NEW TREATMENT FOR COMPLICATIONS FROM VACCINIA IMMUNIZATION

Release Date:  October 20, 1999

RFA:  AI-00-001

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date: December 15, 1999
Application Receipt Date: January 19, 2000 

PURPOSE

As part of DHHS-wide efforts on the civilian defense from 
possible bioterrorism threat, the Division of Microbiology 
and Infectious Diseases (DMID), National Institute of 
Allergy and Infectious Diseases (NIAID), National Institutes 
of Health (NIH), invites research proposals directed toward 
replacing human vaccinia immune globulin with a safe, 
effective, easily produced immunologically-based therapeutic 
preparation. The goal is to develop and test a therapeutic 
preparation that could be used to treat complications, 
usually disseminated infection that might occur during 
immunization against smallpox with vaccinia. Additionally, 
the reagent from this project might prove useful for 
treatment of smallpox infection itself.

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, "New Treatment for 
Complications from Vaccinia Immunization," is related to the 
priority area(s) of immunization and infectious diseases.  
Potential applicants may obtain a copy of "Healthy People 
2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and 
non-profit organizations; public and private institutions, 
such as universities, colleges, hospitals, laboratories, 
units of State and local governments; and eligible agencies 
of the Federal government.  Foreign institutions are not 
eligible to apply however foreign investigators may 
participate as collaborators, consultants or subcontractors.  
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to 
undertake this program will be the Cooperative Agreement 
(U01), an "assistance" mechanism, rather than an 
"acquisition" mechanism, in which substantial NIH scientific 
and/or programmatic involvement with the awardee is 
anticipated during the performance of the activity.  Under 
the cooperative agreement, the NIH purpose is to support 
and/or stimulate the recipient's activity by involvement in 
and otherwise working jointly with the award recipient in a 
partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity.  Details 
of the responsibilities, relationships, and governance of a 
study funded under cooperative agreement(s) are discussed 
later in this document under the section Terms and 
Conditions of Award.

The total project period for applications submitted in 
response to this RFA may not exceed five years.  At present, 
the NIAID is administratively limiting the duration of U01 
cooperative agreements to four years; this administrative 
limitation may change in the future.  At this time, the 
NIAID has not determined whether or how this solicitation 
will be continued beyond the present RFA.

FUNDS AVAILABLE

The estimated total funds (direct and facilities and administrative 
(F&A) costs) available for the first year of support for all awards made 
under this RFA will be $350,000.  However, depending on 
Fiscal Year 2000 appropriations, this amount may increase. 
In Fiscal Year 2000 the NIAID plans to fund approximately 1-
2 awards.  Although this program is provided for in the 
financial plans of the NIAID, awards pursuant to this RFA 
are contingent upon the availability of funds for this 
purpose and the receipt of a sufficient number of applications 
of high scientific merit.  Funding beyond the first and subsequent 
years of the grant will be contingent upon satisfactory progress 
during the preceding years and availability of funds.

RESEARCH OBJECTIVES

Background

Given recent terrorism incidents and the access to modern 
biological technologies, there is an increasing possibility 
that biological agents might be used by terrorists against 
the U.S.  Consequently, in mid-1998, federal agencies were 
instructed to take significant steps to protect the civilian 
population against the consequences of biological and other 
unconventional terrorist attacks. One major area in the 
Department of Health and Human Services (DHHS) anti-
bioterrorism initiative has been to create and maintain a 
stockpile of pharmaceuticals for use if mass 
prevention/treatment programs are needed. This Request for 
Application (RFA) will support the possible immunization of 
civilians against smallpox virus infection.

Of the potential organisms that might be used in 
bioterrorism, the impact on the health of the U.S. by 
smallpox virus is formidable. Mortality rates from smallpox 
infection can be 30%. The U.S. population is highly 
susceptible because most people are no longer vaccinated and 
older vaccinees are losing their immunity to the virus. 
There is very little vaccine stockpiled either in the U.S. 
or globally to respond to a terrorist attack, and there is 
no drug currently available to treat smallpox. 

The classic smallpox vaccine licensed in the U.S. was 
prepared from calf lymph.  If smallpox virus is used as an 
agent of bioterrorism, selected vaccination of at-risk 
civilian populations might be needed.  The classic vaccine 
causes a relatively high level of immunization complications 
and is contraindicated in such populations as the immune-
suppressed, pregnant females and the very young.  A 
preparation of pooled vaccinia immune globulin has been used 
in the past as a treatment for complications arising from 
vaccinia immunization. However, this material is now in 
short supply and future availability is uncertain, as, with 
the cessation of universal vaccination, there are few 
hyperimmune individuals who could serve as plasma donors.  
This Request for Applications (RFA) will help develop an 
immunotherapeutic preparation that could be used instead of 
vaccinia immune globulin to treat complications that might 
occur during mass immunization with vaccinia virus.

Research Objectives and Scope

The objective of this solicitation is to stimulate 
preclinical research in the development and testing of 
immunologically-based therapeutic preparations aimed at the 
effective treatment of acute vaccinia-related complications, 
usually viral dissemination, resulting from immunization 
against smallpox with vaccinia virus.  These 
immunotherapeutic agents should include, but are not limited 
to, neutralizing monoclonal antibodies.  Other immune-based 
approaches, such as intervention with cytokines, may also be 
appropriate.

TERMS AND CONDITIONS OF AWARD

The administrative and funding instrument used for this 
program is the cooperative agreement (U01), an "assistance" 
mechanism (rather than an "acquisition" mechanism), in which 
substantial NIH scientific and/or programmatic involvement 
with the awardee is anticipated during the performance of 
the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's 
activity by involvement in and otherwise working jointly 
with the award recipient in a partner role, but it is not to 
assume direction, prime responsibility, or a dominant role 
in the activity. 

Consistent with this concept, the dominant role and prime 
responsibility for the activity resides with the awardees 
for the project as a whole, although specific tasks and 
activities in carrying out the research will be shared among 
the awardees and the NIAID Scientific Coordinator. 

Cooperative agreements are subject to the administrative 
requirements outlined in OMB circulars A-102 and A-110.  All 
pertinent HHS, PHS, and NIH grant regulations, policies and 
procedures, with particular emphasis on PHS regulations at 
42 CFR part 52 and HHS regulations at CFR 45 Part74, are 
applicable. These special terms and conditions pertaining to 
the scope and nature of the interaction between the NIAID 
and the investigators will be incorporated in the Notice of 
Grant Award.  However, these terms will be in addition to,  
not in lieu of, the customary programmatic and financial 
negotiations that occur in the administration of cooperative 
agreements. 

1.   AWARDEE RIGHTS AND RESPONSIBILITIES

Awardees will have primary responsibility for defining the 
research objectives, approaches and details of the projects 
within the guidelines of the RFA and for performing the 
scientific activity. Specifically, awardees have primary 
responsibility as described below.

a.  The Principal Investigator defines the details for the 
project within the guidelines of the RFA, retains primary 
responsibility for the performance of the scientific 
activity, and agrees to accept close assistance of NIAID 
staff in aspects of scientific and technical management of 
the project in accordance with the terms mutually agreed 
upon prior to the award.

b.  The awardee is to plan and conduct the research 
stipulated in the application and to ensure that the results 
obtained are analyzed and published in a timely manner.  
Awardees will retain custody of and have primary rights to 
the data developed under these awards, subject to Government 
rights of access consistent with current HHS, PHS, and NIH 
policies.

c.  The awardee is to participate in an annual meeting of 
investigators funded under this RFA and other NIAID-
supported smallpox-related activities to discuss progress 
and strategies for future research.  These other activities 
include an orthopoxvirus genomics facility, drug design and 
discovery, and in vitro and animal model evaluations.

2.  NIAID STAFF RESPONSIBILITIES

Assistance via Cooperative Agreement differs from the 
traditional research grant in that, in addition to the 
normal programmatic and administrative stewardship 
responsibilities, the component awarding the Cooperative 
Agreement anticipates substantial programmatic involvement 
during performance of the project.  NIAID staff assistance 
is to participate in, but not direct, the research to ensure 
that important disease targets are addressed.  The Acute 
Viral Diseases Program Officer, Virology Branch, DMID will 
serve as Scientific Coordinator and will participate as a 
member of the research team.  The Scientific Coordinator 
will interact with the Principal Investigators and Co-
investigators in the overall research planning and in data 
analysis.  During performance of the award, the NIAID 
Scientific Coordinator may provide appropriate assistance by 
participating in the design of research group activities; 
advising in the selection of sources or resources; 
coordinating or participating in collection and/or analysis 
of data; and, advising in management and technical 
performance.  The Scientific Coordinator may assist with 
arrangements for the further evaluation, both in vitro and 
in animal models, of agents resulting from this research.  
However, the role of NIAID will be to facilitate and not to 
direct the activities. Specifically, it is presently 
envisioned that the NIAID will be actively engaged in the 
facilitation of components including assisting the awardees 
in:

a.  Collaborative participation in overall research planning  
and data analysis.  Specifically, the NIAID Scientific 
Coordinator may suggest studies within the scope of the 
award's objectives and research activities; may present to 
the investigators experimental findings from published 
sources or from contract projects in support of these 
suggestions; may participate in the design of experiments; 
and may participate in the analysis of results.

b.  Provision of needed resources and information that may 
not be otherwise available to the investigator.  This may 
include the provision of data from testing conducted in 
resource contract laboratories subject to the terms of 
confidentiality agreements with drug sponsors.

c.  In the event that an awardee's research results in a 
procedure or a product that requires testing of a nature 
beyond the awardee's capabilities, the NIAID Scientific 
Coordinator may provide resources available to the Institute 
for comprehensive preclinical efficacy evaluations.  To aid 
this development, NIAID-supported contractors who engage in 
preclinical evaluation of potential antiviral compounds can 
further evaluate any immunologically-based preparations 
developed by investigators supported by this RFA. The 
contractors can provide in vitro and in vivo screening 
against vaccinia and other poxviruses.

d.  For studies of monoclonal antibodies, the Scientific 
Coordinator will provide advice on specific epitopes pursued 
and coordinate decisions as to humanization of any murine 
monoclonals.

e.  The Scientific Coordinator will arrange collaborative 
communications with any federal agencies, such as the United 
States Army Medical Research Institute of Infectious 
Diseases (USAMRIID), that may be involved in similar 
studies. 

f.  The NIAID Scientific Coordinator will organize an annual 
symposium in Bethesda, Maryland at which the principal 
investigators will discuss their progress.  This will 
facilitate overall program planning and development, the 
evaluation of the feasibility of the attempted approaches, 
and will promote productive interactions among the 
successful applicants.  The NIAID Scientific Coordinator 
will also ensure the participation in this symposium of 
investigators from other NIAID preclinical and clinical 
programs to provide the most relevant antiviral expertise 
possible to facilitate planning for future research and 
expedite the design and development of novel antiviral 
agents.

3.  Arbitration

Any disagreement that may arise on scientific or 
programmatic matters (within the scope of the award) between 
award recipients and the NIAID may be brought to 
arbitration.  An arbitration panel will be composed of three 
members -- one selected by the individual awardee in the 
event of an individual disagreement, a second member 
selected by the NIAID, and the third member with expertise 
in the relevant area and selected by the two prior members 
will be formed to review any scientific or programmatic 
issue that is significantly restricting progress.  While the 
decisions of the Arbitration Panel are binding, these 
special arbitration procedures will in no way affect the 
awardee's right to appeal an adverse action in accordance 
with PHS regulations at 42 CFR Part 50, subpart D, and HHS 
regulations at 45 CFR Part 16.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 15, 
1999, a letter of intent that includes a descriptive title 
of the overall proposed research; the name, address and 
telephone number of the Principal Investigator; and the 
number and title of this RFA.  In addition, the letter of 
intent should identify other "key personnel" whom will be 
involved in the research and their institutions. Although 
the letter of intent is not required, is not binding, does 
not commit the sender to submit an application, and does not 
enter into the review of subsequent applications, the 
information that it contains allows NIAID staff to estimate 
the potential review workload and to avoid conflict of 
interest in the review.  The letter of intent is to be sent 
to Dr. Anna Ramsey-Ewing at the address listed under 
INQUIRIES.

APPLICATION PROCEDURES

Applicants are strongly encouraged to call NIAID program 
staff with any questions regarding the responsiveness of 
their proposed project to the goals of this RFA.  

Applications are to be submitted on the grant application 
for PHS 398 (rev. 4/98).  These forms are available at most 
institutional offices of sponsored research; 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: grantsinfo@nih.gov; and on the internet at 
https://grants.nih.gov/grants/funding/phs398/phs398.html

For purposes of identification and processing, item 2a on 
the face page of the application must be marked "YES" and 
the RFA number "AI-00-001" and the words "New Treatment for 
Complications from Vaccinia Immunization" must be entered 
on the face page.

The RFA label and line 2 of the application should both 
indicate the RFA number.  The RFA label must be affixed to 
the bottom of the face page.  Failure to use this label 
could result in delayed processing of the application such 
that it may not reach the review committee in time for 
review.

The sample RFA label available at: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has 
been modified to allow for this change.  Please note this is 
in pdf format.

Applications must be received by January 19, 2000. 
Applications not received as a single package on the receipt 
date or not conforming to the instructions contained in PHS 
398 (rev. 4/98) Application Kit will be judged non-
responsive and will be returned to the applicant. 

If the application submitted in response to this RFA is 
substantially similar to a grant application already 
submitted to the NIH for review, but that has not yet been 
reviewed, the applicant will be asked to withdraw either the 
pending application or the new one.  Simultaneous submission 
of identical applications will not be allowed, nor will 
essentially identical applications be reviewed by different 
review committees.  Therefore, an application that is 
essentially identical to one that has already been reviewed 
cannot be submitted in response to this RFA.  This does not 
preclude the submission of substantial revisions of 
applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

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

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express mail or courier service)

At the time of submission, two additional exact copies of 
the grant application and all five sets of any appendix 
material must be sent to Dr. Anna Ramsey-Ewing at the 
address listed under INQUIRIES.

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 should be included with the 
application.

REVIEW CONSIDERATIONS  

Review Considerations

Upon receipt, applications will be reviewed for completeness 
and adherence to the Special Instructions above by the NIH 
Center for Scientific Review and for responsiveness by NIAID 
staff; those judged to be incomplete will be returned to the 
applicant without review.  Those considered to be non-
responsive will be returned without review.

Applications that are complete and responsive to the RFA 
will be evaluated for scientific and technical merit by an 
appropriate peer review group convened by the NIAID.  As 
part of the initial merit review, a process will be used by 
the initial review group in which all applications receive a 
written critique and undergo a process in which only those 
applications deemed to have the highest scientific merit 
will be discussed, assigned a priority score, and receive a 
second level review by the National Advisory Allergy and 
Infectious Diseases Advisory Council.

Review Criteria

The criteria to be used in the evaluation of grant 
applications are listed below.  To put those criteria in 
context, the following information is contained in 
instructions to the peer reviewers.

The goals of NIH-supported research are to advance our 
understanding of biological systems, improve the control of 
disease, and enhance health.  The reviewers will comment on 
the following aspects of the application in their written 
critiques in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of 
these goals.  Each of these criteria will be addressed and 
considered by the reviewers in assigning the overall score 
weighting them as appropriate for each application.  Note 
that the application does not need to be strong in all 
categories to be judged likely to have a major scientific 
impact and thus deserve a high priority score.  For example, 
an investigator may propose to carry out important work that 
by its nature is not innovative but is essential to move a 
field forward.

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?

In addition to the above criteria, in accordance with NIH 
policy, all applications will also be reviewed with respect 
to the following:

o  The adequacy of plans to include both genders, minorities 
and their subgroups, and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment 
and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in 
relation to the proposed research

o  The adequacy of the proposed protection for humans, 
animals or the environment, to the extent they may be 
adversely affected by the project  proposed in the 
application.

AWARD CRITERIA
  
Funding decisions will be made on the basis of scientific 
and technical merit as determined by peer review, program 
balance, and the availability of funds.  The earliest 
anticipated date of award is September 1, 2000.

INQUIRIES  
  
Written and telephone inquiries concerning this RFA are 
encouraged.  The opportunity to clarify any issues or 
questions from potential applicants is welcome.

Direct inquiries regarding programmatic (research scope and 
eligibility) issues to:  

Dr. James M. Meegan  
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases  
Room 3137
6700-B Rockledge Dr. MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7453
FAX:  (301) 496-8030
E-Mail: jm75v@nih.gov
  
Direct inquiries regarding review issues; address the letter 
of intent to; and mail two copies of the application and all 
five sets of appendices to:
  
Anna Ramsey-Ewing, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Rockledge-B Building, Room 
6700-B Rockledge Drive MSC 7630
Bethesda, MD  20892-7630
(zip for express mail is 20817)
Telephone:  (301) 435-8536
FAX:  (301) 402-2638
E-Mail:  AR15O@NIH.GOV

Direct inquiries regarding fiscal matters to:  

Annette Hanopole  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
6700-B Rockledge Drive MSC 7614, Room 2122
Bethesda, MD  20892-7614
(zip for express mail is 20817)
Telephone:  (301) 496-7075
Fax: (301) 480-3780
E-mail:  ahanopole@niaid.nih.gov

Schedule

Letter of intent receipt date: December 15, 1999 
Application receipt date:      January 19, 2000 
Scientific review date:        June, 2000
Advisory Council date:         September, 2000
Earliest award date:           September, 2000

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 
Citations are Sec. 93.856, Microbiology and Infectious 
Diseases Research, and No. 93.855 - 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 and 
contract recipients to provide a smoke-free workplace and 
promote the non-use of all tobacco products. In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or, in some cases, any 
portion of a facility) in which regular or routine 
education, library, day care, health care or early childhood 
development services are provided to children.  This is 
consistent with the PHS mission to protect and advance the 
physical and mental health of the American people.

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