Additional authors include, Dieter Mielke (laboratory science), Bo Zhang (biostatistics), and Daniel Griffin (community engagement) with moderators Drs. Zoe Moodie and Guido Ferrari

The rapporteurs compiled their experiences and take-aways from the HVTN 2023 Full Group Meeting to outline where the HVTN is, where the HVTN wants to go, and importantly how the HVTN can get there.

The mandate of HVTN is to support and promote the development of efficacious preventive strategies against HIV-1 transmission. The HVTN physician scientists rely on the results from the central laboratory work, results from SDMC statistical analysis, and the voices from the community in order to develop safe and effective vaccine clinical trials. During the May 2023 Full Group Meeting, we were introduced extensively to additional vaccine strategies aimed at inducing broadly neutralizing antibody (bnAbs) responses considered the gold standard to prevent transmission by protecting our cells from getting infected by HIV-1. We learned which HIV envelope epitopes are most desirable and why, and how to design a trial using surrogate biomarkers as endpoints. We also got updates on current vaccine trials which will inform both iterative trials in our Discovery Medicine Program, as well as when to collaborate with manufacturers for large scale efficacy trials, all the while continuing to keep our community first.

During the meeting, there was a strong emphasis on the role that antibodies will play in prevention as well as in treatment of HIV infection, including innovative changes to their structure that will allow for improvements in their ability to recognize the majority of the circulating HIV-1 (referred to as breadth) and at low concentration in the body (referred to as potency) all the way to making their manufacturing more economical. Given the prior results showing a single antibody will be insufficient for preventing infection due to the level of viral diversity, the numerous antibody combination phase I and II trials in the pipeline will provide important information on the effectiveness of a multi-antibody (“mAb combination”) approach.

To optimize the breadth and potency of our mAb administration strategies, one important theme of the May 2023 HVTN Full Group Meeting was to use a combination of monoclonal antibodies for HIV-1 prevention. For this effort, it is crucial to determine how to best predict the potential impact of the mAB combinations once infused. Dr. Yunda Huang discussed an important quantity, termed predicted serum neutralization 80% inhibitory dilution titer (PT80), as a promising biomarker of the projected efficacy of a bnAb regimen. To provide some details, this biomarker PT80 is obtained by dividing the serum concentration of a bnAb by the in vitro 80% inhibitory concentration (concentration of the mAb that prevents 80% of the maximum level of infection of cells in our laboratory tests) of the bnAb against a target HIV-1 viral strain. In practice, because (1) the serum concentration of a bnAb would decay between two bnAb infusions and (2) many HIV-1 viral strains are circulating in a geographic region, researchers would calculate a summary PT80 by averaging over a representative panel of circulating HIV-1 viral strains and over the inter-infusion period. Using data derived from the Antibody Mediated Prevention trials, researchers estimated a relationship between the biomarker PT80 and the prevention efficacy of a bnAb regimen. This relationship is useful when designing a future clinical trial involving possibly different monoclonal antibodies and different dosing/schedule. In fact, the biomarker has been used in planning a second antibody mediated prevention trial involving three antibodies targeting different epitopes. What would such a trial look like? Dr. Holly Janes discussed three potential trial designs, including (Design I) involving two bnAb study groups (Dose A and Dose B) and a placebo group, all on top of a standard HIV-1 prevention package (referred as MOSAICO-type design); (Design II) involving two bnAb study groups and a partially effective active control group (e.g., daily oral TDF/FTC), on top of a standard HIV-1 prevention package, and the goal is to demonstrate the superiority of the bnAb regimen (referred as HPTN 084-type design); (Design III) involving two bnAb study groups and a highly effective active control group (e.g., CAB-LA), on top of a standard HIV-1 prevention package, and the goal is to demonstrate that the bnAb regimen is non-inferior compared to the CAB-LA (referred as the HPTN 083-type design). Each study design varies in the number of participants required, ranging from ∼5,000 in Design I to ∼10,000 in Design III.

In addition to the passive administration of bnAbs to prevent transmission, we heard updates on the numerous phase I clinical trials of vaccine concepts to elicit bnAbs that included  immunogens like Envelope trimer- and mRNA-based vaccine strategies. Seeing these trials in progress, having been conceptualized from research conducted over the last decade, was exciting. In particular, the promising results from the mRNA trials presented in this meeting suggest this will be a robust platform that will allow for rapidly iterating toward appropriate vaccine immunogens. In addition, we heard the initial report of the detection of neutralizing antibodies targeting a tier 2 autologous virus and heterologous viruses – largely understood to be required for an effective HIV vaccine – in two separate trials provided hope that the field is on the right track toward an effective vaccine.

Throughout the meeting, there was an emphasis on updating reagents to more accurately measure responses elicited by vaccines and the breadth/potency of antibodies. There were several presentations which highlighted the development of new panels of viruses isolated in the last five years, as opposed to the historical panels developed over a decade ago. Updating these reagents will allow laboratories to better predict the breadth and magnitude of a response against currently circulating strains and iterate toward the most effective prevention strategies.

In the specific session of community engagement, we heard that the community wants a deeper connection attached to meaningful involvement. CABs still have a general sense that scientists are including them as a checking-of-the-box exercise and not truly incorporating community-generated lessons. This meaningful involvement can be achieved through developing deeper relationships with members and leadership across CABs, community slides with great influence on why this science matters and where it will take us, and greater involvement and inclusion of trans and gender-non-confirming persons. Finally, the importance of adapting communication when describing people involved in studies. This is achieved by increasing the use of people-first language, reducing conversations of 'at-risk' individuals, and making sure all participants have access to translation services of their choice.