PKG00264149-instructions.pdf

Centers for Disease Control and Prevention

National Center for Immunization and Respiratory Diseases Extramural Research Program

Office

US Enhanced Surveillance Network to Assess Burden, Natural History, and Effectiveness of

Vaccines to Prevent Enteric and Respiratory Viruses in Children

RFA-IP-21-002

Application Due Date: 02/08/2021

US Enhanced Surveillance Network to Assess Burden, Natural History, and Effectiveness of

Vaccines to Prevent Enteric and Respiratory Viruses in Children

RFA-IP-21-002

TABLE OF CONTENTS

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

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

Part 1. Overview Information Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations National Center for Immunization and Respiratory Diseases Notice of Funding Opportunity (NOFO) Title US Enhanced Surveillance Network to Assess Burden, Natural History, and Effectiveness of Vaccines to Prevent Enteric and Respiratory Viruses in Children Activity Code U01 – Research Project - Cooperative Agreement

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

RFA-IP-21-002

Assistance Listings (CFDA) Number(s) 93.185 Category of Funding Activity:

Health NOFO Purpose The goal of this Notice of Funding Opportunity (NOFO) is to support a network of US institutions to develop and implement standard research protocols to conduct prospective active surveillance for: a) acute gastroenteritis (AGE) due to norovirus, rotavirus and other enteric viruses; b) acute respiratory illnesses (ARI) due to respiratory viruses including, but not limited to, influenza, RSV, parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses (including EV-D68), adenoviruses, and coronaviruses (including SARS-CoV-2); and c) acute flaccid myelitis (AFM) syndrome and multisystem inflammatory syndrome in children (MIS-C) among pediatric patients seeking healthcare at medical institutions. The network should also provide accurate estimates of the effectiveness in this population of influenza, rotavirus, COVID-19 and other vaccines against respiratory or enteric virus-associated illnesses projected to become available during the period of performance (e.g., RSV, norovirus). Participating institutions should identify AGE, ARI, AFM and MIS-C illnesses among pediatric patients seeking healthcare or diagnostic testing for acute illness in inpatient, outpatient and emergency departments. Recipients should enroll patients meeting standard symptom criteria, and confirm viral infection using approved molecular assays. Vaccine effectiveness (VE) estimates will be calculated. Estimates of VE, burden of disease, and information on the natural history of disease will be used to: a) inform best practices for diagnosis and treatment protocols; b) inform vaccine recommendations; and c) assess public health impact of vaccination and public health programs to prevent viral illness-related healthcare encounters and medical visits among pediatric populations.

Key Dates Publication Date: To receive notification of any changes to RFA-IP-21-002, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link. An email address is needed for this service.

Letter of Intent Due Date: 01/07/2021

Application Due Date: 02/08/2021

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. Applications must be submitted using the Application Submission System & Interface for Submission Tracking (ASSIST) module which is a web-based service used for the preparation and submission of grant applications to CDC through Grants.gov. ASSIST provides the ability for applicants to prepare their applications online, and offers the applicant additional capabilities including the ability to preview the application image, validate the application against required business rules, and prepopulate data from an applicant organization's records, therefore identifying issues earlier in the application submission process.

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: 04/13/2021

Secondary Review: 05/13/2021

Estimated Start Date: 09/01/2021

Expiration Date: 02/09/2021 Due Dates for E.O. 12372: Due no later than 60 days after the application receipt date.

Required Application Instructions

**ELECTRONIC APPLICATION SUBMISSION VIA ASSIST IS PREFERRED**

It is recommended that applicants use ASSIST for the electronic preparation and submission of applications through Grants.gov to CDC. ASSIST is an alternative method to prepare and submit applications, and provides many features to facilitate the application submission process which improves data quality (e.g., pre-population of organization data, pre-submission validation of business rules, and preview of the application image used for review). Use of the Grants.gov downloadable Adobe application packages and submission process will still be supported.

https://www.grants.gov

It is critical that applicants follow the instructions in the SF 424 (R&R) 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.

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.

Telecommunications for the Hearing Impaired: TTY 1-888-232-6348 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, B, or C).

Each application must address both objectives under Mandatory Core Component A and may apply for either or both Optional Components B and C.

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

Component A: 15 pages Component B: 5 pages Component C: 5 pages

Executive Summary

Purpose: The goal of this Notice of Funding Opportunity (NOFO) is to support a network of US institutions to develop and implement standard research protocols to conduct prospective active surveillance for: a) acute gastroenteritis (AGE) due to norovirus, rotavirus and other enteric viruses; b) acute respiratory illnesses (ARI) due to respiratory viruses including, but not limited to, influenza, RSV, parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses (including EV-D68), adenoviruses, and coronaviruses (including SARS-CoV-2); and c) acute flaccid myelitis (AFM) syndrome and multisystem inflammatory syndrome in children (MIS-C) among pediatric patients seeking healthcare at medical institutions. The network should also provide accurate estimates of the effectiveness in this population of influenza, rotavirus, COVID-19 and other vaccines against respiratory or enteric virus-associated illnesses projected to become available during the period of performance (e.g., RSV, norovirus).

Participating institutions should identify AGE, ARI, AFM and MIS-C illnesses among pediatric patients seeking healthcare or diagnostic testing for acute illness in inpatient, outpatient and emergency departments. Recipients should enroll patients meeting standard symptom criteria, and confirm viral infection using approved molecular assays.

http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf

Vaccine effectiveness (VE) estimates should be calculated. Estimates of VE, burden of disease, and information on the natural history of disease will be used to: a) inform best practices for diagnosis and treatment protocols; b) inform vaccine recommendations;

and c) assess public health impact of vaccination and public health programs to prevent viral illness-related healthcare encounters and medical visits among pediatric populations.

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 $68,250,000. The estimated number of awards is up to seven (7) for each component.

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) is $13,650,000 with individual awards estimated to range from $1,600,000 to $1,950,000 for all components combined. The estimated total funding (direct and indirect) for the entire project period is $68,250,000. The project period is anticipated to run from 09/01/2021 to 08/31/2026.

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. Applications may include multiple PDs/PIs (Co-PIs) and, if so, must include a Leadership Plan that describes the roles, responsibilities and working relationships of the identified PDs/PIs (Co-PIs). However, only one PD/PI may be the primary CDC contact for the award and should be listed first in the application; this contact PD/PI must be at the recipient institution and must be indicated as such in the application.

Number of Applications. Only one application per institution (normally identified by having a unique DUNS number) is allowed.

Application Type. New.

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

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

Part 2. Full Text

Section I. Funding Opportunity Description

Statutory Authority

Public Health Service Act, Section 317 [42 U.S.C. 247b(k)(1)], 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

1. Background and Purpose This Notice of Funding Opportunity (NOFO) seeks to support a network of US medical institutions to conduct prospective, active surveillance for acute gastroenteritis (AGE) and acute respiratory illnesses (ARI), as well as associated syndromes, including acute flaccid myelitis (AFM) and multisystem inflammatory syndrome in children (MIS-C), in inpatient, emergency department (ED), and outpatient clinical settings, and among asymptomatic healthy controls.

Respiratory viruses are a major cause of morbidity in young children. The burden of pediatric respiratory viral illness and its impact on public health resources make vaccine development and implementation a high priority. In addition to new vaccines, new diagnostic and therapeutic approaches for respiratory viruses are also developing rapidly. Therefore, it is important to establish active surveillance programs to assess the current characteristics of acute respiratory illness epidemiology as well as the impact of future interventions against respiratory viruses in the US.

Population-based surveillance for viral respiratory and enteric illness and associated syndromes, such as AFM and MIS-C, will allow more accurate determination of the rates of disease, natural history and risk factors for infections, and associated complications over time, and provide an infrastructure for evaluation of the impact of existing vaccines (e.g., for influenza, rotavirus) and of new vaccines as they become licensed (e.g., for RSV, norovirus and SARS-CoV-2).

Importantly, active surveillance for ARI will provide the necessary platform to estimate influenza vaccine effectiveness in preventing pediatric influenza hospitalizations. In addition, active surveillance for viruses such as RSV and SARS-CoV-2 will provide critical data to better understand and document the disease burden among US infants and children, and to assess the future impact of vaccines under development and/or being assessed in clinical trials. Moreover, active surveillance for acute respiratory illnesses is an important component of prompt detection of outbreaks of emerging pediatric viral pathogens, such as SARS-CoV-2 and EV-D68, and is necessary to assess the need for the development of future interventions against such viral illnesses. Finally, current national surveillance for multisystem inflammatory syndrome in children (MIS-C) relies on reporting from healthcare providers to local, state, and territorial health departments. Determining the burden of MIS-C using active, population-based surveillance will be important to fully define the burden of MIS-C in children.

In addition, rotavirus and norovirus are problems of significant public health importance, causing severe acute gastroenteritis among infants and children. Neither of these viral infections is nationally notifiable in the United States and testing for these infections is not always performed when a child seeks medical care for AGE. Thus, it is important to conduct active surveillance among infants and children who are hospitalized and are visiting the ED or clinic for symptoms of AGE, followed by laboratory confirmation of the causative pathogen.

In 2006, the Advisory Committee on Immunization Policy (ACIP) recommended universal rotavirus vaccination of US infants with RotaTeq (Merck and Co.), followed in 2008 with the recommendation to add Rotarix (GSK Biologicals) to the US rotavirus immunization schedule.

With these rotavirus vaccines now widely used among US infants, active post-licensure surveillance is necessary to: 1) monitor the impact of rotavirus vaccination in reducing the morbidity and mortality from severe rotavirus gastroenteritis; 2) evaluate rotavirus vaccine effectiveness in field use and identify and determine the causes of possible vaccine failure; and

3) monitor the distribution of rotavirus strains.

After rotavirus, the leading cause of severe AGE among US children is norovirus. There is currently no vaccine against norovirus on the US market, but vaccines and prophylaxes are currently under development. Active surveillance for norovirus is necessary to: 1) better understand and document the disease burden attributable to norovirus among US infants and children; and 2) to monitor the distribution of norovirus genogroups and genotypes.

References

1. Campbell AP, Ogokeh C, Lively JY, et al. Vaccine effectiveness against influenza hospitalizations and emergency department visits among children in the United States, 2018–2019. Pediatrics, in press (accepted 20 Aug 2020)

2. Feldstein L, Ogokeh C, Rha B, et al., for the New Vaccine Surveillance Network.

Vaccine Effectiveness Against Influenza Hospitalization Among Children in the United States, 2015–2016. J Pediatric Infect Dis Soc, Epub 28 Feb 2020. PMID: 32108879.

3. Hall CB, Weinberg GA, Blumkin AK, et al. Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics 2013; 132:e341- 8.

4. Kujawski SA, Midgley CM, Rha B, et al. Enterovirus D68-Associated Acute Respiratory Illness - New Vaccine Surveillance Network, United States, July-October, 2017 and 2018. MMWR Morb Mortal Wkly Rep. 2019;68(12):277-280.

5. Rha B, Curns AT, Lively JY, et al. Respiratory Syncytial Virus-Associated Hospitalizations Among Young Children: 2015–2016 [published online ahead of print, 2020 Jun 16]. Pediatrics. 2020;e20193611. doi:10.1542/peds.2019-3611.

6. Rha B, Lively JY, Englund JA, et al. SARS-CoV-2 Infections in Children - Multi- Center Surveillance, United States, January-March 2020 [published online ahead of print, 2020 Jun 18]. J Pediatric Infect Dis Soc. 2020;piaa075. doi:10.1093/jpids/piaa075.

7. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S.

Children and Adolescents. N Engl J Med. 2020; 383:334-346. https://doi.org/10.1056 /NEJMoa2021680

8. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem Inflammatory Syndrome in Children in New York State. N Engl J Med. 2020; 383:347-58. https://doi.org/10.1056 /NEJMoa2021756.

9. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19–Associated Multisystem Inflammatory Syndrome in Children — United States, March–July 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(32):1074-1080. https://www.cdc.gov/mmwr/volumes/69/wr /mm6932e2.htm?s_cid=mm6932e2_w.

https://doi.org/10.1056/NEJMoa2021680 https://doi.org/10.1056/NEJMoa2021680 https://doi.org/10.1056/NEJMoa2021756 https://doi.org/10.1056/NEJMoa2021756 https://www.cdc.gov/mmwr/volumes/69/wr/mm6932e2.htm?s_cid=mm6932e2_w https://www.cdc.gov/mmwr/volumes/69/wr/mm6932e2.htm?s_cid=mm6932e2_w

10. Lopez A, Lee A, Guo A, et al. Vital Signs: Surveillance for Acute Flaccid Myelitis — United States, 2018. MMWR Morb Mortal Wkly Rep 2019;68:608–614. DOI:

http://dx.doi.org/10.15585/mmwr.mm6827e1external icon

11. Payne DC, Vinje J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, Hall CB, Chappell J, Bernstein D, Curns AT, Wikswo M, Hall AJ, Lopman B, Shirley S, Parashar UD. Norovirus and medically attended gastroenteritis in US children. New Engl J Med 2013; 368:1121–30.

12. Payne DC, Englund JA, Weinberg GA, Halasa NB, Boom JA, Staat MA, Selvarangan Moffatt ME, Johnston SH, Mijatovic-Rustempasic S, Esona MD, Tate JE, Curns AT, Wikswo ME, Sulemana I, Bowen MD, Parashar UD. Association of Rotavirus Vaccination with Inpatient and Emergency Department Visits Among Children Seeking Care for Acute Gastroenteritis, 2010-2016. JAMA Netw Open. 2019 Sep 4;2(9):e1912242. doi: 10.1001/jamanetworkopen.2019.12242. PubMed PMID:

31560386;

13. Wikswo ME, Parashar UD, Lopman B, Selvarangan R, Harrison CJ, Azimi PH, Boom JA, Sahni LC, Englund JA, Klein EJ, Staat MA, McNeal MM, Halasa N, Chappell J, Weinberg GA, Szilagyi PG, Esona MD, Bowen MD, Payne DC. Evidence for Household Transmission of Rotavirus in the United States, 2011-2016. J Pediatric Infect Dis Soc. 2019 Feb 7. doi: 10.1093/jpids/piz004. PubMed PMID:30753568.

Healthy People 2030 and other National Strategic Priorities This NOFO is aligned with the HP2030 objectives for:

Infectious Disease: https://health.gov/healthypeople/objectives-and-data/browse-objec tives/infectious-disease and

Vaccination: https://health.gov/healthypeople/objectives-and-data/browse-objectives /vaccination.

This NOFO is aligned with the following CDC Public Health Priorities:

Excellence in surveillance, epidemiology, and laboratory science and services.

Advance evidence-based health policies (e.g., vaccination).

Prevent illness, injury, disability, and premature death (e.g., infectious diseases).

Public Health Impact The burden of these diseases, their impact on public health resources, and the lack of alternative measures to control these diseases, make vaccines a high priority. Therefore, it is important to establish active surveillance programs in order to assess the current characteristics of acute viral illness epidemiology as well as to inform future surveillance programs that may monitor the impact of future interventions against viral infections causing ARI or AGE in the US. Funded activities will provide an active US pediatric disease surveillance system to assess a wide spectrum of AGE and ARI pathogens and conduct evaluations related to existing and potential public health interventions, including:

Vaccine effectiveness for licensed vaccines including rotavirus and influenza and https://health.gov/healthypeople/objectives-and-data/browse-objectives/infectious-disease https://health.gov/healthypeople/objectives-and-data/browse-objectives/infectious-disease https://health.gov/healthypeople/objectives-and-data/browse-objectives/vaccination https://health.gov/healthypeople/objectives-and-data/browse-objectives/vaccination vaccine effectiveness for vaccines licensed in the future (such as for SARS-CoV-2);

Burden and natural history of disease for pathogens and pediatric infectious disease transmission dynamics;

Informing vaccination/therapeutic policy and development, vaccine impacts for targeted and vulnerable populations, and socioeconomic and microbiological environments potentially relevant to these public health interventions.

Results from research conducted under this notice of funding opportunity 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-IP16-004: Enhanced Surveillance for New Vaccine Preventable Diseases (http ://www.grants.gov/web/grants/search-grants.html, Keyword: RFA-IP16-004;

Opportunity Status: Archived).

2. Katz EM, Gautam R, Bowen MD. 2017.Evaluation of an alternative recombinant thermostable Thermus thermophilus (rTth)-based real-time reverse transcription-PCR kit for detection of rotavirus A. J Clin Microbiol 55:1585–1587.

https://doi.org/10.1128/JCM.00126-17.

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

4. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2019–2020 MMWR Recommendations and Reports / August 23, 2019 / 68(3);1–21. https://www.cdc.gov /mmwr/volumes/68/rr/rr6803a1.htm

5. Nix WA, Oberste MS, Pallansch MA. Sensitive, semi-nested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 2006;44:2698–704.

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 both objectives under Mandatory Core Component A and may also address either or both Optional Components B and C. 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).

Objectives/Outcomes

A. Mandatory Core Component A for Years 1 through 5, up to $1,100,000 per year (direct and indirect costs) per award for both Mandatory Objectives 1 and 2. Both http://www.grants.gov/web/grants/search-grants.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 https://www.cdc.gov/mmwr/volumes/68/rr/rr6803a1.htm https://www.cdc.gov/mmwr/volumes/68/rr/rr6803a1.htm

Objectives must be addressed as part of the Mandatory Core Component A.

Mandatory Objective 1: Population-based active surveillance for respiratory and enteric viral pathogens in pediatric inpatient and emergency department settings and asymptomatic controls.

Establish and operate a surveillance platform for pediatric viral pathogens in order to achieve the following objectives:

1. Perform prospective, active surveillance to determine the etiology and burden of inpatient and emergency department (ED) acute viral respiratory and enteric diseases among the pediatric population.

2. Characterize the clinical and epidemiologic factors of pediatric infections (including in asymptomatic children) through active surveillance.

3. Evaluate vaccine effectiveness and impact of vaccines and other interventions (e.g., immunoprophylaxis with antiviral agents or other therapeutics) available or projected to become available during the period of performance.

The application should address all of the stated objectives and include, at a minimum, the following information in the submission:

1. Describe the setting of the proposed surveillance site with a defined pediatric catchment population in a geographically defined area to conduct year-round surveillance activities.

Applications should include, at a minimum, details of study activities that address the following:

a. Provide detailed description(s) of each proposed participating medical institution where patients will be enrolled (e.g., physical description, patient volume, number of pediatric hospital beds, etc.) and a demonstration of institutional support regarding patient enrollment (e.g., access to admissions data and other relevant data sources for screening and enrollment, successful navigation of institutional review board approvals for pediatric surveillance and clinical research, etc.).

i. Letters of support from participating agencies, institutions, organizations, laboratories, and consultants as indicated in the application’s operational plan are encouraged.

b. Describe the geographic area and population base in which the surveillance site will operate, including population denominators for calculating disease rates. (Establishing population-based surveillance is desirable; a minimum population-base of approximately 500,000 persons of all ages in the catchment area is expected to be sufficient.)

i. Describe the demographics of the proposed population base, including a description of various special populations as they relate to the proposed activities of the site.

c. Describe the estimated proportion of children in the catchment area who would be captured by the medical institution’s hospital, ED, and outpatient settings (for asymptomatic controls) where surveillance would take place.

d. Describe investigators’ experience in conducting surveillance activities in pediatric populations.

e. Provide a timeline and explanation to describe how surveillance activities will begin no later than November 1, 2021.

2. Describe how active, prospective surveillance activities among children with acute gastroenteritis (AGE) and acute respiratory illness (ARI) will be conducted in surveillance hospitals, emergency departments (EDs), as well as in asymptomatic “healthy control” (HC) children at outpatient well-child visits (see Table 1) consistent with previously used methods (applicants may refer to listed publications and previous surveillance network at the following website: https://www.cdc.gov/surveillance/nvsn/index.html.)

Table 1. Summary of surveillance enrollment activities

Subject group (by illness)

Targeted Pathogen Enrollment period

Age group (years)

Clinical setting

AGE AGE pathogens (1) Year-round <18 Inpatient and ED

ARI ARI pathogens (2) Year-round <18 Inpatient and ED

Healthy controls AGE and ARI pathogens (1,2)

Year-round <18 Well child clinics

(1) AGE pathogens include: norovirus, rotavirus.

(2) ARI pathogens include: influenza, RSV, parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses (including EV-D68), adenoviruses, and coronaviruses (including SARS-CoV-2).

The application should include, at a minimum, details of study activities to:

a. Describe procedures to systematically screen patients for eligibility and enroll consenting subjects in the following settings:

i. In the inpatient settings, screen admissions and systematically enroll children with ARI and/or AGE in the inpatient setting at least 5 days per week during the enrollment period.

1. For ARI cases, goal enrollment is at least ~60% of inpatient subjects found to be eligible for surveillance during the year. In addition; goal enrollment during influenza season is approximately 400 inpatient enrollees aged 6 months to 17 years with ARI;

sites able to enroll more than 400 patients should specify this in the application. (Refer to section on estimating influenza VE in hospitalized children below.)

2. For AGE cases, goal enrollment for inpatient and ED patients combined should be a minimum of 75% of eligible cases during the year.

ii. In the ED, screen ED patients and systematically enroll children evaluated in the ED with AGE and/or ARI at least 4 days per week during the enrollment period.

1. For ARI cases, goal enrollment is at least ~50% of ED patients found to be eligible for surveillance during the year.

2. For AGE cases goal enrollment for inpatient and ED patients combined should be a https://www.cdc.gov/surveillance/nvsn/index.html minimum of 75% of eligible cases during the year.

iii. Screen outpatient clinic settings and systematically enroll asymptomatic “healthy controls” at least 1 day per week during the period of active surveillance to meet target enrollments established with technical assistance from CDC to determine optimal ratio of cases to controls.

iv. Conduct quality control activities and provide summary tables at regular intervals (e.g., every 2 weeks) about patient screening and enrollment using information that includes patient counts along with key demographic information such as age group.

b. Describe procedures to collect epidemiological and clinical information from enrolled subjects through parent/guardian interviews and medical record reviews. These should include, but are not limited to:

i. Admission and discharge diagnoses (ICD-10 codes)

ii. Symptoms

iii. Onset of illness

iv. Clinical outcomes (e.g., death, discharge or transfer)

v. Risk factors (e.g., underlying medical conditions, high-risk conditions/behaviors, exposure history)

vi. Vaccination history

vii. Markers for the course and severity of disease (e.g., duration of hospitalization, ICU admission and dates, mechanical ventilation, hypoxia);

viii. Treatments received such as use of antiviral or immune modulatory drugs (with dates)

ix. Clinical radiographic and laboratory results including virologic testing

x. Medical costs.

c. Additional information should be collected to assess household transmission dynamics (i.e., number or household occupants, rooms, etc.), vaccination policies (school, local), targeted and vulnerable populations, and socioeconomic factors (household income, etc.) relevant to public health interventions.

d. Describe procedures to collect study specimens from enrolled children (with goal from at least 70% of enrolled), including stool specimens from children enrolled in AGE surveillance, respiratory (i.e., nasal and throat swabs) specimens from children enrolled in ARI surveillance, and both stool and respiratory specimens from healthy control subjects.

i. Describe approaches to collect any salvaged clinical specimens (e.g., whole blood, sera, plasma, cerebrospinal fluid, and/or other types) that have been already collected from the enrolled subject by the medical institution for clinical purposes (i.e., collected independently of this surveillance activity) after clinically indicated testing is completed, for further testing. If this would be only possible for a subset of those enrolled, please describe any limitations, as well as any conditions placed upon their use.

e. Describe procedures to process, test, store, and ship study specimens.

i. For stool specimens, describe procedures to process, aliquot, store, extract, and test specimens by approved real-time RT-PCR assays for norovirus and rotavirus and ship duplicate aliquots of specimens for further characterization. Participate in CDC-sponsored proficiency testing.

ii. For respiratory specimens, describe the procedures to process, aliquot, and store locally, including multiple aliquots of specimens (original, lysis buffer, extracted sample) with a system for tracking inventory of aliquots; ship duplicate aliquots of specimens in a timely way to laboratories as needed for further characterization. Describe procedures to perform following activities:

1. Perform approved, timely, sensitive nucleic acid-based diagnostics for respiratory pathogens including, but not limited to. influenza, RSV, parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses (including EV-D68), adenoviruses, and coronaviruses (including SARS-CoV-2).

a. For influenza, describe the molecular diagnostic assays (nucleic acid-based influenza assays) that will be used to detect influenza viruses, including influenza A virus subtypes and influenza B lineage.

i. Include relevant published reports and information from product package insert identifying test sensitivity and specificity and the ability to detect influenza types A and B, as well as A subtypes A(H3N2) and A(H1N1)pdm09 and B lineage (Yamagata and Victoria) viruses.

ii. Describe information on experience and competency with these methods (e.g., number of assays run/year; comparisons to other assays or results from validation studies, other measures of proficiency; letters of support; and publications).

b. For SARS-CoV-2, describe approved, standardized, validated molecular assays used to detect SARS-CoV-2 and provide evidence of competency in the use of the approved molecular assay.

2. Participate in CDC-sponsored proficiency testing and ongoing quality control monitoring among sites (e.g., circulating a sample of specimens among sites for testing).

3. Describe the plan and process to support recurring shipment of aliquots (1 ml) from a subset of positive specimens to other laboratories for further characterization, sequencing and for other surveillance purposes.

iii. For salvaged clinical specimens, describe procedures to store and ship to other laboratories as needed for further characterization.

3. Describe approaches to evaluate performance and impact of vaccines and other interventions (e.g., immunoprophylaxis with antiviral agents or other therapeutics) projected to become available during the period of performance. Describe methodology for collecting vaccination data (for rotavirus, influenza, and other pathogens for which vaccines may be developed, such as SARS-CoV-2) with accuracy and completeness (e.g., dose, type, dates of administration, vaccine manufacturer) for enrolled subjects that will enable accurate evaluations of vaccine effectiveness, coverage, and impact in the population.

a. Evaluate rotavirus vaccination performance in the United States. For example, evaluations should include vaccine effectiveness (VE), exploring potential waning immunity, explanations for the post-licensure biennial trend in rotavirus incidence and sustained population protection, the performance of rotavirus vaccines in vulnerable populations, and monitoring reassortant and emerging rotavirus strains.

b. Assess influenza vaccine effectiveness (VE) in preventing laboratory-confirmed influenza infections among hospitalized children with ARI less than 18 years of age (i.e., information on underlying conditions, medical outcomes, antiviral use, and vaccination;

collected specimen testing for influenza A subtypes and B lineages). Aggregated data from the participating sites should be used to estimate VE using a test-negative study design (influenza positive patients are cases and influenza negative patients are controls) for each influenza season. Applications should include, at a minimum, details addressing all the following in the application.

i. Describe procedures to achieve the goal study sample size enrollment each influenza season (approximately 400 enrollees aged 6 months to 17 years with ARI during the influenza season; sites able to enroll more than 400 patients should specify this in the application). Provide descriptions of previous experience in enrollment of hospital patients (e.g., ability to screen and enroll patients and to meet target enrollment and patient participation [number enrolled/number eligible]).

ii. For children aged 6 months to 17 years, describe plans to verify parent-reported influenza vaccination status with validated records (e.g., electronic medical records, electronic vaccine registries or medical abstraction from health care providers, pharmacy chains, schools, and other potential vaccine providers) to obtain current season influenza vaccination status (including vaccination date(s), vaccine type, manufacturer, and lot number) and vaccination status from prior seasons.

iii. Describe methods to determine VE of maternal vaccination to prevent influenza infection among children less than 6 months of age, including methods to obtain current season influenza vaccination status (including vaccination date(s), vaccine type, and manufacturer) using maternal self-report and verification from electronic medical records, real-time electronic vaccine registries or medical abstraction from health care providers, pharmacy chains, and other potential vaccine providers.

iv. Use local influenza surveillance data to assess onset of influenza season and trigger enrollment (i.e., with local enrollment triggered by 2 consecutive weeks of increasing detection of influenza viruses by molecular diagnostic assays conducted as part of pre-enrollment surveillance).

c. Methods for determining COVID-19 vaccination (once vaccines become available), vaccine type, date of vaccination and number of doses will depend upon documentation of COVID-19 vaccination in electronic medical records, real-time electronic vaccine registries or medical abstraction from health care providers, non-traditional providers, public health departments, schools, and other potential vaccine providers.

4. Perform other assessments and evaluations of surveillance network data with technical assistance from CDC. In addition to assessments of vaccine performance, the site should conduct the following assessments and evaluations:

a. Generate baseline surveillance data (including incidence rate estimates of hospitalizations, and emergency department visits, and clinical and epidemiologic characterizations of illness) for vaccine-preventable pathogens (e.g., influenza, rotavirus), pathogens projected to be potentially vaccine-preventable during the period of performance (e.g. norovirus, respiratory syncytial virus, EV-D68, and SARS-CoV-2), and for other AGE and ARI pathogens (such as; parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses adenoviruses, and coronaviruses) in order to assess the need for development of vaccines and other interventions.

5. Describe procedures to perform timely, uniform, consistent, secure, and accurate data collection and transmission with technical assistance from CDC.

a. Provide timely reporting (e.g., within 1–2 weeks) of case counts with key demographic and clinical information and testing results.

b. Conduct routine data cleaning activities with technical assistance from CDC to ensure data quality for short-term (e.g., within 1–2 weeks for key data variables) and longer-term (e.g., routinely during the course of surveillance year for all data variables) goals (e.g., data for early/interim VE estimates).

c. Manage standardized data dictionaries and Application Programming Interface (API) tokens with technical assistance from CDC.

Mandatory Objective 2: Surveillance and epidemiologic characterization of acute flaccid myelitis (AFM) syndrome in children.

Conduct surveillance activities for acute flaccid myelitis (AFM), to include the following:

1. Define baseline rates of AFM in pediatric sites through active case finding using the following case definition: patients meeting the clinical criterion for AFM (acute onset of flaccid limb weakness) and a spinal MRI showing at least some gray matter involvement (https://www.cdc.gov/acute-flaccid-myelitis/hcp/case-definitions.html)

a. Conduct active surveillance for AFM on inpatient pediatric and neurology services in hospitals within the defined catchment area.

b. Establish incident rates of AFM among hospitalizations and in the defined catchment area.

2. Compare rates of AFM to rates of circulating respiratory and gastrointestinal infections at each site.

3. Characterize the clinical spectrum of pediatric AFM and describe differences between other similar neurologic conditions. Collect information on epidemiologic and clinical factors, including but not limited to admission and discharge diagnoses, vaccination history, risk factors, markers for the course and severity of disease, treatments such as use of antiviral drugs, clinical radiographic and laboratory results including virologic testing (for comparison to research testing).

B. Optional Component B for Years 1 through 5, $350,000 per year (direct and indirect https://www.cdc.gov/acute-flaccid-myelitis/hcp/case-definitions.html costs) per award.

Population-based active surveillance for respiratory and enteric viral pathogens in outpatient settings.

Establish and operate surveillance for pediatric viral pathogens among children presenting to outpatient care with acute respiratory illness (ARI) and acute gastroenteritis (AGE).

The application should address all of the stated objectives and include, at a minimum, the following information in the submission:

1. Describe how active, prospective surveillance activities among children with ARI and AGE presenting to surveillance site outpatient care (e.g., clinics, clinic associated facilities) will be conducted consistent with methods described for inpatient/ED patient surveillance detailed in core component above (see Mandatory Component A above).

a. In outpatient care settings, systematically enroll children evaluated for AGE and/or ARI at least 3 days per week during the year.

i. For ARI cases, goal enrollment is at least ~50% of outpatient patients found to be eligible for surveillance during the periods of active surveillance.

ii. For AGE cases, goal enrollment is at least ~50% of outpatient patients with a stool sample found to be eligible for surveillance during the year.

b. Describe procedures to collect epidemiological and clinical information from enrolled subjects through parent/guardian interviews and medical record reviews.

c. Describe procedures to collect study specimens from enrolled children, including stool specimens from children enrolled in AGE surveillance, respiratory (i.e., nasal and throat swabs) specimens from children enrolled in ARI surveillance.

d. Describe procedures to process, test, store, and ship study specimens, consistent with methods described for inpatient/ED patient surveillance detailed in core component above (see Mandatory Component A). This includes performing approved, timely, sensitive nucleic acid-based diagnostics for respiratory pathogens including, but not limited to, influenza, RSV, parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses (including EV-D68), adenoviruses, and coronaviruses (including SARS-CoV-2).

e. For stool specimens, describe procedures to process, aliquot, store, extract, and test specimens by approved real-time RT-PCR assays for norovirus and rotavirus and ship duplicate aliquots of specimens to other laboratories for further characterization. Participate in CDC-sponsored proficiency testing.

2. Perform evaluations of surveillance network data with technical assistance from CDC, including:

a. Generate baseline surveillance data (including incidence rate estimates of outpatient visits, and clinical and epidemiologic characterizations of outpatient illness) for vaccine-preventable pathogens (e.g., influenza, rotavirus), pathogens projected to be potentially vaccine-preventable during the period of performance (e.g., norovirus, respiratory syncytial virus, EV-D68, and SARS-CoV-2), and for other ARI and AGE pathogens (such as; parainfluenza viruses, human metapneumovirus, rhinoviruses, enteroviruses adenoviruses, and coronaviruses) in order to assess the need for development of vaccines and other interventions.

3. Describe procedures to perform timely, uniform, consistent, secure, and accurate data collection and transmission with technical assistance from CDC, consistent with methods described for inpatient/ED patient surveillance detailed in core component above (see Mandatory Component A).

C. Optional Component C for Years 1 through 5, $500,000 per year (direct and indirect costs) per award Determine incidence, spectrum of disease and risk factors associated with multisystem inflammatory syndrome in children (MIS-C).

The objective of this surveillance component will be to identify and characterize children meeting the case definition for MIS-C during the project period, including risk factor evaluation and description of long-term sequelae. The current CDC case definition for MIS-C is as follows (https://www.cdc.gov/mis-c/hcp/) but may be refined over time:

An individual aged less than 21 years presenting with fever*, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (greater than two) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND

No alternative plausible diagnoses; AND Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

*Fever greater than 38.0°C for 24 or more hours, or report of subjective fever lasting 24 or more hours.

**Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin.

Applications should include descriptions of the following activities:

1. Define incidence rates of MIS-C in pediatric sites through active case finding.

a. Conduct active surveillance for MIS-C on inpatient pediatric hospital wards and intensive care units in hospitals within the catchment area using the current CDC case definition (https://www.cdc.gov/mis-c/hcp/). Applications should describe active case finding procedures that can include (but are not limited to):

i. Use of prospective surveillance activities performed under Components A and/or B.

ii. Review of documented positive laboratory results for current or recent SARS-CoV- 2 infection by RT-PCR (or other molecular assay), serology, or antigen test.

iii. Identification of patients who have received treatment such as intravenous immunoglobulin (IVIG).

iv. Case finding through consultation with critical care, infectious disease, and rheumatology specialists.

b. Establish incidence rates of MIS-C among hospitalizations and in the defined catchment area.

c. If the CDC case definition is expanded to include milder disease during the project period, expand surveillance to define incidence of MIS-C among children evaluated in emergency departments and outpatient settings in the defined catchment area.

2. Describe the spectrum of clinical characteristics and phenotype of MIS-C, including phenotypes and diagnostic criteria that differentiate between MIS-C and acute COVID-19.

a. Collect information on epidemiologic and clinical factors including, but not limited to, admission and discharge diagnoses, vaccination history, risk factors, markers for the course and severity of disease, treatments such as use of antiviral drugs, clinical radiographic and laboratory results including virologic testing (for comparison to research testing).

3. Conduct studies to elucidate risk factors for MIS-C, including identifying host risk factors (age, sex, race/ethnicity, underlying conditions, host genomics, microbiome, severity of acute infection/quantitative and qualitative immune response), environmental risk factors (increased likelihood of infection/exposure, medications), population-level risk factors (density, socioeconomic status, occupational patterns, household characteristics), and viral risk factors (genetic characterization, viral load).

4. Describe the administration of therapeutics for MIS-C, including investigational and off-label medications, including treatment strategies by MIS-C phenotype, initiation relative to days from hospital presentation, and outcomes.

5. Characterize the extent and time to recovery, and describe long-term outcomes and clinical sequelae (e.g., cardiac and other organ systems) by medical record review and parent interview(s) and/or electronic survey(s) at pre-determined intervals.

Target Population The target…