National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Purpose

Background

Congenital infection with human cytomegalovirus (HCMV) is the most common infectious cause of disability in newborn infants. While congenital HCMV (cCMV) infection is asymptomatic at birth in the majority of cases, according to the Centers for Disease Control and Prevention (CDC), it results in brain damage/developmental delays, sensorineural hearing loss or death in 12.7% of newborns. An additional 13.5% of asymptomatic children develop permanent sequalae over time. cCMV infection occurs in between 0.2% and 0.7% of newborns in the United States and other developed nations, with even higher prevalence in the developing world. Women who acquire a primary HCMV infection during pregnancy have an increased chance of transmitting the infection to the developing fetus, with 32% of primary maternal infections resulting in congenital HCMV transmission. However, at a population level, more cases of congenitally acquired infections occur when the mother has pre-existing seroimmunity, indicating a non-primary infection. It is not clear whether the cCMV infections are the result of newly acquired HCMV infections or reactivated HCMV infections in the mother and what level or type of immunity may be necessary to prevent transmission to the developing fetus.

There is no licensed vaccine for HCMV. In Vaccines for the 21st Century, A Tool for Decisionmaking, the Institute of Medicine determined that a vaccine targeting cCMV had the potential to deliver both substantial reductions in morbidity and mortality and significant net cost savings. While numerous candidate cCMV vaccines have been developed, none has yet demonstrated sufficient efficacy to advance to Phase III trials, although the results have provided encouraging evidence of feasibility. A recombinant HCMV glycoprotein B (gB) vaccine showed some efficacy in preventing primary infection in young women and adolescents and provided benefit to HCMV-seronegative solid organ transplant recipients. DNA vaccines based on gB and the immunodominant T-cell target pp65 reduced viremia in hematopoietic stem cell transplant patients.

A critical contributor to the design of new HCMV vaccine candidates will be the identification of immune biomarkers that correlate with protection against infection or disease after vaccination. A variety of approaches can be used to identify such Correlates of Protection (COP), including analysis of the protection offered in vaccine efficacy trials and by natural infection.

We are seeking to conduct a case-control immune biomarker study, leveraging a large number of clinical specimens collected from pregnant women and their infants as part of the multi-country Zika in Infants and Pregnancy (ZIP) study. The ZIP study was initiated in June 2016, in the midst of the large Zika epidemic in the Americas, to study the natural history of Zika infection in pregnant women and its effect on the infants born to Zika-infected and uninfected mothers. The study has currently enrolled about 6200 women (independently from their Zika status) and their babies (about 4000). The goal of this CMV case-control immune biomarker study is to elucidate the rates of congenital CMV (cCMV) infection in babies from this highly-HCMV seropositive maternal cohort, the factors associated with transmission of HCMV infection in seropositive women and, in particular, the COP in seropositive women that prevent transmission. We will identify a sub-cohort of cCMV-infected babies and their mothers, as well as matched uninfected control pairs, perform a range of relevant virologic and immunologic assessments on the available specimens, and perform statistical analyses to determine the association of maternal immune-response variables with cCMV risk. Available specimens include longitudinal maternal serum, plasma, urine, whole blood, saliva, breast milk, cord blood, vaginal swabs, placenta and amniotic fluid; and infant saliva, serum and urine. PBMCs from a small subset of the volunteers have also been cryopreserved.

Given the large number of immunological assays and associated component immunological variables that could potentially be evaluated as correlates, the limited specimen volumes, and the lack of clear rationales for preferring certain immunological assays, this RFI seeks information that will inform the selection of those assays and identify the investigators that are qualified and interested in performing such assays.

Information Requested

Organizations are invited to provide information regarding immunologic assays that they believe will be valuable for establishing COP against cCMV in this cohort. This might include assays that measure the levels, quality and function (e.g., viral neutralization activity) of the antibody response, and cell mediated immunity (including T cell and NK function). Virologic or other assays that might be able to differentiate between CMV reactivation versus re-infection in the mothers also are a priority. Additional tests could be proposed with a proper justification.

The following assay features should be addressed:

• The specific immunologic parameter(s) being measured;
• The basis for the assay’s potential relevance to protection against cCMV;
• A description of the procedure, including the requirements for type and quantity of specimen(s), additional reagents (including specific viral strains and antigens needed), instrumentation and processing time;
• False positive rate(s), and the population(s) to which they apply;
• Dynamic range of the readout in representative HCMV seropositive population(s);
• Reproducibility on replicate samples.
  

Inclusion of supporting data for all claims regarding the assay(s) described is strongly encouraged.

In addition, this RFI is seeking to identify laboratories/groups that are qualified and interested in performing selected immunological test as part of a larger scientific collaboration.

Submitting a Response

All comments must be submitted electronically to NIAIDCMVCOP2019@niaid.nih.gov by 11:59:59 pm (ET) on . Responses must be submitted as a single attached document in MS Word or pdf format.

Responses to this RFI are voluntary. Do not include any proprietary, classified, confidential, trade secret, or sensitive information in your response. The responses will be reviewed by NIH staff, and individual feedback will not be provided to any responder. The Government will use the information submitted in response to this RFI at its discretion. The Government reserves the right to use high level summaries of the submitted information in reports, in summaries of the state of the science, in any possible resultant solicitation(s), grant(s), or cooperative agreement(s), or in the development of future funding opportunity announcements.

This RFI is for information and planning purposes only and shall not be construed as a solicitation, grant, or cooperative agreement, or as an obligation on the part of the Federal Government, the NIH, or individual NIH Institutes and Centers to provide support for any ideas identified in response to it. The Government will not pay for the preparation of any information submitted or for the Government’s use of such information. No basis for claims against the U.S. Government shall arise as a result of a response to this request for information or from the Government’s use of such information.

Inquiries

Please direct all inquiries to:

Dr. Christopher Beisel
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-292-1096
Email: cbeisel@nih.gov

Dr. Nahida Chakhtoura
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6872
Email: nahida.chakhtoura@nih.gov