BASIC RUBELLA RESEARCH LEADING TO IMPROVED RUBELLA VACCINES

NIH GUIDE, Volume 22, Number 20, June 4, 1993



PA NUMBER:  PA-93-090



P.T. 34



Keywords:

  Vaccine 

  Infectious Diseases/Agents 

  Viral Studies (Virology) 

  Immunology 



National Institute of Allergy and Infectious Diseases

National Institute of Arthritis and Musculoskeletal and Skin Diseases



PURPOSE



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

the National Institute of Arthritis and Musculoskeletal and Skin

Diseases (NIAMS) invite investigator-initiated research grant

applications to pursue the development of safer vaccines to protect

women against rubella infection (German measles). Multidisciplinary

approaches, including basic research in virology and molecular

immunology, are needed to identify and characterize the rubella virus

gene products that are required for induction of durable immunity and

those that are associated with adverse effects, particularly

manifestations of joint disease.  Research in this area also might lead

to an understanding of the high female/male incidence ratio of adverse

reactions in adults.  In addition to vaccines with fewer adverse

side-effects, a further goal is to develop safe vaccines that can be

used in pregnant women to prevent fetal infection and congenital

rubella syndrome (CRS).



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 (PA), Basic Rubella Research Leading to Improved Rubella

Vaccines, is related to the priority area of immunization and

infectious diseases.  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



Research grant 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.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible for the First Independent

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



MECHANISMS OF SUPPORT



Applications considered appropriate responses to this announcement are

the investigator-initiated research project grant (R01) and the FIRST

award (R29).



RESEARCH OBJECTIVES



Background



Until the introduction of a live attenuated vaccine in 1970, rubella

was a common febrile disease of childhood.  The most serious effects of

rubella--abortions, miscarriages, stillbirths and fetal

anomalies--follow infection during early pregnancy.  The average cost

of a single case of CRS, caused by infection of the fetus with rubella,

is estimated to be well over $200,000.



The current licensed vaccine works well in children.  By blocking the

spread of rubella, it has been effective in dramatically reducing, but

not eliminating, the yearly incidence of CRS in the United States.

From 1970 to 1989, there was a steady reduction in the number of annual

cases of rubella. However, compared to 1988, the yearly incidence of

rubella cases and rubella in patients 15 years of age or older,

increased twofold in 1989, and threefold in 1990.  Although the total

number of cases was still small (0.4 cases per 100,000 in 1990), this

re-emergence of natural rubella led to a campaign to increase

vaccination coverage in all age groups, and thus more and more adult

women are being immunized against rubella.



Unfortunately, as a public health tool, the current vaccine has some

deficiencies.  This live vaccine, like natural rubella, causes

transient joint symptoms in a significant proportion of women

vaccinees.  Historical reports of natural epidemics also mention

increased arthropathy predominantly in adult women.  Currently in the

U.S., an increasing percentage of women entering child-bearing age have

not been immunized against rubella.  When these adult women receive

rubella vaccine, acute joint complaints are common, occurring in up to

25 percent of previously seronegative vaccinees.  These symptoms

usually last from one day to three weeks.  Investigators in Canada

recently reported that 5 to 11 percent of adult female vaccinees

develop a more severe, persistent or recurring arthropathy.  There also

have been reports that these complications increase with the age of the

vaccinee, and/or the presence of low or incomplete rubella immunity

(perhaps representing a waning antibody response from an earlier

childhood immunization).  Another limitation of the current vaccine is

that it is not recommended for use in women who may be pregnant,

because the vaccine virus can be transmitted to the fetus.



Research Objectives and Experimental Approaches



Basic research on rubella is now at a low level in the U.S.  Our

primary objective is to stimulate research on rubella so that data are

available to develop improved vaccines which would protect women of

childbearing age without causing undesirable side effects and without

fear of fetal infection.  Success in this endeavor will require basic

research in virology, immunology, genetics, and pathogenesis.  Studies

are needed to identify and characterize rubella virus gene products

required for induction of durable immunity, and those associated with

adverse effects.  Research is encouraged to discover the role of viral

components, and the importance of the response of the host, in the

induction of inflammation and symptoms of acute and persistent

arthritis.  Studies would include genetic analysis of clinically

characterized vaccine strains to determine if strain-specific variation

leads to a propensity for growth in human synovial cells and

association with persisting joint symptoms in adult vaccinees.

Research in this area also might provide an understanding of the high

female/male incidence ratio of adverse reactions in adults.



Research projects are sought which investigate topics including, but

not limited to those listed below.



o  Establishment of the quantitative and qualitative differences

between vaccine-induced and naturally-induced immunity against rubella.



o  Determination of which rubella antigens are required to safely

elicit long-lasting protective humoral and cellular immunity.



o  Characterization of the viral correlates of virulence and

attenuation.



o  Elucidation of those factors contributing to vaccine-induced adverse

events.  Analysis of the host and viral factors that contribute to

immune and inflammatory responses associated with arthritis, and

establishment of the molecular and cellular mechanisms causing joint

inflammation.



o  Development of an animal model of rubella which parallels human

disease, and allows elucidation of viral and host factors contributing

to immunity and immunization-induced adverse events.



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 research grant application form

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

deadlines February 1, June 1 and October 1.  Application kits are

available at most institutional offices of sponsored research 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) 594.7248.  The title and number of

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

application.



The original and five legible copies of the application must be sent or

delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



FIRST (R29) applications must include at least three sealed letters of

reference attached to the face page of the original application.  FIRST

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 for Research Resources

may wish to identify the GCRC as a resource for conducting the proposed

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

director or Principal Investigator could be included with the

application.



REVIEW CONSIDERATIONS



Applications in response to this announcement will be assigned on the

basis of established PHS 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 of

the applications considered to have significant and substantial merit,

a secondary review will be by the appropriate national advisory council

or board.



AWARD CRITERIA



Applications will compete for available funds with all other R01 and

R29 applications considered to have significant and substantial merit.

The following will be considered when making funding decisions:

relative scientific merit, program relevance, availability of funds.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Dr. James M. Meegan

Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases

Solar Building, Room 3A16

Bethesda, MD  20892

Telephone:  (301) 496-7453

FAX:  (301) 496-8030



Dr. Susana A. S. Sztein

Rheumatic Diseases Branch

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 405

Bethesda, MD  20892

Telephone:  (301) 594-9953

FAX:  (301) 594-9673



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



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

No. 93.856, Microbiology and Infectious Disease Research.  Grants will

be awarded under the authority of the Public Health Service Act, Title

III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and

administered under PHS grants 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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