Foa_Content_of_RFA-IP-24-045 Final.pdf

Centers for Disease Control and Prevention

NATIONAL CENTER FOR IMMUNIZATION AND RESPIRATORY DISEASES

Network of Community Cohorts for Monitoring Changes in Respiratory Virus Epidemiology (Pandemic Preparedness Cohorts)

RFA-IP-24-045

02/20/2024

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 Network of Community Cohorts for Monitoring Changes in Respiratory Virus Epidemiology (Pandemic Preparedness Cohorts) Activity Code U01 – Research Project - Cooperative Agreements

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

RFA-IP-24-045

Assistance Listings Number(s) 93.083 Category of Funding Activity HL - Health NOFO Purpose The purpose of this Notice of Funding Opportunity (NOFO) is to establish: 1) a multi-site community-based cohort study that would allow close monitoring of the burden of acute respiratory illness in the community, contributions of various respiratory viruses to this burden, and the impact of vaccination and other interventions on risk of infection and/or severe outcomes, and 2) a case-ascertained household transmission study (or multi-site study) that would support ongoing assessment of transmission dynamics of respiratory viruses of interest and factors (i.e., demographic, clinical, or household-level factors) that may impact transmission.

While hospital-based platforms are key to assessing frequency and risk factors for severe disease, community-based platforms are essential for understanding age-specific incidences of infection, risk factors for infection, socioeconomic burden of infections (such as days of work/school lost), and the clinical spectrum of illness. They are important for characterizing the immune response to infection or reinfection and long-term outcomes, and they are key to understanding the impact of individual- and household-level mitigation factors (including but not limited to vaccination) on all of these measures. This type of network may be especially useful for detecting changes in any of these factors when a new virus or viral variant begins circulating.

Case-ascertained household transmission studies are well-positioned to quickly and efficiently enable us to understand transmission dynamics of respiratory viruses (or sublineages/types of existing viruses that undergo frequent mutation, such as SARS-CoV-2 and influenza) and assess potential mitigation factors. These studies can also be valuable for characterizing viral shedding dynamics and infectiousness. These studies were key during the COVID-19 pandemic to understanding if changes in hospitalization rates were due to changes in transmissibility/infection rates versus changes in severity of illness. They are also great resources for assessing how history of vaccination or prior history of infection effect transmission to close contacts.

This NOFO would build on the lessons learned during the COVID-19 pandemic and establish a consolidated network of community cohorts to monitor a range of respiratory viruses among community members who develop symptoms of acute respiratory illness. Incorporation of multi-pathogen testing will allow us to better understand the relative contribution of various viruses to the overall community burden of respiratory disease now in the post-pandemic setting, and how the clinical spectrum of these illnesses compare, in a setting in which multiple new preventive products are becoming available. This would also support the establishment of a case-ascertained transmission study (or multi-site study) that would be able to assess SARS- CoV-2, Respiratory Syncytial Virus (RSV), and other prioritized respiratory viruses on an ongoing basis.

The combination of these studies will generate much greater visibility on risk factors for infection and the effectiveness of various interventions in reducing infections and viral transmission, factors that are relevant to reducing overall morbidity and mortality related to respiratory viruses. Should a new variant or virus arrive, this platform would be well positioned to further expand testing to better understand potential concerns like proportion symptomatic, timing of transmission, likelihood of asymptomatic transmission and other related questions.

Such questions may be key to developing public health guidance should additional mitigation measures become necessary.

Key Dates Publication Date:

To receive notification of any changes to RFA-IP-24-045, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link.

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https://www.grants.gov/

Letter of Intent Due Date:

01/19/2024 01/19/2024

Application Due Date:

02/20/2024 02/20/2024

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 11:59 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 application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review:

04/25/2024 Secondary Review:

05/22/2024 Estimated Start Date:

08/01/2024 Expiration Date:

02/21/2024 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 40 pages.

http://grants.nih.gov/support/index.html mailto:commons@od.nih.gov https://grants.nih.gov/grants/how-to-apply-application-guide.html

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

NOTE: This NOFO includes four components: Component A1, A2, B and C. There are no limits to which components an applicant may apply. An applicant may apply for one, or all, or any combination of these components, with one exception: Component A2 applicants must also apply for Component A1, whereas Component A1 applicants are not required to apply for Component A2. Component A2 awards can only be made to the award recipients of Component A1.

The Research Strategy component of the Research Plan is limited to 40 pages maximum, including 12 pages each for Component A1, B and C, and no more than 4 pages for Component A2.

Executive Summary

• Purpose: The purpose of this NOFO would be to: 1) establish a network of community-based cohorts, including diverse age groups (e.g., 0-5 years old, 5-17 years old, 18-64 years old, and 65+ years old, etc.), demographic characteristics (e.g., race/ethnicity, gender, etc.), and regions in the US to support ongoing monitoring of changes in respiratory virus epidemiology in the years following the COVID-19 pandemic with the potential of also including in-depth immunologic studies in a limited number of sites; and

2) establish a case-ascertained household transmission study (or multi-site study) to monitor transmissibility of respiratory viruses and the impact of vaccination and other mitigation measures on transmission to close contacts. The combination of these networks will enhance preparedness to quickly obtain data on infection risk, transmission, and effectiveness of preventive measures in response to a novel virus or variant. Note: this is a multi-component NOFO, which includes four (4) components: A1, A2, B and C. There are no limits to which components an applicant may apply. An applicant may apply for one, or all, or any combination of these components, with one exception: Component A2 applicants must also apply for Component A1, whereas Component A1 applicants are not required to apply for Component A2. Component A2 awards can only be made to Component A1 award recipients.

• 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 project period is $95,250,000. The number of awards will be no more than nine (9), including: five (5) Component A1, two (2) Component A2 (included in the five (5) of Component A1), three (3) Component B, and one (1) Component C. 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) will be $19,050,000 with each individual awards as:

$2,400,000 for Component A1, $500,000 for Component A2, $1,600,000 for Component B, and $1,250,000 for Component C. The estimated total funding (direct and indirect) for the entire project period will be $95,250,000. The project period is anticipated to run from 08/01/2024 to 07/31/2029.

• 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.

Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply. NOTE: CDC does not make awards to individuals directly.

• 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] number) is allowed.

• Application Type. New

• Application Materials. See Section IV.1 for application materials. Please note that

SF424 (R&R) Form H is to be used when completing the application package. Please see https://grants.nih.gov/grants/how-to-apply-application-guide.html

Section I. Funding Opportunity Description Statutory Authority Public Health Service Act, Section 317; 42 U.S.C. 247b(k)(1) and 42 U.S.C. 247b(k)(2)

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 Analyses of data from the Global Burden of Disease study indicate that there were over 17 billion reported cases of upper respiratory infection globally (representing over 40% of all illness episodes captured in that study) and an additional 489 million reported cases and 2.5 million deaths due to lower respiratory tract infection in 2019.

Since emerging as a novel respiratory virus, SARS-CoV-2 alone is reported to have caused over 750 million diagnosed infections and nearly 7 million deaths globally. Over the past three years, over 75% of the US population are estimated to have been infected with SARS-CoV-2, many people more than once, and over 95% of US adults now have antibodies against COVID-19 either from infection, vaccination, or both. Underlying immunity and the widespread availability of treatment has drastically changed the COVID-19 pandemic landscape when compared to 2020; however, COVID-19 remained the 4th most common cause of death and leading infectious cause in the US in 2022. Close monitoring of this virus is still required, as it continues to evolve and acquire mutations that increase its ability to evade the immune response, sustaining the risk for further increases in cases, hospitalizations, and deaths.

RSV is another respiratory virus for which the immune landscape may be changing drastically over the next few years. RSV is estimated to cause over 2 million outpatient visits, over 200,000 hospitalizations, and over 10,000 deaths, each year in the US, with children younger than 5 years old making up the majority of cases and adults older than 65 years old accounting for the majority of deaths. In the fall of 2023, CDC recommended new RSV vaccines for certain adults older than 60 years old and pregnant persons, and long-lasting monoclonal antibodies to reduce the risk of severe RSV in infants. These new preventive products have the potential to drastically change the burden of disease for this virus which is currently the most common cause of hospitalization in infants in the US.

At the start of the COVID-19 pandemic, infrastructure for understanding the epidemiology of a rapidly evolving virus in real-time was limited. Given the long lead time required for the US Government to start new projects, CDC harnessed a variety of studies and platforms designed for other purposes to begin collecting the specimen and survey data it needed to understand COVID- 19 risk, burden, severity, immunity, and long-term sequelae. Because these projects were funded through emergency response funds, they were often time limited.

Currently, for SARS-CoV-2, RSV, and most other respiratory viruses, the majority of the platforms used to monitor the burden of illness and the effectiveness of preventive measures are hospital- and laboratory-based surveillance networks. These networks provide CDC with geography-specific estimates of hospitalizations and deaths, or for the laboratories, numbers of patients tested for particular respiratory viruses and the percentage that test positive. Changes in the percent positivity is considered a marker for increased transmission, although testing for respiratory viruses at health centers is generally not standardized or routine. As a result, the markers we currently have generally lag behind the actual increases in infections and cases. In addition, changes in hospitalization and deaths may occur due to a combination of transmissibility and severity; the relative contribution of each of these sources can be difficult to disentangle without additional data on the overall burden of disease.

It is likely that these studies only show us the tip of the iceberg when it comes to the overall burden and impact of these respiratory viruses, and they are not well-equipped to capture populations that do not readily access healthcare. Understanding the burden of disease, including loss of school/work, long-term morbidity, and equity challenges that results in differential healthcare access require community- or population-based epidemiologic studies.

The purpose of this NOFO is to: 1) establish and sustain a network of community-based cohorts, including diverse age groups, demographic characteristics, and regions in the US to support ongoing monitoring of changes in respiratory virus epidemiology in the years following the COVID-19 pandemic with the potential of also including in-depth immunologic studies in a limited number of sites; and 2) establish and sustain a case-ascertained household transmission study (or multi-site study) to monitor transmissibility of prioritized respiratory viruses and the impact of vaccination and other mitigation measures on transmission to close contacts. The combination of these networks will enhance CDC preparedness to quickly obtain data on infection risk, transmission, and effectiveness of preventive measures in response to a novel virus or variant.

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 specific efforts and use culturally appropriate interventions and strategies that are tailored for the communities for which they are intended.

Healthy People 2030 and other National Strategic Priorities This NOFO will enable CDC to track the annual (or when relevant more frequent) incidence of acute respiratory illness among a community-based cohort, incidence of symptomatic infection for a wide range of respiratory viruses, and transmissibility of multiple respiratory viruses in a household setting. As such, this NOFO supports the following Health and Human Service (HHS) Strategic Plan topic areas:

Strategic Goal 2: Safeguard and Improve National and Global Health Conditions and Outcomes

Strategic Objective 2.1: Improve capabilities to predict, prevent, prepare for, respond to, and recover from disasters, public health and medical emergencies, and threats across the nation and globe.

https://www.cdc.gov/socialdeterminants/index.htm https://www.hhs.gov/about/strategic-plan/2022-2026/goal-2/objective-2-1/index.html

Strategic Goal 4: Restore Trust and Accelerate Advancements in Science and Research for All

Strategic Objective 4.1: Improve the design, delivery, and outcomes of HHS programs by prioritizing science, evidence, and inclusion.

Strategic Objective 4.2: Invest in the research enterprise and the scientific workforce to maintain leadership in the development of innovations that broaden our understanding of disease, healthcare, public health, and human services resulting in more effective interventions, treatments, and programs.

Strategic Objective 4.3: Strengthen surveillance, epidemiology, and laboratory capacity to understand and equitably address diseases and conditions.

Strategic Objective 4.4: Improve data collection, use, and evaluation, to increase evidence-based knowledge that leads to better health outcomes, reduced health disparities, and improved social well-being, equity, and economic resilience.

Public Health Impact The approach described in this NOFO will allow for community-based surveillance of respiratory virus infections and allow close monitoring for changes in respiratory virus epidemiology that may signal a change in transmission, severity, or effectiveness of preventive efforts requiring additional public health or broader intervention. This has been designed to capture the type of data that was needed to make public health decisions during the COVID-19 pandemic, but also to capture this data across a range of respiratory viruses, age groups, and geographies.

These activities support multiple strategic priorities within CDC, including:

Coronavirus and other Respiratory Viruses Division (CORVD) Strategic Priority (Coronavirus and Other Respiratory Viruses Division (CORVD) | NCIRD | CDC)

• Track and study respiratory viruses through surveillance, lab tests, and epidemiologic studies on infection, outcomes, and the efficacy of treatment and prevention

National Center for Immunization and Respiratory Disease (NCIRD) Strategic Priority (Office of the Director (OD) | NCIRD | CDC):

• Improve prevention, detection, and control of respiratory disease threats, including

COVID-19

CDC’s 2022-2027 Strategic Plan: Advancing Science and Health Equity (Core Capabilities (cdc.gov))

• Develop and deploy world-class data and analytics

• Build on the current foundation for strong global health capacity and domestic preparedness.

Relevant Work Over the last few years, CDC has funded multiple limited-term contracts, that are either ended or to be ended before this NOFO starts, with SARS-CoV-2 specific objectives shared with many of https://www.hhs.gov/about/strategic-plan/2022-2026/goal-4/objective-4-1/index.html https://www.hhs.gov/about/strategic-plan/2022-2026/goal-4/objective-4-2/index.html https://www.hhs.gov/about/strategic-plan/2022-2026/goal-4/objective-4-3/index.html https://www.hhs.gov/about/strategic-plan/2022-2026/goal-4/objective-4-4/index.html https://www.cdc.gov/ncird/careers/corvd.html https://www.cdc.gov/ncird/careers/corvd.html https://www.cdc.gov/ncird/careers/office-director.html https://www.cdc.gov/ncird/careers/office-director.html https://www.cdc.gov/about/strategic-plan/capacity-priority.html https://www.cdc.gov/about/strategic-plan/capacity-priority.html https://www.cdc.gov/surveillance/projects/dmi-initiative/index.html the primary objectives in this NOFO. Some of the publications from the contracts or from projects of similar study designs as the one(s) described here are below.

Component A1: CDC-funded Longitudinal Community Cohort Studies

Sample protocols/study designs:

• Post-COVID Conditions: CDC Science | CDC (See list of prospective cohort studies)

• Arizona Healthcare, Emergency Response, and Other Essential Workers Surveillance (Az

Heroes) Study (cdc.gov)

• JMIR Research Protocols - Research on the Epidemiology of SARS-CoV-2 in Essential

Response Personnel (RECOVER): Protocol for a Multisite Longitudinal Cohort Study

• Study protocol for the Innovative Support for Patients with SARS-COV-2 Infections

Registry (INSPIRE): A longitudinal study of the medium and long-term sequelae of SARS-CoV-2 infection | PLOS ONE

• CASCADIA: a prospective community-based study protocol for assessing SARS-CoV-2 vaccine effectiveness in children and adults using a remote nasal swab collection and web-based survey design | BMJ Open

Sample publications/outputs:

1. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States | Nature Medicine

2. Infectious viral shedding of SARS-CoV-2 Delta following vaccination: A longitudinal cohort study - PubMed (nih.gov)

3. Association of Initial SARS-CoV-2 Test Positivity With Patient-Reported Well-being 3 Months After a Symptomatic Illness | Public Health | JAMA Network Open | JAMA Network

4. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021 | MMWR (cdc.gov)

5. Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance — Eight U.S. Locations, December 2020–August 2021 | MMWR (cdc.gov)

6. Risk Factors for Reinfection with SARS-CoV-2 Omicron Variant among Previously Infected Frontline Workers - Volume 29, Number 3—March 2023 - Emerging Infectious Diseases journal - CDC

Component A2: Recent CDC-funded Respiratory Virus Immunology Studies

Sample protocols/study designs:

• Post-COVID Conditions: CDC Science | CDC (See list of prospective cohort studies)

• Arizona Healthcare, Emergency Response, and Other Essential Workers Surveillance (Az

Heroes) Study (cdc.gov)

• JMIR Research Protocols - Research on the Epidemiology of SARS-CoV-2 in Essential

Response Personnel (RECOVER): Protocol for a Multisite Longitudinal Cohort Study https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-science.html https://www.cdc.gov/vaccines/covid-19/downloads/AZ-heroes-cohort-study.pdf https://www.cdc.gov/vaccines/covid-19/downloads/AZ-heroes-cohort-study.pdf https://www.researchprotocols.org/2021/12/e31574/ https://www.researchprotocols.org/2021/12/e31574/ https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264260 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264260 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264260 https://bmjopen.bmj.com/content/13/7/e071446 https://bmjopen.bmj.com/content/13/7/e071446 https://bmjopen.bmj.com/content/13/7/e071446 https://www.nature.com/articles/s41591-020-0877-5 https://www.nature.com/articles/s41591-020-0877-5 https://pubmed.ncbi.nlm.nih.gov/36095030/ https://pubmed.ncbi.nlm.nih.gov/36095030/ https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799116 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799116 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799116 https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e4.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e4.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e4.htm https://wwwnc.cdc.gov/eid/article/29/3/22-1314_article https://wwwnc.cdc.gov/eid/article/29/3/22-1314_article https://wwwnc.cdc.gov/eid/article/29/3/22-1314_article https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-science.html https://www.cdc.gov/vaccines/covid-19/downloads/AZ-heroes-cohort-study.pdf https://www.cdc.gov/vaccines/covid-19/downloads/AZ-heroes-cohort-study.pdf https://www.researchprotocols.org/2021/12/e31574/ https://www.researchprotocols.org/2021/12/e31574/

• CASCADIA: a prospective community-based study protocol for assessing SARS-CoV-2 vaccine effectiveness in children and adults using a remote nasal swab collection and web-based survey design | BMJ Open

Sample publication/outputs:

1. Shedding of Culturable Virus, Seroconversion, and 6-Month Follow-up Antibody Responses in the First 14 Confirmed Cases of Coronavirus Disease 2019 in the United States | The Journal of Infectious Diseases | Oxford Academic (oup.com)

2. Twelve-Month Follow-up of Early COVID-19 Cases in the United States: Cellular and Humoral Immune Longevity | Open Forum Infectious Diseases | Oxford Academic (oup.com)

3. Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses | Clinical Infectious Diseases | Oxford Academic (oup.com)

4. Neutralizing Antibody Response to Pseudotype Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Differs Between mRNA-1273 and BNT162b2 Coronavirus Disease 2019 (COVID-19) Vaccines and by History of SARS-CoV-2 Infection | Clinical Infectious Diseases | Oxford Academic (oup.com)]

Component B: CDC-funded Respiratory Virus Transmission Studies

Sample protocols/study design

• Respiratory Virus Transmission Network (RVTN) | CDC

Sample publications/outputs:

1. Patterns of Virus Exposure and Presumed Household Transmission among Persons with Coronavirus Disease, United States, January–April 2020 - Volume 27, Number 9— September 2021 - Emerging Infectious Diseases journal - CDC

2. Transmission of SARS-COV-2 Infections in Households — Tennessee and Wisconsin, April–September 2020 | MMWR (cdc.gov)

3. Household Transmission of SARS-CoV-2 from Children and Adolescents | NEJM

4. Behaviors Associated With Household Transmission of SARS-CoV-2 in California and

Colorado, January 2021–April 2021 - PMC (nih.gov)

5. Magnitude and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2

(SARS-CoV-2) Household Transmission: A Longitudinal Cohort Study | Clinical Infectious Diseases | Oxford Academic (oup.com)

6. Association of Culturable-Virus Detection and Household Transmission of SARS-CoV- 2, California and Tennessee, 2020–2022 | The Journal of Infectious Diseases | Oxford Academic (oup.com)

7. SARS-CoV-2 B.1.1.529 (Omicron) Variant Transmission Within Households — Four U.S. Jurisdictions, November 2021–February 2022 | MMWR (cdc.gov)

8. Scientific Brief: SARS-CoV-2 Transmission | CDC

Additional Background:

1. Global burden of upper respiratory infections in 204 countries and territories, from 1990 to 2019 (thelancet.com) https://bmjopen.bmj.com/content/13/7/e071446 https://bmjopen.bmj.com/content/13/7/e071446 https://bmjopen.bmj.com/content/13/7/e071446 https://academic.oup.com/jid/article/224/5/771/6161320?login=true https://academic.oup.com/jid/article/224/5/771/6161320?login=true https://academic.oup.com/jid/article/224/5/771/6161320?login=true https://academic.oup.com/ofid/article/9/3/ofab664/6497883?login=true https://academic.oup.com/ofid/article/9/3/ofab664/6497883?login=true https://academic.oup.com/ofid/article/9/3/ofab664/6497883?login=true https://academic.oup.com/cid/article/76/10/1822/6964677?login=true https://academic.oup.com/cid/article/76/10/1822/6964677?login=true https://academic.oup.com/cid/article/76/10/1822/6964677?login=true https://academic.oup.com/cid/article/75/1/e827/6470720?login=true https://academic.oup.com/cid/article/75/1/e827/6470720?login=true https://academic.oup.com/cid/article/75/1/e827/6470720?login=true https://academic.oup.com/cid/article/75/1/e827/6470720?login=true https://www.cdc.gov/flu/vaccines-work/respiratory-virus-transmission-network.html https://wwwnc.cdc.gov/eid/article/27/9/20-4577_article https://wwwnc.cdc.gov/eid/article/27/9/20-4577_article https://wwwnc.cdc.gov/eid/article/27/9/20-4577_article https://www.cdc.gov/mmwr/volumes/69/wr/mm6944e1.htm https://www.cdc.gov/mmwr/volumes/69/wr/mm6944e1.htm https://www.nejm.org/doi/10.1056/NEJMc2031915?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069230/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069230/ https://academic.oup.com/cid/article/75/Supplement_2/S193/6631204?login=true https://academic.oup.com/cid/article/75/Supplement_2/S193/6631204?login=true https://academic.oup.com/cid/article/75/Supplement_2/S193/6631204?login=true https://academic.oup.com/jid/article/227/12/1343/7006820?login=true https://academic.oup.com/jid/article/227/12/1343/7006820?login=true https://academic.oup.com/jid/article/227/12/1343/7006820?login=true https://www.cdc.gov/mmwr/volumes/71/wr/mm7109e1.htm https://www.cdc.gov/mmwr/volumes/71/wr/mm7109e1.htm https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/sars-cov-2-transmission.html https://www.thelancet.com/action/showPdf?pii=S2589-5370%2821%2900266-2 https://www.thelancet.com/action/showPdf?pii=S2589-5370%2821%2900266-2

2. Trends in the global burden of lower respiratory infections: the knowns and the unknowns (thelancet.com)

3. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard with Vaccination Data

4. Provisional Mortality Data — United States, 2022 | MMWR (cdc.gov)

5. COVID-19 Data Review: Update on COVID-19–Related Mortality | CDC

6. RSV Surveillance and Research | CDC

2. Approach This NOFO includes four components: Component A1, A2, B and C. There are no limits to which components an applicant may apply. An applicant may apply for: 1) one; 2) all, or 3) any combination of Component A, B and C. However, applicants applying for Component A2 must also apply for Component A1, whereas Component A1 applicants are not required to apply for Component A2. Component A2 awards can only be made to the award recipients of Component A1.

Applicants should indicate clearly in the application the geographical location and catchment areas in HHS regions for each Component applying for.

Component A1: Longitudinal cohort with weekly symptom screening and symptomatic swabbing ($2,400,000 each for 5 awards annually)

Focus:

The focus of this component is to establish and sustain a community-based cohort to:

• Monitor the incidence and burden of respiratory illness

• Assess for changes in respiratory virus epidemiology and clinical outcomes

• Assess participant knowledge, attitudes, and practices with regard to preventative measures

• Assess the effectiveness of interventions such as non-pharmaceuticals, pharmaceuticals, and vaccines in preventing disease

Outcomes:

Primary outcomes will include annual/seasonal incidence of SARS-Cov-2, RSV, and other key respiratory viruses (e.g., adenovirus, human metapneumovirus, human seasonal coronaviruses, influenza, parainfluenza viruses, rhinovirus/enterovirus) and effectiveness of vaccines in preventing symptomatic infection.

Each awardee will be expected to recruit a minimum of 2000 individuals per site, ideally in households; included household and individuals should be demographically diverse.

Applications should aim to recruit participants across the age-spectrum, with a roughly equal split of ages younger than 5 years old, 5-17 years old, 18-64 years old, and 65+ years old, in order to facilitate age-specific sub-analysis across the full network.

Activities:

Activities for this component should include the following:

• Weekly screening for symptoms of respiratory illness https://www.thelancet.com/action/showPdf?pii=S1473-3099%2822%2900445-5 https://www.thelancet.com/action/showPdf?pii=S1473-3099%2822%2900445-5 https://covid19.who.int/ https://covid19.who.int/ https://www.cdc.gov/mmwr/volumes/72/wr/mm7218a3.htm https://www.cdc.gov/coronavirus/2019-ncov/science/data-review/index.html https://www.cdc.gov/rsv/research/index.html

• Self-collection of nasal swabs for symptomatic participants

• Multi-pathogen testing of all swabs including common respiratory viruses (e.g., SARS-

CoV-2, RSV-A/B, adenovirus, human metapneumovirus, human seasonal coronaviruses, influenza, parainfluenza viruses, rhinovirus/enterovirus, including enterovirus D68) in real-time

• Genomic sequencing of a subset of samples

• Retention/banking of all specimens for a defined amount of time for possible supplemental testing

• Post-illness surveys to assess healthcare use, use of therapeutics, school absence/loss of work, symptoms, duration of symptoms and incidence of post-acute sequelae

• Baseline and periodic updating of receipt of vaccines and other prophylactic measures from the immunization information systems, electronic medical records (when available), and self-report

Applicants may propose additional activities:

• Asymptomatic swabbing; this may, for example, occur during particular seasons, for particular viruses of interest, or triggered by apparent changes in viral transmission

• Assessment or use of different specimen types (e.g., saliva)

• More extensive genomic testing and analysis

Sample size:

Applicants are strongly encouraged to provide a sample size justification that demonstrates that their sampling plan has adequate power (over 80%) to measure their site-specific annual/seasonal incidence of infection, across a range of respiratory viruses to within ±2 percentage points with a 95% confidence interval, if the true incidence falls between 2%-20%. Additional sample size information should include power to estimate incidence for potentially smaller subgroups (e.g., children younger than 5 years old or adults older than 65 years old).

Component A2: In-depth immunologic assessments ($500,000 each for 2 awards that are awarded with Component A1 annually)

Applicants applying for Component A1 may apply for Component A2 to be awarded with additional funds to support more in-depth immunologic testing among participants.

Focus:

The purpose of this testing will include: to monitor existing immunity to respiratory viruses, allow for analyses of how well respiratory virus antibody assays (beyond COVID-19) correlate with protection, and support greater analysis of how immunity to respiratory viruses wanes with time after infection, vaccination, or both. Neutralization studies, such as for SARS-CoV-2 (including variants), and RSV subtypes, or enterovirus D68 (EV-D68), may also be included to monitor how well participants are able to neutralize particular viral strains, new viral variants, or following use of new preventative products (vaccines, monoclonal antibodies).

Activities:

Activities implemented in this component will include:

• Collection of specimens for performance of serologic assessments. Time points will likely include a baseline/enrollment, and then at least twice a year (e.g., before and after the typical respiratory virus season). Additional targeted testing may include post-infection, and post-vaccination testing to measure immunologic response to both;

• Testing of specimens including the use of quantitative, semi-quantitative binding antibody tests, and potentially neutralization studies to monitor the immune response;

• Storage of specimens, with the potential for sending additional specimens to CDC for further analysis as needed.

Component B: Case-ascertained Household Transmission ($1,600,000 each for 3 awards annually)

Focus:

This component aims to better understand the transmission dynamics of SARS-CoV-2, RSV, and other prioritized respiratory viruses in CDC’s mission. Through prior collaborations and research efforts, it seems that the most efficient way to study transmission of respiratory viruses is through case-ascertained household transmission studies. In this design, individuals with recent laboratory-confirmed infections are enrolled, and their household members are followed to detect respiratory virus infection. In this way, case-ascertained household transmission studies are resource-efficient, as they identify a highly exposed population that can be followed prospectively to describe many epidemiologic factors associated with infection. However, they are challenging to implement and conduct, as they are resource-intensive.

Activities:

Applicants who apply for this component should describe the source of their household index cases (and how these will be identified in a timely manner) and their manner of recruiting household contacts to participate in this study. This may or may not include index cases identified through Component A1. Applicants should further describe requirements for proportion of required household contacts who will participate, sampling frequency and specimen types, power to assess differences in secondary transmission, risk factors for infection and transmission, and fraction of cases that are asymptomatic, with their proposed approach.

Applicants should describe how they will enroll and assess a minimum of 100 households per year during the project period. Different respiratory viruses may be prioritized for case-ascertained household transmission during different years of funding (e.g., year 1 may prioritize SARS-CoV-2 or RSV, and subsequent years may prioritize other viruses). Applications should include a plan for how to do the following:

• Identify and recruit individuals with infections across the spectrum of illness from asymptomatic (if possible) to those seeking outpatient care for an illness.

• Enroll and evaluate (test) other household members immediately after someone is infected. Methods should be creative to circumvent likely challenges but also be able to enroll sufficient numbers of households over annual or seasonal periods of virus circulation.

• Enroll sufficient sample size to meet research objectives; this may be accomplished through Component A participation, traditional recruitment strategies using those seeking outpatient care for an illness, or novel approaches to identify symptomatic and asymptomatic individuals who are infected.

• Collect serial symptom surveys and respiratory specimens for viral PCR testing to describe all household members and identify all infections within a given time frame (e.g., two weeks from time of exposure/first household infection but may vary depending on which virus is being targeted).

• Provide access to data and lab results to CDC in a timely way in order to provide the situational awareness that is now commonly requested of CDC.

Applicants may propose additional activities, such as:

• Additional specimen collection and/or testing to evaluate comparative performance of specimens or tests;

• Viral culture, genomic sequencing, or additional laboratory testing and analysis;

• Conducting environmental swabbing, wastewater, or aerosol specimen testing to better understand respiratory virus shedding and transmission within households.

Component C: Data Hub/Analytic Support ($1,250,000 for 1 award annually)

Focus:

Applicants may apply to serve as a data hub for communicating and managing data across the partners and support analytics in order to ensure the timely sharing and release of data. The awardee will serve as a central coordinating partner across all components and partners in collaboration with CDC.

Activities:

Applicants should demonstrate how to conduct the activities for this component as below:

• Support harmonized protocol development across sites in collaboration with CDC.

• Develop data entry and data management tools.

• Serve as a warehouse of data across all partner sites.

• Merge data files, clean data, and develop analytic datasets.

• Lead and support projects under this NOFO in completing key analytic products to accomplish primary objectives.

• Develop internal dashboards to track study progress.

• Develop outward facing dashboards displaying incidence and other key measures in real time, ideally updated weekly.

• Set up and coordinate cohort study meetings with CDC and other component award recipients, takes meeting minute notes, and develop and maintain a tracking system for all study activities.

Objectives/Outcomes Component A1: Longitudinal cohort with weekly symptom screening and symptomatic swabbing ($2,400,000 each for 5 awards annually)

• Estimate the annual/seasonal incidence of symptomatic respiratory virus infection by pathogen across the age spectrum using a multi-site network of community-based cohorts. Outputs to include:

o Age-stratified annual incidence of symptomatic respiratory virus illness – by respiratory pathogen; and proportion of symptomatic infection attributed to each (e.g., SARS-CoV-2, respiratory syncytial virus, adenovirus, human metapneumovirus, human seasonal coronaviruses, influenza, parainfluenza, rhinovirus/enterovirus) o Estimated burden of respiratory virus illnesses including acute morbidity, short term loss of school/work, long-term morbidity and, long term loss school/work – by respiratory pathogen

• Estimate effectiveness of respiratory virus vaccines and preventive measures and assess benefits of treatment for respiratory virus infection. Outputs to include:

o Real-world effectiveness of key preventive measures against symptomatic infection, including respiratory virus vaccines (COVID-19 and RSV) o Assessment of treatment uptake and comparison of outcomes (severity, long-term morbidity) among persons with treated and untreated respiratory virus infections

• Monitor changes in perceptions and receptiveness to respiratory virus interventions over time, including:

o Assessment of uptake of key interventions (vaccines, therapeutics, non-pharmaceutical interventions), and predictors of uptake o Assess knowledge, attitudes, perceptions, and behaviors regarding these interventions

• Develop platform that can be used to perform in-depth investigations of newly emerging or evolving respiratory pathogens, through monitoring clinical course and describing/assessing:

o Clusters of new symptom presentation o Changes in healthcare seeking and/or hospitalization o Reports of long-term sequelae following infection o Link above factors to sequencing data as appropriate

Component A2: In-depth Serologic Assessments ($500,000 for 2 awards that have applied for and awarded with Component A1 annually)

• Monitor immune response and characterize duration of immunity to SARS-CoV-2, RSV, and other viruses as feasible through assessing longitudinal virus-specific antibodies across one or more respiratory virus seasons.

• Assess post-infection (and post-reinfection) and post-vaccination immune responses, especially in regard to ability to neutralize new variants/sub-variants when they arise.

• Assess serologic correlates of protection against subsequent virus-specific symptomatic illness episodes.

• Use serologic responses after the typical respiratory season to capture infections missed by symptomatic surveillance and testing (e.g., asymptomatic infections)

• Among young children, assess age of seroconversion against respiratory viruses to gain a better understanding of timing of initial infections and acquisition of infection-induced immunity.

Component B: Case-ascertained Household Transmission ($1,600,000 each for 3 awards annually)

• Evaluate epidemiologic and clinical risk factors for respiratory virus infection and transmission.

• Compare household secondary attack rates for specific respiratory virus/viruses of interest.

• Characterize the spectrum and duration of symptoms associated with respiratory virus infection, including stratified by patient characteristics.

• Estimate the frequency of symptomatic and asymptomatic respiratory virus infections among index case-patients and household contacts.

• Determine the timing and relationship of viral shedding relative to symptoms within infected individuals.

• Describe viral shedding over the time course of infections.

• If possible, assess environmental contamination of respiratory viruses within households.

• If possible (or if needed), validate new diagnostic tests and/or specimen types for various respiratory viruses. This may include relative comparison of antigen tests to PCR tests, performance of various types of specimens collected for testing, or comparing performance of test types and specimen types based on individual-level characteristics (e.g., age or symptom status).

Component C: Data Hub/Analytic Support ($1,250,000 for 1 award annually)

• Ensure and promote harmonization of approach for each component across participating sites.

• Ensure and promote data quality.

• Ensure and promote rapid analysis of data for dissemination to the public or use by policymakers.

• Support real-time monitoring and when possible, information sharing through dashboards and similar tools.

Target Population For Component A1, applicants should demonstrate that they can recruit a minimum of 2000 participants per site and then sustain a cohort of this size throughout the evaluation period, with replacement as needed should there be withdrawals. Participants should be enrolled as households whenever possible. Awardees should aim to recruit participants across the age-spectrum, with a roughly equal split between four age categories: 1) younger than 5 years old, 2) 5-17 years old, 3) 18-64 years old, and 4) 65+ years old, in order to facilitate age-specific sub-analysis across the full network.

For Component B, applicants should demonstrate that they will be able to enroll at least 100-150 households per year, and they should describe how index patients will be identified in order to assess transmission of a variety of respiratory pathogens. Applicants should further describe requirements for proportion of required household contacts who must participate, sampling frequency and specimen types, power to assess differences in secondary transmission, risk factors for infection and transmission, and fraction of cases…