CONGENITAL CYTOMEGALOVIRUS:  UNDERSTANDING INFECTION AND SEQUELAE

NIH GUIDE, Volume 22, Number 9, March 5, 1993



PA NUMBER:  PA-93-061



P.T. 34



Keywords:

  Infectious Diseases/Agents 

  Pathogenesis 

  Viral Studies (Virology) 



National Institute of Allergy and Infectious Diseases

National Institute of Child Health and Human Development

National Institute on Deafness and Other Communication Disorders



PURPOSE



The National Institute of Allergy and Infectious Diseases (NIAID),

the National Institute of Child Health and Human Development (NICHD),

and the National Institute on Deafness and Other Communication

Disorders (NIDCD) invite investigator-initiated research applications

for support of basic studies needed to establish the knowledge base

for the development of prototype vaccines to prevent symptomatic

congenital cytomegalovirus (CMV) infection and/or reduce the

associated severe sequelae.  Emphasis is on the role of host and

virus factors in determining disease pathogenesis and outcome of

congenital CMV infections.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This Program

Announcement, Congenital CMV:  Understanding Infection and Sequelae,

is related to the priority areas of immunization and infectious

diseases, maternal and infant health, and diabetes and chronic

disabling conditions.  Potential applicants may obtain a copy of

"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or

"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)

through the Superintendent of Documents, Government Printing Office,

Washington, DC 20402-0325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by domestic and foreign, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of state and local

governments, and eligible agencies of the Federal government.

Foreign institutions are ineligible for the First Independent

Research Support and Transition (FIRST) (R29) award.  Applications

from minority individuals and women are encouraged.



MECHANISMS OF SUPPORT



Applications considered appropriate responses to this announcement

are the research project grants (R01) and the FIRST award (R29).



RESEARCH OBJECTIVES AND SCOPE



Background



In utero CMV infection affects 40,000 children annually in the US,

with 7,500 to 10,000 children having severe sequelae including

progressive and profound deafness, mental retardation and learning

disabilities.   In the US, congenital CMV infection may be the cause

of 20 to 40 percent of congenital deafness and is as frequent a cause

of mental retardation as the fragile X-chromosome.  CNS damage from

congenital CMV infection exceeds that due to any other infectious

cause.  CMV is the most common intrauterine infection in humans,

occurring in 0.4 to 2.3 percent of all infants born alive.  Of the

40,000 congenital CMV infections, ten percent are symptomatic; 90

percent of symptomatic children suffer severe CNS sequelae and many

of them require lifetime custodial care at an annual cost of $1.86

billion.  Annually, congenital CMV infection results in 7,500

severely impaired children.  Of the asymptomatically infected

children, 15 percent have sequelae that while less severe, impact

substantially on their lives.



The highest risk for symptomatic congenital CMV infection is among

infants born to mothers who have had primary infection during

pregnancy.  Although transmission patterns may differ, infants born

to seronegative women of both high and low socioeconomic status are

at risk, with infants of disadvantaged adolescent women being at

greatest risk.



On March 12-13, 1992, the NICHD and the NIAID co-sponsored a workshop

on congenital CMV infection.  While substantial progress has been

made in defining congenital CMV infection, there are still

significant gaps in knowledge of the host and viral factors that

determine viral transmission, disease pathogenesis and outcome, and

severity of sequelae.  Based on the severity of symptomatic

congenital CMV disease, a vaccine that prevented symptomatic disease

and/or moderated sequelae, even if not preventing infection, would be

of significant benefit.  (Copies of the workshop summary are

available from the program officials listed below.  Other references

include:  Morbidity and Mortality Weekly Reports, vol. 41, No. SS-2,

April 24, 1992, pps 35-44 and Yow MD and Demmler GJ, New England

Journal of Medicine, vol. 326, 1992, pps 702-3.)



Additionally, CMV is the single most important infectious agent

affecting recipients of organ transplants, with at least two or three

of these patients developing CMV infection/reactivation one to four

months after transplantation.  CMV retinitis occurs in 6-15 percent

of AIDS patients; the minimum prevalence of CMV enterocolitis is

estimated as 2.5 percent of AIDS patients.  Although antiviral

therapy has reduced the morbidity and mortality from CMV in

immunocompromised individuals, knowledge gained from research in

response to this program announcement may facilitate the development

of vaccine or other immunological strategies to help these patient

groups as well.



o  Research Objectives and Experimental Approaches



The focus of applications submitted in response to this program

announcement should be the definition of the factors disposing to or

preventing the development of congenital CMV infection, disease, and

sequelae.  The long term goal of this research is accrual of

knowledge for the development of vaccines to prevent congenital CMV

disease and/or reduce the associated severe sequelae.



Examples of issues that need to be addressed include, but are not

limited to:



o  determination of serological and cellular correlates of protective

human immunity.  Assessment of these correlates does not necessarily

require study of pregnant women.  Because CMV disease manifestations

vary with the nature and degree of immunodeficiency, studies of

defined groups of moderately immunocompromised individuals could

provide an opportunity to correlate immune profile with disease

pathogenesis.  Studies measuring mucosal immunity, correlating

specific cellular and humoral responses with level of virus

excretion, or comparing primary infection with

reactivation/persistent infection are also very relevant to this

issue;



o  development of animal models of congenital infection.  Such models

should have infection outcomes that parallel human disease and could

be used to study host factors, including the effect on outcome of

gestational age of infection, maternal immune status, and

reactivation vs primary infection;



o  determination of factors that impact on disease transmission and

outcome such as: age of gestation, maternal protective immunity, role

of primary infection vs. secondary infection vs reactivation;



o  determination of the effect of CMV strain variation on host

response, disease or outcome;



o  determination of the virus site of latency and CMV trafficking in

the lymphoid system;



o  assessment of the occurrence of deficits in asymptomatically

infected children; and of host and viral factors which predispose to

mental retardation;



o  assessment of the occurrence of early- and late-onset hearing loss

and of vestibular dysfunction;



o  assessment of the prevalence in seropositive individuals of

B-cells and/or T-cells reactive with vaccine prototype antigens or

assessment of immune response or efficacy in animal models.  The

purpose of such studies would be to determine whether a prototype was

an appropriate vaccine candidate.  Vaccine trials are not within the

scope of this announcement.



Applications may address one or several issues, but should retain a

common theme and focus in addressing those issues.  Because issues of

virology, immunology, epidemiology, neurology, neurology, audiology,

and pathology may need to be addressed in a coordinated manner,

collaboration among investigators having expertise in these and other

appropriate disciplines is encouraged.  When individuals are at

different institutions, individual R01 applications may include

consortium arrangements.



Collaborative arrangements with on-going clinical studies or trials

that provide patient material at little or no-cost to the proposed

grant application are encouraged.  Such arrangements should be

clearly delineated in the application.  The description should

include sufficient information to permit scientific evaluation of the

studies proposed.  Among issues to include are the number and type of

specimens/patients, patient population characteristics (including

gender and minority composition; see STUDY POPULATIONS below),

overall goals of the collaborative project, remaining term of the

project and IRB approval of the project.  If substantial interactions

and costs with ongoing projects are proposed, a consortium agreement

can be developed and submitted to support this additional research

aspect.



If statistical analysis is anticipated, the methodologies and

personnel involved should be described in the application and evident

in the study design.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities and women

in study populations so that research findings can be of benefit to

all persons at risk of the disease, disorder or condition under

study; special emphasis must be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

that disproportionately affect them.  This policy is intended to

apply to males and females of all ages.  If women or minorities are

excluded or inadequately represented in clinical research,

particularly in proposed population-based studies, a clear compelling

rationale must be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information must be included in the form PHS 398

(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in

Section 5,  Human Subjects.  Applicants are urged to assess carefully

the feasibility of including the broadest possible representation of

minority groups.  However, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans (including American Indians or Alaskan

Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale

for studies on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The usual NIH policies concerning research on human subjects also

apply. Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines:  February 1, June 1, and October 1.  The receipt dates for

applications for AIDS-related research are:  January 2, May 1, and

September 1.



Application kits are available at most institutional offices for

sponsored research or business offices and may be obtained from the

Office of Grants Inquiries, Division of Research Grants, National

Institutes of Health, Westwood Building, Room 449, Bethesda, MD

20892, telephone (301) 496-7441.  The title and number of the

announcement must be typed in Section 2a on the face page of the

application and the "YES" box marked.



The completed original and five legible copies must be sent or

delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



FIRST (R29) award applications must include at least three sealed

letters of reference attached to the face page of the original

application.  FIRST award applications submitted without the required

number of reference letters will be considered incomplete and will be

returned without review.



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center of Research Resources

may wish to identify the Center as a resource for conducting the

proposed research.  If so, a letter of agreement from the GCRC

Program Director must be included in the application material.



Special Instructions



In order to facilitate interaction among the investigators who

successfully respond to this program announcement, program staff

plans to hold workshops in the Bethesda/Rockville area in calendar

years 1995 and 1997.  Applicants may request travel funds for this

purpose in the application.



REVIEW PROCEDURES



Applications will be assigned on the basis of established Public

Health Service Referral Guidelines.  Applications will be reviewed

for scientific and technical merit by study sections of the Division

of Research Grants, NIH, and in accordance with the standard NIH peer

review procedures.  Following scientific-technical review, the

applications will receive secondary review by the appropriate

national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications assigned to that ICD.  The following will be considered

when making funding decisions:  quality of the proposed project as

determined by peer review, program balance among research areas of

the announcement, and availability of funds.  Generally, the interval

between receipt of applications and earliest award is 10 months for

non-AIDS applications and six months for AIDS-related applications.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Susan B. Spring, Ph.D.

Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases

Solar Building, Room 3A-14

Bethesda, MD  20892

Telephone:  (301) 496-7453

FAX:  (301) 402-0804



Charlotte Catz, M.D.

Center for Research for Mothers and Children

National Institute of Child Health and Human Development

Building 6100, Room 4B-03

Bethesda, MD  20892

Telephone:  (301) 496-5575

FAX:  (301) 402-2085



Kenneth Gruber, Ph.D.

Division of Communication Sciences and Disorders

National Institute on Deafness and Other Communication Disorders

Executive Plaza South, Room 400B

Rockville, MD  20892

Telephone:  (301) 402-3458

FAX:  (301) 402-6251



Direct inquiries regarding fiscal matters to:



Mr. Todd Ball

Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B35

Bethesda, MD  20892

Telephone:  (301) 496-7075



Mr. Edgar D. Shawver

Office of Grants and Contracts

National Institute of Child Health and Human Development

Building 6100, Room 8A-17

Bethesda, MD  20892

Telephone:  (301) 496-1303



Ms. Sharon Hunt

Division of Extramural Activities

National Institute on Deafness and Other Communication Disorders

Executive Plaza South, Room 400B

Rockville, MD  20892

Telephone:  (301) 402-0909



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.856, Microbiology and Infectious Disease Research;

93.865, Research for Mothers and Children; 93.173 NIDCD.  Awards are

made under authorization of the Public Health Service Act, Title IV,

Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC

241 and 285) and administered under PHS grant policies and Federal

Regulations at 42 CFR Part 52 and 45 CFR Part 74.  This program is

not subject to the intergovernmental review requirements of Executive

Order 12372 or Health Systems Agency review.



.

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