Study Effect of West Nile Virus Infection on Outcomes of Pregnancy in Humans

Announcement Type: New.

Funding Opportunity Number: 04213.

Catalog of Federal Domestic Assistance Number: 93.283.

Key Dates:

Letter of Intent Deadline: June 15, 2004.

Application Deadline: July 6, 2004.

I. Funding Opportunity Description

Authority: This program is authorized under section 317(k)(2) of the Public Health Service Act, (42 U.S.C. 247b(k)(2)), as amended.

Purpose and Research Objectives: The purpose of the program is to determine whether West Nile Virus (WNV) infection of pregnant women has adverse effects on the outcomes of pregnancy and to measure and describe the effects, if any, on the health of children born to women who were infected with WNV during their pregnancy.

This program addresses the “Healthy People 2010” focus area of Immunization and Infectious Diseases.

Measurable outcomes of the program will be in alignment with the following performance goal for the National Center on Birth Defects and Developmental Disabilities: To improve the understanding and find the causes and risk factors for birth defects and developmental disabilities in order to develop prevention strategies.

WNV, a single-stranded RNA flavivirus with antigenic similarities to Japanese encephalitis and St. Louis encephalitis viruses, is transmitted to humans primarily through the bite of infected mosquitoes. Flavivirus infection during pregnancy has been rarely associated with both spontaneous abortion and neonatal illness, and these viruses have not been known to cause birth defects in humans. In 2002, a 20-year old woman developed WNV encephalitis during the 27th week of pregnancy. At 38 weeks of gestation she delivered a live infant who appeared normal but on further examination had chorioretinitis and cystic cerebral tissue destruction. Tests for cytomegalovirus, rubella virus, herpes simplex virus, lymphocytic choriomeningitis virus, enterovirus, and toxoplasma provided no evidence that any of these agents had infected the infant. IgM antibody to WNV was found in cord blood and in the infant's serum and cerebrospinal fluid, indicating that the infant had acquired WNV infection in utero. WNV nucleic acid was found in the placenta and umbilical cord tissue. Although it is not possible to establish a direct link between WNV and the abnormalities seen in this infant, the abnormalities observed are consistent with those observed in intrauterine infections with other agents, suggesting that they may be related to WNV intrauterine infection. Three other instances of maternal WNV infection were investigated in 2002; in all three instances the infants were born at full term with normal appearance and without laboratory evidence of WNV infection, but cranial imaging studies and ophthalmologic examinations were not performed.

During 2002 a total of 4,156 cases of WNV illness in humans, including 2,942 cases of neuroinvasive disease, were reported to the Centers for Disease Control and Prevention (CDC) from state health departments. During 2003 over 9,100 cases of WN illness, including over 2,600 cases of neuroinvasive disease were reported to CDC. CDC is currently following over 70 women who were reported to have had WNV disease during pregnancy in 2003.

The proportion of WNV infections during pregnancy that result in congenital infection of the newborn is unknown. The spectrum of clinical abnormalities associated with intrauterine infections with other agents is wide and includes embryonic death and resorption, abortion and stillbirth, prematurity, intrauterine growth retardation and low birth weight, developmental anomalies and teratogenesis, congenital disease, and persistent postnatal infection. The case described above from 2002 suggests that intrauterine transmission of WNV in some instances may have deleterious consequences, but the spectrum of abnormalities and degree of risk of intrauterine transmission are currently unknown. Improved understanding of these issues is essential to allow appropriate counseling of women exposed to WNV and to fully appreciate the impact of this emerging infection.

In December of 2003, the Division of Vector-Borne Infectious Diseases (DVBID) of the National Center for Infectious Diseases (NCID), and the Division of Birth Defects and Developmental Disabilities (DBDDD) of the National Center on Birth Defects and Developmental Disabilities (NCBDDD) sought the opinion of experts on the evaluation of congenital infections to develop interim guidelines for the evaluation of infants born to mothers who were infected with WNV during their pregnancy. These guidelines included careful evaluation of physical characteristics, growth, development, and hearing for these infants and ophthalmologic and dysmorphologic evaluations and imaging of the brain for infants with evidence of congenitally acquired WNV infection. Data obtained from these evaluations will need to be collected and carefully reviewed in order to better understand the effects of WNV on pregnancy and infant outcomes.

Activities: Recipient activities for this program are as follows:

(1) Develop a procedure for study subject enrollment. Collaborate with staff at DVBID and DBDDD to enroll women who have been infected with WNV during pregnancy into the study using the WNV pregnancy registry maintained by DVBID as a primary source for enrollment. Additional sources of enrollment may be used upon mutual agreement between the recipient and CDC.

(2) Develop a procedure for enrollment of pregnant women who have not been infected with WNV to serve as study controls.

(3) Develop a study protocol detailing the study design, sample size calculations, study timeline, and provisions to maintain confidentiality of study subjects.

(4) Ensure that all WNV-infected women enrolled in the study have been or are reported to the state health department for the state in which they reside.

(5) Evaluate outcomes of all pregnant women in the study to include documentation of complications of pregnancy, miscarriage, premature delivery and health of live-born infants according to the interim guidelines published in the Morbidity and Mortality Weekly Report, Volume 53, February 27, 2004, pages 154-157. Because of uncertainty regarding diagnostic tests for congenital WNV infection; for purposes of this project, all infants born to women who were suspected to be infected with WNV during the first trimester of their pregnancy should receive the evaluation recommended for infants suspected to have congenital WNV infection, subject to consent of the parents. Infants born to women suspected to have been infected with WNV during the second or third trimester of pregnancy should be evaluated as indicated in the interim guidelines mentioned above. More detailed evaluation may be proposed by the recipient subject to ethical human research review and approval of project staff at DVBID and DBDDD.

(6) Publish and disseminate program results.

CDC Responsibilities: In this cooperative agreement, CDC Scientists (Scientific Liaisons) within the DBDDD/NCBDDD and the DVBID/NCID are an equal partner with scientific and programmatic involvement during the conduct of the project through technical assistance, advice, and coordination. These Scientific Liaisons will:

(1) Participate in the development of the protocol.

(2) Participate in the analysis, interpretation, and reporting of findings in the scientific literature and other media to the community at large and the public policy community within the Federal government.

(3) Participate in data management, analysis of data, and interpretation and dissemination of findings.

(4) Provide scientific consultation and technical assistance in the design and conduct of the project, including protocol adherence, outcome measures, and analytical approaches in participation with the recipient organization.

CDC Scientific Program Administrator (SPA)

The CDC NCBDDD will appoint an SPA, apart from the NCBDDD and DVBID Scientific Liaisons who will:

(1) Serve as the Program Official for the funded research institutions.

(2) Carry out continuous review of all activities to ensure objectives are being met.

(3) Attend Coordination Committee meetings for purposes of assessing overall progress and for program evaluation purposes.

(4) Provide scientific consultation and technical assistance in the conduct of the project as requested.

(5) Conduct site visits to recipient institutions to determine the adequacy of the research and to monitor performance against approved project objectives.

Collaborative Responsibilities

The planning and implementation of the cooperative aspects of the study will be effected by a Coordination Committee consisting of the Principal Investigator from the participating institution and the CDC Scientific Liaisons. This Coordinating Committee will formulate a plan for cooperative research.

At periodic coordination committee meetings, the group will: (1) Make recommendations on the study protocol and data collection approaches; (2) discuss the target populations that have been or will be recruited; (3) identify and recommend solutions to unexpected study problems; and (4) discuss ways to efficiently coordinate study activities and best practices.

II. Award Information

Type of Award: Cooperative agreement. CDC involvement in this program is listed in the Activities Section above.

Fiscal Year Funds: 2004.

Approximate Total Funding: $350,000.

Approximate Number of Awards: One.

Approximate Average Award: $350,000. (This amount is for the first 12-month budget period, and includes both direct and indirect costs.)

Floor of Award Range: None.

Ceiling of Award Range: $350,000 in initial budget period. If you request a funding amount greater than the ceiling of the award range, your application will be considered non-responsive, and will not be entered into the review process. You will be notified that your application did not meet the submission requirements. Based upon budget constraints, requests for financial assistance are subject to reduction in accordance with available resources.

Anticipated Award Date: September 1, 2004.

Budget Period Length: 12 months.

Project Period Length: Four years. Throughout the project period, CDC's commitment to continuation of awards will be conditioned on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and the determination that continued funding is in the best interest of the Federal government.

III. Eligibility Information

III.1. Eligible Applicants

Applications may be submitted by public and private non-profit organizations and by governments and their agencies, such as:

• Public non-profit organizations.
• Private non-profit organizations.
• Universities.
• Colleges.
• Research Institutions.
• Hospitals.
• State and local governments or their bona fide agents (this includes the District of Columbia, the Commonwealth of Puerto Rico, the Virgin Islands, the Commonwealth of the Northern Marianna Islands, American Samoa, Guam, the Federated States of Micronesia, the Republic of the Marshall Islands, and the Republic of Palau).
• Political subdivisions of States (in consultation with States).

A bona fide agent is an agency/organization identified by the State as eligible to submit an application under the State eligibility in lieu of a State application. If you are applying as a bona fide agent of a State or local government, you must provide a letter from the State as documentation of your status. Place this documentation behind the first page of the application form.

III.2. Cost Sharing or Matching

Matching funds are not required for this program.

III.3. Other

Individuals Eligible to Become Principal Investigators: Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for CDC programs.

Other Eligibility Requirements: If your application is incomplete or non-responsive to the requirements listed below, it will not be entered into the review process. You will be notified that your application did not meet submission requirements.

Applicants must: (1) Document their present infrastructure, capacity, expertise, and experience in conducting clinical and epidemiological evaluations of birth defects and/or infectious diseases with a national sample; and (2) have in the past shown their ability to identify and enroll women with West Nile Virus or related birth defects and/or infectious diseases in studies related to infections during pregnancy and with related case controls.

Applicants must provide specific evidence to substantiate this capacity, experience, and expertise. Through documentation of two pages in length, applicants must provide specific evidence that they can fully meet these eligibility criteria in order to be considered for formal review. This information must be included as part of the application and inserted immediately after the Face Page of the application.

Note:

Title 2 of the United States Code Section 1611 states that an organization described in Section 501(c)(4) of the Internal Revenue Code that engages in lobbying activities is not eligible to receive Federal funds constituting an award, grant, or loan.

IV. Application and Submission Information

IV.1. Address To Request Application Package

To apply for this funding opportunity, use application form PHS 398 (OMB number 0925-0001 rev. 5/2001). Forms and instructions are available in an interactive format on the CDC Web site, at the following Internet address: http://www.cdc.gov/od/pgo/forminfo.htm .

Forms and instructions are also available in an interactive format on the National Institutes of Health (NIH) Web site at the following Internet address: http://grants.nih.gov/grants/funding/phs398/phs398.html .

If you do not have access to the Internet, or if you have difficulty accessing the forms on-line, you may contact the CDC Procurement and Grants Office Technical Information Management Section (PGO-TIM) staff at: 770-488-2700. Application forms can be mailed to you.

IV.2. Content and Form of Submission

Letter of Intent (LOI)

The LOI must be written in the following format:

• Maximum number of pages: Two.
• Font size: 12-point unreduced.
• Paper size: 8.5 by 11 inches.
• Page margin size: One-inch margins.
• Printed only on one side of page.
• Single spaced.
• Written in plain language; avoid jargon.

The LOI must contain the following information: name, address, and telephone number of the proposed Principal Investigator, number and title of this program announcement, names of other key personnel, designations of collaborating institutions and entities, and an outline of the proposed work, recruitment approach, and expected outcomes.

Application: Follow the PHS 398 application instructions for content and formatting of your application. For further assistance with the PHS 398 application form, contact PGO-TIM staff at (770) 488-2700, or contact GrantsInfo, telephone (301) 435-0714, e-mail: GrantsInfo@nih.gov.

You must submit a signed original and five copies of your application form. The PHS 398 grant application form requires the applicant to enter the project title on page 1 (Form AA, “Face Page”) and the project description (abstract on page 2).

The main body of the application narrative should not exceed 30 single-spaced pages. This narrative research plan should address activities to be conducted over the entire project period. Please note that this maximum number of pages allowed exceeds the maximum number of pages (25 pages) indicated in the PHS 398 grant application form (“Research Grant Table of Contents”).

Additional information may be included in the application appendices. The appendices will not be counted toward the narrative page limit. This additional information may include curriculum vitae and resumes for key project staff, organizational charts, letters of support, etc.; and should be limited to those items relevant to the requirements of this announcement.

All material must be typewritten, with 10 characters per inch type (12 point) on 81/2 by 11 inch white paper with one inch margins, no headers or footers (except for applicant-produced forms such as organizational charts, c. vitae, graphs and tables, etc). Applications must be held together only by rubber bands or metal clips, and not bound together in anyway (including attachments/appendices).

You are required to have a Dun and Bradstreet Data Universal Numbering System (DUNS) number to apply for a grant or cooperative agreement from the Federal government. Your DUNS number must be entered on line 11 of the face page of the PHS 398 application form. The DUNS number is a nine-digit identification number, which uniquely identifies business entities. Obtaining a DUNS number is easy and there is no charge. To obtain a DUNS number, access http://www.dunandbradstreet.com or call 1-866-705-5711. For more information, see the CDC Web site at: http://www.cdc.gov/od/pgo/funding/pubcommt.htm.

Additional requirements that may require you to submit additional documentation with your application are listed in section “VI.2. Administrative and National Policy Requirements.”

IV.3. Submission Dates and Time

Letter of Intent (LOI) Deadline Date: June 15, 2004.

CDC requests that you send a LOI if you intend to apply for this program. Although the LOI is not required, not binding, and does not enter into the review of your subsequent application, the LOI will be used to gauge the level of interest in this program, and will allow CDC to plan the application review.

Application Deadline Date: July 6, 2004.

Explanation of Deadlines: Applications must be received in the CDC Procurement and Grants Office by 4 p.m. eastern time on the deadline date. If you send your application by the United States Postal Service or commercial delivery service, you must ensure that the carrier will be able to guarantee delivery of the application by the closing date and time. If CDC receives your application after closing due to: (1) Carrier error, when the carrier accepted the package with a guarantee for delivery by the closing date and time, or (2) significant weather delays or natural disasters, you will be given the opportunity to submit documentation of the carrier's guarantee. If the documentation verifies a carrier problem, CDC will consider the application as having been received by the deadline.

This announcement is the definitive guide on application submission address and deadline. It supersedes information provided in the application instructions. If your application does not meet the deadline above, it will not be eligible for review, and will be discarded. You will be notified that your application did not meet the submission requirements.

CDC will not notify you upon receipt of your application. If you have a question about the receipt of your application, first contact your courier. If you still have a question, contact the PGO-TIM staff at: 770-488-2700. Before calling, please wait three days after the application deadline. This will allow time for applications to be processed and logged.

IV.4. Intergovernmental Review of Applications

Executive Order 12372 does not apply to this program.

IV.5. Funding Restrictions

Restrictions, which must be taken into account while writing your budget are that project funds cannot be used to supplant other available applicant or collaborating agency funds for construction or for lease or purchase of facilities or space.

If you are requesting indirect costs in your budget, you must include a copy of your indirect cost rate agreement. If your indirect cost rate is a provisional rate, the agreement must be less than 12 months from the application due date.

IV.6. Other Submission Requirements

LOI Submission Address

Lisa T. Garbarino, Public Health Analyst, National Center on Birth Defects and Developmental Disabilities, CDC, 1600 Clifton Road, Mailstop E-87, Atlanta, Georgia 30333. E-mail address: lgt1@cdc.gov.

Application Submission Address: Submit the original and five copies of your application by mail or express delivery service to: Technical Information Management—PA, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, Georgia 30341.

Applications may not be submitted by fax or e-mail at this time.

V. Application Review Information

V.1. Review Criteria

You are required to provide measures of outcome and effectiveness that will demonstrate the accomplishment of the various identified objectives of the cooperative agreement. Measures of effectiveness must relate to the performance goals stated in the “Purpose” section of this announcement. Measures must be objective and quantitative, and must measure the intended outcome. These measures of effectiveness must be submitted with the application and will be an element of evaluation.

The goals of CDC-supported research are to advance the understanding of biological systems, improve the control and prevention of disease and injury, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score.

Under the evaluation criteria noted below, applicants must describe how they will address the program components as they relate to the Purpose and Research Objectives, and Recipient Activities as cited in this Announcement.

Your application will be evaluated against the following criteria:

1. Background/Understanding/Competency, including:

a. Identification of the problem and justification for the study, including accounts of understanding of West Nile Virus and its association with human illness, morbidity, and mortality;

b. Accounts as to the level of review of relevant literature undertaken and the discussion of the foundation in science being utilized in addressing the purpose of the research;

c. Description of the understanding of the implications and interrelationships between the vector and human host responses;

d. Accounts of the applicants understanding of the possible association between West Nile Virus infection and outcomes of pregnancy in humans;

e. Discussion of the unique capabilities residing in the applicant organization in conducting clinical and epidemiological evaluations of birth defects and/or infectious diseases on a national basis;

f. Description of the study goals, objectives and/or hypotheses, and

g. Intended use and applicability of study findings.

2. Research Approach and Organizational Capacity, including:

a. The overall strength and feasibility of the research design with an emphasis on pregnant women and the health of children born to women who were infected with West Nile Virus during pregnancy;

b. Presentation of how the applicant is fully able to identify and enroll women with West Nile Virus during pregnancy and related case controls;

c. Description and justification of the study population, including case definitions, number of participants, selection criteria, and methods for recruiting, enrolling, and sustaining participation;

d. Description of the consent process, including procedures for informing participants about the study and methods for obtaining consent;

e. The detailed description of the research design and all follow-up protocols, including access to a national sample;

f. Description of all study instruments including survey questionnaires, and a discussion of their reliability and validity;

g. Data handling and analysis plans, including statistical methodology, data entry, storage, and disposition; and

h. Plans for disseminating and reporting results to multiple (and applicant-identified) target audiences.

3. Investigators/Collaborators/and Management Plans, including:

a. Description of the major collaborators and their explicit contributions to project objectives;

b. Discussion of investigator(s) qualifications, roles, tasks, time commitments, and responsibilities; and

c. Detailed work plan with specific time frames for implementation of the project. This includes the presentation of overarching goals for the full four-year project period with a detailed work plan outlining monthly or quarterly objectives covering the first two budget years.

4. Evaluation Plan, including:

a. Description of how progress will be monitored and evaluated over the entire course of the research;

b. The extent to which project goals are to be attained and specific objectives accomplished; and

c. Description of expected outcomes and how the overall effectiveness of the research will be determined.

5. Budget Description and Justification: This includes the comprehensiveness and adequacy of the proposed budget in relation to program operations, collaborations, and services; and the extent to which the budget is reasonable, clearly justified, accurate, and consistent with the purposes of this research.

6. Protections: Does the application adequately address the requirements of title 45 CFR part 46 for the protection of human subjects? This criteria will not be scored; however, an application can be disapproved if the research risks are sufficiently serious and protection against risks is so inadequate as to make the entire application unacceptable.

7. Inclusion: Does the application adequately address the CDC policy requirements regarding the inclusion of women, ethnic, and racial groups in the proposed research? This includes:

a. The proposed plan for the inclusion of both sexes and racial and ethnic minority populations for appropriate representation.

b.The proposed justification when representation is limited or absent.

c. A statement as to whether the design of the study is adequate to measure differences when warranted.

d. A statement as to whether the plans for recruitment and outreach for study participants include the process of establishing partnerships with community(ies) and recognition of mutual benefits.

V.2. Application Review Process

Applications will be reviewed by CDC staff for completeness by the Procurement and Grants Office (PGO) and for responsiveness by NCBDDD as outlined in the “Other Eligibility Requirements”. Incomplete applications and applications that are non-responsive will not advance through the review process. Applicants will be notified that their application did not meet submission requirements and will not receive further consideration.

Applications, which are complete and responsive, will be subject to a preliminary evaluation (triage) by the scientific review group (Special Emphasis Panel—SEP) to determine if the application is of sufficient technical and scientific merit to warrant further review by the SEP.

Applications that are determined to be non-competitive will not be considered, and the SEP will notify the investigator/program director and the official signing for the applicant organization. A dual review process will then evaluate those applications determined to be competitive.

V.3. Anticipated Award Date

September 1, 2004.

VI. Award Administration Information

VI.1. Award Notices

If your application is to be funded, you will receive a Notice of Grant Award (NGA) from the CDC Procurement and Grants Office. The NGA shall be the only binding, authorizing document between the recipient and CDC. The NGA will be signed by an authorized Grants Management Officer, and mailed to the recipient fiscal officer identified in the application. Unsuccessful applicants will receive notification of the results of the application review by mail.

VI.2. Administrative and National Policy Requirements

45 CFR Parts 74 and 92

For more information on the Code of Federal Regulations, see the National Archives and Records Administration at the following Internet address: http://www.access.gpo.gov/nara/cfr/cfr-table-search.html.

The following additional requirements apply to this project:

• AR-1 Human Subjects Requirements.
• AR-2 Requirement for Inclusion of Women and Racial and Ethnic Minorities in Research.
• AR-9 Paperwork Reduction Act Requirements.
• AR-10 Smoke-Free Workplace Requirements.
• AR-11 Healthy People 2010.
• AR-12 Lobbying Restrictions.
• AR-14 Accounting Systems Requirements.
• AR-15 Proof of Non-Profit Status.
• AR-22 Research Integrity.
• AR-25 Release and Sharing of Data.

Additional information on these requirements can be found on the CDC Web site at the following Internet address: http://www.cdc.gov/od/pgo/funding/ARs.htm.

VI.3. Reporting

You must provide CDC with an original, plus two copies of the following reports:

1. Interim progress report, (PHS 2590, OMB Number 0925-0001, rev. 5/2001), on a date to be determined for your project for each subsequent budget year. The progress report will serve as your non-competing continuation application, and must contain the following elements:

a. Current Budget Period Activities and Objectives.

b. Current Budget Period Financial Progress.

c. New Budget Period Program Proposed Activities and Objectives.

d. Budget.

e. Additional Requested Information.

f. Measures of Effectiveness.

2. Financial status report and annual report, no more than 90 days after the end of the budget period.

3. Final financial and performance reports, no more than 90 days after the end of the project period.

These reports must be sent to the Grants Management Specialist listed in the “Agency Contacts” section of this announcement.

VII. Agency Contacts

For general questions about this announcement, contact: Technical Information Management Section (PGO-TIM), CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, Georgia 30341. Telephone: 770-488-2700.

For program technical assistance, contact: Lisa T. Garbarino, Public Health Analyst, National Center on Birth Defects and Developmental Disabilities, CDC, 1600 Clifton Road, Mailstop E-87, Atlanta, Georgia 30333. E-mail address: lgt1@cdc.gov; telephone: 404-498-3979.

For financial, grant management, or budget assistance, contact: Sylvia Dawson, Grants Management Specialist, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, Georgia 30341. Telephone: 770-488-2771; e-mail: snd8@cdc.gov.