Full Text AI-92-05

PREPARATION FOR AIDS/HIV VACCINE EVALUATIONS

NIH GUIDE, Volume 21, Number 8, February 28, 1992

RFA:  AI-92-05

P.T. 34

Keywords: 
  AIDS 
  Vaccine 
  Genetics 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  March 30, 1992
Application Receipt Date:  May 13, 1992

PURPOSE

The purpose of this Request for Applications (RFA) is to support
developmental projects designed to establish collaborative studies,
involving U.S. and foreign institutions, that (1) develop baseline data
for determining the feasibility of conducting AIDS/HIV vaccine trials
in international settings and (2) develop capabilities at international
sites to conduct HIV vaccine efficacy trials.  The NIAID anticipates
initiating clinical trials of AIDS/HIV vaccines by December 1993 at
domestic sites and shortly thereafter at international locations.

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 RFA,
Preparation for AIDS/HIV Vaccine Evaluations, is related to the
priority of HIV infections.  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- 0473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic 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.  All applicants must
demonstrate the existence of a collaborative relationship with a
foreign institution and the potential for productivity in the area of
epidemiologic research related to HIV/AIDS vaccine testing.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Successful applicants funded under this RFA will be supported through
the NIH Exploratory/Developmental Grant (R21) to encourage the
development of new research activities.  For this RFA, the R21 grant
mechanism is used to develop the capability to conduct AIDS/HIV vaccine
clinical trials in international settings.

The total project period for applications submitted in response to the
present RFA may not exceed two years.

This RFA is a one-time solicitation.  Although there are no current
plans to reissue this RFA at any future time, the NIAID may invite
competitive renewal applications upon expiration of the initial funding
period, contingent on the continued availability of funds for this
purpose, adequate progress in research, and the continued need to
stimulate research in this area.

FUNDS AVAILABLE

The NIAID has set aside $3,000,000 for funding the total costs for the
initial year of this RFA.  The total first-year cost of individual
applications, including direct and indirect costs, may not exceed
$600,000 per year.  It is anticipated that five to six awards shall be
made for the first year dependent upon receipt of a sufficient number
of applications of high scientific merit.  Awards pursuant to this RFA
are contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background on Funding Institutions

The Division of AIDS (DAIDS), NIAID, has a primary mission to identify
means of preventing, treating, and curing HIV infection and AIDS.  The
DAIDS has a broad interest in virology, immunology, pathogenesis,
epidemiology, diagnosis, and discovery and development of drugs and
vaccines for both HIV and opportunistic infections.  Within the DAIDS,
the Epidemiology Branch and the Vaccine Research and Development Branch
will share responsibility for overseeing the development and execution
of Preparation for AIDS/HIV Vaccine Evaluations (PAVE) projects.

The Epidemiology Branch (EB), within the Clinical Research Program
(CRP) of DAIDS, has the responsibility to plan and direct a program of
research grants, contracts, and training in support of the
identification of risk factors and co-factors for the transmission of
HIV, and the study of the natural history of HIV infection, related
retroviruses, and associated opportunistic infections.  The Vaccine
Research and Development Branch, (VRDB) within the Basic Research and
Development Program (BRDP) of DAIDS, has primary responsibility to plan
and direct a comprehensive program for the discovery and development of
vaccines for the prevention of HIV and related retroviral infections.
The Branch has undertaken a lead role in organizing scientists into the
National Cooperative Vaccine Development Groups (NCVDG-AIDS) for the
development of new vaccine candidates and AIDS Vaccine Evaluation Units
(AVEU) for phase I and II clinical trials of vaccine candidates.  The
VRDB and the EB are also implementing plans to prepare for large scale
vaccine efficacy trials by identifying suitable study populations and
by building appropriate working relationships with national and
international agencies, health departments, community-based
organizations, and universities.

Technical Background

The international manifestations of the AIDS pandemic have long
provided special challenges as well as unique opportunities for
biomedical research.  Important differences are found in the natural
history of HIV/AIDS in different countries and regions.  A number of
scientific studies have documented higher rates of heterosexual and
perinatal transmission in some developing countries than has been
observed in North America and Europe.  This transmission may relate, to
a limited degree, to socio-cultural and behavioral factors found
internationally.  In some areas, transmission may be facilitated by the
prevalence of cofactors, especially other sexually transmitted diseases
(STDs).  It is also possible that biological characteristics of the HIV
strains or genetic susceptibility of different hosts may correlate with
transmissibility.

In addition to advances in epidemiologic research, evidence has been
accumulating regarding the safety of candidate HIV vaccines in Phase I
and II trials.  Vaccine protection of non-human primates from HIV or
SIV infection has been reported in some studies and led to recognition
that there is need for the expeditious development of an infrastructure
for vaccine efficacy trials.  Vaccine efficacy trials can be most
efficiently conducted in cohorts of uninfected volunteers who are
likely to continue to experience high rates of HIV transmission despite
other preventive interventions.  However, before efficacy trials can be
appropriately designed, antecedent studies must be conducted to obtain
critical epidemiologic and virologic information pertinent to the
proposed study community and to gain operational experience in field
management techniques.  Phase I/II pilot trials, designed to confirm
that safety, reactogenicity, and immunogenicity of the HIV candidate
vaccine(s) is/are acceptable in specific populations at high risk of
transmission also must precede vaccine efficacy trials.

While this RFA is not soliciting and will not provide funding for HIV
vaccine trials, NIAID intends, through a separate contractual funding
mechanism, to support Phase I/II HIV pilot vaccine trials (to determine
safety, reactogenicity and immunogenicity in high-risk populations) and
Phase III efficacy trials in the future.  PAVE projects will be
competitive for future funding for vaccine pilot and efficacy trials
dependent upon their success in:  (1) identifying one or more suitable
high-seroincidence cohorts for vaccine testing, including demonstrating
capacity for cohort recruitment and retention; (2) documenting HIV
seroincidence in a high-risk cohort; (3) demonstrating the ability to
collect, store, and ship specimens for assessing HIV seroincidence; and
(4) developing and/or strengthening vaccine trial infrastructure at a
foreign site including establishment of foreign government and
population support of participation in the vaccine trials.  An
additional criterion for eventual support of HIV vaccine trials at a
PAVE site will be the availability of a suitable HIV vaccine candidate.

Detailed Research Objectives

This RFA seeks to fund developmental projects designed to establish
collaborative research studies, involving U.S. and foreign
institutions, that (1) provide baseline data for determining the
feasibility of conducting AIDS/HIV vaccine trials in international
settings and (2) prepare international research sites to conduct HIV
vaccine efficacy trials.  The specific objectives of this RFA are to:

o  define the incidence of HIV infection in population groups at
high-risk of acquiring HIV infection;

o  identify selected biological and behavioral co-factors of adult
and/or perinatal transmission of HIV;

o  collaborate in research that studies the distribution of genetic and
antigenic variants of HIV in different population groups; and,

o  strengthen the infrastructure and field management capacity to
undertake potential future HIV vaccine efficacy trials.

To achieve the objectives of this RFA, all PAVE applicants must provide
detailed plans leading to the development of the capability to
undertake vaccine trials. Plans should address five components of
vaccine site preparedness:

o  HIV Transmission Research;
o  Selected Co-Factors of HIV Transmission;
o  HIV Genetic and Antigenic Variation Determination
o  Training; and,
o  Core Services.

1.  HIV Transmission Research:  All PAVE applications must contain
detailed plans to document HIV seroincidence in at least one high-risk
cohort.  It is anticipated that transmission studies will involve such
populations as HIV- discordant couples, male and female commercial sex
workers and/or their clients, patients at STD clinics, or other
specially identified high-risk persons in clinical or occupational
settings.  HIV-infected pregnant women and newborns from HIV
seropositive mothers may also be recruited for studies of perinatal
transmission.  It is anticipated that individual PAVE projects will
focus their efforts on one or two potentially high-risk cohorts.  In
some populations, nearly all sexually active young adults may be at
high risk for HIV acquisition and therefore a population-based cohort
would be suitable.  Design of the cohort study should maximize the
ability to identify population groups with highest risk for HIV
infection.  This may be best achieved with innovative techniques of
"open cohorts" in which recruited participants with diminishing or
lower risk are followed for a finite period and enrollment continues
for persons at highest risk.  Although the size of cohorts selected for
study will depend upon statistical analysis of the anticipated levels
of transmission with a reasonable degree of confidence in the
seroincidence estimates, most applications should plan and budget for
a cohort size of about 2,000 persons because that will best simulate
the field management challenges in possible future efficacy trials.

Applications should include a discussion of the feasibility of
organizing high risk cohorts within a geographic area based upon
antecedent information about the existence and accessibility of such
populations (e.g., clinic records, seroprevalence studies).  Study
designs must include convincing discussion of field study techniques
that are successful in maintaining long-term contact with high-risk
cohorts and that have in place appropriate surveillance systems to
diagnose and document newly-acquired HIV infections.

2.  Selected Co-Factors of HIV Transmission:  Each PAVE application
must include plans for research that will document and quantify the
influence of potentially important biological and behavioral
transmission cofactors.  In view of the recognized importance of other
STDs in HIV transmission, PAVE applicants should consider inclusion of
protocols that document the prevalence and potential role of such
cofactors in the study population, including syndromes and populations
which, to date, have received inadequate attention.

Other possible co-factors of HIV transmission that should be considered
in the research design, depending upon the types of high risk cohorts
under study, could include:  (a) the presence or absence of concurrent
infections, (b) stage or severity of disease in the infected individual
who may be the source of new infection, (c) age, (d) parity, (e)
race/ethnicity, (f) circumcision status in men, (g) cervical ectopy
status in women, (h) condom and/or contraceptive use, and other
relevant factors.  Possible behavioral co-factors of transmission
(e.g., type of sexual practices, number of sexual partners, nature of
sexual networks, menstrual and/or non-menstrual coital bleeding,
douches, vaginal suppositories or other agents, drug use,) should also
be considered, whenever appropriate, in research design.  Research
relating to co-factors of HIV transmission will be especially critical
in countries or areas where other public health intervention efforts
are underway to diminish transmission (e.g., promotion of condom use;
active STD surveillance, diagnosis and treatment; and targeted programs
for sex workers and their clients).

3.  HIV Genetic and Antigenic Variation Determination:  Each PAVE
application must include a sampling strategy for obtaining 50 virus
isolates (e.g, viably preserved cells or fresh heparinized whole blood)
from HIV-infected individuals who are representative of the population
that would be suitable for enrollment in potential future vaccine pilot
and efficacy trials.  Serum should also be collected from these same
individuals.  Plans should include provision for shipment of isolates
and serum to Rockville, Maryland, where the NIAID will provide PAVE
awardees with access to laboratories for genetic sequencing and
immunological variation analysis at no cost to the PAVE project.  These
services will support the PAVE awardee in the optimal evaluation of
endemic HIV variants of relevance to vaccine design and testing.

4.  Training:  All PAVE applicants must include plans for training
foreign nationals in research technologies related to the preparation
and conduct of a HIV vaccine clinical trial.  Training should result in
the transfer of appropriate technology and assist in developing
self-direction and self-sufficiency in research in the foreign country.
The areas of training may include, but are not limited to:  HIV
epidemiology, laboratory techniques for HIV detection, laboratory
assessment of vaccine immunogenicity, and clinical trials statistical
methods.  Although funding for this training can be supported within
PAVE projects, proposals will be judged to be most competitive and
cost-efficient if they are able to coordinate and secure financing for
training plans from other sources such as the NIH Fogarty International
Center, PAHO/WHO, the NIAID AIDS Vaccine Evaluation Units (AVEU), the
"International Course in Surveillance and Applied Epidemiology for HIV
and AIDS" of the CDC, private foundations, or other appropriate funding
organizations.  To the extent possible, NIAID staff may assist in
facilitating the identification of such funding sources.

5.  Core Services:  To provide for common administrative and technical
support of the scientific components of the PAVE, applications must
include a description and budget for a core services component.  This
component could cover three types of service units:  Administration,
Laboratory Services, and Data Management.

A.  Administration:  PAVE applicants must present an organizational
structure and plan for the effective management of the developmental
research including the identification of senior U.S. and foreign
scientist staff, "on-site manager(s)" and other key staff.  Plans must
also be made for the U.S. Principal Investigator and a key principal
foreign project manager to participate in a single two-day "Progress
Review Meeting" in Washington DC after nine months of activities.  In
addition, the U.S. Principal Investigator must plan on a one-day
meeting with NIAID staff for a review of initial plans within 60 days
of award of grant and again for progress reviews after six months, 15
months, 18 months and 21 months from the date of award.

B.  Laboratory Services:  Applicants must present clear plans to
establish and maintain a high quality HIV diagnostic laboratory
facility at the foreign site, including adequate procedures for
specimen collection, storage, shipment, and quality control.  It is
recommended that PAVE projects develop or utilize a central laboratory
service for project needs although, in selected circumstances, the use
of several laboratory sites for different types of analyses may be more
advantageous and is acceptable if coordination can be assured.
Essential local laboratory capability for the PAVE should include HIV
ELISA and Western Blot, relevant methods for diagnosis of STDs, and
basic hematologic and clinical chemistry testing.  Projects will also
be expected to retain serum samples at -70 C conditions in a repository
maintained in the foreign site for the duration of the project.  Other
U.S. or foreign-based laboratory studies that are essential to the
specific proposed research activities should be carefully justified.

C.  Data Management:  Applicants must assure that plans and staffing
are adequate to ensure appropriate management of research data,
including:  development of forms, data input, processing, and timely
analysis.  It is recommended that data management services be
centralized in each PAVE project.

SPECIAL REQUIREMENTS

All applicants for a PAVE grant MUST satisfactorily address the
following items:

l.  Applicants must develop and submit milestones/timeliness for each
of the five research components (see preceding section) that identify
major steps and anticipated accomplishments.  Milestones could include
such events as:  (1) initiation and completion of recruitment of a
high-risk cohort, (2) follow-up visits for cohort members, (3) initial
analysis of seroincidence in the cohort, (4) acquisition and shipment
of specimens for genetic and antigenic variation determination, and (5)
training of foreign staff.

2.  Applicants must document that a potentially productive
institutional relationship has been established between the U.S. and
foreign institution(s) collaborating in the PAVE project.  If the PAVE
project builds upon an existing international collaborative research
relationship, applicants must cite scientific publications and
presentations at international scientific conferences that have
resulted from such collaboration.  The application must include one or
several letters of agreement from representatives of the relevant
foreign institution(s) AND from the appropriate institution of the
foreign government in which foreign components of the research will be
conducted (e.g., Ministry of Health, National AIDS Commission, National
AIDS Control Program).  Applicants are reminded that NIH regulations do
not permit grant funds to be expended on customs payments to foreign
governments.  It will be desirable for the foreign government to
provide a letter agreeing to permit duty-free importation of equipment
and supplies necessary for the PAVE project and to facilitate the
transfer of laboratory specimens and samples from the foreign site for
analysis in U.S. laboratories.

3.  Applicants must describe, to the extent known, other vaccine
preparation efforts in the foreign site, including those that may be
sponsored by a foreign or an international organization; and, whenever
applicable, describe the relationship between these efforts and the
PAVE.

4.  If any protocol or component includes the use of clinical
facilities, applicants must provide specific information pertaining to
present patient load and projections for patient enrollment and
follow-up in clinical investigations.  In addition, a detailed
description of the facilities must be provided and must include
availability of equipment, reliability of supply systems and electrical
power, training of personnel, and maintenance of quality control
procedures.

5.  Since most of the research will be conducted in a foreign country,
funds must be allocated accordingly.  The NIAID has determined that at
least 70 percent of all direct costs should be spent in the foreign
country.  If the budget request shows the foreign component to be less
than 50 percent, the application will be returned to the applicant
without further review.  If the budget request shows a foreign
component of between 50 to 69 percent, a strong justification must be
provided for the reduced foreign component.  These justifications will
be considered on a case-by-case basis.

6.  Applications must assure that research participants will be
provided treatment consistent with the standards of care for the
country in which the PAVE is located, for any STD diagnosed in any
component of the PAVE.

7.  The NIAID assures that all specimens and viral isolates sent to the
NIAID for genetic and antigenic variation analysis (See Detailed
Research Objectives, Paragraph 3., HIV Genetic and Antigenic Variation
Determination) will be used exclusively for this purpose.  No other
uses will be made of these materials without express written agreement
between the U.S. and foreign authorities responsible for the PAVE
project.

8.  Each of the five components of the research plan (see previous
section on Detailed Research Objectives) must have a separate budget
and each must include justifications for all requested costs.  The
milestone chart must be used to determine timing of budget requests.

The budget must include requests for the Principal Investigator to
travel to Washington three times a year, and for one key personnel at
the foreign site to travel to Washington once in the first year.

Because the intent is that 70 percent of all directs costs be spent in
the foreign country, applicants must identify in the budget, costs that
are considered foreign and those that are considered domestic.  The
listing below provides some guidance for identifying foreign and
domestic costs:

o  All costs for foreign personnel and all equipment and supplies used
at the foreign site must be identified as foreign.

o  Travel for staff from the foreign site to the U.S. will be
considered a foreign cost.  Travel of U.S. staff to the foreign site
will be considered a domestic cost.

o  Equipment and supplies purchased in the U.S. but shipped and used at
the foreign site will be considered foreign.

o  Salary for personnel, employed by the U.S. applicant but spending 80
percent or more of their committed time at the foreign site, will be
considered foreign.

o  Travel and supplies for the training of foreign personnel will be
considered foreign.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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 which 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 must 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 in Section 2, A-D
of the Research Plan AND summarized in Section 2, E. 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 should
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 application will be returned.

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 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.

Protection of Human Subjects

Applicant institutions are reminded that adequate protection for human
subjects in international collaborative research is an essential
requirement for the NIH.  Awardee institutions, each subordinate entity
to the Awardee and each performance site, whether institutions or
independent investigators, must agree that the rights and welfare of
human subjects involved in research under this cooperative agreement
shall be protected in accordance with 45 CFR 46.  As a condition of
award, not as a condition of application, applicants and affiliated
performance sites are required to designate an IRB and possess an
applicable assurance of compliance which has been approved by the
Office for Protection from Research Risks (OPRR) of the NIH.
Applicants will be notified if additional information is required on
this matter.

LETTER OF INTENT

Prospective applicants are encouraged to submit a letter of intent, by
March 30, 1992, that includes a brief description of the study
population and the thrust of research activities; the names of the
principal and other key investigators, if known; the identity of the
U.S. and foreign institutions involved in the collaboration; and the
number and title of this RFA.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of applications.
It allows NIAID staff to estimate the potential review workload and
avoid conflict of interest in the review.

The letter of intent is to be sent to:

Robert D. Fischer, M.D., M.P.H
Epidemiology Branch, DAIDS
National Institute of Allergy and Infectious Diseases
Solar Building
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-6177
FAX:  (301) 402-1506

For overnight or courier service, letters are to be sent to the same
address BUT USE "Rockville, MD 20852" in place of "Bethesda, MD 20892,"

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for this grant.  These forms are available at most U.S.
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda MD 20892, telephone 301/496-7441.

The RFA label available in the form PHS 398 must be affixed at the
bottom of the face page of the original signed application.  Failure to
use this label could result in delayed processing of the application
such that it may not reach the received committee in time for review.

To assure the identification of the application with this RFA, mark
"Yes" in item 2 of the face page of the application and type
"Preparation for AIDS/HIV Vaccine Evaluation, RFA AI-92-05".

Submit a signed, typewritten original application, including the
Checklist, and three signed, exact, single-sided photocopies, in one
single package to:

APPLICATION RECEIPT OFFICE
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the same time, two exact copies of the application must be sent
directly to:

Dianne E Tingley, Ph.D.
Scientific Review Administrator
AIDS Review Section, DEA
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C34
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818

If sending the application by overnight mail or courier service to Dr.
Tingley, send the application to the above address BUT USE "Rockville
MD 20852" in place of "Bethesda, MD 20892."

Applications must be received by May 13, 1992.  If an application is
received after that date, it will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG also will not accept any application that
is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications
already reviewed, but such applications must include an introduction
addressing the previous critique.

Applications will be reviewed by NIAID staff to determine completeness
and responsiveness.  Incomplete applications will be returned to the
applicant without further consideration.  If the application is not
responsive to the RFA, it will be returned to the applicant.

Those applications that are complete and responsive may be subjected to
triage by an NIAID peer review group to determine scientific merit
relative to the other applications received in response to this RFA.
The NIH reserves the right to withdraw from competition those
applications judged as non-competitive and will so notify the
applicants.

Those applications judged to be competitive for award will be further
reviewed for scientific and technical merit by the AIDS Research Review
Committee convened by the Division of Extramural Activities, NIAID,
during July 1992.  The final level of review will be provided by the
National Advisory Allergy and Infectious Diseases Council in September
1992.

REVIEW CONSIDERATIONS

The application must be directed to the objectives specifically
identified in this RFA.  Additional factors that will be considered in
the scientific and technical review of the application will include:

o  completeness and feasibility of the plans (including proposed
milestones and timetables) for meeting the objectives of this RFA;

o  documented evidence of commitment of the foreign institution and the
foreign government to the research collaboration;

o  administrative experience and competence of the Principal
Investigator and key staff in the development, implementation, and
management of international research and training programs including
seroincidence and vaccine studies;

o  adequacy of the existing physical facilities and resources of the
collaborating domestic and foreign institutions;

o  applicant's accommodation to the NIH policy for including women and
minorities in study populations and sensitivity to the foreign
country's culture;

o  evidence within the research design of the promotion of technology
transfer and the development of self-direction and self-sufficiency in
the foreign country research team;

o  evidence that human subjects are adequately protected, and that
clinical data and biohazard safety monitoring are accorded a high
priority.

Applicant institutions are encouraged to discuss their research plans
with the in-country missions of the U.S. Agency for International
Development and the local offices of the World Health Organization or
Pan American Health Organization in the countries in which the PAVE
will be situated.  Letters of support for the project from these
in-country missions of the above identified agencies are desirable but
not required prior to grant submission.

AWARD CRITERIA

The anticipated date of award is September 30, 1992.

The following will be considered in making funding decisions:

o  quality of the proposed project as determined by peer review
o  availability of funds
o  program balance among research areas of the announcement
o  geographic distribution among applications under consideration

The training component of applications will be judged on cost
efficiency and adequacy of coordinating and securing financing from
other sources.

Approved grants will be funded for up to two years.

Continued support for PAVE projects beyond the first year will be based
on the satisfactory performance and demonstrated ability of the grantee
to assemble and retain cohorts that may be of importance in future HIV
vaccine trials.  The NIAID will make the judgment on funding the second
year of the developmental project based on the annual report and
information gained from interim program review meetings.  Criteria used
to evaluate the progress of PAVE projects will include:

o  success in recruitment and retention of a high-risk seronegative
cohort;

o  adequate precision in the measurement of seroincidence rates;

o  adequate field management, laboratory, trained staff, and patient
and specimen transportation infrastructure;

o  continuing foreign country support for the project;

o  foreign and U.S.-based ethics review groups capable of judging a
vaccine research plan;

o  adequate capacity to collect and ship blood specimens for required
laboratory studies including the maintenance of a local repository of
serum samples from the cohort;

o  sociopolitical environment conducive to completion of an HIV vaccine
pilot study;

o  likelihood that a site could eventually do a full-scale HIV vaccine
efficacy study;

o  cost-efficiency of site research capacity; and

o  appropriate geographic distribution of awards.

INQUIRIES

Questions regarding programmatic aspects of and responsiveness to this
RFA may be directed to:

Robert D. Fischer, M.D., M.P.H.
Epidemiology Branch, DAIDS
National Institute of Allergy and Infectious Diseases
Solar Building
6003  Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-6177
FAX:  (301) 402-1506

Inquiries regarding matters pertaining to the review of this
application may be directed to:

Dianne E Tingley, Ph.D.
Scientific Review Administrator
AIDS Review Section, DEA
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C34
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818

Inquiries regarding fiscal matters may be addressed to:

Jane Unsworth
Chief, DAIDS Section
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

For overnight and courier service, correspondence to the above persons
may be sent to the same address BUT USE "Rockville, MD 20852" in place
of "Bethesda, MD 20892"

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.856, Microbiology and Infectious Disease Research and No. 93.855
Immunology, Allergic and Immunologic Diseases Research.  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 grants policies and Federal
Regulation 42 CFR 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.

Authority for the international aspects of this program are provided by
Public Law 86-610, the "International Health Research Act of 1960" and
Public Law 100-607, the "Health Omnibus Program Extension Act of 1988."

SELECTED REFERENCES

INTERNATIONAL HIV TRANSMISSION EPIDEMIOLOGY Bartholomew C, Cleghorn F.
Retroviruses in Caribbean.  Bull Pan Am Health Organ 1989; 23-76-80.

Berkley SF, Widy-Wirski R, Okware SI, Downing R, Linnan MJ, White KE,
Sempala S.  Risk factors associated with HIV infection in Uganda.  J
Infect Dis 1989; 160:22-30.

Berkley S, Naamar W, Okware S, Downing R, Konde-Lule J, Wawer M,
Musagara M, and Musgrave S  AIDS and HIV Infeciton in Women in Uganda
- Are Women More Infected than Males?  AIDS 4, 1990; pp. 1237-42.

Boulos R, Halsey N, Holt E, Ruff A, Brutus J, Quinn T, Adrien M, Boulos
C.  HIV-1 in Haitian women.  J AIDS, 1990; 3:721- 728.

Boulos R, Halsey H, Holt E, Ruff A, Brutus JR, Quinn M, Boulos C.
HIV-1 Infection in Haitian Women 1982-1988.  J AIDS 1990; 721-8.

Cameron DW, Simonsen JN, D'Cost LJ, Ronald AR, Maitha GM, Gakinya MN,
Cheang M, Ndinya-Achola JO, Piot P, Brunham RC, et al.  Female to male
transmission of human immunodeficiency virus type 1: risk factors for
seroconversion in men.  Lancet 1989; 2:402-7.

Carael M, Van de Perre PH, Lepage PH, Allen S, Nsengumuremyi F, Van
Goethem C, Ntahorutaba M, Nzaramba D, Clumeck N.  Human
Immunodeficiency virus transmission among heterosexual couples in
Central Africa.  AIDS 1988; 2:201-205

Holmberg SD, Horsburgh CR Jr, Ward JW, Jaffee HW, AIDS Commentary.
Biologic Factors in Sexual Transmission of Human Immunodeficiency Virus
1989  JID July;160(1):116-25

Holmes KK, Kreiss J.  Heterosexual transmission of human
immunodeficiency virus: overview of a neglected aspect of the AIDS
epidemic.  J AIDS 1988; 1:602-10.

Hudson CP, Hennis AJ, Kataaha P, Lloyd G, Moore AT, Sutehall GM,
Whetstone R, Wreghitt T, Karpas P.  Risk factors for the spread of AIDS
in rural Africa: evidence from a comparative seroepidemiological survey
of AIDS, hepatitis B and syphilis in southwestern Uganda.  AIDS 1988;
2-255-60.

Izazola JA, Valedespino JL, Gortmaker SL, Townsend J, Becker J,
Palacios-Martinez M, Mueller N, Sepulveda Amor J.  HIV-1 Seropositivity
and Behavioral and Sociological Risks Among Homosexual and Bisexual Men
in Six Mexican Cities.  JAIDS, 1991; 4:614-22.

Laga M, Taelman H, Van der Stuyft P, Bonneux L, Vercauteren G, Piot P.
Advanced immunodeficiency as a risk factor for heterosexual
transmission of HIV.  AIDS 1989; 3:361-6.

Moss GB, Clemetson D, D'Costa L, Plummer FA, Ndinya-Achola JO, Reilly
M, Holmes KK, Piot P, Maitha GM, Hillier SL; et al Association of
Cervical Ectopy with Heterosexual Transmission of Human
Immunodeficiency Virus: Results of a Study of Couples in Nairobi, Kenya
  1991 JID  Sept; 164(3):588-91

O'Farrell N, Windsor I.  Enhanced transmission of HIV to women in South
Africa [letter].  Br Med J 1989; 298:1035.

Plummer, FA Simonsen, JN, Cameron DW, Ndinya-Achola JO, Kreiss JK,
Gakinya M, Waiyaki P, Karasira P, Cheang M, Piot P, Ronald AR, Bosire
M, Kimata J, D'Costa LJ, Ngugi E.  Co-factors in male-female sexual
transmission of HIV.  J Infect Dis 1990. 163:233-9.

Risk factors for male to female transmission of HIV.  European Study
Group.  Br Med J 1989; 298:411-5.

Schmutzhard E, Fuchs D, Hengster P, Hausen A, Hofbauer J, Pohl P,
Rainer J, Reibnegger G, Tibyampansha D, Werner ER, et al. Retroviral
infections (HIV-1, HIV-2, and HTLV-I) in rural northwestern Tanzania.
Clinical findings, epidemiology, and association with infections common
in Africa.  Am J Epidemiol 1989;130-309-18.

Simonsen JN, Plummer FA, Ngugi EN, Black C, Kreiss JK, Gakinya MN,
Veracuteren G, Slaney L, Koss J, D'Costa LJ, Ndinya-Achola JO, Karasira
P, Kimata J, Piot P, Cheang M, Ronald AR.  Human immunodeficiency virus
infection among lower socioeconomic prostitutes in Nairobi. AIDS. 1990;
4:139-44.

Vermund SH, Sheon AR, Ebner SC, Fischer RD.  Transmission of human
immunodeficiency virus.  Chapter 6, pgs. 81-136, published in AIDS
Research Reviews, Vol. 1, edited by Koff WC, Wong-Staal F, Kennedy RC,
Marcel Dekker, Inc., New York, 1991.

VACCINE REFERENCES

Ada GL. The immunological principles of vaccination. Lancet l990;
337:523-6.

Barrett N, Eder G, Dorner F.  Characterization of a vaccinia derived
recombinant HIV-1 gp160 candidate vaccine and its immunogenicity in
chimpanzees. In: Biotechnology and Therapeutics (Putney S, ed.) Marcel
Dekker, New York/Basel (In press).

Berman PW, Gregory TJ, Riddle L, Nakamura GR, Champe MA, Porter JP,
Wurm FM, Hershberg RD, Cobb EK, Eichberg JW. Protection of chimpanzees
from infection by HIV-1 after vaccination with recombinant glycoprotein
gp120 but not gp160.  Nature 1990; 345:622-5.

Berzofsky JA.  Approaches and issues in the development of vaccines
against HIV.  J Acquir Immune Defic Syndr 1991; 4:451-9.

Cooney EL, Collier AC, Greenberg PD, Coombs RW, Zarling J, Arditti DE,
Hoffman MC, Hu S-L, Corey L.  Safety of and immunological response to
a recombinant vaccinia virus vaccine expressing HIV envelope
glycoprotein. Lancet 1991; 337:567-72.

Dixon D, Rida W.  AIDS vaccine trials: Some design issues including
sample size calculation.  In: Program Abstracts Booklet, Joint
Statistical Meetings, Atlanta, Georgia, August 18-22, 1991: American
Statistical Association 1991.

Dolin R, Graham BS, Greenberg SB, Tacket CO, Belshe RB, Midthun K,
Clements ML, Gorse GJ, Horgan BW, Atmar RL, Karzon DT, Bonnez W, Fernie
BF, Montefiori DC, Stablein DM, Smith GE, Koff WC, and the NIAID AIDS
Vaccine Clinical Trials Network. The Safety and immunogenicity of a
human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate
vaccine in humans.  Ann Intern Med 1991; 114: 119-127.

Fauci AS, Gallo RC, Koenig S, Salk J, Purcell RH. Development and
evaluation of a vaccine for human immunodeficiency virus (HIV)
infection. Ann Intern Med. 1989;110: 373-85.

Girard M, Kieny MP, Pinter A, Barre-Sinoussi F, Nara P, Kolbe H, Kusumi
K, Chaput A, Reinhart T, Muchmore E, et al. Immunization of chimpanzees
confers protection against challenge with human immunodeficiency virus
1991; 88:542-6.

Global Programme on AIDS. General Statement from the Consultation on
Criteria for International Testing of Candidate HIV Vaccines. 27
February to 2 March, 1989, World Health organization, Geneva.

Koff WC. Advances in AIDS vaccine development. ASM News 1991; 57:73-6.

Koff WC, Fauci AS  Human rials of AIDS Vaccines: Current Status and
Future Directions.  AIDS, 1989: S125-129

Koff WC, Hoth DF. Development and testing of AIDS Vaccines. Science
l988; 24l:426-32.

Moss B.  Vaccinia virus: a tool for research and vaccine development.
Science 1991: 252:1662-7.

Orenstein WA, Bernier, RG, Hinman AR. Assessing vaccine efficacy in the
field.  Epidemiologic Review l988; l0:2l2-4l.

Palca J. The sobering geography of AIDS. Science 1991: 252:372-3.

Redfield RR, Birx DL, Ketter N, Tramont E, Polonis V, Davis C, Brundage
JF, Smith G, Johnson S, Fowler A, Wierzba T, Shafferman A, Volvovitz F,
Oster C, Burke D, and the Military Medical Consortium for Applied
Retroviral Research.  Phase I evaluation of the safety and
immunogenicity of immunization with recombinant gp160 in patients with
early human immunodeficiency virus infection. N Engl J Med 1991;
324:1677-84.

Schultz AM, Koff WC  Prospects for an AIDS Vaccine (in) Seminars in
Immunology, Volume 2, 1990, pages 351-360 Saunders Scientific
Publications, Philadelphia;  Editor: Milich DR

Wintsch J., Chaignat, C-L, Braun, D.G., Jeannet, M. et al. Safety and
immunogenicity of a genetically engineered Human Immunodeficiency Virus
vaccine.  J Infect Dis 1991;163:219-225.

Zagury D, Bernard I, Cheynier R, et al.  A group-specific anamnestic
reaction against HIV-1 induced by a candidate vaccine against AIDS.
Nature 1988, 332:728-31.

.

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