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Principal Investigator: Genevieve Giny Fouda Amou ou
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2022
Award: $343,969
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT – Project 2
Globally, about 600,000 young adults (15-24 years of age) became infected with HIV-1 in 2017. Young women
age 15-19 years are most affected, and HIV-infection in this age group continue to rise. Therefore, a vaccine to
prevent HIV acquisition in young adults remains a top priority and needs to be effective prior to sexual debut.
The induction of broadly neutralizing antibodies (bnAbs) represents a major goal in HIV vaccine design. Yet, so
far, preclinical vaccine trials have only yielded modest results in eliciting bnAbs. Thus, novel vaccine strategies
are needed. Here, we propose to employ an HIV Env mRNA vaccine and to start vaccination in early life to
allow for the necessary time to develop bnAbs. Our rationale is based on data that bnAbs in HIV-infected
infants develop earlier and at higher frequencies compared to HIV-infected adults. Furthermore, bnAbs in HIV-
infected infants exhibit lower somatic hypermutation and, in contrast to adults, are more frequently directed
against multiple epitopes. These findings suggest that the infant immune landscape might be better equipped
for the development of bnAbs. Indeed, infants have higher frequencies of follicular T helper (TFH) cells that are
critical in driving germinal center B cell responses. Our mRNA vaccines will be packaged in lipid nanoparticles
(LNPs) that exert potent adjuvant activity for TFH and allow for sustained antigen release; both criteria have
been associated with neutralization breadth. Our preliminary data confirm that a nucleoside-modified HIV Env
gp160 mRNA-LNPs can induce potent TFH and GC responses and promote the induction of tier 1 and tier 2
nAbs in adult rhesus macaques (RMs). Based on this premise, we hypothesize that an HIV Env gp160
mRNA-LNP vaccine administered in early life allows for the time to mature vaccine-induced antibody
responses with broadly neutralizing and/or Fc-mediated effector functions that can be boosted in childhood,
and that protection against HIV acquisition in adolescence is superior to that achieved by vaccination in
preadolescence. We will test this hypothesis by comparing the immunogenicity of the same HIV vaccine given
either to infant or to preadolescent RMs and determine the protective efficacy against intrarectal SHIV
acquisition in adolescence (Aim 1). By applying several systems biology approaches and bioinformatic
pipelines, we will identify the developmental pathways resulting in bnAb responses. We will use system
immunology approaches to characterize the molecular and microbial signatures that accompany effective
vaccination within each of the age groups, further refining the vaccine strategies, including adjuvant design
(Aims 2 and 3). To enhance the translational potential of our NHP studies, we will perform an analysis of
Hepatitis B vaccine-induced B cell responses in rhesus and human infants in parallel. These data are expected
to inform the optimal age, intervals, number of boosts, and immune cell and microbial interactions that must be
generated through vaccination and adjuvant selection to achieve protective immunity.
Terms: <12-20 years old><19 year old><19 years of age><21+ years old><7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Adolescence><Adult><Adult Human><Affect><Africa South of the Sahara><Age><Age-Years><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Automobile Driving><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Blood Plasma><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Childhood><Collaborations><Data><Development><Envelope Protein><Epitopes><Exhibits><Formulation><Frequencies><Generations><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Goals><HBV Vaccine><HIV><HIV Infections><HIV vaccine><HIV-1><HIV-I><HIV/AIDS Vaccines><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatitis B Vaccines><Hepatitis B virus vaccine><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Ig Somatic Hypermutation><IgG><Immune><Immune system><Immunes><Immunity><Immunoglobulin G><Immunoglobulin Somatic Hypermutation><Immunology><Individual><Inducer Cells><Inducer T-Lymphocytes><Infant><Infection><Kinetics><LAV-HTLV-III><Life><Link><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Malawi><Mediating><Messenger RNA><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Fingerprinting><Molecular Profiling><Molecular Stereochemistry><Mutation><Nucleosides><Nyasaland><Pathway interactions><Plasma><Plasma Serum><Proteins><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Reticuloendothelial System, Serum, Plasma><Rhesus><Rhesus Macaque><Rhesus Monkey><Rodent><Rodentia><Rodents Mammals><SHIV><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Structure of germinal center of lymph node><Sub-Saharan Africa><Subsaharan Africa><System><Systems Biology><Targeted DNA Modification><Targeted Modification><Testing><Time><Translations><Vaccination><Vaccine Design><Vaccines><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Woman><adolescence (12-20)><adolescent woman><adolescent women><adult youth><adulthood><age 19 years><age group><ages><allergic/immunologic body system><allergic/immunologic organ system><base><bio-informatics pipeline><bioinformatics pipeline><biomarker signature><conformation><conformational state><design><designing><developmental><driving><efficacy study><env Antigens><env Gene Products><env Polyproteins><env Protein><genome mutation><gp160><human immunodeficiency virus vaccine><immunogen><immunogenicity><infancy><infant infection><infantile><infected infant><initiation of sexual activity><interest><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><microbial><microbial interaction><microbial signature><microbiome><microorganism interaction><molecular profile><molecular signature><neutralizing antibody><new vaccines><next generation vaccines><nineteen year old><nineteen years old><non-human primate><nonhuman primate><novel><novel vaccines><pathway><pediatric><pre-adolescent><pre-clinical><preadolescence><preclinical><predictive signature><preteen><prevent><preventing><protective efficacy><response><sexual debut><sexual initiation><simian HIV><simian human immunodeficiency virus><somatic hypermutation><tool><translational potential><vaccination study><vaccination trial><vaccine against hepatitis B><vaccine antibodies><vaccine induced antibodies><vaccine response><vaccine responsiveness><vaccine strategy><vaccine study><vaccine trial><vaccine-induced antibodies><vaccine-induced response><viral infection><virus infection><virus-induced disease><young adult><young adulthood><young woman>