Extraumural Applied Research Program in Emerging Infections; Novel Methods for Identification of Emerging Infections

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

[Announcement Number 778]

Extraumural Applied Research Program in Emerging Infections;

Novel Methods for Identification of Emerging Infections

Introduction

The Centers for Disease Control and Prevention (CDC) announces the

availability of fiscal year (FY) 1997 funds for competitive cooperative

agreements and/or grants to support applied research on emerging

infections.

The CDC is committed to achieving the health promotion and disease

prevention objectives of Healthy People 2000, a national activity to

reduce morbidity and mortality and improve the quality of life. This

announcement is related to the priority area of Immunization and

Infectious Diseases. (For ordering a copy of Healthy People 2000, see

the section WHERE TO OBTAIN ADDITIONAL INFORMATION.)

Authority

This program is authorized under Sections 301 and 317 of the Public

Health Service Act, as amended (42 U.S.C. 241 and 247b).

Smoke-Free Workplace

CDC strongly encourages all grant recipients to provide a smoke-

free workplace and to promote the non-use of all tobacco products, and

Public Law 103-227, the Pro-Children's Act of 1994, prohibits smoking

in certain facilities that receive Federal funds in which education,

library, day care, health care and early childhood development services

are provided to children.

Eligible Applicants

Applications may be submitted by public and private non-profit

organizations and governments and their agencies. Thus, universities,

colleges, research institutions, hospitals, other public and private

organizations, including State and local governments or their bona fide

agents, federally recognized Indian tribal governments, Indian tribes

or Indian tribal organizations, and small, minority- and/or women-owned

businesses are eligible to apply.

Note: An organization described in section 501(c)(4) of the

Internal Revenue Code of 1986 which engages in lobbying activities

shall not be eligible to receive Federal funds constituting an

award, grant, contract, loan, or any other form.

Availability of Funds

Approximately $1,205,000 is available in FY 1997 to fund 7 to 11

awards in six specific focus areas as follows:

Focus Area #1

Evaluating Algorithms to Diagnose Emerging Causes of Infectious

Diarrhea: Approximately $480,000 is available to make 2-3 awards with a

maximum project period of 3 years.

Focus Area #2

Rapid Identification of Emerging and Unusual Pathogenic Bacteria by

Partial 16S rRNA Sequencing: Approximately $60,000 is available to make

one award with a maximum project period of 3 years.

Focus Area #3

Development and Evaluation of Improved Tests for Malaria Diagnosis

in the United States: Approximately $100,000 is available to make 1-2

awards with a maximum project period of 2 years.

Focus Area #4

Development of Improved Diagnostic Tests for Leishmaniasis:

Approximately $150,000 is available to make 1-2 awards with a maximum

project period of 2 years.

Focus Area #5

Identification of Unrecognized Etiologic Agents in Idiopathic

Sexually Transmitted Disease Syndromes: Approximately $300,000 is

available to make one to two awards with a maximum project period of 2

years.

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Focus Area #6

Development of Non-culture Molecular Epidemiologic Detection/Typing

Methods for Treponema pallidum or Haemophilus ducreyi: Approximately

$115,000 is available to make one award for a maximum project period of

2 years.

For Focus Areas 2 and 3, only cooperative agreement applications

will be accepted. For Focus Areas 1, 4, 5, and 6, either grant or

cooperative agreement applications will be accepted.

Applicants must specify the type of award for which they are

applying, either grant or cooperative agreement. CDC will review all

applications in accordance with the Evaluation Criteria section of this

announcement. Before issuing awards, CDC will determine whether a grant

or cooperative agreement is the appropriate instrument based upon the

need for substantial CDC involvement in the project.

It is expected that awards will begin on or about August 30, 1997,

and will be made for a 12-month budget period within a project period

of up to three years (maximum project period varies by Focus Area--see

above). Funding estimates may vary and are subject to change.

Continuation awards within the project period will be made on the

basis of satisfactory progress and availability of funds.

Use of Funds

Restrictions on Lobbying

Applicants should be aware of restrictions on the use of Department

of Health and Human Services (HHS) funds for lobbying of Federal or

State legislative bodies. Under the provisions of 31 U.S.C. Section

1352 (which has been in effect since December 23, 1989), recipients

(and their subtier contractors) are prohibited from using appropriated

Federal funds (other than profits from a Federal contract) for lobbying

Congress or any Federal agency in connection with the award of a

particular contract, grant, cooperative agreement, or loan. This

includes grants/cooperative agreements that, in whole or in part,

involve conferences for which Federal funds cannot be used directly or

indirectly to encourage participants to lobby or to instruct

participants on how to lobby.

In addition, the FY 1997 Departments of Labor, HHS, and Education,

and Related Agencies Appropriations Act, which became effective October

1, 1996, expressly prohibits the use of 1997 appropriated funds for

indirect or ``grass roots'' lobbying efforts that are designed to

support or defeat legislation pending before State legislatures.

Section 503 of this new law, as enacted by the Omnibus Consolidated

Appropriations Act, 1997, Division A, Title I, Section 101(e), Pub. L.

No. 104-208, (September 30, 1996), provides as follows:

Sec. 503(a) No part of any appropriation contained in this Act

shall be used, other than for normal and recognized executive-

legislative relationships, for publicity or propaganda purposes, for

the preparation, distribution, or use of any kit, pamphlet, booklet,

publication, radio, television, or video presentation designed to

support or defeat legislation pending before the Congress, * * * except

in presentation to the Congress or any State legislative body itself.

(b) No part of any appropriation contained in this Act shall be

used to pay the salary or expenses of any grant or contract recipient,

or agent acting for such recipient, related to any activity designed to

influence legislation or appropriations pending before the Congress or

any State legislature.

Background

Once expected to be eliminated as a public health problem,

infectious diseases remain the leading cause of death worldwide. In the

United States and elsewhere, infectious diseases increasingly threaten

public health and contribute significantly to the escalating costs of

health care.

In 1992, the Institute of Medicine of the National Academy of

Sciences published a report entitled Emerging Infections, Microbial

Threats to Health in the United States highlighting the threat of

emerging infections and making specific recommendations to address the

threat. This report emphasized a critical leadership role for CDC in a

national effort to detect and control infectious disease threats.

In partnership with other Federal agencies, State and local health

departments, academic institutions, and others, CDC has developed a

plan for revitalizing the nation's ability to identify, contain, and

prevent illness from emerging infectious diseases. The plan, Addressing

Emerging Infectious Disease Threats; A Prevention Strategy for the

United States, identifies objectives in four major areas: surveillance,

applied research, prevention and control, and infrastructure.

Under the objective for applied research, the plan proposes to

integrate laboratory science and epidemiology to optimize public health

practice in the United States. One component of these efforts is to

implement an extramural program for research in emerging infectious

disease surveillance, epidemiology, and prevention, which will fill the

gaps in existing support for such research. In FY 1996, CDC initiated

the Extramural Applied Research Program in Emerging Infections (EARP)

and made competitive grant and cooperative agreement awards to seven

institutions for projects in the areas of antimicrobial resistance and

tickborne diseases. In FY 1997, CDC will make additional competitive

grant and/or cooperative agreement awards in two areas: hepatitis C

virus infection and novel methods for identification of emerging

infections. This announcement specifically addresses novel methods for

identification of emerging infections and solicits applications in the

following six specific focus areas:

Focus Area #1: Evaluating Algorithms To Diagnose Emerging Causes of

Infectious Diarrhea

Without specific diagnostic algorithms, health professionals and

laboratories do not know when to test for many emerging diarrheal

disease pathogens. CDC will assist in the development of guidelines for

health professionals that recommend when to order specific diagnostic

tests for patients with diarrheal diseases, and for diagnostic

laboratories that recommend what diangostic tests to perform. Lack of

guidelines such as these severely limits the ability of laboratories to

adequately detect and report cases of infectious diarrhea caused by

emerging pathogens such as Cyclospora cayetanensis, Cryptosporidium

parvum, Escherichia coli 0157:H7, and common viral agents. Health

professionals may consider tests to identify diarrheal pathogens to be

too expensive and of low yield. Laboratories are reluctant to conduct

routine surveillance for many emerging pathogens, since to do so would

require expensive additional testing procedures. It might be cost-

effective, however, for health professionals and laboratories to test

for these and other pathogens under specific circumstances once

guidelines are available.

For example, during the waterborne outbreak of cryptosporidiosis in

Milwaukee in 1993, CDC scientists discovered that a simple 3-component

screening algorithm would increase the positive predictive value that a

stool specimen contained detectable C. parvum oocysts from 27 percent

to 63 percent. Another recent CDC study of the diagnosis of C. parvum

reported that laboratories in Connecticut that tested for C. parvum

only upon physician request reported a positivity rate of 2.8

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percent compared with a rate of 5.2 percent for laboratories that used

multiple critiera. In a large multi-center study the rate of isolation

of E. coli 0157:H7 from patients with diarrhea increases from 0.4

percent among all patients to 7.8 percent among patients with visibly

bloody stools.

In addition to factors that are present for all health care

providers under capitated managed care where health care providers

receive a flat fee per patient seen, there are additional incentives to

reduce the number of disgnostic tests performed unless they can be

shown clearly as cost-beneficial. Current data are inadequate, however,

to calculate the cost or the benefit of performing specific diagnostic

tests or starting empiric treatment for specific clinical

presentations. As increasing proportions of the population receive

their health care under systems of capitated managed care, we are

likely to see more empiric treatment of diarrhea with no confirmatory

tests for the etiology of the illness.

Focus Area #2--Rapid Identification of Emerging and Unusual Pathogenic

Bacteria by Partial 16S rRNA Sequencing

Standard batteries of biochemical tests are no longer adequate to

identify a growing number of emerging and unusual bacterial pathogens.

Specialized procedures are necessary for identification of emerging and

unusual pathogenic strains that are difficult or impossible to identify

in the average clinical laboratory. 16S rRNA sequencing is one

specialized procedure that has the potential to allow for rapid

molecular identification of pathogens. Many species of bacteria could

be identified on the basis of their full 16S rRNA sequence. Sequences

of many unusual and emerging bacterial pathogens, as well as their

presumed non-pathogenic relatives, need to be determined and entered

into sequence databases. It should then be possible to rapidly identify

most pathogenic species on the basis of a unique partial sequence, and

to use this methodology to largely replace routine identification

methods.

Focus Area #3--Development and Evaluation of Improved Tests for Malaria

Diagnosis in the United States

Every year, approximately 1,000 cases of malaria are reported in

the United States (U.S.). Nineteen deaths due to malaria were recorded

in the U.S. during the period 1992-1994. Of particular concern, cases

of locally transmitted malaria have been reported practically on an

annual basis in densely populated areas (New York City, Houston, and

Palm Beach County, Florida). The substantial U.S. public health impact

of malaria is very likely to increase in the future due to increased

international travel combined with a worldwide resurgence of malaria.

This resurgence is attributable to factors such as inadequate control

programs, increasing drug and insecticide resistance, and global

warming.

This situation must be addressed by vigilant surveillance and

prompt clinical management of all cases of malaria occurring in the

U.S. Both strategies require a timely and correct diagnosis of the

disease. However, available information indicates that malaria

diagnosis is not optimally performed in the U.S. In a recent survey of

samples sent to CDC's National Malaria Reference Laboratory (NMRL) by

various health institutions (including State health departments,

hospitals, and commercial laboratories), the diagnosis made by the NMRL

differed from that made at the health institution in 21 percent of the

samples. This is due mainly to the fact that the international accepted

method for diagnosing malaria (the microscopic examination of a Giemsa-

stained blood smear) requires a degree of microscopy experience that

most clinical laboratorians in the U.S. lack due to their infrequent

contact with malaria samples.

One solution to this problem would be a diagnostic test that

depends, not on the experience and skills of a microscopist, but on

more objective, quantifiable criteria. Several malaria diagnostic tests

that follow this approach are currently on the market or in various

development phases. Such tests identify malaria parasites by nucleic

acid fluorescence or by detecting parasite-specific antigens or

enzymes. However, none of these tests satisfy all desirable criteria

for a malaria diagnostic tool applicable to clinical laboratory

practice in the U.S. Such criteria include: (a) sensitivity at least

equal to that of microscopy (4) parasites per ul. of blood), (b)

detection of all 4 known species of human malaria parasites, (c)

specificity above 95 percent, (d) simplicity of performance, and (e)

rapidity of execution (results available in less than 1 hour). In

addition, none of these tests have been adequately evaluated under

strictly controlled conditions in U.S. health facilities.

Focus Area #4--Development of Improved Diagnostic Tests for

Leishmaniasis

Leishmaniasis, a parasitic infection caused by several species of

protozoa in the genus Leishmania, can cause serious, sometimes fatal,

disease in humans. Leishmaniasis is considered by the World Health

Organization to be one of the top five parasitic infections afflicting

mankind today. The infection is transmitted through the bite of

infected sandflies and occurs in several forms: cutaneous, mucosal, and

visceral leishmaniasis. The mucosal form can result in disfiguring

destruction of the nose and mouth, while the visceral form, as

indicated by the name, localizes in the viscera and bone marrow and

results in severe and life-threatening infection. Leishmaniasis in its

various forms occurs throughout the tropical areas of Central and South

America, in countries around the Mediterranean Sea, and in the Middle

East, Africa, and portions of South East Asia. The disease is currently

viewed as being epidemic in India and Sudan. U.S. citizens traveling to

endemic areas, especially Central and South America, are exposed and

frequently acquire infection.

Currently available serologic assays for viscerotrophic

leishmaniasis have unacceptable sensitivity and specificity levels,

both for the species of Leishmania causing the infection as well as for

determining whether the person has an active infection or past

exposure. Diagnostic laboratories have not been able to adequately

resolve this issue because of poor assay performance. The U.S. Congress

and the Department of Defense have been concerned about the possibility

that leishmaniasis accounts for symptoms in some individuals with Gulf

War Syndrome, and the need for better diagnostic tests is repeatedly

raised in Congressional hearings. Since currently available tests have

unacceptable sensitivity and/or specificity levels or are highly

invasive with a significant false negative rate, there is a clear need

for improved diagnostic capabilities related to leishmaniasis,

especially the viscerotrophic form thought to occur in the Gulf War

Syndrome. The development of a suitably formatted assay to detect

Leishmania infections would allow diagnostic laboratories to be able to

distinguish current infections from past exposure and to begin to

differentiate the causative agents.

Suspected cases of cutaneous leishmaniasis are routinely diagnosed

through microscopic examination of stained histologic sections taken

from the lesion site. In some instances, the number of organisms is

high and the infection can be diagnosed microscopically with little

difficulty. However, in many instances there are few organisms and

microscopic

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examination does not permit confirmation of infection. Immunohistologic

staining with appropriate monoclonal/polyclonal antibodies or molecular

based probes might provide much more sensitive approaches.

Focus Area #5--Identification of Unrecognized Etiologic Agents in

Idiopathic Sexually Transmitted Disease Syndromes

For a significant proportion of clinical cases of male unrethritis

and pelvic inflammatory disease (PID) in women, no demonstrated

etiology can be found. It is likely that other unidentified sexually

transmitted organisms have yet to be identified in these syndromes. In

the U.S., urethritis in men is a common sexually transmitted infection;

over 200,000 cases of gonorrhea were reported to CDC and over 250,000

cases of non-specific urethritis were seen by private physicians in

1995. Besides Neisseria gonorrhoeae, urethritis in men can be caused by

Chlamydia trachomatis, Trichomonas vaginalis, Herpes Simplex Virus

(HSV), Mycoplasma genitalium, and Ureaplasma species; however, no

etiologic agent can be identified in nearly 25 percent of cases. Among

women with PID, C. trachomatis, N. gonorrhoeae, and vaginal anaerobes

are recognized etiologic agents, yet in 25-50 percent of cases, no

causal organisms can be identified.

Potentially unidentified agents could emerge and become significant

public health problems as gonorrhea and chlamydial infections are

successfully controlled. There is suggestive evidence that this is

occurring. For example, in Seattle where gonorrhea and chlamydial

infections have been controlled, approximately 70 percent of the

urethritis in local men has no known etiology. It is likely that

similar agents are involved in PID. The identification of additional

agents for urethritis in men, which may also be associated with PID in

women, will help develop better prevention strategies for this costly

and serious complication. Available data strongly suggest that there

are unidentified sexually transmitted organisms associated with

idiopathic syndromes such as urethrities in men and PID.

Focus Area #6--Development of Nonculture Molecular Epidemiologic

Detection/Typing Methods for Treponema pallidum or Haemophilus ducreyi

Most genital ulcer disease (GUD) is caused by one or more of three

sexually transmitted agents; Haemophilus ducreyi, Treponema pallidum,

and HSV. GUD caused by the bacterial agents H. ducreyi and T. pallidum

accounts for approximately 17,000 cases each year in the U.S. Bacterial

GUD infections also occur frequently in developing countries and

several out-breaks of chancroid (H. ducreyi) in the U.S. have been

directly traced to importation of strains from overseas. Along with the

morbidity associated with primary infections with these organisms, a

serious potential sequelae is the development of syphilis, including

neuro- and congential syphilis.

Bacterial GUDs may be easily cured with antimicrobial agents if the

etiologic agents are accurately diagnosed (although antimicrobial

resistance is emerging in H. ducreyi). Examination of ulcers with

microbiologic and research polymerase chain reaction (PCR) detection

methods indicate that it is not possible to accurately determine the

etiology of infections by the physical appearance of the ulcers. The

diagnosis of these agents is further complicated by the fact that T.

pallidum cannot be cultured in vitro and H. ducreyi may be recovered

from fewer than 50 percent of specimens from infected patients.

Development of non-culture methods for detecting and typing strains of

T. pallidum and H. ducreyi in ulcer specimens would allow medical

practitioners to more quickly determine the etiology of and effectively

treat GUDs. It would also allow researchers to determine the molecular

epidemiology of these infections, identify strain type associated with

antimicrobial resistance, and devise and monitor targeted control

methods to eliminate GUD.

Purpose

The purpose of the Extramural Applied Research Program in Emerging

Infections (EARP) is to provide financial and technical assistance for

applied research projects on emerging infections in the U.S. As a

component of EARP, the purpose of this grant/cooperative agreement

announcement is to provide assistance for projects addressing novel

methods for identification of emerging infections. Specifically,

applications are solicited for projects addressing any of the following

six focus areas:

Focus Area #1

Evaluating Algorithms to Diagnose Emerging Causes of Infectious

Diarrhea. The objective is to determine the costs and effectiveness of

different diagnostic algorithms for emerging agents of infectious

diarrhea.

Focus Area #2

Rapid Identification of Emerging and Unusual Pathogenic Bacteria by

Partial 16S rRNA Sequencing. The objective is to develop a rapid

identification system using 16S rRNA sequencing for emerging, atypical,

and unclassified pathogenic bacteria.

Focus Area #3

Development and Evaluation of Improved Tests for Malaria Diagnosis

in the U.S. The objective is to develop and evaluate a malaria

diagnostic test that does not require microscopic examination of blood

smears and: (a) is at least as sensitive as microscopy (4 parasites per

ul. of blood), (b) can detect all 4 known species of human malaria

parasites, (c) has a specificity of at least 95 percent, (d) is simple

to perform, and (e) can provide results in less than 1 hour.

Focus Area #4

Development of Improved Diagnostic Tests for Leishmaniasis. The

objective is to develop improved diagnostic assays for viscerotrophic

and cutaneous forms of leishmaniasis that are formatted using modern

immunologic and molecular tools. The assays would be formatted in such

a way that they would be readily transferable to laboratories, provide

acceptable sensitivity and specificity for the detection and diagnosis

of Leishmania infections in humans, and when performed under

appropriate conditions, provide the degree of accuracy necessary so

that specific medical treatments can be safely initiated.

Focus Area #5

Identification of Unrecognized Etiologic Agents in Idiopathic

Sexually Transmitted Disease Syndromes.

Focus Area #6

Development of Non-culture Molecular Epidemiologic Detection/Typing

Methods for Treponema pallidum or Haemophilus ducreyi.

Applicants may submit separate applications for projects in one or

more focus areas. (See section on APPLICATION for detailed

instructions.)

Program Requirements

In conducting activities to achieve the purpose of this program,

the recipient will be responsible for the activities under A.

(Recipient Activities), and CDC will be responsible for conducting

activities under B. (CDC Activities):

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A. Recipient Activities

Focus Area #1

1. Evaluate Algorithms to Diagnose Emerging Causes of Infectious

Diarrhea:

a. Identify a patient population where health professionals will be

encouraged to collect stool specimens on all patients presenting with

diarrhea.

b. Determine the etiology of infectious diarrhea in patients who

seek medical care for diarrhea by collecting and testing clinical

specimens for bacterial enteric pathogens such as Salmonella, Shigella,

Campylobacter, Escherichia coli 0157, Listeria monocytogenes, and

Yersinia, viral pathogens such as rotovirus, enteric adenovirus and

astrovirus, and parasitic pathogens such as Cyclospora cayetanesis and

Cryptosporidium parvum.

c. Collect information on patients for whom stool specimens are

ordered such as specific signs and symptoms reported by patients at

their first medical encounter, prior treatment, and epidemiologic

exposures such as a history of foreign travel.

d. Develop diagnostic algorithms using clinical characteristics

associated with identification of pathogens in stool specimens to

increase the positive predictive value of diagnostic tests.

e. Determine the cost-effectiveness of the diagnostic algorithms.

f. Publish and/or otherwise disseminate the study findings.

Focus Area #2

1. Perform Rapid Identification of Emerging and Unusual Pathogenic

Bacteria by Partial 16S rRNA Sequencing:

a. Identify appropriate known pathogenic and control bacterial

strains and design and conduct a blinded comparison study to determine

the utility of 16S rRNA sequencing for the rapid identification of

pathogenic bacterial strains.

(1) Fully sequence 16S rRNA of selected strains to update the

database of sequences.

(2) Retrospectively identify by partial 16S sequencing, strains

that have been previously biochemically identified.

(3) Prospectively identify by partial 16S rRNA sequencing all

strains received as unknowns in the CDC Special Bacteriology Reference

Laboratory (CDC will perform standard biochemical identification tests

and cell wall fatty acid analyses on the same strains.). Compare

accuracy, time, and cost of each method. Where there are disagreements,

identify strains by the gold standard of DNA relatedness.

(4) Conduct comparative sequencing studies on selected strains to

determine reproducibility, accuracy, and variability of sequencing and

of identification.

b. Publish and/or otherwise disseminate the study findings.

Focus Area #3

1. Develop and Evaluate Improved Tests for Malaria Diagnosis in the

United States:

a. Develop a new diagnostic test or improve currently available

test(s) that: (a) are at least as sensitive as microscopy (4 parasites

per ul. of blood), (b) able to detect all 4 known species of human

malaria parasites, (c) have a specificity of at least 95 percent, (d)

are simple to perform, and (e) can provide results in less than 1 hour.

Field-robustness and distinctive diagnostic reaction (e.g., color

change) are desirable characteristics.

b. Conduct a first phase of evaluation of the new or improved

test(s). This should involve testing clinical samples for malaria under

blinded conditions and using mainly samples collected from non-human

primates experimentally infected with human malaria parasites and

malaria-infected human blood samples, both of which can be made

available by CDC.

c. Conduct field evaluations of the test(s) in endemic countries

(e.g., a large-scale assessment in a short time period where n>=500)

and in U.S. facilities. The actual U.S. field testing will likely

require a longer time period due to low frequency of malaria, and

should involve collaboration with State health departments, hospitals,

and commercial laboratories.

d. Publish and/or otherwise disseminate results.

Focus Area # 4

1. Develop an Improved Diagnostic Test for Leishmaniasis:

a. Develop new or improved assay(s) for viscerotrophic or cutaneous

leishmaniasis that provide significantly better sensitivity and

specificity than currently available assays.

b. Evaluate the assay(s) (e.g., through blinded evaluation of

selected panels of sera). CDC can provide limited assistance in

preparing serum panels, parasite isolates, animal model support, and

outlets to the field.

c. Publish and/or otherwise disseminate results.

Focus Area # 5

1. Identify Unrecognized Etiologic Agents in Idiopathic Sexually-

Transmitted Disease Syndromes:

a. Obtain swab specimens from 18 to 39 year old sexually active men

with urethritis attending sexually transmitted disease clinics. In

those samples for which no etiology can be identified either by

traditional laboratory methods (e.g., culture) or specific DNA

amplification methods (polymerase chain reaction or ligase chain

reaction for N. gonorrhoeae, C. trachomatis and M. genitalium), use

molecular biological tools to identify causative infectious agents. One

example of an appropriate approach would be: Extract DNA, amplify 16S

rRNA-specific DNA by polymerase chain reaction (PCR) using several sets

of universal bacterial primers, and sequence the amplified DNA directly

with an automated sequencer. Clone the amplified material into

Escherichia coli, and sequence the inserts using automated sequencing.

Use the sequences to search existing Genbank files for relatedness with

known organisms. This approach has been used successfully to identify

the agents of cat scratch fever, bacillary angiomatosis, Whipple's

disease, and the putative agent of Kaposi's sarcoma. Although this

approach will identify only new bacterial etiologies, the favorable

response of idiopathic urethritis and PID to antibiotic therapy

suggests bacterial causation.

b. Publish and/or otherwise disseminate results.

Focus Area #6

1. Develop Non-culture Molecular Epidemiologic Detection/Typing

Methods for Treponema pallidum or Haemophilus ducreyi:

a. Develop comprehensive methods for detecting and typing strains

of T. pallidum and/or H. ducreyi in ulcer specimens with the vitro

materials. In the case of T. pallidum, the method(s) developed should

be able to differentiate between the T. pallidum subspecies pallidum,

pertenue, and endemicum.

b. Determine if the methods developed can be used to detect/type

strains in ulcer specimens.

c. In the event that previously untyped strains are identified in

the evaluation phase, expand the typing system to include new types.

d. Publish and/or otherwise disseminate results.

B. CDC Activities

1. Research Project Grants (Focus areas 1, 4, 5, and 6 only)

A research project grant is one in which substantial programmatic

involvement by CDC is not anticipated by the recipient during the

project period. Applicants for grants must demonstrate the ability to

conduct the proposed research with minimal

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assistance, other than financial support, from CDC. This includes

possessing sufficient resources for clinical, laboratory, and data

management services and level of scientific expertise to achieve the

objectives described in their research proposal without substantial

technical assistance from CDC.

2. Cooperative Agreements

In a cooperative agreement, CDC is available to assist recipients

in conducting the proposed research. The application should be

presented in a manner that demonstrates the applicant's ability to

address the research problem in a collaborative manner with CDC. In

addition to the financial support provided, CDC may collaborate by: (a)

providing technical assistance in the design and conduct of the

research, (b) performing selected laboratory tests as appropriate and

necessary, (c) participating in data management, the analysis of

research data, and the interpretation and presentation of research

findings, and (d) providing biological materials (e.g., strains,

reagents, etc.) as necessary for studies.

Technical Reporting Requirements

An original and two copies of a narrative progress reports are

required semiannually. The first semiannual report is required with

each year's non-competing continuation application and should cover

program activities from date of the previous report (or date of award

for reporting in the first year of the project).

An original and two copies of the second semiannual progress and

Financial Status Report (FSR) are due 90 days after the end of each

budget period and should cover activities from the date of previous

report. Progress reports should address the status of specific project

objectives and should include copies of any publications resulting from

the project.

The final performance report and FSR are required no later than 90

days after the end of the project period. All reports should be

directed to the CDC Grants Management Officer at the address referenced

in the following section.

Application Process

Notification of Intent To Apply

In order to assist CDC in planning and executing the evaluation of

applications submitted under this Program Announcement, all parties

intending to submit application(s) are requested to inform CDC of their

intention to do so as soon as possible but not later than 10 business

days prior to the application due date. Notification should include:

(1) name and address of institution; (2) name, address, and phone

number of contact person, and (3) which focus area(s) application(s)

will be submitted for.

Notification can be provided by facsimile, postal mail, or

electronic mail (E-mail) to Sharron Orum, Grants Management Officer,

Grants Management Branch, Procurement and Grants Office, Centers for

Disease Control and Prevention (CDC), 255 East Paces Ferry Road, NE.,

Room 300, Mailstop E-18, Atlanta, Georgia 30305, facsimile: (404) 842-

6513, Internet: SP[email protected].

Application

Applicants may apply for assistance for projects in one or more of

the six separate focus areas identified under PURPOSE and PROGRAM

REQUIREMENTS section above. IF APPLICANT IS APPLYING FOR ASSISTANCE FOR

MORE THAN ONE FOCUS AREA, A SEPARATE AND COMPLETE APPLICATION MUST BE

SUBMITTED FOR EACH FOCUS AREA.

All applicants must develop their application(s) in accordance with

PHS Form 398, information contained in this grant/cooperative agreement

announcement, and the instructions outlined below. In order to ensure

an objective, impartial, and prompt review, applications must conform

to the following instructions:

General Instructions

Due to the need to reproduce copies of the applications for the

reviewers, ALL pages of each application MUST be in the following

format:

1. The original and two (2) copies of the application must be

UNSTAPLED and UNBOUND.

2. All pages must be clearly numbered, and a complete index to the

application and its appendices must be included.

3. All materials must be typewritten, single-spaced, using a font

no smaller than size 12, and on 8\1/2\'' by 11'' white paper.

4. Any reprints, brochures, or other enclosures must be copied onto

8\1/2\'' by 11'' white paper by the applicant. NO BOUND MATERIALS WILL

BE ACCEPTED in the narrative or appendices.

5. All pages must be printed on ONE side only, with at least 1''

margins, headers, and footers.

Special Instructions

The application narrative for each application/focus area must not

exceed 10 pages (excluding budget and appendices). Unless indicated

otherwise, all information requested below must appear in the

narrative. Materials or information that should be part of the

narrative will not be accepted if placed in the appendices. The

application narrative must contain the following sections in the order

presented below. (REMINDER: If proposing projects under multiple focus

areas, submit a separate and complete application for each project):

1. Abstract:

Provide a brief (two pages maximum) abstract of the project.

Clearly identify the specific focus area being addressed and the

project period proposed (not to exceed maximum as indicated in

AVAILABILITY OF FUNDS section). Clearly identify the types of award

that is being applied for--grant or cooperative agreement.

2. Background and Need:

Discuss the background and need for the proposed project.

Demonstrate a clear understanding of the purpose and objectives of the

focus area.

3. Capacity and Personnel:

Describe applicant's past experience in conducting activities

similar to that being proposed. Describe applicant's resources,

facilities, and professional personnel that will be involved in

conducting the project. Include, in an appendix, curriculum vitae for

all professional personnel involved with the project. Describe plans

for administration of the project and identify administrative

resources/personnel that will be assigned to the project. Provide, in

an appendix, letters of support from all key participating non-

applicant organizations, individuals, etc. (if any), which clearly

indicate their commitment to participate as described in the

operational plan. Do not include letters of support from CDC personnel.

Letters of support from CDC will not be accepted. Award of a grant or

cooperative agreement implies CDC participation as outlined in the

PROGRAM REQUIREMENTS section of this announcement.

4. Objectives and Technical Approach:

Present specific objectives for the proposed project which are

measurable and time-phased and are consistent with the PURPOSE and

RECIPIENT ACTIVITIES sections for the specific focus area. Present a

detailed operational plan for initiating and conducting the project

which clearly and appropriately addresses these objectives (if

proposing a multi-year project, provide a detailed description of

first-year activities and a brief overview of subsequent-year

activities).

[[Page 36539]]

Clearly identify specific assigned responsibilities for all key

professional personnel. Include a clear description of applicant's

technical approach/methods which are directly relevant to the above

objectives. Describe specific study protocols or plans for the

development of study protocols. Describe the nature and extent of

collaboration with CDC (if proposing a cooperative agreement) and/or

others during various phases of the project. Describe in detail a plan

for evaluating progress toward achieving process and outcome project

objectives.

5. Budget:

Provide a line-item budget and accompanying detailed, line-by-line

justification that demonstrates the request is consistent with the

purpose and objectives of this program. If requesting funds for any

contracts, provide the following information for each proposed

contract: (1) Name of proposed contractor, (2) breakdown and

justification for estimated costs, (3) description and scope of

activities to be performed by contractor, (4) period of performance,

and (5) method of contractor selection (e.g., sole-source or

competitive solicitation). (See sample budget included in application

package.)

Note: If indirect costs are requested from CDC on a new or

continuation application, a copy of the organization's current

negotiated Federal indirect cost rate agreement or cost allocation

plan must be provided.

6. Human Subjects:

Whether or not exempt from DHHS regulations, if the proposed

project involves human subjects, describe adequate procedures for the

protection of human subjects. Also, ensure that women, racial and

ethnic minority populations are appropriately represented in

applications for research involving human subjects.

Evaluation Criteria

The applications will be reviewed and evaluated according to the

following criteria:

1. Background and Need (10 points)

Extent to which applicant demonstrates a clear understanding of the

background, purpose, and objectives of the focus area being addressed.

2. Capacity (45 points)

Extent to which applicant describes adequate resources and

facilities (both technical and administrative) for conducting the

project. Extent to which applicant documents that professional

personnel involved in the project are qualified and have past

experience and achievements in research related to that proposed as

evidenced by curriculum vitae, publications, etc. If applicable, extent

to which applicant includes letters of support from non-applicant

organizations, individuals, etc., and the extent to which such letters

clearly indicate the author's commitment to participate as described in

the operational plan.

3. Objectives and Technical Approach (45 points total)

a. Extent to which applicant describes objectives of the proposed

project which are consistent with the purpose of the focus area being

addressed and which are measurable and time-phased. (10 points)

b. Extent to which applicant presents a detailed operational plan

for initiating and conducting the project which clearly and

appropriately addresses all Recipient Activities for the specific

programmatic focus area being addressed. Extent to which applicant

clearly identifies specific assigned responsibilities of all key

professional personnel. Extent to which the plan clearly describes

applicant's technical approach/methods for conducting the proposed

studies and extent to which the approach/methods are appropriate and

adequate to accomplish the objectives. Extent to which applicant

describes specific study protocols or plans for the development of

study protocols that are appropriate for achieving project objectives.

Extent to which applicant meets CDC requirements regarding the

inclusion of women, racial and ethnic minority populations are

appropriately represented in applications involving human research.

Extent to which applicant describes adequate and appropriate

collaboration with CDC (if proposing a cooperative agreement) and/or

others during various phases of the project. (30 points)

c. Extent to which applicant provides a detailed and adequate plan

for evaluating progress toward achieving project process and outcome

objectives. If the proposed project involves notifiable conditions, the

degree to which applicant describes an adequate process for providing

necessary information to appropriate State and/or local health

departments. (5 points)

4. Budget (not scored)

Extent to which the proposed budget is reasonable, clearly

justifiable, and consistent with the intended use of grant/cooperative

agreement funds.

5. Human Subjects (not scored)

If the proposed project involves human subjects, whether or not

exempt from the Department of Health and Human Services (DHHS)

regulations, the extent to which adequate procedures are described for

the protection of human subjects. Note: Objective Review Group (ORG)

recommendations on the adequacy of protections include: (1) protections

appear adequate and there are no comments to make or concerns to raise,

(2) protections appear adequate, but there are comments regarding the

protocol, (3) protections appear inadequate and the ORG has concerns

related to human subjects, or (4) disapproval of the application is

recommended because the research risks are sufficiently serious and

protection against the risks are inadequate as to make the entire

application unacceptable.

Executive Order 12372 Review

This program is not subject to Executive Order 12372 Review.

Public Health System Reporting Requirements

This program is not subject to the Public Health System Reporting

Requirements.

Catalog of Federal Domestic Assistance Number

The Catalog of Federal Domestic Assistance Number is 93.283.

Other Requirements

Paperwork Reduction Act

Projects that involve the collection of information from ten or

more individuals and funded by the grant/cooperative agreement will be

subject to review and by the Office of Management and Budget (OMB)

under the Paperwork Reduction Act.

Human Subjects

If the proposed project involves research on human subjects, the

applicant must comply with the Department of Health and Human Services

Regulations (45 CFR Part 46) regarding the protection of human

subjects. Assurance must be provided to demonstrate that the project

will be subject to initial and continuing review by an appropriate

institutional review committee. The applicant will be responsible for

providing evidence of this assurance in accordance with the appropriate

guidelines and form provided in the application kit.

In addition to other applicable committees, Indian Health Service

(IHS) institutional review committees also must review the project if

any component of IHS will be involved or will support the research. If

American Indian community is involved, its tribal

[[Page 36540]]

government must also approve that portion of the project applicable to

it.

Women, Racial and Ethnic Minorities

It is the policy of the Centers for Disease Control and Prevention

(CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR)

to ensure that individuals of both sexes and the various racial and

ethnic groups will be included in CDC/ATSDR-supported research projects

involving human subjects, whenever feasible and appropriate. Racial and

ethnic groups are those defined in OMB Directive No. 15 and include

American Indian, Alaskan Native, Asian, Pacific Islander, Black and

Hispanic. Applicants shall ensure that women, racial and ethnic

minority populations are appropriately represented in applications for

research involving human subjects. Where clear and compelling rationale

exist that inclusion is inappropriate or not feasible, this situation

must be explained as part of the application. This policy does not

apply to research studies when the investigator cannot control the

race, ethnicity and/or sex of subjects. Further guidance to this policy

is contained in the Federal Register, Vol. 60, No. 179, pages 47947-

47951, dated Friday, September 15, 1995.

Animal Subjects

If the proposed project involves research on animal subjects, the

applicant must comply with the ``PHS Policy on Humane Care and Use of

Laboratory Animals by Awardee Institutions.'' An applicant organization

proposing to use vertebrate animals in supported activities must file

an Animal Welfare Assurance with the Office for Protection from

Research Risks at the National Institutes of Health.

Application Submission and Deadline

The original and five copies of each application PHS Form 398 must

be submitted to Sharron Orum, Grants Management Officer, Grants

Management Branch, Procurement and Grants Office, Centers for Disease

Control and Prevention (CDC), 255 East Paces Ferry Road, NE., Room 300,

Mailstop E-18, Atlanta, Georgia 30305, on or before August 8, 1997.

1. Deadline: Applications shall be considered as meeting the

deadline if they are either:

(a) Received on or before the deadline date; or

(b) Sent on or before the deadline date and received in time for

submission to the objective review group. (Applicants must request a

legibly dated U.S. Postal Service postmark or obtain a legibly dated

receipt from a commercial carrier or U.S. Postal Service. Private

metered postmarks shall not be acceptable as proof of timely mailing.)

2. Late Applications: Applications which do not meet the criteria

in 1(a) or 1(b) above are considered late applications. Late

applications will not be considered and will be returned to the

applicant.

Where To Obtain Additional Information

To receive additional written information call (404) 332-4561. You

will be asked to leave your name, address, and telephone number and

will need to refer to Announcement 778. You will receive a complete

program description, information on application procedures, and

application forms.

If you have questions after reviewing the contents of all the

documents, business management technical assistance may be obtained

from Oppie M. Byrd, Grants Management Specialist, Grants Management

Branch, Procurement and Grants Office, Centers for Disease Control and

Prevention (CDC), 255 East Paces Ferry Road, NE., Room 314, Mailstop E-

18, Atlanta, Georgia 30305, telephone (404) 842-6546, facsimile (404)

842-6513, E-mail [email protected].

Programmatic technical assistance may be obtained from the

following individuals:

Focus Area #1

Evaluating Algorithms to Diagnose Emerging Causes of Infectious

Diarrhea: Robert V. Tauxe, M.D., M.P.H., or David L. Swerdlow, M.D.,

National Center for Infectious Diseases, Division of Bacterial and

Mycotic Diseases, Centers for Disease Control and Prevention (CDC),

1600 Clifton Road, NE., Mailstop A-38, Atlanta, Georgia 30333, (for Dr.

Tauxe) telephone (404) 639-2206, E-mail address [email protected], (for Dr.

Swerdlow) telephone (404) 639-3234, E-mail address [email protected].

Focus Area #2

Rapid Identification of Emerging and Unusual Pathogenic Bacteria by

Partial 16S rRNA Sequencing: Don J. Brenner, Ph.D, National Center for

Infectious Diseases, Division of Bacterial and Mycotic Diseases,

Centers for Disease Control and Prevention (CDC), 1600 Clifton Road,

NE., Mailstop D-11, Atlanta, Georgia 30333, telephone (404) 639-2841,

E-mail address [email protected].

Focus Area #3

Development and Evaluation of Improved Tests for Malaria Diagnosis

in the United States: Phuc P. Nguyen-Dinh, M.D., National Center for

Infectious Diseases, Division of Parasitic Diseases, Centers for

Disease Control and Prevention (CDC), 1600 Clifton Road, NE., Mailstop

F-13, Atlanta, Georgia 30333, telephone (770) 488-4435, E-mail address

[email protected].

Focus Area #4

Development of Diagnostic Tests for Leishmaniasis: Mark L.

Eberhard, Ph.D., or Marianna Wilson, M.S., National Center for

Infectious Diseases, Division of Parasitic Diseases, Centers for

Disease Control and Prevention (CDC), 1600 Clifton Road, NE., Mailstop

F-13, Atlanta, Georgia 30333, (for Dr. Eberhard) telephone (770) 488-

4419, E-mail address [email protected], (for Ms. Wilson) telephone (770)

488-4431, E-mail address [email protected].

Focus Area #5

Identification of Unrecognized Etiologic Agents in Idiopathic

Sexually Transmitted Disease Syndromes: Consuelo Beck-Sague, M.D., or

Cheng-Yen Chen, Ph.D., National Center for Infectious Diseases,

Division of AIDS/HIV, STD, and TB Laboratory Research, Centers for

Disease Control and Prevention (CDC), 1600 Clifton Road, NE., Mailstop

C-12 (Dr. Beck-Sague) or G-39 (Dr. Chen), Atlanta, Georgia 30333, (for

Dr. Beck-Sague) telephone (404) 639-3467, E-mail [email protected], (for Dr.

Chen) telephone (404) 639-1535, E-mail address [email protected].

Focus Area #6

Development of Non-culture Molecular Epidemiologic Detection/Typing

Methods for Treponema pallidum or Haemophilus ducreyi: Victoria Pope,

Ph.D., or David L. Trees, Ph.D., National Center for Infectious

Diseases, Division of AIDS/HIV, STD, and TB Laboratory Research,

Centers for Disease Control and Prevention (CDC), 1600 Clifton Road,

NE., Mailstop D-13, Atlanta, Georgia 30333, (for Dr. Pope) telephone

(404) 639-3224, E-mail address [email protected], (for Dr. Trees) telephone

(404) 639-2134, E-mail address [email protected].

Please refer to Announcement Number 778 when requesting information

regarding this program.

You may also obtain this announcement from one of two Internet

sites on the actual publication date: CDC's homepage at http://

www.cdc.gov or at the Government Printing Office homepage (including

free on-line access to the Federal Register at http://

www.access.gpo.gov).

Potential applicants may obtain a copy of Healthy People 2000 (Full

Report, Stock No. 017-001-00474-0) or Healthy People 2000 (Summary

Report,

[[Page 36541]]

Stock No. 017-001-00473-1) referenced in the INTRODUCTION through the

Superintendent of Documents, Government Printing Office, Washington,

D.C. 20402-9325, telephone (202) 512-1800.

Dated: July 1, 1997.

Joseph R. Carter,

Acting Associate Director for Management and Operations Centers for

Disease Control and Prevention (CDC).

[FR Doc. 97-17703 Filed 7-7-97; 8:45 am]

BILLING CODE 4163-18-M