Full Text PA-97-097 THE IMPACT OF IMMUNE SENESCENCE AND MATURATION ON VACCINE RESPONSIVENESS IN THE ELDERLY NIH GUIDE, Volume 26, Number 28, August 22, 1997 PA NUMBER: PA-97-097 P.T. Keywords: National Institute on Aging National Institute of Allergy and Infectious Diseases PURPOSE The National Institute on Aging (NIA), and the National Institute of Allergy and Infectious Diseases NIAID, National Institutes of Health (NIH), invite applications to evaluate control measures (i.e., vaccines and therapeutic agents) for infectious diseases in the elderly and to enhance the understanding of the immune response to infection and immunizations in this at risk population. In addition to the clinical evaluation of candidate vaccines and therapeutic agents, there is a special emphasis on defining the mechanisms that lead to the decline in immune function and responsiveness (i.e., immunosenescence) with age. Innovative studies are sought that will develop vaccination strategies applicable for the elderly or that define approaches that direct specific types of immune responses which may lead to enhanced vaccine effectiveness towards various infectious agents. When assessing the immune response to immunization in aged populations, possible approaches may include incorporating established vaccines that may be used in this population such as pneumococcal, influenza, varicella, and hepatitis b. This Program Announcement solicits applications for research designed to enhance the overall understanding of mechanisms that account for the differential sensitivity to vaccines of young and older adult populations. Through the use of clinical research comparing younger and elderly adults using licensed vaccines and therapeutic agents, studies can be conducted to examine differences in: a) vaccine safety/reactogenicity; b) optimal dose and schedule; c) immunogenicity; d) transmissibility of infections from younger and older adults to uninfected individuals and how this is effected by immunization; e) resistance to infection and colonization; f) efficacy; and g) duration of immunity and protection. 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), ?THE IMPACT OF IMMUNE SENESCENCE AND MATURATION ON VACCINE RESPONSIVENESS IN THE ELDERLY?, is related to the priority areas of Immunization and Infectious Diseases, and Immunosenescence. Potential applicants may obtain a copy of ?Healthy People 2000? (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473) through the Superintendent of Document, Government Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800). ELIGIBILITY 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 not eligible for First Independent Research Support Transition (FIRST) R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01) and FIRST award (R29) applications may be submitted in response to this announcement. Applications for R01 grants may request up to five years of support; applications for R29 grants must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. An investigator planning to submit an application requesting $500,000 or more in direct costs for any budget period is advised that he or she must contact Institute program staff listed under INQUIRIES before submitting the application to obtain agreement from program staff that the Institute or Center will accept the application for consideration of award. An application of such a size received without prior staff concurrence and identification of that contact will be returned to the applicant without review. Investigators are referred to the policy update notice in the NIH Guide for Grants and Contracts, Volume 25, Number 14, May 3, 1996. Applicants proposing human intervention studies are referred to the NIA policy notice in the NIH Guide for Grants and Contracts, Volume 25, Number 33, October 4, 1996. RESEARCH OBJECTIVES Background: Over the past 50 years, the widespread use of vaccines has been a major factor in improving the health of people worldwide. Immunizations are among the most cost-effective means of protecting the public?s health. Children in particular, have benefited from immunization programs to such an extent that diseases like paralytic poliomyelitis have been eliminated and the incidence of others, including rubella and measles, has been significantly reduced. However, in the U.S., the immunization of adults does not receive the same priority as the immunization of children, even though deaths from vaccine preventable diseases such as influenza and pneumococcal infections occur predominantly in adults, especially the elderly. It is estimated that in the U.S., there are approximately 300,000-500,000 hospital discharges annually for pneumococcal pneumonia alone. For pneumococcal pneumonia, pneumonia in general, and pneumonia occurring during influenza outbreak periods, the risks of hospitalization are increased substantially in patients with chronic cardiopulmonary disease, stroke, diabetes mellitus, and cancer. Mortality caused by influenza and pneumococcal infections is substantial; an estimated 40,000 deaths from pneumococcal infections and 10,000 to 40,000 excess influenza-associated deaths occur each year. Of these deaths, 85% or more are among persons 65 years or older. Studies show that elderly adults are at increased risk of disease caused by encapsulated bacteria including Haemophilus influenzae and Streptococcus pneumoniae. The ability of the elderly to mount a substantial antibody response to polysaccharide antigens is dependent, in part, on their health status. Studies have shown healthy elderly individuals to respond in a normal fashion to pneumococcal polysaccharides when compared to healthy young controls, while those with chronic illness or high-risk conditions such as chronic obstructive pulmonary disease, chronic cardiac disease, alcoholism, diabetes, and renal failure respond poorly and are not protected. Furthermore, some serotypes associated with S. pneumoniae may be less immunogenic in the elderly than in younger adults. In a prospective, case-controlled study, the protective efficacy of polysaccharide pneumococcal vaccine progressively declined with advancing age and time since vaccination, falling from an aggregate efficacy of 93% in individuals less than 55 years of age within three years of vaccination, to 32% among those over age 75 who were last vaccinated more than five years earlier. These results highlight the concept that the response of older adults to current polysaccharide vaccines may be suboptimal, and that the duration of immunity provided by the polysaccharide vaccine is uncertain. Thus, the immune system at the extremes of life appears less efficient at mounting an effective antibody response to encapsulated pathogens, as evidence by the increased susceptibility of infants and the elderly to these pathogens including the pneumococcus. The world's elderly population (65 and over) in 1991 numbered nearly half a billion persons and is expected to exceed one billion by the year 2020. In most countries, the elderly population is growing faster than the population as a whole. In at least 30 countries, 15% or more of the entire population is age 60 or over and 57% live in developing countries. The oldest old segment (85 and over) of the world's elderly population numbers approximately 50 million, representing one-tenth of all elderly. Unlike the elderly as a whole, the oldest old today are more likely to reside in developed (54%) than in developing countries. The numerical growth of older populations around the world poses challenges to national public health care policies. This increasing number of elderly persons poses even more of a problem in light of the fact that various disease rates have increased, or at least have remained stable, in addition to the increasing and serious clinical problem associated with antimicrobial drug resistance. Research Objectives and Scope: Innovative research applications are sought that expand the current knowledge of senescence as it applies to the immune system and its expression following immunization and natural infection. The emphases of this PA are on: 1) identifying the determinants of the relative non-responsivity to vaccination in the elderly as compared to younger individuals; and 2) development of approaches to enhance immune responsiveness in the elderly. Studies proposed should address not only the differences in immune response between younger and older persons but also the variation observed within the older population. This should help explain differences among older persons in susceptibility to infection and protection conferred by immunization. Examples of research topics of interest include, but are not limited to, the following: o Age-related deficiencies in response to vaccine-related antigens; discovering the basic causes of vaccine failure such as T cell receptor antagonism, alterations in antigen-processing pathways, memory responses to different microbial polysaccharides, and the influence of previous infections and pathogen exposures on inducing protective immune responses; o Effect of aging on functional antibody activity,isotype responses, IgG subclass activity, cell-mediated immunity cytotoxic lymphocytes in particular), antibody affinity, avidity, and V-region expression, and their relative importance for predicting clinical outcome; o Changes in the colonization, transmission, and response to antimicrobial treatment for pathogenic and drug resistant forms of microorganisms; o Effect of age on clinical presentation, severity and course of disease, as well as the effects of stress, nutrition, and co-morbidities, and concurrent medication on the immune response (with special attention to the response on priming and boosting)and clinical course; o Approaches to modulating the immune response in the elderly including the use of adjuvants, conjugate formulations, immune modulators, regimens for administering multiple doses etc.; o Clinical and epidemiological studies of infectious diseases in nursing homes and retirement facilities where immune senescence, transmission, and exposure may complicate immune intervention; o Studies of varicella vaccines in older individuals to limit reactivation of herpes zoster and to reduce the occurrence and severity of zoster infection and post-herpetic neuralgia. o The relation between colonization and invasive disease in the elderly; o Gender differences in response to various types of vaccines; and o Response to mucosal immunization using different licensed and new candidate vaccines (e.g., DNA vaccines). INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects of the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the ?NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research?, which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted on the standard application deadlines as indicated on the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES" and the PA number and the PA title, ?The Impact of Immune Senescence and Maturation on Vaccine Responsiveness in the Elderly,? 2. The completed, signed original and five legible, single-sided copies of the application must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) FIRST (R29) awards 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. FIRST (R29) award applications must also be prepared according to the requirements of Just-In-Time procedures, as announced in the NIH Guide for Grants and Contracts, Volume 25, Number 10, March 29, 1996. There may be a significant delay in the processing and review of a FIRST award application that has not been prepared according to the instructions in the NIH Guide notice. 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 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. REVIEW CONSIDERATIONS Review Procedures: Applications 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, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria: (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic (research scope, eligibility and responsiveness) issues may be directed to: Stanley Slater, M.D. Deputy Associate Director for Geriatrics Geriatrics Program National Institute on Aging Gateway Building, Room 3E327 7201 Wisconsin Avenue Bethesda, Maryland 20892-9205 Telephone: (301) 496-6761 Fax: (301) 402-1784 EMAIL: slaters@gw.nia.nih.gov David L. Klein, Ph.D. Bacterial Respiratory Diseases Program Officer Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3B03 6003 Executive Blvd. Bethesda, MD 20892-7640 Telephone: (301) 496-5305 Fax: (301) 496-8030 EMAIL: dk27a@nih.gov Direct inquiries regarding fiscal matters to: Cynthia Riddick Grants Management Office National Institute on Aging Gateway Building, Room 2C 7201 Wisconsin Avenue Bethesda, Maryland 20814 Telephone: (301) 496-1472 Fax: (301) 402-3672 EMAIL: RiddickC@GW.NIA.NIH.GOV William Powell Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B26 6003 Executive Blvd. Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Fax: (301) 480-3780 Email: Wpowell@MERCURY.NIAID.NIH.GOV AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is (No. 93.866 - Immunology, Allergy, and Transplantation Research. Awards will be administered under PHS grants policies and Federal Regulations 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 review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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