Foa_Content_of_RFA-IP-22-004.pdf

Centers for Disease Control and Prevention

NATIONAL CENTER FOR IMMUNIZATION AND RESPIRATORY DISEASES

US Platform to Measure Effectiveness of Seasonal Influenza, COVID-19 and other Respiratory Virus Vaccines for the Prevention of Acute Illness in Ambulatory Settings

RFA-IP-22-004

05/09/2022

Table of Contents 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

Overview Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations Components of Participating Organizations:

National Center for Immunization and Respiratory Diseases Notice of Funding Opportunity (NOFO) Title US Platform to Measure Effectiveness of Seasonal Influenza, COVID-19 and other Respiratory Virus Vaccines for the Prevention of Acute Illness in Ambulatory Settings Activity Code 93.185

Notice of Funding Opportunity Type New Agency Notice of Funding Opportunity Number

RFA-IP-22-004

Assistance Listings Number(s) 93.185,93.083 Category of Funding Activity HL - Health NOFO Purpose The goal of this funding announcement is to: 1) support a network of US institutions that can identify laboratory-confirmed cases of acute respiratory illness due to influenza, SARS-CoV-2, and other viruses of major public health concern, among patients seeking healthcare for acute respiratory illness and related symptomology, and 2) provide accurate estimates of the effectiveness of influenza, COVID-19, and other vaccines against respiratory virus-associated illness in that population. Participating institutions should identify illnesses among ambulatory patients seeking healthcare or diagnostic testing for acute illness. Applicants applying for Component A should: 1) enroll patients meeting standard symptom criteria, 2) confirm viral infection using approved molecular assays, 3) estimate influenza and SARS-CoV-2 vaccine effectiveness (VE) using a test-negative study design, and 4) perform viral genomic characterization of select respiratory specimens from enrolled participants. Applicants applying for Component B should propose performing data coordination activities for the network of Component A awardees. Optional Component C, D or E studies may be proposed only by those applying for Component A. Optional Component C is to conduct a case-ascertained household transmission study; Optional Component D is to conduct an immunologic study of the responses to influenza and COVID-19 virus vaccination; and Optional Component E is to perform complex laboratory assays and analyses of influenza viral genomics. Estimates of vaccine effectiveness against these illnesses will be used to inform vaccine recommendations and assess public health impact of vaccination programs to prevent viral illness-related healthcare encounters and medical visits among persons of all ages.

Key Dates Publication Date:

To receive notification of any changes to RFA-IP-22-004, 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:

The LOI date will generate once the Synopsis is published if Days or a Date are entered.

04/08/2022

Application Due Date:

05/09/2022 05/09/2022

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

Applicants will use a system or platform to submit their applications through Grants.gov and eRA Commons to CDC. ASSIST, an institutional system to system (S2S) solution, or Grants.gov Workspace are options. ASSIST is a commonly used platform because it provides a validation of all requirements prior to submission and prevents errors.

For more information on accessing or using ASSIST, you can refer to the ASSIST Online Help Site at: https://era.nih.gov/erahelp/assist. Additional support is available from the NIH eRA Service desk via http://grants.nih.gov/support/index.html.

E-mail: commons@od.nih.gov Phone: 301-402-7469 or (toll-free) 1-866-504-9552.

Hours: Monday - Friday, 7 a.m. to 8 p.m. Eastern Time, excluding Federal holidays.

Note: HHS/CDC grant submission procedures do not provide a grace period beyond the application due date time to correct any error or warning notices of noncompliance with https://www.grants.gov/ http://grants.nih.gov/support/index.html mailto:commons@od.nih.gov application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review:

06/30/2022 Secondary Review:

08/09/2022 Estimated Start Date:

09/30/2022 Expiration Date:

05/10/2022 Required Application Instructions It is critical that applicants follow the instructions in the How to Apply - Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both in the Application Guide and the NOFO) 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.

Page Limitations: Pages that exceed the page limits described in this NOFO will be removed and not forwarded for peer review, potentially affecting an application's score.

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

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

An applicant may apply for Component A or Component B but not both. In both the Research Strategy and Project Summary/Abstract (Description) sections of the application, clearly list the proposed component project by name and identify it as either applying for Component A or Component B. A Component B award will not be made if no Component A award is made.

If applying for Component A plus one or more Optional Components, in both the Research Strategy and Project Summary/ Abstract (Description) sections, the application should clearly list each proposed component project by name (i.e., identify the proposed project as Component A, C, D or E).

Applications for Component A must address all three objectives under Component A; those applying under Component A may also apply for one or more of the Optional Components C, D or E but must not apply for Component B; those applying for Component B must not apply for any of the other components. If an applicant applies for both Component A and Component B, neither application will move forward to peer review and neither will be eligible for award.

Within the total 25-page limit for the Research Strategy of the Research Plan section of the application, the page limit for EACH Component is limited as follows:

https://grants.nih.gov/grants/how-to-apply-application-guide.html

Component A: 10 pages Component C: 5 pages Component D: 5 pages Component E: 5 pages

The page limits remain the same for each Component whether an applicant applies for only Component A or for Component A plus one or more Optional Components (e.g., if an applicant applies for only Component A, the page limit for the Component A Research Strategy is 10 pages; if an applicant applies for Component A and one or more Optional Components, the page limit for the Component A Research Strategy is 10 pages – the same principle applies to Components C, D, and E – the page limits will always remain at 5 pages each).

Component B: 25 pages

(Please see Section IV.2 of this NOFO for more detailed information regarding application format).

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. Pages that exceed page limits described in this NOFO will be removed and not forwarded for peer review, potentially affecting an application's score.

Executive Summary Purpose: The goal of this funding announcement is to: 1) support a network of US institutions that can identify laboratory-confirmed cases of acute respiratory illness due to influenza, SARS-CoV-2, and other viruses of major public health concern, among patients seeking healthcare for acute respiratory illness and related symptomology, and 2) provide accurate estimates of the effectiveness of influenza, COVID-19, and other vaccines against respiratory virus-associated illness in that population. Participating institutions should identify illnesses among ambulatory patients seeking healthcare or diagnostic testing for acute illness. Applicants applying for Component A should: 1) enroll patients meeting standard symptom criteria, 2) confirm viral infection using approved molecular assays, 3) estimate influenza and SARS-CoV-2 vaccine effectiveness (VE) using a test-negative study design, and 4) perform viral genomic characterization of select respiratory specimens from enrolled participants. Applicants applying for Component B should propose performing data coordination activities for the network of Component A awardees. Optional Component C, D or E studies may be proposed only by those applying for Component A. Optional Component C is to conduct a case-ascertained household transmission study; Optional Component D is to conduct an immunologic study of the responses to influenza and COVID-19 virus vaccination; and Optional Component E is to perform complex laboratory assays and analyses of influenza viral genomics. Estimates of vaccine effectiveness against these illnesses will be used to inform vaccine recommendations and assess public health impact of vaccination programs to prevent viral illness-related healthcare encounters and medical visits among persons of all ages.

Mechanism of Support: U01 – Research Project - Cooperative Agreement Funds Available and Anticipated Number of Awards: The estimated total funding available, including direct and indirect costs, for the entire five (5)-year period of performance is $107,500,000. The anticipated number of awards will be up to eight (8):

seven (7) for Component A and one (1) for Component B. It is anticipated that up to five

(5) Component C awards will be made, up to four (4) Component D awards will be made and one (1) Component E award will be made. Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications.

Because the nature and scope of the proposed research will vary from application to application, it is also anticipated that the size and duration of each award may also vary.

The total amount awarded, and the number of awards will depend upon the number, quality, duration, and cost of the applications received.

Budget and Project Period: The estimated total funding (direct and indirect) for the first year (12-month budget period) ranges from $15,000,000 (for Component A [$14,000,000] and B [$1,000,000] only) to $21,500,000 (for Components A, B, C, D and E) with individual awards ranging from $2,000,000 (Component A only) to $4,200,000 (Components A [$2,000,000], C [$700,000], D [$500,000], and E [$1,000,000]). A Component B award will not be made if no Component A award is made. The estimated total funding (direct and indirect) for the entire project period for all components is $107,500,000. The project period is anticipated to run from 09/01/2022 to 08/31/2027.

Application Research Strategy Length: Page limits for the Research Strategy are clearly specified in Section IV. “Application and Submission Information” of this announcement.

Eligible Institutions/Organizations. Institutions/organizations listed in Section III. of this announcement 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 for each application.

Number of Applications. Only one application per institution (normally identified by having a unique entity identifier [UEI]) is allowed.

Application Type. New, Type I Application Materials. See Section IV.1 for application materials. Please note that

Form G is to be used when completing the application package.

Section I. Funding Opportunity Description Statutory Authority

Public Health Service Act, Section 301 [42 U.S.C. 241], as amended.

Coronavirus Preparedness and Response Supplemental Appropriations Act, 2020, Public

Law 116-123.

Coronavirus Aid, Relief, and Economic Security (CARES) Act, Public Law 116-136.

Paycheck Protection Program and Health Care Enhancement Act, Public Law 116-139.

American Rescue Plan Act of 2021, Public Law 117-2.

1. Background and Purpose Since the 2004-2005 influenza season, CDC has worked with collaborating institutions to evaluate the effectiveness of seasonal influenza vaccines for the prevention of medically attended acute respiratory infection in populations targeted for annual vaccination. Because influenza viruses are constantly evolving, and vaccines are reformulated every year, annual estimates of the effectiveness of influenza vaccines in preventing influenza and its associated complications are needed to evaluate the protection provided by vaccination programs and to inform future vaccine virus selection. Each year in the United States, influenza viruses infect up to 20% of the population, 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. 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 NOFO seeks to support a network of research institutions to estimate the annual effectiveness of influenza and COVID-19 vaccination to prevent laboratory-confirmed, acute respiratory illness and to provide additional information on factors associated with vaccine effectiveness.

Since early 2020, COVID-19 has caused dramatically increased morbidity, mortality, and healthcare burden associated with viral infections across all age groups. The first COVID-19 vaccines were approved under Emergency Use Authorization by the FDA in December 2020 and additional COVID-19 vaccines are under development. In November 2021, COVID-19 vaccination was recommended for all persons aged ≥5 years, and expanded recommendations for vaccination of younger children are expected following authorization or approval of COVID-19 vaccines in children aged <5 years. The COVID-19 pandemic has also changed the nature of healthcare encounters, including increased use of telemedicine for evaluation of individuals with mild illness, decreased in-person health facility consultations, and use of testing centers not directly linked to health facilities or healthcare systems. These changes will affect the ability of research institutions to evaluate the effectiveness of both COVID-19 and seasonal influenza vaccines against medically attended acute respiratory illness.

With widespread use of COVID-19 vaccines in the general population, observational studies of authorized and licensed vaccines will be needed to evaluate vaccine effectiveness in “real world” populations, settings, and age groups which are not generally included in clinical trials.

Comparable data from multiple sites are required to accurately assess and estimate effectiveness of vaccines against COVID-19, influenza, and potentially other respiratory viruses of major public health concern. Consented research studies may add to understanding of vaccine effectiveness estimates and potential biases arising from the use of large databases of electronic medical record and immunization data that do not require patient contact. Respiratory virus vaccine effectiveness networks provide an opportunity to conduct studies of effectiveness of multiple vaccines administered in the same population for prevention of acute respiratory illness.

The network of research institutions established under this NOFO should contribute to studies of the effectiveness of seasonal and pandemic influenza vaccines and COVID-19 vaccines for the prevention of medically attended acute respiratory illnesses in ambulatory settings.

Most current research to assess VE against medically attended outpatient illness uses a test-negative study design. Patients seeking care for acute respiratory illness (ARI), or other syndromes, are recruited for study enrollment and systematically tested for infection using sensitive molecular-based diagnostic assays (e.g., RT-PCR). Test-positive patients are identified as study cases and test-negative patients as controls. The use of sensitive diagnostic testing reduces biases that can affect VE estimates. During periods of viral circulation, influenza and SARS-CoV-2 viruses may attribute 10-40% of persons with healthcare consultations for potential influenza- or COVID-19-associated illness, depending upon the influenza season and SARS-CoV-2 transmission. Also, infected patients seeking healthcare within 10 days of symptom onset are likely to test positive by molecular assays for influenza or SARS-CoV-2, so that test-negative, symptomatic patients are likely not to be infected with these pathogens and can be used as a comparison group to estimate vaccine effectiveness.

Health Equity CDC supports efforts to improve the health of populations disproportionately affected by infectious diseases by maximizing the health impact of public health services, reducing disease incidence, and advancing health equity.

A health disparity occurs when a health outcome is seen to a greater or lesser extent between populations. Health disparities in infectious diseases are inextricably linked to a complex blend of social determinants that influence which populations are most disproportionately affected by these infections and diseases.

Social determinants are conditions in the places where people live, learn, work, and play that affect a wide range of health and quality-of life-risks and outcomes (https://www.cdc.gov/socialdeterminants/index.htm ). These include conditions for early childhood development; education, employment, and work; food security, health services, housing, income, and social exclusion. Health equity is a desirable goal that entails special efforts to improve the health of those who have experienced social or economic challenges. It requires:

Continuous efforts focused on elimination of health disparities, including disparities in health and in the living and working conditions that influence health, and

Continuous efforts to maintain a desired state of equity after health disparities are eliminated.

Applicants should use data, including social determinants data, to identify communities within their jurisdictions that are disproportionately affected by infectious diseases and related diseases and conditions, and plan activities to help eliminate health disparities. In collaboration with partners and appropriate sectors of the community, applicants should consider social determinants of health in the development, implementation, and evaluation of program specific efforts and use culturally appropriate interventions and strategies that are tailored for the communities for which they are intended.

https://www.cdc.gov/socialdeterminants/index.htm

Healthy People 2030 and other National Strategic Priorities The CDC NCIRD within HHS is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2030" (https://www.cdc.gov/nchs/healthy_people/hp2030/hp2030.htm) and to measuring program performance as stipulated by the Government Performance and Review Act (GPRA).

This Notice of Funding Opportunity (NOFO) is in alignment with the “Healthy People 2030” priority focus areas, Immunization and Infectious Diseases and HHS Strategic Plan Goals and Objectives: Strategic Goal 2: Protect the Health of Americans Where They Live, Learn, Work, and Play: (https://www.hhs.gov/about/strategic-plan/strategic-goal-2/index.html).

Public Health Impact Vaccination plays a critical role in reducing illness due to influenza and SARS-CoV-2 and in preventing disease transmission. Identification of factors associated with vaccine-induced protection, and reasons for lack of effectiveness, should increase understanding of how different vaccines work against circulating viruses and virus variants in different age groups and among people with underlying medical conditions, and inform the development of new vaccine or vaccine formulations and improved vaccination strategies. Several types of vaccines may be available, and the proposed network will help evaluate effectiveness of multiple vaccine types in different populations and across age groups for which vaccination is recommended. In addition, proposed study activities should contribute to the validation of vaccination status, assess potential limitations with electronic medical records and immunization registries, and aid in the interpretation of vaccine effectiveness estimates from different study designs. Finally, the proposed network will contribute data to describe the epidemiology and burden of respiratory illness due to influenza and SARS-CoV-2 viruses among patients seeking healthcare. Results from research conducted under this NOFO should yield high impact public health findings and/or strategies that should contribute to a reduction in overall burden to healthcare and improve the health of the US population.

Relevant Work

1. RFA-IP16-002: 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-IP16-002;

Opportunity Status: Archived)

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

3. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2020-2021. MMWR.

Recommendations and Reports / August 21, 2020 / 69(8);1– 24 (http://dx.doi.org/10.15585/mmwr.rr6908a1)

References:

1. Belongia EA, Kieke BA, Donahue JG, et al. Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004-2005 season to the 2006-2007 season. J Infect Dis. 2009;199(2):159-67. doi: 10.1086/595861.

https://www.cdc.gov/nchs/healthy_people/hp2030/hp2030.htm https://www.hhs.gov/about/strategic-plan/strategic-goal-2/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/flu/professionals/diagnosis/molecular-assays.htm http://dx.doi.org/10.15585/mmwr.rr6908a1

2. Chung JR, Rolfes MA, Flannery B, et al. Effects of Influenza Vaccination in the United States during the 2018-2019 Influenza Season. Clin Infect Dis. 2020. doi:

10.1093/cid/ciz1244.

3. Dawood FS, Chung JR, Kim SS, et al. Interim Estimates of 2019-20 Seasonal Influenza Vaccine Effectiveness - United States, February 2020. MMWR Morb Mortal Wkly Rep.

2020 Feb 21;69(7):177-182.

4. 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).

5. 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.

6. Ferdinands JM, Gaglani M, Martin ET, et al. Prevention of Influenza Hospitalization Among Adults in the United States, 2015-2016: Results from the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN). J Infect Dis. 2019;220(8):1265- 1275.

7. Flannery B, Kondor RJG, Chung JR, et al. Spread of Antigenically Drifted Influenza A(H3N2) Viruses and Vaccine Effectiveness in the United States During the 2018-2019 Season. J Infect Dis. 2020 Jan 1;221(1):8-15.

8. 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.

9. 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.

10. Jackson, M.L. and J.C. Nelson. The test-negative design for estimating influenza vaccine effectiveness. Vaccine, 2013. 31(17): p. 2165-8.

11. 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.

12. Jackson ML, Chung JR, Jackson LA, et al. Influenza Vaccine Effectiveness in the United States during the 2015-2016 Season. N Engl J Med. 2017;377(6):534-543.

13. Kim SS, Flannery B, Foppa IM, et al. Effects of prior season vaccination on current season vaccine effectiveness in the US Flu VE Network, 2012-13 through 2017-18. Clin Infect Dis. 2020:ciaa706.

14. 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.

15. 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.

16. 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.

17. Rolfes MA, Flannery B, Chung JR, et al. Effects of Influenza Vaccination in the United States During the 2017-2018 Influenza Season. Clin Infect Dis. 2019;69(11):1845-1853.

18. 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.

19. Tenforde MW, Chung J, Smith ER, et al. Influenza vaccine effectiveness in inpatient and outpatient settings in the United States, 2015 - 2018. Clin Infect Dis. 2020. doi:

10.1093/cid/ciaa407.

20. 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.

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

Each application MUST address either Component A or Component B (but not both). If an applicant applies for both Component A and Component B, neither application will move forward to peer review and neither will be eligible for award. If no Component A award is made, no Component B award will be made.

Component A applications may include Optional Components C, D or E.

Component B applications may NOT include Optional Components C, D or E.

Each component and its accompanying budget and budget justification must be clearly identified in the application using clear headings/identifiers (please see Section IV.2 of this NOFO for more detailed information regarding application format). Components will be scored and rank ordered separately but only one Component A application is needed, regardless of the number of Optional Components (C, D, or E) included.

Objectives/Outcomes A. Component A, up to $2,000,000 per year (direct and indirect costs) per award for all three objectives. All three Objectives below must be addressed as part of Component A. Up to seven (7) awards.

Objective 1: Vaccine Effectiveness of Influenza and COVID-19 Vaccines in Children and Adults from Ambulatory Settings

Establish a platform to estimate effectiveness (VE) of seasonal influenza and COVID-19 vaccines against respiratory viral illnesses in preventing laboratory-confirmed illness among children and adults with mild or moderate illness seeking care in ambulatory settings. The application should address all the following objectives and include, at a minimum, the following information in the submission:

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 and COVID-19 incidence activity during periods of viral circulation among populations targeted for vaccination in the source population (e.g., at least 1000 total enrollees in targeted populations to represent the distribution of cases across the age spectrum, i.e., young children, adolescents, working age adults and older adults).

b. Describe procedures for enrollment in a research study of symptomatic individuals from the source population seeking healthcare or diagnostic testing for clinical syndromes compatible with influenza, SARS-CoV-2, or other respiratory virus infection. 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 respiratory specimens from enrolled patients.

d. Describe approaches to collection of acute- and convalescent-phase blood specimens from a subset of enrollees to conduct serologic studies.

e. Describe study patient identification and enrollment protocols to achieve a goal of >60% participation among screened and eligible participants who are invited to participate in the research study.

f. Describe methods to identify and correct possible problems with study enrollment, including participation of <50% of eligible persons and failure to meet sample size.

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

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

2. Describe how symptomatic individuals seeking care for possible influenza- or COVID- 19-associated illness will be identified and enrolled during periods of viral circulation during influenza seasons 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 source populations from which eligible individuals will be screened for eligibility and how they will be contacted and invited to participate. Include information for each research institution 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 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.

b. Provide plans and IRB considerations for pathogen testing in research or clinical laboratories that meet requirements for providing test results to patients when results are of public health importance, including information for isolating persons with COVID-19 and reporting to public health authorities for contact tracing and isolation of contacts.

c. Describe facility policies on patient enrollment in clinical research (e.g., are research staff able to obtain lists of potentially eligible individuals to contact).

Inability to screen for eligibility and obtain patient identifiers would be a major obstacle for study enrollment.

d. Describe proposed partnerships and the methods of local surveillance that will be used to identify periods of influenza and SARS-CoV-2 virus circulation during which enrollment should take place. Define the specific study enrollment period and duration of enrollment envisioned under this award.

e. Descriptions of previous experience enrolling patients in research studies conducted in ambulatory settings are useful and encouraged, including strategies to achieve high rates of participation among approached patients and information from previous studies comparing target enrollment to actual number enrolled by enrollment type (i.e., in-person and remotely by telephone or other method).

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 symptomatic individuals seeking care for acute respiratory illness (defined according to standard criteria) within 10 days of illness onset.

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

Influenza virus or SARS-CoV-2 detection in 14% of patients meeting inclusion criteria.

VE estimate = 50%.

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

Seven network sites.

Possible stratification by age group, targeted population, virus genetic group.

Alpha=0.05, Power= 0.80.

The application should demonstrate the capacity to enroll a minimum of 1000 participants during periods of viral circulation (7000 total for all seven awardees) to identify approximately 1000 laboratory-confirmed cases of influenza and COVID-19 viral illnesses to estimate vaccine effectiveness by virus, target population or age group. It is expected that during periods of increased influenza or SARS-CoV-2 circulation in the source population, higher numbers of laboratory-confirmed cases would be enrolled, allowing additional VE estimates by age-group and virus genetic group or variant.

4. Identify laboratory-confirmed cases of influenza and COVID-19 illnesses by virus type/subtype or variant using standardized, validated molecular assays (with assays and reagents approved by CDC). The application should:

a. Provide evidence of competency in the use of the approved molecular assay or evidence that the contracting laboratory performing the testing has expertise with the 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 capacity to obtain residual clinical or diagnostic specimens, collect research specimens, aliquot specimens and prepare shipments of aliquots (0.5-1.0

ml) for viral characterization, sequencing, special research studies and for other WHO Influenza Collaborating Center or COVID-19 surveillance purposes and contract laboratories or similar research. For planning purposes, assume specimen shipments will occur every 2 to 4 weeks during periods of enrollment and will include completed specimen submission forms (supplied by CDC). Include a description of how respiratory specimens will be stored and whether additional specimen aliquots will be available.

5. Describe methods to document current and prior season vaccination status, including vaccination date(s), number of doses, vaccine type, and manufacturer. Participant self-report or parent report of child vaccination may be needed to determine the completeness of electronic data sources. 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. Evidence of experience and competence with methods to document and verify vaccination status is helpful.

b. Describe recent evaluations of self-reported and documented 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 or vaping) 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 and COVID-19 illnesses).

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, antiviral and antibiotic use (date and drugs), complications of illness (hospitalization, subsequent medical encounters, and procedures during the 90-day period following enrollment) and diagnostic codes associated with medical encounters (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, test results and status of data collection; and

b. Provide data for VE estimates according to established timelines, normally 4 to 6 weeks after the beginning of enrollment for interim estimates.

10. Propose methods to evaluate accuracy of vaccine effective estimates among enrolled participants, including collection of demographic, clinical COVID-19 and influenza testing and vaccination data from persons with medically attended acute respiratory illnesses in the health system, or source population, from which participants were enrolled but who were not approached or screened for study eligibility.

11. Propose methods to routinely collect health system data on patients with medically attended acute respiratory illness, including demographic, clinical COVID-19 and influenza testing and vaccination data, to contribute to biweekly estimates of rates of healthcare encounters for influenza- and COVID-19-associated illness in ambulatory settings and numbers of healthcare visits averted through vaccination, as well as to annual estimates of influenza- and COVID-19-related disease burden. Applications should indicate how data on source populations and participants will be shared with other sites to provide a combined estimate of incidence.

Objective 2: Influenza and SARS-CoV-2 Viral Genomic Sequencing

Establish a protocol to obtain influenza and SARS-CoV-2 viral sequences from specimens collected among infected participants in the proposed outpatient network. Anticipated activities and analyses may include:

1. Routine collection of influenza and SARS-CoV-2 samples by network sites.

2. Performance of influenza and SARS-CoV-2 sequencing using approved protocols and platforms.

3. Annotation of influenza subtype/lineage/clades/subclades and SARS-CoV-2 lineage.

4. Delivery of results including Global Initiative on Sharing Avian Influenza Data (GISAID) identifiers.

Objective 3: SARS-CoV-2 Surveillance and COVID-19 Vaccine Effectiveness among Ambulatory Patients During Periods when Influenza Viruses are not Circulating (potentially year-round)

If SARS-CoV-2 virus circulates during periods when influenza viruses are not detected at network sites, a goal would be to directly measure VE for licensed COVID-19 vaccines against acute respiratory illness among patients seeking healthcare within this network. Applications should address plans to test for SARS-CoV-2 among eligible patients enrolled before or after the influenza season. In addition, sites should contribute to multi-site evaluations of COVID-19 vaccine effectiveness comparing COVID-19 test-positive patients to patients who test negative for SARS-CoV-2. All applications should address the following:

1. Describe the current capacity and diagnostic test methods available in the healthcare system serving the source population for the core component for the detection of COVID-19 viruses, including molecular assays, rapid diagnostics, specimen collection, availability of residual specimens, eligible populations for testing.

2. Describe the methods (see above) that would be used to obtain COVID-19 vaccination data (vaccine type, date(s) and number of doses received).

B. Component B: Network Coordination Center, $1,000,000 per year (direct and indirect costs). Up to one (1) award.

This NOFO intends to fund a single Network Coordinating Center (NCC – Component B) to formalize operational standards and provide comprehensive support to all institutions receiving funding under the Component A and Optional Component C, D or E awards described in this NOFO; however, the NCC will not enroll or collect data from participants. The NCC will provide support under four key functional areas: 1) Coordination and Logistics; 2) Development of Protocols and Standard Operating Procedures (SOPs); 3) Operations and Data Management;

and 4) Statistical Analysis and Dissemination of Findings. Listed below are examples of support that the NCC should provide:

Coordination and Logistics

Provide logistical support for video conferencing and in-person meetings that include US Flu VE Network collaborators and CDC investigators.

Provide regular updates and reports.

Establish and maintain an external network SharePoint site (e.g., IRB approvals, study protocols, Standard Operating Procedures (SOPs), publications, staffing contacts) for network coordination.

Establish and implement a communications plan for the network that includes regular updates to public-facing websites with links to publicly available network data, documents, and publications.

Development of Protocols and Standard Operating Procedures (SOPs)

Coordinate review and updates to protocols, consent forms and translations, data collection instruments, SOPs and training materials to assist with standardization of research methods across the network.

Standardize SOPs for enrollment and data collection, processing, completeness, quality, management, analysis, security, storage, and sharing.

Operations and Data Management

Build a database in REDCap, housed and managed at the NCC site.

Develop and implement Quality Assurance and Quality Control plans.

Provide dashboard monitoring and reporting to the networks and committees.

Coordinate IRB approvals for network sites.

Coordinate responses and maintain documentation from network sites related to CDC-sponsored proficiency testing.

Provide statistical support, as needed, for data analysis and sample size calculations and input.

Centralize data management, quality assurance, and data cleaning operations for network sites.

Develop weekly dashboard reports.

Assist network sites with technical instruction, data standards, quality control and assurance.

Statistical Analysis and Dissemination of Findings

Support development of manuscripts and presentations, including tracking. Provide support to sites to report results through publications in peer-reviewed journals.

Create reports and summaries for sites and network-specific committees.

C. Optional Component C: Household Transmission of Respiratory Viruses, $700,000 per year (direct and indirect costs). Up to five (5) awards.

Understanding household transmission of respiratory viruses and whether vaccination reduces transmission is important for informing public health activities and new vaccine technologies.

Applications should propose a case-ascertained household transmission design to capture secondary infections within a household to estimate the effectiveness of vaccination against transmission. The proposed design should collect information on the clinical spectrum of associated illness among household contacts, measure pathogen transmission dynamics, and understand individual-level and household-level factors that modify transmission.

The design should address how index cases would be identified (from activities in the core component that identify laboratory-confirmed viral infection or other sources of laboratory-confirmed cases) and the approximate number of people and households that could be recruited.

The application should describe how the recipient will identify and approach sufficient numbers of index cases with laboratory-confirmed infection to reach enrollment targets of 150 index cases/households for a given pathogen, allowing for refusals or low participation rates.

The design should address how quickly the index and household patient could be enrolled. Ideally, laboratory confirmation of infection in the index case would occur within 2-3 days after illness onset (maximum 5 days after onset). Eligible households would have at least one susceptible individual besides the index case and would exclude congregate living settings.

Document the ability to identify a mix of index patients from across all age groups, but with enrollment of roughly 50% pediatric index patients (aged <18 years). At a minimum, sites should be able to conduct two (2) home visits: the first visit occurring no more than 2 days after identifying the index case and a second, follow-up visit occurring 7-10 days later.

Describe the systematic collection of information and specimens from household members (including the index case), as well as the methods of laboratory testing to confirm infection in household contacts. Method and frequency of respiratory or blood specimen collection and plans for those specimens are required elements.

o All participating household contacts, regardless of symptoms, should have respiratory specimens collected at the first and follow-up visits and, ideally, daily during follow-up. This will facilitate identification of contacts with detectable respiratory virus infection, including those with asymptomatic infection, and follow-up specimens will also enable some assessment of the duration of viral shedding.

o Designs should address the types of specimens that will be collected, which may include respiratory specimens, saliva, or blood specimens to characterize transmission or susceptibility to infection.

o Potential co-variates of interest to collect from index and household participants may include factors such as: age, relationship to index case, underlying health conditions, vaccination status, socio-economic status, contact patterns between household members, level of exposure/contact outside the home (i.e., social network / contact surveys), infecting virus, antiviral treatment, vaccine history of individuals, and household characteristics.

o Designs should plan to collect information on non-pharmaceutical interventions and adherence to public health recommendations to reduce transmission of influenza, SARS-CoV-2 and other respiratory viruses investigated.

Awarded site partners are expected to collaborate to create a common protocol and research methods across sites.

D. Optional Component D: Immunologic Study of Response to Influenza and COVID-19 Virus Vaccination, $500,000 per year (direct and indirect costs). Up to four (4) awards.

The recipient of this Component should recruit and enroll 150 to 200 subjects who are eligible to receive specific influenza and COVID-19 vaccines and for whom the vaccines are recommended, to study the immune responses to vaccination. The application should describe the vaccination strategy and how the investigators will collect, process, store, and ship paired serum specimens to a designated laboratory for testing. The application should describe the investigators’ willingness to participate in cross-site decisions on specific influenza and COVID- 19 vaccines and populations to be examined (for example, live-attenuated influenza vaccine in children and adolescents, or high dose inactivated vaccine in persons aged ≥65 years) and interpretation of influenza vaccine response. Applications should:

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 for laboratory testing. Paired sera will be tested using standard, validated procedures.

Identify priority groups for investigation of cell-mediated immune responses; describe experience or…