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Principal Investigator: Sallie R. Permar
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $307,383
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT – PROJECT 3
Congenital cytomegalovirus (cCMV) is the most common in utero infection, affecting approximately 1 in
every 200 newborns and causing devastating neurologic impairment in 1 in 5 infected infants. Placental
transmission of CMV is significantly reduced in women experiencing reinfection (3-4%) compared to
women experiencing CMV infection for the first time during pregnancy (30-40%), suggesting that
maternal CMV-specific adaptive immunity can protect against cCMV infection. However, to effectively
reduce cCMV prevalence, the protective effects of vaccine-elicited immunity must supersede that of
natural immunity. Several challenges have limited CMV vaccine development, including the numerous
immune evasion mechanisms of the virus. One of these mechanisms is viral Fc receptors (vFcȖRs) that
bind the Fc region of IgG, which our team showed in vitro to interfere with host Fc-mediated antibody
effector functions that we showed to be critical immune factors for preventing cCMV transmission. In
our model of primary CMV infection in pregnant rhesus macaques (RM), we identified three vFcȖRs
encoded by rhesus CMV (RhCMV). Utilizing an engineered vFcȖR-deleted RhCMV, we determined that
while the 'vFcȖR virus could reach a similar peak viremia as the parental full-length virus (FL-RhCMV),
it was cleared from the blood significantly earlier. Conversely, CD4+ T cell depletion of pregnant RM
dams and subsequent infection with 'vFcȖR restored viremia to FL-RhCMV levels. While this revealed
that placental transmission does not require the presence of vFcȖRs, it highlights their role in limiting
antibody effectiveness in vivo. Therefore, the goal of this project is to develop and test CMV vaccine
strategies that will interrupt the action of vFcȖRs in cCMV transmission in the RM model. We
hypothesize that addition of passive or active vaccination against RhCMV vFcȖRs to an entry
glycoprotein-based vaccine strategy will enhance plasma Fc receptor-mediated IgG functions and
protect against cCMV transmission in a nonhuman primate model. Specifically, we will define immunity
against vFcȖRs in natural immunity and after immunization (Aim 1), define the impact of passive
antibodies against vFcȖRs on the protective effect of pre-existing anti-RhCMV antibodies on cCMV
transmission (Aim 2), and determine the ability of inclusion of vFcȖR antigens with a viral entry
glycoprotein (gB) mRNA-LNP vaccine to enhance protection against cCMV in the RM model (Aim 3).
This preclinical assessment of a novel CMV vaccine strategy will inform and de-risk potential human
clinical trials seeking to reduce the most common infectious cause of birth defects and brain damage.
Terms: <0-4 weeks old><7S Gamma Globulin><Acquired brain injury><Active Immunization><Active vaccination><Affect><Antibodies><Antibody Response><Antigen Receptors><Antigens><Binding><Birth Defects><Blood><Blood Reticuloendothelial System><Brain Injuries><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CMV><CMV glycoprotein B><CMV infection><CMV vaccine><Cells Placenta-Tissue><Clinical Trials><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Cytomegalic Inclusion Disease><Cytomegalovirus><Cytomegalovirus Infections><Cytomegalovirus Vaccines><Data Analyses><Data Analysis><Development><Disease><Disorder><Effectiveness><Engineering><Fc Receptor><Fetal Diseases><Gestation><Globulins><Glycoproteins><Goals><HCMV><Human><IgG><Immune Evasion><Immune response><Immunity><Immunization><Immunochemical Immunologic><Immunocompetent><Immunoglobulin G><Immunologic><Immunologic Factors><Immunologic Receptors><Immunological><Immunological Factors><Immunological Receptors><Immunological response><Immunologically><Immunologics><Impairment><In Vitro><Inclusion Disease><Infection><Innate Immunity><Interruption><Length><M mulatta><M. mulatta><Macaca mulatta><Maternal-Fetal Exchange><Measures><Mediating><Messenger RNA><Modeling><Modern Man><Molecular Interaction><Monkeys><Native Immunity><Natural Immunity><Neurologic><Neurological><Newborn Infant><Newborns><Non-Specific Immunity><Nonspecific Immunity><Normal Placentoma><Passive Immunization><Placenta><Placenta Embryonic Tissue><Placentome><Plasma Enhancement><Pregnancy><Prevalence><Prevention><Receptor Inhibition><Receptor Protein><Rhesus><Rhesus Macaque><Rhesus Monkey><Risk><Role><Salivary Gland Virus Disease><Salivary Gland Viruses><Serum Globulins><T cell response><T-Cell Depletion><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Testing><Time><Transmission><Transplacental Exposure><Vaccinated><Vaccination><Vaccines><Variant><Variation><Vertical Disease Transmission><Viral><Viral Interference><Viral Receptor><Viremia><Virus><Virus Receptors><Woman><Work><adaptive immunity><antibody receptor><brain damage><brain-injured><cohort><congenital CMV><congenital cytomegalovirus><congenital cytomegalovirus infection><cytomegalovirus glycoprotein B><cytomegalovirus group><data interpretation><data modeling><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><embryo/fetus disorder><evaluate efficacy><examine efficacy><experience><fetal disorders><fetal loss><fetus disorder><fetus loss><high risk><host response><immune competent><immune evasive><immune receptor><immune system response><immunogen><immunogenicity><immunologic substance><immunological substance><immunoresponse><improved><in utero><in vivo><infant infection><infected infant><interfering virus><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><maternal-fetal interface><model of data><model the data><modeling of the data><mother to child transmission><newborn child><newborn children><non-human primate><nonhuman primate><novel><passive antibodies><passive vaccination><pre-clinical assessment><pre-clinical evaluation><preclinical assessment><preclinical evaluation><pregnant><prevent><preventing><protective effect><rational design><receptor><receptor binding><receptor bound><receptor function><response><seropositive><social role><transmission process><vaccine candidate><vaccine development><vaccine efficacy><vaccine strategy><viraemia><viral sepsis><virology><virusemia>