HIV/AIDS Vaccine and Antibody Development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Eliciting a protective immune response to viruses characterized by significant genetic diversity is a significant scientific challenge first addressed by efforts to develop a vaccine to prevent HIV-1 infection. Significant progress has occurred in the multidisciplinary science required to rationally design HIV-1 vaccine antigens. First, advances in structural biology have enabled the visualization of HIV envelope glycoproteins that are targets of virus-neutralizing antibodies and rational structure-guided design of candidate vaccine antigens. Second, techniques to rapidly isolate antigen-specific B cells enabled the discovery of broadly neutralizing antibodies and the discovery of sites of vulnerability on HIV glycoproteins that could be targeted by vaccination. Finally, immunological insights into the stimulation and maturation of B cells identified key genetic, functional, and structural landmarks that define the evolution of a broadly neutralizing antibody from a germline-encoded antibody molecules with no antiviral activity. VRC HIV-1 vaccine efforts leverage all three conceptual advances to stimulate and mature specific lineages of B lymphocytes encoding antibodies capable of inhibiting diverse strains of HIV-1 through the recognition of structurally defined sites of vulnerability. The establishment of structure-guided vaccine principals for HIV-1 have now guided similar approaches to develop vaccines for many unmet public health needs, with considerable success. Fundamental and technical insights arising from the HIV-1 vaccine program continue to advance science in other fields at the VRC and beyond. Broadly neutralizing antibodies that bind multiple distinct sites of vulnerability have been discovered by VRC-investigators and others in the field. Translating these advances into vaccine candidates is accomplished through structural studies to identify molecules that stabilize the presentation antibody epitope to the immune system in a context that limits off-target antibody responses to other surfaces. The use of generative artificial intelligence (AI)- guided design approaches in ongoing efforts has the potential to dramatically accelerate these efforts. Antigen designs targeting epitopes within the envelope CD4 binding site (CD4bs), the membrane proximal external region (MPER), variable glycan-containing loops, and the conserved fusion peptide are underway. How the immune response is shaped by the timing, location, and context of vaccination remains incompletely understood. This project seeks to advance a fundamental understanding of this immunology in the context of our HIV-1 program. Vaccines to mature specific HIV-1 B cell lineage require a sequence of HIV antigens to stimulate the unique developmental pathway required to develop a broadly neutralizing antibody. We continue to evaluate different vaccine regimens and routes of administration to vaccine strategies. These efforts include the structure and timing of viral antigens to stimulate (prime) and boost the B cell and antibody response. Research to identify optimal adjuvants to enhance immunity is also conducted. Broadly neutralizing monoclonal antibodies have significant potential in the prevention and treatment of HIV-1 infection. To increase the potency and utility of HIV-1 broadly neutralizing antibodies (bNAbs), we are using structure guided approaches to modify antibodies to enhance the breadth, potency, and pharmacokinetics of HIV-1 monoclonal antibodies. Further, studies to evaluate how changes in antibodies impact recognition by the host response, alter specificity, or change manufacturability are also conducted. One innovative way to increase an antibodies capacity to bind genetically and antigenically diverse viral strains is to engineer antibodies to bind multiple distinct epitopes simultaneously. This is achieved through the design of a single antibody molecule that includes the antigen binding fragments of multiple different bNAbs. We are also working to develop multispecific anti-HIV-1 antibodies that combine two or three different anti-HIV-1 specificities in one IgG-like molecule for both HIV-1 prevention and therapy. This technology has broad application to the development of antibody biologics for infectious disease, cancer, and other case uses.