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Principal Investigator: Sallie R. Permar
Organization: DUKE UNIVERSITY
Fiscal Year: 2020
Award: $244,720
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT – Project 1
There is a critical need to protect adolescents and young adults from HIV infection through the development of
an early life vaccine strategy that elicits protective immunity prior to sexual debut. However, to date, efforts to
develop a vaccine that can elicit protective broadly neutralizing antibodies (bnAbs) have been challenged both
by limited engagement of bnAb epitopes by germline B cell receptors and levels of somatic hypermutation
needed for achievement of bnAb, as well as the likely need for long term boosting and several years time to
evolve the B cell responses towards broad neutralization. Two recent findings suggest that the low risk of HIV
acquisition in the period between breastfeeding and sexual debut might provide unique window and immune
landscape for vaccine-induced bnAb production: 1) the high capacity of the pediatric immune system over that
of adults for the development of bnAb responses during HIV infection, and 2) the remarkably low somatic
hypermutation level in bnAbs isolated from HIV-infected children, which may provide the opportunity to direct
development of bnAb B cell clones through vaccination. Yet, there is a gap in our understanding of the
potential advantages of the early life immune system over that of adults for induction of bnAbs via vaccination.
Thus, Project 1 proposes to compare immune response to long-term immunization with the bnAb germline-
targeting native-like HIV Env trimer: BG505 GT1.1 SOSIP trimer immunogen initiated in infancy compared to
that of pre-adolescents (as well as comparison to BG505 Env mRNA infant vaccination in Project 2).
Specifically, Aim 1 of this project will test the hypothesis that the unique flexibility of the early life immune
system and differential B cell tolerance mechanisms will allow enhanced engagement and evolution of B cell
clones through bnAb germline-targeting SOSIP immunization compared to that in older monkeys. Aim 2 will
test the hypothesis that the initiation of HIV B cell lineage vaccination in early life compared to preadolescence
will result in antibody maturation that will translate into enhanced protective vaccine efficacy against HIV
acquisition prior to sexual debut. Finally, Aim 3 will test the hypothesis that early life immunologic and
microbiologic signatures predict the development of HIV-neutralizing responses to SOSIP vaccination by
working with the Program's Integrated Systems Immunology Core, to assess the transcriptomic and
microbiome signatures that associated with the induction of bnAb precursor and tier 2 virus neutralization
responses. Furthermore, to establish translatability, we will compare the overall kinetics of vaccine-elicited
somatic hypermutation in U.S and Malawian infants to that of infant monkeys. Taken together, the results of
this Project will provide critical information about age-specific vaccine-elicited immune responses relevant to
refining HIV Env vaccine strategies that take advantage of immune development, such as target population,
vaccine schedule, novel adjuvants, and long term boosting that will be needed to achieve a high level of bnAb
induction in human populations.
Terms: <0-11 years old><0-4 weeks old><12-20 years old><21+ years old><AIDS Virus><Achievement><Achievement Attainment><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Adjuvant><Adolescence><Adolescent><Adolescent Youth><Adolescent and Young Adult><Adult><Adult Human><Affect><Age><Antibodies><Antigenic Determinants><Antigens><B blood cells><B cell><B cell receptor><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Birth><Blood Plasma><Breast Feeding><Breast fed><Breastfed><Breastfeeding><Cell Body><Cell Lineage><Cells><Child><Child Youth><Childhood><Children (0-21)><Clinical Trials><Clone Cells><Development><Epitopes><Evaluation><Evolution><Frequencies><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Genetic Alteration><Genetic Change><Genetic defect><HIV><HIV Infections><HIV immunization><HIV vaccine><HIV/AIDS Vaccines><HTLV-III Infections><HTLV-III-LAV Infections><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Ig Somatic Hypermutation><Immune><Immune response><Immune system><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunoglobulin Somatic Hypermutation><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunology><Immunostimulation><Inducer Cells><Inducer T-Lymphocytes><Infant><Infusion><Infusion procedures><Kinetics><LAV-HTLV-III><Life><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Messenger RNA><Microbiology><Modern Man><Monkeys><Mutation><Newborn Infant><Newborns><Parturition><Pathway interactions><Patients><Plasma><Plasma Serum><Population><Probability><Production><Receptors, Antigen, B-Cell><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Risk><SHIV><Schedule><Sexual Transmission><Somatic Cell><Specificity><System><T cell response><Target Populations><Testing><Time><Translating><Vaccination><Vaccines><Virus><Virus-HIV><active followup><adolescence (12-20)><adult animal><adulthood><age dependent><age related><ages><allergic/immunologic body system><allergic/immunologic organ system><children><childrens'><comparative efficacy><compare efficacy><design><designing><develop a vaccine><development of a vaccine><developmental><efficacy study><flexibility><flexible><follow up><follow-up><followed up><followup><genome mutation><global gene expression><global transcription profile><host response><human immunodeficiency virus vaccine><immunogen><immunogenicity><immunoresponse><individual heterogeneity><individual variability><individual variation><infancy><infant infection><infantile><infected infant><infected neonate><infected newborn><initiation of sexual activity><juvenile><juvenile human><mRNA><mature animal><microbial><microbiome><neonatal infection><neutralizing antibody><newborn child><newborn children><newborn infection><non-human primate><nonhuman primate><novel><pathway><pediatric><pediatric HIV><pediatric human immunodeficiency virus><pre-adolescent><preadolescence><predictive signature><preteen><prevent><preventing><programs><protective effect><rectal><response><sexual debut><sexual initiation><sexually transmitted><simian HIV><simian human immunodeficiency virus><somatic hypermutation><transcriptome><transcriptomics><trial design><vaccination strategy><vaccination study><vaccination trial><vaccine development><vaccine efficacy><vaccine formulation><vaccine response><vaccine study><vaccine trial><youngster>