HIV Vaccines Clinical Trials Network Leadership and Operations Center

About This Grant

This proposal outlines the scientific agenda of the Leadership and Operations Center of the HIV Vaccine Trials Network (HVTN), which has pioneered immunological approaches to HIV prevention. One of the major accomplishments of the HVTN in this grant period has been the conduct of 3 vaccine and 2 monoclonal antibody (mAb) efficacy trials that have provided proof of principle that 1) broadly neutralizing antibodies (bnAbs) can prevent HIV acquisition and 2) vaccine approaches that elicit non-neutralizing antibodies, even cross-clade non-neutralizing antibodies, are not effective. These trials provide a new roadmap for HIV prevention: induction of bnAbs is the path to an effective HIV vaccine. This proposal describes a novel fast-track Discovery Medicine phase 1 program to assess, in an iterative fashion, candidate trimers, germline and lineage-based vaccines designed to elicit bnAbs in adults and HIV-1–exposed infants. This program integrates novel candidate immunogens using sequential immunizations with B-cell sequencing to elicit mature functional bnAbs. The HVTN utilizes 13 geographically diverse core sites and another 10-14 protocol specific sites for its studies in the US. International research sites are also critical to HVTN’s scientific strategy and directly advance public health goals to end the HIV epidemic in the U.S. Conducting trials in high-incidence international settings allows the HVTN to evaluate prevention strategies more rapidly with smaller sample sizes and substantially lower cost, thereby accelerating the advancement of prevention interventions for the U.S. population. The use of international sites also enables evaluation of diverse HIV subtypes and supports the identification of immune correlates of protection in locations with sufficient endpoint accrual. The HVTN 703 study showed the remarkable benefit of mAb therapy for preventing HIV in women; it enrolled 1,700 women in sub-Saharan Africa and followed them for two years to show bnAbs could prevent HIV. This contrasts with a proposed 11,000-women study requiring 4 years of follow-up if conducted only in the U.S. We are now designing a combination passive immunization bnAb study in the U.S. to begin in 2028 rather than a 2034 start date if past foundational studies could not be conducted efficiently with high prevalence international sites. Vaccine clinical trials involve a complex interplay between clinical trial sites, HVTN laboratories, computational scientists, and our operational, training, mentoring, and fiscal management teams; these interactions are described in the application. The clinical, laboratory and statistical infrastructure we have built for immune-based prevention of HIV will also be used to assist in tuberculosis vaccine development. Our network integrates community representatives and community advisory boards into all our research process and conduct. We will also continue to develop the next generation of vaccine scientists and expand our scientific collaborations to engage the scientific community to utilize the extensive specimen and data repositories we have established. The overall goal of the HVTN in this proposal is to develop immune-based preventive interventions that will reduce HIV acquisition in adults and infants by more than 80%.