies, because the efficacy of the latter is constrained by the development of resistant HIV strains.”
During the roundtable, featured speakers focused on the ideal target-product profile, which, they maintain, includes:
- bNAbs co-formulated for fixed dosing
- Subcutaneous administration
- A dosing interval of two to three months
“We all know that a single product or approach will not be enough to stop the HIV pandemic,” said Devin Sok, Ph.D., of the IAVI Neutralizing Antibody Center, who spoke about optimization of bNAbs for HIV prevention. In the long term, Sok argued, a safe and effective vaccine will be essential to ending AIDS worldwide. But in the short and medium term, passive immunization with bNAbs can provide long-acting prevention against HIV as work toward a vaccine proceeds. In contrast to traditional small-molecule approaches to PrEP, he noted, bNAbs promise to offer long-acting (three months or longer) activity from a single dose; good tolerability with minimal side effects; and an injectable form of delivery that may be more “discreet” than oral tablets.
bNAbs: The Future of HIV Intervention?
Treatment and prevention of HIV have come a long way in the past 30 years. We now have five major classes of antiretroviral agents—nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs), and entry inhibitors (EIs). But while ART based on these small-molecule drugs is safe and effective, it is not a cure. In addition, no successful vaccine is currently available for either treating or preventing HIV.
Now, a new paradigm may be approaching. From the first pair of large-scale prevention trials to smaller clinical trials, to animal models, preclinical studies, and basic science, volumes of new data are shaping the future of HIV treatment and prevention. The future is coming over the horizon, and if a growing array of scientists have anything to say about it, that future is bNAbs.