RFA-IP-16-002 12 16 15.pdf

Centers for Disease Control and Prevention

National Center for Immunization and Respiratory Diseases Extramural Research Program Office

Annual Estimates of Influenza Vaccine Effectiveness for Preventing Medically Attended

Laboratory-Confirmed Influenza in the United States

RFA-IP-16-002

Application Due Date: 01/11/2016

Annual Estimates of Influenza Vaccine Effectiveness for Preventing Medically Attended Laboratory-Confirmed Influenza in the United States

RFA-IP-16-002

TABLE OF CONTENTS

Part 1. Overview Information Key Dates Required Application Instructions Executive Summary

Part 2. Full Text Section I. Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 1. Overview Information Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations National Center for Immunization and Respiratory Diseases Extramural Research Program Office (NCIRD

ERPO)

National Center for Immunization and Respiratory Diseases (NCIRD) Funding Opportunity Announcement (FOA) Title Annual Estimates of Influenza Vaccine Effectiveness for Preventing Medically Attended Laboratory-Confirmed Influenza in the United States Activity Code U01 Research Project Cooperative Agreements

Funding Opportunity Announcement Type New Funding Opportunity Announcement Number

RFA-IP-16-002

Catalog of Federal Domestic Assistance (CFDA) Number(s) 93.185 Category of Funding Activity:

Health FOA Purpose The goal of this Funding Opportunity Announcement (FOA) is to support a network of US institutions that can obtain reliable vaccination information for a population and provide accurate estimates of annual influenza vaccine effectiveness (VE) to prevent influenza-associated illness in that population. Participating institutions will coordinate enrollment of patients with acute respiratory illness (ARI), confirm influenza infection using a standardized reverse-transcription PCR (RT-PCR) assay, and estimate VE using a test-negative study design. Interim VE estimates during the influenza season and end-of-season VE estimates will be used to inform vaccine recommendations and assess public health impact of influenza vaccination programs to prevent influenza-related illness and medical visits among persons of all ages. In addition, this network will compare VE for specific vaccine types available in the US. This network will serve as an emergency response resource in the event of an influenza pandemic to assess VE to prevent medically-attended illness associated with pandemic influenza.

NOTE: Section VIII. "Other Information" has been amended to include a "Summary of the Conference Call held on Thursday, December 3, 2015 with Potential Applicants" on pages 38-42.

Key Dates Publication Date: To receive notification of any changes to RFA-IP-16-002, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link. An email address is needed for this service.

Letter of Intent Due Date: 12/14/2015

Application Due Date: 01/11/2016 http://grants.nih.gov/grants/funding/ac_search_results.htm?text_curr=U01&Search_Type=Activity&Search.x=16&Search.y=3 http://www.grants.gov

Application Due Date: 01/11/2016

On-time submission requires that electronic applications be error-free and made available to CDC for processing from eRA Commons on or before the deadline date. Applications must be submitted to and validated successfully by Grants.gov/eRA Commons no later than 5:00 PM U.S. Eastern Time. Note:

HHS/CDC grant submission procedures do not provide a period of time beyond the application due date to correct any error or warning notices of noncompliance with application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review: 02/15/2016

Secondary Review: 03/11/2016

Estimated Start Date: 07/01/2016

Expiration Date: 01/12/2016 Due Dates for E.O. 12372: Due no later than 60 days after the application receipt date.

Required Application Instructions It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this FOA. Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Note: The Research Strategy component of the Research Plan is limited to 25 pages.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Telecommunications for the Hearing Impaired: TTY 1-888-232-6348

Executive Summary Purpose. Influenza is an important cause of morbidity, mortality, and healthcare burden across all age groups. Because influenza viruses are constantly changing and vaccines are reformulated every year, annual estimates of the effectiveness of influenza vaccines in preventing illness due to influenza infection and its associated complications are needed in order to evaluate the protection provided by annual, nationwide vaccination programs. The goal of this Funding Opportunity Announcement (FOA) is to support a network of US institutions that can obtain reliable vaccination information for a population and provide accurate estimates of annual influenza vaccine effectiveness (VE) to prevent medically-attended, influenza-associated illness in the population for whom influenza vaccination is recommended. Estimating influenza VE as soon as possible after the start of a seasonal influenza epidemic or pandemic, and monitoring it over time, are important to guide vaccination policies for influenza control. Estimation of VE depends upon accurate assessment of vaccination status, laboratory-confirmed disease outcomes, timing of illness and vaccination, and assessment of other factors that may affect vaccine use and immune response to vaccination. Moreover, a number of potential modifiers of vaccine response and vaccine effectiveness have been identified, including individual factors (age, prior vaccination), environmental factors (exposure to cigarette smoke), viral factors (influenza type and subtype) and infectious disease factors. This FOA intends to solicit applications that describe plans to identify and control for a variety of potential confounders in each proposed analysis. In addition, this network will allow comparison of VE data for specific vaccine types available in the US and serve as an emergency response resource in the event of an influenza pandemic. Results from research conducted under this funding opportunity announcement will yield high impact public health findings and/or strategies that will contribute to a reduction in the overall healthcare burden and improve the health of the US population. Participating institutions awarded http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf under this FOA will coordinate enrollment of patients aged 6 months and older with acute respiratory illness (ARI) and influenza infection will be confirmed using a standardized reverse-transcription PCR assay. Participating sites will contribute data to CDC to estimate VE using a test-negative study design. Applications should describe plans to identify and control for a variety of potential confounders in each proposed analysis. Annual VE estimates will be used to inform and assess the public health impact of influenza vaccination programs on the prevention of medically-attended, influenza-associated illness.

Mechanism of Support. Cooperative Agreement Funds Available and Anticipated Number of Awards. The estimated total funding for the five-year project period is $30,000,000. The estimated total funding for the first budget period is $5,400,000.

These fund estimates include the budgets for Core Components, Additional Components and Optional Components, which are described in Section II. The anticipated number of Core Component awards is up to five; Additional Component awards is up to five; Optional Component A awards is up to one;

and Optional Component B awards is up to three. The awards issued under this FOA are contingent upon availability of funds, the total number of meritorious applications and the cost of the applications received. See Section II. “Award Information” for funding information by individual component and by year.

Budget and Project Period. The project period will run from 07/01/2016 to 06/30/2021. The estimated average funding (direct and indirect) for the first budget period (7/01/2016 to 6/30/2017) will be up to $1,300,000 per awardee.

Application Research Strategy Length: Page limits for the Research Strategy component of the Research Plan are clearly specified in Section IV "Application and Submission Information" of this funding opportunity announcement.

Eligible Institutions/Organizations. Institutions/organizations listed in Section III.1 are eligible to apply.

Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. NOTE: CDC does not make awards to individuals directly. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply.

Number of PDs/PIs. There will only be one PD/PI per application. If necessary, Co-PI(s) may be listed in the application but only one PI may be the primary CDC contact for the award and this must be indicated in the application.

Number of Applications. Eligible applicant institutions may submit only one application containing multiple components. See Part 2. Section I.2 for further information.

Application Type. New Special Date(s). A potential applicant conference call will be held on Thursday, December 3, 2015 at 12 noon ET. The bridge number is 1-866-662-8986, passcode 8378091.

Application Materials. See Section IV.1 for application materials. Please note that Form C is to be used when downloading the application package.

http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY:

(770) 488-2783.

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority Sections 317, 317(k)(2) of the Public Health Service Act (42 U.S.C. Sections 247b, 247b(k)(2) and 247c), as

Sections 317, 317(k)(2) of the Public Health Service Act (42 U.S.C. Sections 247b, 247b(k)(2) and 247c), as amended.

1. Background and Purpose Influenza is an important cause of morbidity, mortality, and healthcare burden across all age groups. Because influenza viruses are constantly changing and vaccines are reformulated every year, annual estimates of the effectiveness of influenza vaccines in preventing influenza infection and its associated complications are needed in order to evaluate the protection provided by annual, nationwide vaccination programs. Each year in the United States, influenza viruses infect up to 20% of the population and cause hundreds of thousands to millions of medically-attended illnesses and thousands of hospitalizations and deaths. Annual influenza vaccination is the primary influenza prevention strategy and is recommended for all people ≥ 6 months of age in the U.S. Many studies have described the vaccine effectiveness (VE) of seasonal and 2009 pandemic influenza vaccine formulations against laboratory-confirmed symptomatic and medically-attended outpatient influenza illness (Griffin, 2011; Treanor, 2012; Ohmit, 2014; McLean 2014). In recent seasons, effectiveness of influenza vaccines has varied by influenza virus type and subtype or lineage, antigenic match between vaccine and circulating viruses, patient characteristics including age and prior vaccination history, and vaccine type. This FOA seeks to support a network of research institutions to estimate the annual effectiveness of influenza vaccination to prevent laboratory-confirmed, influenza-associated illness and to provide additional information on factors associated with influenza vaccine effectiveness.

The effectiveness of influenza vaccination varies yearly due to continual evolution of circulating virus strains and changes in annual influenza vaccine formulations. Thus, VE estimates from multiple seasons are necessary to estimate the public health impact of different licensed vaccine formulations used in national vaccination programs, including inactivated and live-attenuated vaccines, as well as high dose and standard dose inactivated vaccines currently available for older adults in the US. Observational studies of licensed vaccines add new information about vaccine effectiveness in “real world” populations, settings and age groups, not generally included in clinical trials. Comparable data from multiple years and from multiple sites are required to accurately assess and estimate VE against influenza virus A subtypes and B lineages and for different licensed vaccines.

Most current research to assess VE against influenza ambulatory visits uses a test-negative study design (Jackson, 2013; DeSerres, 2013; Foppa, 2013; Sullivan, 2014). Patients seeking care for acute respiratory illness (ARI) are recruited for study enrollment and systematically tested for influenza infection using sensitive molecular-based diagnostic assays (e.g., RT-PCR) (CDC, 2014). Influenza-positive patients are identified as study cases and influenza-negative patients as controls. The use of sensitive diagnostic testing for influenza reduces biases that can affect VE estimates (Orenstein, 2007; Ferdinands, 2012; Jackson, 2015). During the influenza season, influenza viruses are detected in 10-40% of persons with ARI who seek care in ambulatory care settings, depending upon the influenza season. Also, most patients presenting to ambulatory care for ARI present within 7 days of illness onset, a time when detecting influenza viruses is optimal.

References:

1) De Serres, G., et al. The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials. Euro Surveill, 2013. 18(37).

2) Ferdinands, J.M. and D.K. Shay. Magnitude of potential biases in a simulated case-control study of the effectiveness of influenza vaccination. Clin Infect Dis, 2012. 54(1): p. 25-32.

3) Foppa, I.M., et al. The case test-negative design for studies of the effectiveness of influenza vaccine.

Vaccine, 2013. 31(30): p. 3104-9.

4) Griffin, M.R., et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities. PLoS One, 2011. 6(8): p. e23085.

5) Jackson, M.L. and J.C. Nelson. The test-negative design for estimating influenza vaccine effectiveness.

Vaccine, 2013. 31(17): p. 2165-8.

6) Jackson, M.L. and K.J. Rothman. Effects of imperfect test sensitivity and specificity on observational studies of influenza vaccine effectiveness. Vaccine, 2015. 33(11): p. 1313-6.

7) McLean, H.Q., et al. Influenza vaccine effectiveness in the United States during 2012-2013: variable protection by age and virus type. J Infect Dis, 2015. 211(10): p. 1529-40.

8) Ohmit, S.E., et al. Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates. Clin Infect Dis, 2014. 58(3): p. 319-27.

9) Orenstein, E.W., et al. Methodologic issues regarding the use of three observational study designs to assess influenza vaccine effectiveness. Int J Epidemiol, 2007. 36(3): p. 623-31.

10) Sullivan, S.G., S. Feng, and B.J. Cowling. Potential of the test-negative design for measuring influenza vaccine effectiveness: a systematic review. Expert Rev Vaccines, 2014. 13(12): p. 1571-91.

11) Treanor, J.J., et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. Clin Infect Dis, 2012. 55(7): p. 951-9.

Healthy People 2020 and other National Strategic Priorities The CDC NCIRD within HHS is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2020" (http://www.healthypeople.gov/2020/topicsobjectives2020/default) and to measuring program performance as stipulated by the Government Performance and Review Act (GPRA).

This FOA is in alignment with the “Healthy People 2020” priority focus area, Immunization and Infectious Diseases and HHS Strategic Plan Goals and Objectives: Goal 3 - Advance the Health, Safety, and Well-Being of the American People: http://www.hhs.gov/about/strategic-plan/strategic-goal-3/index.html

Public Health Impact Annual VE estimates will be used to inform and assess the public health impact of influenza vaccination programs on the prevention of medically-attended, influenza-associated illness. In addition, this network will allow comparison of VE data for specific vaccine types available in the US and serve as an emergency response resource in the event of an influenza pandemic. Results from research conducted under this FOA will yield high impact public health findings and/or strategies that should contribute to a reduction in the overall healthcare burden and improve the health of the US population.

Relevant Work

1) FOA (IP-11-003): Annual Estimates of Influenza Vaccine Effectiveness for Preventing Laboratory-Confirmed Influenza in the United States (http://www.grants.gov/web/grants/search-grants.html , Keyword: RFA-IP-11-003; Opportunity Status: Archived)

2) Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection at http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm

3) Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2015–16 Influenza Season, MMWR http://www.cdc.gov/mmwr/previ ew/mmwrhtml/mm6430a3.htm

2. Approach http://www.healthypeople.gov/2020/topicsobjectives2020/default http://www.hhs.gov/about/strategic-plan/strategic-goal-3/index.html http://www.grants.gov/web/grants/search-grants.html http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6430a3.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6430a3.htm

Objectives/Outcomes Whenever possible, applications should include objectives written in the SMART format (e.g., Specific, Measurable, Achievable, Realistic and Time-bound).

Each application MUST address the Core Component and the two Additional Components. In addition, applications may address up to two Optional Components, but no more than one will be awarded to the same applicant.

A. Core Component (Mandatory) for Years 1-5, $800,000 per year (direct and indirect costs):

Assess influenza vaccine effectiveness (VE) in preventing laboratory-confirmed influenza infections among children and adults with medically-attended, acute respiratory illness (MAARI) who present for care in ambulatory settings. The application should address all of the following objectives:

1) Describe research study activities and operations as outlined below. Applications must include, at a minimum, details of study activities to:

a) Document study resources, capabilities and proposed activities to achieve acceptable study sample size enrollments using conservative assumptions of influenza activity during a typical influenza season (e.g., at least 1000 total enrollees with a minimum of 300 in each of three age groups [6 months – 17 years, 18-49 years and 50 years and older], with at least 100 among young children aged 6 months – 8 years and with at least 100 among adults aged ≥65 years);

b) Describe procedures for enrollment of ambulatory patients in a research study at participating health facilities. Describe possible approaches to increase proportion of enrollment (up to 25% of total enrollment) from priority groups, such as children aged 6 months to 8 years and adults aged 65 years and older;

c) Describe procedures for collection of research specimens from all enrolled patients;

d) Describe study patient identification and enrollment protocols to achieve a goal of >60% participation among eligible participants. Describe methods to identify and correct possible problems with study enrollment, including participation of <50% of eligible persons and failure to meet sample size;

e) Obtain detailed patient data from enrolled patients including information on age, co-morbidities and vaccination history for current and prior seasons;

f) Describe methods for validation of vaccination status with medical records, state immunization registries and records from vaccine providers.

2) Describe how patients with ARI will be identified and enrolled during each influenza season covered by the five-year project period. Provide diagrams and/or algorithms demonstrating how patients will be screened for eligibility and describe the participant enrollment forms that will be used to monitor study participation.

a) Provide a detailed description of each participating facility where patients will be enrolled and who will perform the enrollment. Include information for each performance site that indicates compliance with human subjects research protections, including Federal-Wide Assurance numbers (FWAs). Institutions that will establish a reliance on an external organization’s FWA or Institutional Review Board (IRB) should provide information on the appropriate authority for that organization and provide a statement of intent to establish a written agreement between the study institution and the other institution/organization, outlining adherence to requirements of the U.S. Federal Policy for the Protection of Human Subjects. Describe facility policies on patient enrollment in clinical research (e.g., do research staff need to request provider permission before the patient is approached by research staff or do clinical staff need to ask patient permission to have research staff approach patient?). If a clinician step is required at the institution, describe how the site will remove this potentially biasing barrier for this study.

b) Describe proposed partnerships and the methods of local surveillance that will be used to identify the start and end of the influenza season and, therefore, define the specific study enrollment and testing period for their sites.

c) Descriptions of previous experience enrolling patients in research studies conducted in ambulatory settings are useful and encouraged, including strategies to achieve a high rate of participation among approached patients and information from previous studies comparing target enrollment to actual number enrolled.

3) Describe how the following proposed total study sample enrollment populations will be achieved.

a) For each influenza season: Enrollment of a minimum of 1000 ambulatory patients presenting with ARI and cough within 7 days of illness onset.

For planning purposes, the following conservative assumptions were used to estimate sample size populations:

Influenza detection in 14% of patients with ARI meeting inclusion criteria;

VE estimate = 50%;

Vaccine coverage = 50%, with 10% of enrollees with indeterminate vaccination status;

Five network sites, three strata for analysis (e.g., age group, influenza virus type/subtype-specific VE);

Alpha=0.05, Power= 0.80.

Overall, each applicant institution will need to demonstrate the capacity or history to enroll a minimum of 1000 ARI patients per season (this FOA foresees 5000 total for all five awardees to identify a total of 700 influenza-positive cases) to estimate an overall influenza A and B VE each year by age group or VE by influenza virus type/subtype for all ages, depending upon the frequency and distribution of influenza virus types and subtypes. It is expected that during seasons of increased influenza circulation, higher numbers of influenza-positive cases would be enrolled, providing additional age-group specific, vaccine-specific and influenza subtype-specific VE estimates.

4) Diagnose influenza cases by virus type and subtype or lineage using a standardized, validated real-time RT-PCR assay (with probes, primers and reagents approved by CDC). The application should:

a) Provide evidence of competency in the use of the RT-PCR assay or evidence that the contracting laboratory performing the testing has expertise with the RT-PCR assay (e.g., number of these assays run/year; comparisons to other assays or results from validation studies, other measures of proficiency;

letters of support; and publications);

b) Provide a statement of agreement to participate in CDC-sponsored proficiency testing throughout the term of the project. Proficiency testing may include testing a small panel of specimens sent by CDC and reporting results back to CDC within a specified timeframe (generally, 1 month);

c) Describe experience to aliquot specimens and prepare shipments of aliquots (0.5-1.0 ml) for antigenic characterization, sequencing, special research studies and for other WHO Influenza Collaborating Center surveillance purposes performed at CDC and contract laboratories or similar research. For planning purposes, assume specimen shipments will be required every 2 to 4 weeks during the influenza season and will require accompaniment of a completed WHO surveillance form (supplied by CDC). Include a description of how respiratory specimens will be stored and whether leftover specimen aliquots will be available.

5) Describe methods to obtain current season influenza vaccination status (including vaccination date(s), vaccine type, and manufacturer) and prior season vaccination status (including vaccination type) using self-report and verification from electronic medical records, real-time electronic vaccine registries or medical abstraction from health care providers, pharmacy chains, schools, and other potential vaccine providers. The application should describe procedures for verification of self-reported vaccination status, including procedures to obtain documentation of vaccination from providers not captured by electronic medical records or immunization registries.

a) Include vaccination information that will be collected from each study participant/enrollee (e.g., date of

a) Include vaccination information that will be collected from each study participant/enrollee (e.g., date of vaccination for current season vaccination and vaccine provider, receipt of influenza vaccine in prior seasons);

b) Evidence of experience and competence with methods to verify influenza vaccination status is helpful;

c) Describe recent evaluations of self-reported and record/registry-based vaccination status (validation of vaccine verification methods) or describe methods that will be used to evaluate vaccine verification in the first year of the project.

6) Describe methods to collect information from enrolled patients about onset of illness, symptoms, self-reported health status, self-reported illness severity and household characteristics (including number of occupants and cigarette smoking) by patient interview. Describe methods to collect additional information to investigate differences in healthcare utilization among vaccinated and unvaccinated individuals (such as number of outpatient visits for any reason in the preceding 12 month period), and the local practice norms of the medical settings and their health care providers (including any diagnostic testing for influenza).

7) Describe methods to collect post-enrollment information on date of resolution of symptoms, date of return to normal activities and impact of illness on daily activities by electronic survey or telephone interview.

8) Describe methods to collect information from enrolled patients about high-risk medical conditions of influenza, antiviral and antibiotic use (date and drugs), complications of illness (hospitalization, subsequent medical encounters and procedures during the 30-day period following enrollment) and diagnostic codes associated with medical encounters (ICD-9 or ICD-10 codes) (ICD: International Classification of Diseases) using electronic medical records.

9) Describe a plan to:

a) Provide periodic updates (every 2 weeks) on enrollment of cases and controls, RT-PCR results and status of data collection; and

b) Provide data to CDC for interim (mid-season) and end-of-season VE estimates according to established timelines, normally 4-6 weeks after the beginning of enrollment for interim estimates.

10) Propose methods to provide annual estimates of population-based incidence of medically-attended, laboratory-confirmed influenza in ambulatory settings using data from a source population for health facilities where enrollment takes place. Describe a plan to provide incidence data to CDC for annual estimates of influenza-related disease burden.

11) Provide a statement on the research capacity and willingness to serve as an emergency response resource and participate with CDC in pandemic-related studies related to vaccine and antiviral assessments and estimation of incidence outside of normal seasonal study activities, should they be needed.

B. Two Additional Components (Mandatory) for Years 3-5 at $100,000 each, thus $200,000 total per year (direct and indirect costs):

1) Evaluation of disease burden due to respiratory syncytial virus (RSV) and other respiratory viruses during the influenza season

New vaccines are currently under development for RSV. Determining the burden of RSV before and after vaccine introduction would help to evaluate the impact of the new vaccine. If there is a potential for RSV vaccines to become available in the near future, a goal would be to directly measure VE for the new vaccine against medically-attended illness in this network. Sites should be willing to test for RSV and other respiratory viruses using CDC-approved assays (CDC may provide probes, primers and reagents, if applicable). In addition, sites should contribute to multi-site evaluations comparing influenza test-positive patients to patients who test positive for other respiratory viruses to examine effects of influenza vaccination on illness due to other respiratory viruses. All applications should provide responses for the following:

a) Describe the current capability and diagnostic test methods available for the detection of RSV and other respiratory viruses (molecular assays are preferred);

b) Describe the methods that would be used to estimate the population-based incidence of medically-attended illness associated with laboratory-confirmed infection with RSV and other respiratory viruses among adults (18-64), older adults (>65 years), and children (under 18). For this study, disease burden among children <6 months of age will not be determined;

c) Describe the methods that would be used to obtain RSV vaccination data, should RSV vaccines become available.

2) Pandemic Preparedness

In the event of an influenza pandemic, participating sites would be involved in pandemic response activities, including studies to describe the epidemiology of novel influenza virus infection and burden of disease, and to evaluate use and effectiveness of antiviral agents for treatment and effectiveness of seasonal and pandemic influenza vaccines for prevention of pandemic influenza. All applications should provide responses for the following:

a) Capacity to participate with CDC in pandemic-related studies during or outside of the normal seasonal study activities, modify protocol to align with protocols for pandemic-related studies and prepare operational plans for implementation of pandemic studies

b) Willingness to pilot methods that might be needed to conduct pandemic-related studies. For example, identification and collection of respiratory specimens from ill persons triaged by telephone; or collection of post-antiviral treatment specimens from influenza-positive individuals to evaluate for the emergence of antiviral resistance during treatment (tested at a CDC laboratory).

C. Two Optional Components (A and B)

Each applicant may apply for up to two of the Optional Components listed below for Years 1-5; only one Optional Component (A or B) will be funded per applicant and only if the mandatory Core Component is awarded to that applicant.

1) Optional Component A: Evaluation of the development of antibody profiles over multiple influenza seasons in a household cohort (up to $500,000 per year including direct and indirect costs).

Identify and enroll a minimum of 400 households, including young children aged 3 years or younger, to conduct active surveillance for acute respiratory infection among young children and their household members over multiple influenza seasons and to collect serum specimens twice yearly from household members and a subset of children aged <3 years to study the development of antibodies to influenza viruses in young children. Applications should present a strategy to identify and enroll a longitudinal cohort of at least 180 children aged <3 years (n=60 aged <1 year, n=60 aged 1-2 years and n=60 aged 2-3 years) to be followed over two to five influenza seasons, including pre- and post-season serum specimen collection;

collect, process and store serum specimens before and at the end of the influenza season, as well as 4 weeks after influenza vaccination (if applicable); propose a method to collect respiratory specimens from symptomatic young children and their household members within 7 days of illness onset. Applications should present a comprehensive strategy for enrolling households of families including infants and young children, optimizing response rates, and minimizing attrition. The applications should plan to estimate the incidence of laboratory-confirmed influenza infection (of any severity) among young children and household members, estimate vaccine effectiveness and compare these with estimates of VE against medically-attended influenza illness. The application should describe the investigators’ willingness to send serum specimens for investigation by CDC’s influenza laboratory to understand effects of natural infection and vaccination on investigation by CDC’s influenza laboratory to understand effects of natural infection and vaccination on immune responses to reference influenza viruses for the development of antibody profiles. CDC will test paired sera by hemagglutination-inhibition assay methods by a single reference laboratory using standard, validated procedures.

2) Optional Component B: Immunologic study of response to influenza vaccination (up to $300,000 per year including direct and indirect costs).

Recruit and enroll 150 to 200 subjects in priority age groups (6 months-8 years, and adults 65 and older) who are eligible to receive specific influenza vaccines and for whom the vaccines are recommended to study the immune responses to influenza vaccines. The application should describe the vaccination strategy and how the investigators will collect, process, store, and ship paired serum specimens to a reference laboratory designated by CDC. The application should describe the investigators’ willingness to participate in cross-site decisions on specific influenza vaccines and populations to be examined (for example, live-attenuated vaccine in children and adolescents or high dose inactivated vaccine in persons aged ≥65 years) and interpretation of influenza vaccine response.

Applications should:

a) Describe a process to enroll 150 to 200 subjects for collection of serum specimens on or before the date of vaccination and 4 weeks after receipt of vaccine. Specimens will be processed and shipped to the CDC or designated laboratory for influenza testing. The CDC will be responsible for testing paired sera by hemagglutination-inhibition assay methods by a single reference laboratory using standard, validated procedures.

b) Identify priority groups for investigation of cell-mediated immune responses; describe experience or provide evidence that the contracting laboratory has experience with collection, processing and storage of peripheral blood mononuclear cells (PBMC), including measures of cell count and viability; provide letters of support or publications. The CDC will be responsible for testing these specimens.

c) Describe how participants will be enrolled and followed during the study period, including steps to minimize and measure potential selection and attrition biases.

d) Describe how prior vaccination and laboratory-confirmed influenza infection, other medical and health information about the participants gathered from interview, medical record extraction, or chart abstraction can be used to examine the potential modifiers of vaccine response.

Target Population Mandatory components: Children (from 6 months of age) and adult (≥18 years) populations presenting to ambulatory facilities with acute respiratory illness.

Optional components: Healthy children (from 6 months of age) and adult (≥18 years) individuals who agree to enroll in the household or vaccine response studies.

Collaboration/Partnerships This FOA seeks to support a network of US institutions that can obtain reliable vaccination information for a population and provide accurate estimates of annual influenza vaccine effectiveness (VE) to prevent medically-attended, influenza-associated illness in the population for whom influenza vaccination is recommended. The awardees will work cooperatively with CDC and other network site partners to collectively enroll sufficient numbers of the target population to provide interim and end-of-season VE estimates for population subgroups and factors of interest. Investigators from each site and CDC investigators will participate on a steering committee.

Evaluation/Performance Measurement As part of the application, the PI should include measurable goals and aims based on a five-year research project period. The grantee will collaborate with CDC to: (1) establish specific, measurable, achievable, realistic and time-phased (SMART) project objectives for each activity described in the applicant’s project plan, and (2) develop and implement project performance measures that are based on specific programmatic objectives. Also, funded PIs must submit an annual progress report showing their activities and outcomes based on their overall research goals and timeline. For more information on required Reporting, please see Section VI of this FOA.

For all components, the application should include an evaluation/performance measurement plan. Progress should be identified by achievement of relevant milestones which may include, but not limited to:

The type of evaluations (i.e., process, outcome or both) to be conducted.

Key evaluation questions.

Other information (e.g., performance measures to be developed by the applicant).

Potentially available data sources and feasibility of collecting appropriate evaluation and performance data.

Translation Plan For all components, the application should describe how the findings of this work will inform and evaluate influenza vaccine policy and recommendations, including providing annual estimates of influenza vaccine effectiveness against circulating influenza viruses. This section should be understandable to a variety of audiences, including policy makers, practitioners, public health programs, healthcare institutions, professional organizations, community groups, researchers and other potential end users. Describe how the findings could be generalized and scaled to populations and communities outside of the funded project.

Section II. Award Information

Funding Instrument Type: Cooperative Agreement A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed:

New - An application that is submitted for funding for the first time. Includes multiple submission attempts within the same round.

Estimated Total Funding: $30,000,000 Applicants MUST apply for the mandatory Core Component (Years 1-5) and the mandatory two Additional Components (Years 3-5). Applicants may also apply for Optional Component A and Optional Component B (Years 1-5), but only one Optional Component (A or B) will be awarded to an applicant who has been awarded the Mandatory Components (Core and two Additional Components). Awards issued under this FOA are contingent on the availability of funds and submission of a sufficient number of meritorious applications.

Estimated funds available for Mandatory Components (Core plus two Additional Components) per awardee per year:

Year 1: $800,000

Year 2: $800,000

Year 3: $1,000,000

Year 4: $1,000,000

Year 5: $1,000,000

Anticipated Number of Awards for Mandatory Components (Core plus two Additional Components):

Up to five awards

Estimated funds available for Optional Component A is $500,000 per award per year.

Estimated funds available for Optional Component B is $300,000 per award per year.

Anticipated Number of Awards for Optional Components: 1 Optional Component A and up to 3 Optional Component B awards.

Estimated total funding available for first year:

$5,400,000: 5 sites x $800,000 (Core + Additional Components) + 1 x $500,000 Optional Component A + 3 x $300,000 Optional Component B.

Estimated total funding available for entire project period: $30,000,000 ($5,400,000 for each of Years 1 and 2 + $6,400,000 for each of Years 3, 4, and 5)

Anticipated Number of Awards: 5

Ceiling for the Core + Additional Components per awardee per year: $1,000,000.

Floor for the Core + Additional Components per awardee per year: $500,000.

Ceiling for Optional Component A per award per year: $500,000

Floor for Optional Component A per award per year: $200,000.

Ceiling for Optional Component B per award per year: $300,000

Floor for Optional Component B per award per year: $100,000.

The award ceiling and floor and total project period listed below are for the Core + Additional Components.

Awards issued under this FOA are contingent on the availability of funds and submission of a sufficient number of meritorious applications.

Award Ceiling: $1,000,000 Per Project Period Award Floor: $500,000 Per Project Period Total Project Period Length: 5 year(s)

Throughout the project period, CDC's commitment to continuation of awards will depend on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and CDC’s determination that continued funding is in the best interest of the Federal government.

HHS/CDC grants policies as described in the HHS Grants Policy Statement (http://www.hhs.gov/ asfr/ogapa/aboutog/hhsgps107.pdf) will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants Eligibility Category: State governments

County governments City or township governments Special district governments Independent school districts Public and State controlled institutions of higher education Native American tribal governments (Federally recognized) Public housing authorities/Indian housing authorities Native American tribal organizations (other than Federally recognized tribal governments) Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education Nonprofits without 501(c)(3) status with the IRS, other than institutions of higher education Private institutions of higher education Others (see text field entitled "Additional Information on Eligibility" for clarification)

Additional Eligibility Category:

The following types of Higher Education Institutions are always encouraged to apply for CDC support as Public or Private Institutions of Higher Education:

Hispanic-serving Institutions Historically Black Colleges and Universities (HBCUs) Tribally Controlled Colleges and Universities (TCCUs) Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education:

Nonprofits (Other than Institutions of Higher Education)

Governments:

Eligible Agencies of the Federal Government U.S. Territory or Possession

Other:

Native American tribal organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Regional Organizations http://www.hhs.gov/asfr/ogapa/aboutog/hhsgps107.pdf http://www.hhs.gov/asfr/ogapa/aboutog/hhsgps107.pdf

Foreign Organizations: a Foreign Organization is a public or private organization, whether non-profit or for-profit, located in a country other than the United States (U.S.) and its territories that is subject to the laws of the country in which it is located, irrespective of the citizenship of project staff or place of performance.

Bona Fide Agents: a Bona Fide Agent is an agency/organization identified by the state as eligible to submit an application under the state eligibility in lieu of a state application. If applying as a bona fide agent of a state or local government, a legal, binding agreement from the state or local government as documentation of the status is required. Attach with "Other Attachment Forms" when submitting via www.grants.gov.

Federally Funded Research and Development Centers (FFRDCs): FFRDCs are operated, managed, and/or administered by a university or consortium of universities, other not-for-profit or nonprofit organization, or an industrial firm, as an autonomous organization or as an identifiable separate operating unit of a parent organization. A FFRDC meets some special long-term research or development need which cannot be met as effectively by an agency's existing in-house or contractor resources. FFRDC's enable agencies to use private sector resources to accomplish tasks that are integral to the mission and operation of the sponsoring agency. For more information on FFRDCs, go to http:// ecfr.gpoaccess.gov /cgi/t/text/ text-idx?c=ecfr& sid=512ff78311f427c00454772dcf21523a&rgn=div8 &view=text&node=48:1.0.1.6.34.0.1.18& idno=48

2. Foreign Organizations Foreign Organizations are not eligible to apply.

Foreign components of U.S. Organizations are not eligible to apply.

For this announcement, applicants may not include collaborators or consultants from foreign institutions. All applicable federal laws and policies apply.

3. Special Eligibility Requirements Applications submitted under this funding opportunity announcement must not include activities that overlap with simultaneously-funded research under other awards.

If a current awardee of CDC FOA IP11-003 applies to this FOA and the application ranks sufficiently high to be awarded, funding restrictions will apply to ensure no overlap of the budget or project periods with IP11-003 and IP16-002.

4. Justification for Less than Maximum Competition N/A http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=512ff78311f427c00454772dcf21523a&rgn=div8&view=text&node=48:1.0.1.6.34.0.1.18&idno=48 http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=512ff78311f427c00454772dcf21523a&rgn=div8&view=text&node=48:1.0.1.6.34.0.1.18&idno=48 http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=512ff78311f427c00454772dcf21523a&rgn=div8&view=text&node=48:1.0.1.6.34.0.1.18&idno=48

5. Responsiveness If the investigators plan to use their State Health Department laboratory or contract laboratory services for RT-PCR and viral cultures, then documents supporting this partnership must be submitted.

6. Required Registrations Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

(Foreign entities only): Special Instructions for acquiring a Commercial and Governmental Entity (NCAGE) Code: https://eportal.nspa.nato. int/AC135Public/Docs/US%20Instructions%2 0for%20NSPA%20NCAGE.pdf System for Award Management (SAM) – must maintain current registration in SAM (the replacement system for the Central Contractor Registration) to be renewed annually, https://www.sam.gov/portal/SAM/#1.

Grants.gov eRA Commons

All applicant organizations must register with Grants.gov. Please visit www.Grants.gov at least 30 days prior to submitting your application to familiarize yourself with the registration and submission processes.

The “one-time” registration process will take three to five days to complete. However, it is best to start the registration process at least two weeks prior to application submission.

All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization. All registrations must be successfully completed and active before the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

7. Universal Identifier Requirements and System for Award Management (SAM) All applicant organizations must obtain a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements.

The DUNS number is a nine-digit number assigned by Dun and Bradstreet Information Services. An AOR should be consulted to determine the appropriate number.