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Principal Investigator: Shane P Crotty
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $810,280
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Preclinical studies and early stage human trials evaluating passively transferred broadly
neutralizing antibodies (bnAbs) suggest that a vaccine capable of eliciting bnAbs would provide
effective protection from HIV infection. However, the difficulty of inducing bnAbs through
vaccination has led to a focus in the field on vaccine strategies based on sequential immunizations
meant to guide the developing B cell response. These sequential immunization strategies range
from germline targeting to lineage-guided design to immunofocusing, and combinations thereof.
While logical from a structural biology perspective, important immunological questions remain
unanswered for such vaccines: In such a strategy, at what interval should sequential immunogens
be administered? How does competition from antigen-specific but non-neutralizing B cell
precursors impact vaccine “shepherding”? Is this sequential immunization process hindered by
limited T cell help? In addition, vaccines comprised of 4 or more injections will be a challenge to
implement globally. How do we make such a vaccine practical? In this phase R61/R33
application, we propose systematic studies in small animal models to evaluate fundamental
vaccine immunology issues facing such strategies. We proposed several novel approaches to
examine, and potentially solve, these issues: In aim 1 we will characterize the immunology of
staggered sequential immunizations, in aim 2 we develop an approach to delete competitor B
cells during vaccination, in aim 3 we develop vaccines employing augmented T cell help, and in
aim 4, we propose technologies to enable sequential immunogen exposure following a single
injection. We will test these concepts in the context of vaccines aiming to elicit bnAbs against the
CD4 binding site (VRC01-class responses) and the Env fusion peptide, using physiologically
relevant conditions. The most impactful of these immunization strategies will be downselected for
testing in non-human primates (NHP) during the R33 phase, the animal model for HIV
immunization closest to humans. Our work is guided by recent advances by the Irvine, Crotty,
and Silvestri labs in understand GC kinetics, bnAb B cell competition,vaccine delivery systems,
novel adjuvants, and roles of T cell help in rare B cell recruitment.
Terms: <AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Animal Model><Animal Models and Related Studies><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Binding Sites><Cancers><Clinical><Combining Site><Data><Development><Epitopes><Genetic Alteration><Genetic Change><Genetic defect><Germ Lines><Germinal Center><HIV><HIV Infections><HIV immunization><HIV vaccine><HIV/AIDS Vaccines><HTLV-III Infections><HTLV-III-LAV Infections><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Ig Somatic Hypermutation><Immune response><Immunization><Immunize><Immunochemical Immunologic><Immunoglobulin Somatic Hypermutation><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Injections><Kinetics><Knock-in><Knock-out><Knockout><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Malignant Neoplasms><Malignant Tumor><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><Modern Man><Modernization><Murine><Mus><Mutation><Non-Polyadenylated RNA><Peptides><Phase><Physiologic><Physiological><Process><Production><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Reactive Site><Regimen><Ribonucleic Acid><Role><Science><Series><Specificity><Structure of germinal center of lymph node><System><T-Cells><T-Lymphocyte><Technology><Testing><Vaccination><Vaccines><Virus-HIV><Work><adoptive B cell therapy><adoptive B cell transfer><chemotherapy><cost><deliver vaccines><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><engineered immune system><genome mutation><host response><human immunodeficiency virus vaccine><immune engineering><immune system response><immunization strategy><immunoengineering><immunogen><immunoresponse><improved><knockin><mRNA vaccine><mRNA-based vaccine><malignancy><memory CD4 T cell><memory CD4 T lymphocyte><model of animal><mouse model><murine model><neoplasm/cancer><neutralizing antibody><new approaches><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><practical implementation><pragmatic implementation><pre-clinical study><preclinical study><recruit><response><social role><somatic hypermutation><structural biology><thymus derived lymphocyte><vaccination strategy><vaccine delivery><vaccine development><vaccine strategy>