R01AI173333

Identifying and Modeling Immune Correlates of Protection Against Congenital CMV Transmission After Primary Maternal Infection - Abstract

Congenital cytomegalovirus (CCMV) infection is the leading infectious cause of birth defects and brain damage worldwide, leaving >5,000 infants with permanent disabilities each year in the U.S. alone, with a disproportionate proportion in minority populations.

While a vaccine to prevent CCMV has been labeled "TIER 1 PRIORITY" for over 20 years, we remain without a licensed vaccine product, in part due to limited understanding of the types of immune responses that are protective against placental CMV transmission.

Primary infection during pregnancy is high risk for CCMV transmission, yet only approximately a third of mothers acutely-infected during pregnancy will transmit the virus to their infants, suggesting that the rapidity and magnitude of the maternal immune responses plays a role in protection against placental virus transmission.

The overarching goal of this proposal is to define CMV-specific humoral and cellular immune responses associated with reduced risk of fetal transmission and model their impact on placental transmission.

To address this goal, we have access to a unique cohort of 399 acutely CMV-infected transmitting and non-transmitting pregnant women enrolled in the NIH National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Unit (MFMU) CMV Hyperimmune Globulin Trial (NCT01376778).

This trial was a double-blind randomized trial that screened >100,000 pregnant women for acute CMV infection for enrollment to receive either CMV hyperimmune globulin (HIG) or placebo, yet was stopped for futility, creating a unique opportunity to define the acute cellular and humoral immune responses that are associated with transmission risk since HIG infusion after seroconversion did not change transmission risk.

Our hypothesis is that the combination of early, functional CMV-specific IgG responses and CD4+ T cell and specialized innate immune cell responses to primary CMV infection during pregnancy will predict reduced risk of fetal transmission and disease.

The combined strength of this uniquely large acutely CMV-infected pregnant cohort, our expertise in measuring CMV-specific humoral and cellular immune responses, and expertise in novel mathematical and placental organoid models will inform immune targets of CMV vaccine development that will be predicted to reduce the risk of CCMV transmission.

Our specific aims include:
1) Define the CMV-specific IgG binding and functional responses associated with reduced transmission and disease following primary CMV infection in pregnancy;
2) Define the cellular immune responses elicited during primary CMV infection that associate with reduced transmission in pregnancy;
3) Develop an in silico model that can predict candidate CMV vaccine efficacy for prevention of placental transmission based on maternal immune correlates of CCMV transmission and the rate of viral spread in placental organoid models.

Defining immune targets that will reduce fetal transmission and infant disease following primary maternal CMV infection will speed the design of effective vaccines to drastically decrease neurologic impairment and long-term disabilities in children worldwide.

Weill Medical College Of Cornell University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS; TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 93% from $1,696,748 to $3,281,182.