RFA-CK-25-182_20241227.pdf

Centers for Disease Control and Prevention

National Center for Emerging and Zoonotic Infectious Diseases

Enhanced Surveillance and Control of Endemic and Emerging Arboviruses in Puerto Rico

RFA-CK-25-182

02/28/2025

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 Emerging and Zoonotic Infectious Diseases Notice of Funding Opportunity (NOFO) Title Enhanced Surveillance and Control of Endemic and Emerging Arboviruses in Puerto Rico Activity Code U01 – Research Project - Cooperative Agreements

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

RFA-CK-25-182

Assistance Listings Number(s) 93.084 Category of Funding Activity HL - Health NOFO Purpose The purpose of this notice of funding opportunity (NOFO) is to strengthen an established research platform for arboviruses in hospital and community settings in Puerto Rico, identify emerging and endemic pathogens like dengue and Oropouche viruses, improve patient management, and evaluate prevention and control strategies. The core objectives include: 1) strengthen hospital surveillance of acute febrile illness (AFI) to ensure early detection of emerging arboviruses and other pathogens; 2) use the established AFI surveillance platform to conduct clinical research on dengue and other arboviral diseases, including among special populations such as women and children; 3) maintain and enhance the community cohort to assess incidence and prevalence of arboviral infections and other AFIs, while also evaluate the effectiveness of vector control strategies; 4) strengthen and modernize infrastructure for project data management and analysis, ensuring the surveillance platform is capable of handling large, complex datasets in real-time; and 5) strengthen collaborations with the local government, community leaders, and other interest holders to ensure the continuity of the established program while fostering an environment of rapid and effective communication and cooperation.

Key Dates Publication Date:

To receive notification of any changes to RFA-CK-25-182, 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:

01/28/2025

Application Due Date:

02/28/2025

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:

04/15/2025 https://www.grants.gov/ http://grants.nih.gov/support/index.html mailto:commons@od.nih.gov

Secondary Review:

05/15/2025 Estimated Start Date:

09/01/2025 Expiration Date:

03/31/2025 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 12 pages.

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

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

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

Executive Summary

• Purpose: The purpose of this notice of funding opportunity (NOFO) is to strengthen an established research platform for arboviruses in hospital and community settings in Puerto Rico, identify emerging and endemic pathogens like dengue and Oropouche viruses, improve patient management, and evaluate prevention and control strategies. The core objectives include: 1) strengthen hospital surveillance of acute febrile illness (AFI) to ensure early detection of emerging arboviruses and other pathogens; 2) use the established AFI surveillance platform to conduct clinical research on dengue and other arboviral diseases, including among special populations such as women and children; 3) maintain and enhance the community cohort to assess incidence and prevalence of arboviral infections and other AFIs, while also evaluate the effectiveness of vector control strategies; 4) strengthen and modernize infrastructure for project data management and analysis, ensuring the surveillance platform is capable of handling large, complex datasets in real-time; and 5) strengthen collaborations with the local government, community leaders, and other interest holders to ensure the continuity of the established program while fostering an environment of rapid and effective communication and cooperation.

• Mechanism of Support: U01 - Research - Cooperative Agreement

• Funds Available and Anticipated Number of Awards: The estimated total funding available, including direct and indirect costs, for the entire 5-year period of performance is $25,000,000. The number of awards will be one (1). The award issued under this NOFO is contingent upon availability of funds and the quality, duration and cost of the application received.

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

• Budget and Period of performance: The estimated total funding (direct and indirect) for the first year (12-month budget period) will be $5,000,000. The estimated total funding (direct and indirect) for the entire period of performance will be $25,000,000.

The period of performance is anticipated to run from 09/01/2025-08/31/2030.

• 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. CDC does not make awards to individuals directly. Individuals from organizations that are uniquely prepared to examine research relevant to undeserved groups as well as individuals with disabilities are always encouraged to apply.

• Number of PDs/PIs. There will only be one PD/PI for each application.

• Number of applications. Only one application per institution (normally identified by having a unique UEI number) is allowed.

• Application Type. New

• Application Materials. See Section IV.1 for application materials.

Section I. Funding Opportunity Description Statutory Authority Public Health Service Act, Sections 301(a) [42 USC 241] and 317(k)(2) [42 USC 247b], as amended

1. Background and Purpose Dengue, chikungunya, Zika, and Oropouche viruses are emerging or re-emerging arboviruses that have caused significant outbreaks across the Americas in the past decade. Because patients with these arboviral illnesses can present with similar clinical signs and symptoms, including fever, rash, muscle pain and joint pain, identification of the etiologic agent requires diagnostic testing.

Dengue is endemic in more than 100 countries in tropical and subtropical regions of the world, and half of the global human population is at risk for infection. There are an estimated 390 million dengue virus (DENV) infections and 96 million symptomatic disease cases per year.

Dengue virus infection can potentially lead to fatal acute febrile illness.

Chikungunya is an emerging arboviral disease that is characterized by fever and debilitating arthralgia, and multiple reports have demonstrated that arthralgia and arthritis following infection can persist for months or years. Because of high viremia in both the human host and infected mosquitoes, the inability to control mosquito populations, and immunologically naïve human populations, chikungunya outbreaks have typically been explosive, with attack rates ranging from 38% to 63%.

Zika virus infection typically results in a mild illness that self-resolves within a week but is a cause of microcephaly and other severe brain defects following in utero infection in pregnant women. As with chikungunya, Zika virus spreads explosively among naïve populations. Zika virus infection has also been linked to Guillain-Barré syndrome, a potentially fatal autoimmune disorder.

Oropouche virus is an emerging pathogen that began causing outbreaks in late 2023 in endemic Amazon regions and previously unreported areas such as South America and the Caribbean.

Oropouche virus infection typically causes mild illness, but there are increased concerns about its virulence and occurrence of adverse pregnancy outcomes including fetal death and congenital malformations. The association between Oropouche infection, fetal death and congenital abnormalities are currently under investigation. This research requires rapid setup of study cohorts as the outbreaks are explosive and incidence may rise and fall before studies are approved and established.

Dengue virus infections typically occur throughout the year with incidence increasing dramatically during the warm, wet period of the year (June to October). Puerto Rico has the largest US population in a dengue-endemic area and has experienced a continued increase in disease severity and number of cases since dengue first became reportable to the Puerto Rico Department of Health (PRDH) in 1915. In the United States, dengue became a nationally notifiable disease to the Centers for Disease Control and Prevention (CDC) in 2010. In 2014, an outbreak of chikungunya occurred following identification of travel associated cases in Puerto Rico. In 2015 and 2016, large outbreaks of Zika in the Americas also resulted in travel associated cases in Puerto Rico and widespread local transmission. In Puerto Rico, dengue re-emerged in 2020 after an unusually low transmission period following the 2016 Zika outbreak. A dengue outbreak was declared in March 2024, and circulation of DENV-1, DENV-2, and DENV-3 were documented. In 2024, imported cases of Oropouche virus infection were reported among travelers returning to the U.S. from areas experiencing Oropouche outbreaks. Risk for sustained transmission of Oropouche virus in Puerto Rico is currently unknown, but vector competence studies are being performed for U.S. Culicoides spp. of biting midges and mosquito species (Cx.

quinquefasciatus and Aedes aegypti) to understand whether they contribute to Oropouche virus transmission. Vaccines to prevent dengue and chikungunya have been approved. Vaccines for Zika virus disease are all under development and currently there are no vaccine candidates available for Oropouche.

A robust hospital- and community-based surveillance infrastructure is essential for understanding the full clinical spectrum of emerging arbovirus infections. Hospital-based surveillance enables the identification and documentation of severe cases that require hospitalization, providing critical data on the serious manifestations of infection including among pregnant women and the fetus. Meanwhile, community-based surveillance captures a broader picture of virus transmission by detecting asymptomatic and subclinical cases that are often unnoticed. Together, these systems create a comprehensive framework for assessing incidence of infection and disease, establishing cohort studies that track viral and antibody dynamics over time, examining the development of chronic symptoms, and evaluating long-term outcomes. This dual approach not only improves our ability to describe the full burden of disease across a population but also provides an invaluable platform to evaluate the impact of interventions, such as vector control measures, on reducing the incidence of infection and the severity of disease. Despite the implementation of numerous behavioral, environmental, and entomologic strategies aimed at controlling Aedes mosquitoes and other vectors that transmit arboviruses such as dengue, chikungunya, Zika, and potentially Oropouche viruses, none have yet proven to be both sustainable and fully effective at preventing human infections.

In 2012, CDC established several clinical acute febrile illness (AFI) surveillance sites in Puerto Rico (PR) to serve as platforms to study dengue and other AFIs in the differential diagnosis of dengue infections. In 2018, a supplement to the existing cooperative agreement (RFA-CK-15-

002) for AFI surveillance established a longitudinal community-based seroincidence survey in Ponce, PR, to estimate the baseline seroprevalence and annual seroincidence of infection with dengue, chikungunya, and Zika viruses. An AFI surveillance component was added to the community-based platform in 2020 to detect incident cases of arboviral disease using symptom-triggered molecular testing.

The purpose of this notice of funding opportunity (NOFO) is to strengthen an established research platform for arboviruses in hospital and community settings in Puerto Rico, identify emerging and endemic pathogens like dengue and Oropouche viruses, improve patient management, and evaluate prevention and control strategies. The core objectives include: 1) strengthen hospital surveillance of acute febrile illness (AFI) to ensure early detection of emerging arboviruses and other pathogens; 2) use the established AFI surveillance platform to conduct clinical research on dengue and other arboviral diseases, including among special populations such as women and children; 3) maintain and enhance the community cohort to assess incidence and prevalence of arboviral infections and other AFIs, while also evaluate the effectiveness of vector control strategies; 4) strengthen and modernize infrastructure for project data management and analysis, ensuring the surveillance platform is capable of handling large, complex datasets in real-time; and 5) strengthen collaborations with the local government, community leaders, and other interest holders to ensure the continuity of the established program while fostering an environment of rapid and effective communication and cooperation.

Healthy People 2030 and other National Strategic Priorities This NOFO supports the following Healthy People 2030 focus areas:

• Increase the proportion of adults who prepare for a disease outbreak after getting preparedness information — PREP-D02

• Increase the health literacy of the population — HC/HIT-R01

• Increase the proportion of adults who talk to friends or family about their health —

HC/HIT-04

• Explore and expand practice-based continuing education for public health professionals

— PHI-R01

• Expand public health pipeline programs that include service or experiential learning —

PHI-R02

• Enhance the use and capabilities of informatics in public health — PHI R06

• Increase the number of community organizations that provide prevention services —

ECBP-D07

https://odphp.health.gov/healthypeople

• Increase the proportion of schools with policies and practices that promote health and safety — EH-D01

• Reduce preterm births — MICH-07

• Increase the number of individuals trained globally to prevent, detect, or respond to public health threats — GH-D01

• Increase the number of globally important public health events that are tracked and reported — GH-D02

• Increase laboratory diagnostic testing capacity, surveillance, and reporting globally —

GH-D03

This NOFO also supports the following goals of the National Public Health Strategy to Prevent and Control Vector-Borne Diseases (VBDs) in People

• Better understand when, where, and how people are exposed to and get sick or die from VBDs.

• Develop, evaluate, and improve tools, methods, and guidance to diagnose VBDs and their pathogens.

• Develop, evaluate, and improve tools, methods, and guidance to prevent and control VBDs.

• Develop and assess drugs and treatment strategies for VBDs.

• Disseminate and implement public health tools, programs, and collaborations to prevent, detect, diagnose, and respond to VBD threats.

Public Health Impact This NOFO is critical for advancing public health by strengthening the capacity to understand, prevent, and respond to arboviral disease threats. The surveillance and research supported by this initiative will significantly enhance the knowledge of the etiology, epidemiology, and severity of arboviral diseases, enabling more timely and effective public health interventions. By improving preparedness for vector-borne disease outbreaks, the project supported by this NOFO will help reduce devastating morbidity and mortality, protect vulnerable populations including children and families, and mitigate the long-term physical and emotional toll these diseases can cause.

Furthermore, this project will directly contribute to improvements in public health program delivery and outcomes. The project will provide the evidence base needed to refine surveillance systems, tailor interventions, and optimize resource allocation, ultimately leading to more efficient and impactful public health practices. Strengthening the ability to control and prevent arboviral diseases will not only lower disease in endemic territories but also prevent introduction of new viruses to the continental United States and bolster global health security by reducing the threat of cross-border transmission. This NOFO is essential to safeguarding public health and ensuring a more resilient future in the face of emerging disease threats.

Relevant Work CDC has collaborated with partners to conduct hospital- and community-based surveillance for AFIs and vector-borne diseases in Ponce, Puerto Rico, for more than 12 years. The following documents provide relevant work regarding acute febrile illness and vector-borne disease control in this region and others.

Previous studies in the Ponce Region:

https://www.cdc.gov/vector-borne-diseases/php/data-research/national-strategy/index.html https://www.cdc.gov/vector-borne-diseases/php/data-research/national-strategy/index.html

• Adams LE, Hitchings MDT, Medina FA, Rodriguez DM, Sánchez-González L, Moore H, Whitehead SS, Muñoz-Jordán JL, Rivera-Amill V, Paz-Bailey G. Previous Dengue Infection among Children in Puerto Rico and Implications for Dengue Vaccine Implementation. Am J Trop Med Hyg. 2023 Jun 12;109(2):413-419. doi:

10.4269/ajtmh.23-0091.

• Phillips MT, Sánchez-González L, Shragai T, Rodriguez DM, Major CG, Johansson MA, Rivera-Amill V, Paz-Bailey G, Adams LE. Quantifying the relationship between arboviral infection prevalence and human mobility patterns among participants of the Communities Organized to Prevent Arboviruses cohort (COPA) in southern Puerto Rico.

PLoS Negl Trop Dis. 2023 Dec 15;17(12):e0011840. doi: 10.1371/journal.pntd.0011840.

• Paz-Bailey G, Sánchez-González L, Torres-Velasquez B, Jones ES, Perez-Padilla J, Sharp TM, Lorenzi O, Delorey M, Munoz-Jordan JL, Tomashek KM, Waterman SH, Alvarado LI, Rivera-Amill V. Predominance of Severe Plasma Leakage in Pediatric Patients With Severe Dengue in Puerto Rico. J Infect Dis. 2022 Nov 28;226(11):1949- 1958. doi: 10.1093/infdis/jiac165.

• Quandelacy TM, Adams LE, Munoz J, Santiago GA, Kada S, Johansson MA, Alvarado LI, Rivera-Amill V, Paz-Bailey G. Reduced spread of influenza and other respiratory viral infections during the COVID-19 pandemic in southern Puerto Rico. PLoS One.

2022 Apr 27;17(4):e0266095. doi: 10.1371/journal.pone.0266095.

• Santiago GA, Flores B, González GL, Charriez KN, Huertas LC, Volkman HR, Van Belleghem SM, Rivera-Amill V, Adams LE, Marzán M, Hernández L, Cardona I, O'Neill E, Paz-Bailey G, Papa R, Muñoz-Jordan JL. Genomic surveillance of SARS-CoV-2 in Puerto Rico enabled early detection and tracking of variants. Commun Med (Lond). 2022 Aug 11;2:100. doi: 10.1038/s43856-022-00168-7.

• Adams LE, Sánchez-González L, Rodriguez DM, Ryff K, Major C, Lorenzi O, Delorey M, Medina FA, Muñoz-Jordán JL, Brown G, Ortiz M, Waterman SH, Rivera-Amill V, Paz-Bailey G. Risk factors for infection with chikungunya and Zika viruses in southern Puerto Rico: A community-based cross-sectional seroprevalence survey. PLoS Negl Trop Dis. 2022 Jun 13;16(6):e0010416. doi: 10.1371/journal.pntd.0010416.

• Tomashek KM, Lorenzi OD, Andújar-Pérez DA, Torres-Velásquez BC, Hunsperger EA, Munoz-Jordan JL, Perez-Padilla J, Rivera A, Gonzalez-Zeno GE, Sharp TM, Galloway RL, Glass Elrod M, Mathis DL, Oberste MS, Nix WA, Henderson E, McQuiston J, Singleton J, Kato C, García Gubern C, Santiago-Rivera W, Cruz-Correa J, Muns-Sosa R, Ortiz-Rivera JD, Jiménez G, Galarza IE, Horiuchi K, Margolis HS, Alvarado LI. Clinical and epidemiologic characteristics of dengue and other etiologic agents among patients with acute febrile illness, Puerto Rico, 2012-2015. PLoS Negl Trop Dis. 2017 Sep 13;11(9):e0005859. doi: 10.1371/journal.pntd.0005859.

Background information about dengue and other arboviruses can be found in the following references:

• Paz-Bailey G, Adams LE, Deen J, Anderson KB, Katzelnick LC. Dengue. Lancet. 2024 Feb 17;403(10427):667-682. doi: 10.1016/S0140-6736(23)02576-X. Epub 2024 Jan 24.

• Cattarino L, Rodriguez-Barraquer I, Imai N, Cummings DAT, Ferguson NM. Mapping global variation in dengue transmission intensity. Sci Transl Med. 2020 Jan 29;12(528):eaax4144. doi: 10.1126/scitranslmed.aax4144.

• Wong JM, Rivera A, Volkman HR, Torres-Velasquez B, Rodriguez DM, Paz-Bailey G, Adams LE. Travel-Associated Dengue Cases - United States, 2010-2021. MMWR Morb Mortal Wkly Rep. 2023 Jul 28;72(30):821-826. doi: 10.15585/mmwr.mm7230a3.

• Tian N, Zheng JX, Guo ZY, Li LH, Xia S, Lv S, Zhou XN. Dengue Incidence Trends and Its Burden in Major Endemic Regions from 1990 to 2019. Trop Med Infect Dis. 2022 Aug 12;7(8):180. doi: 10.3390/tropicalmed7080180.

• Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue.

Nature. 2013 Apr 25;496(7446):504-7. doi: 10.1038/nature12060.

• Shafie AA, Moreira ED Jr, Vidal G, Di Pasquale A, Green A, Tai R, Yoong J.

Sustainable Dengue Prevention and Management: Integrating Dengue Vaccination Strategies with Population Perspectives. Vaccines (Basel). 2024 Feb 12;12(2):184. doi:

10.3390/vaccines12020184.

• Files MA, Hansen CA, Herrera VC, Schindewolf C, Barrett ADT, Beasley DWC, Bourne N, Milligan GN. Baseline mapping of Oropouche virology, epidemiology, therapeutics, and vaccine research and development. NPJ Vaccines. 2022 Mar 17;7(1):38. doi:

10.1038/s41541-022-00456-2.

• Guagliardo SAJ, Connelly CR, Lyons S, Martin SW, Sutter R, Hughes HR, Brault AC, Lambert AJ, Gould CV, Staples JE. Reemergence of Oropouche Virus in the Americas and Risk for Spread in the United States and Its Territories, 2024. Emerg Infect Dis. 2024 Oct 1;30(11). doi: 10.3201/eid3011.241220.

• Morrison A, White JL, Hughes HR, Guagliardo SAJ, Velez JO, Fitzpatrick KA, Davis EH, Stanek D, Kopp E, Dumoulin P, Locksmith T, Heberlein L, Zimler R, Lassen J, Bestard C, Rico E, Mejia-Echeverri A, Edwards-Taylor KA, Holt D, Halphen D, Peters K, Adams C, Nichols AM, Ciota AT, Dupuis AP 2nd, Backenson PB, Lehman JA, Lyons S, Padda H, Connelly RC, Tong VT, Martin SW, Lambert AJ, Brault AC, Blackmore C, Staples JE, Gould CV. Oropouche Virus Disease Among U.S. Travelers - United States, 2024. MMWR Morb Mortal Wkly Rep. 2024 Sep 5;73(35):769-773. doi:

10.15585/mmwr.mm7335e1.

The following studies provide information and examples about the effectiveness and sustainability of community-based vector-borne disease control projects:

• Andersson N, Nava-Aguilera E, Arosteguí J, Morales-Perez A, Suazo-Laguna H, Legorreta-Soberanis J, Hernandez-Alvarez C, Fernandez-Salas I, Paredes-Solís S, Balmaseda A, Cortés-Guzmán AJ, Serrano de Los Santos R, Coloma J, Ledogar RJ, Harris E. Evidence based community mobilization for dengue prevention in Nicaragua and Mexico (Camino Verde, the Green Way): cluster randomized controlled trial. BMJ.

2015 Jul 8;351:h3267. doi: 10.1136/bmj.h3267.

• Quintero J, Ronderos Pulido N, Logan J, Ant T, Bruce J, Carrasquilla G. Effectiveness of an intervention for Aedes aegypti control scaled-up under an inter-sectoral approach in a Colombian city hyper-endemic for dengue virus. PLoS One. 2020 Apr 1;15(4):e0230486.

doi: 10.1371/journal.pone.0230486.

• Roiz D, Wilson AL, Scott TW, Fonseca DM, Jourdain F, Müller P, Velayudhan R, Corbel V. Integrated Aedes management for the control of Aedes-borne diseases. PLoS

Negl Trop Dis. 2018 Dec 6;12(12):e0006845. doi: 10.1371/journal.pntd.0006845.

Erratum in: PLoS Negl Trop Dis. 2022 Mar 22;16(3):e0010310. doi:

10.1371/journal.pntd.0010310.

• Taborda A, Chamorro C, Quintero J, Carrasquilla G, Londoño D. Cost-effectiveness of a Dengue Vector Control Intervention in Colombia. Am J Trop Med Hyg. 2022 Apr 18;107(1):180–5. doi: 10.4269/ajtmh.20-0669.

The following references may be helpful for evaluation and implementation of novel vector control methods, if selected by the community.

• Morrison AC, Reiner RC Jr, Elson WH, Astete H, Guevara C, Del Aguila C, Bazan I, Siles C, Barrera P, Kawiecki AB, Barker CM, Vasquez GM, Escobedo-Vargas K, Flores- Mendoza C, Huaman AA, Leguia M, Silva ME, Jenkins SA, Campbell WR, Abente EJ, Hontz RD, Paz-Soldan VA, Grieco JP, Lobo NF, Scott TW, Achee NL. Efficacy of a spatial repellent for control of Aedes-borne virus transmission: A cluster-randomized trial in Iquitos, Peru. Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2118283119. doi:

10.1073/pnas.2118283119.

• Utarini A, Indriani C, Ahmad RA, Tantowijoyo W, Arguni E, Ansari MR, Supriyati E, Wardana DS, Meitika Y, Ernesia I, Nurhayati I, Prabowo E, Andari B, Green BR, Hodgson L, Cutcher Z, Rancès E, Ryan PA, O'Neill SL, Dufault SM, Tanamas SK, Jewell NP, Anders KL, Simmons CP; AWED Study Group. Efficacy of Wolbachia- Infected Mosquito Deployments for the Control of Dengue. N Engl J Med. 2021 Jun 10;384(23):2177-2186. doi: 10.1056/NEJMoa2030243.

• Lozano S, Pritts K, Duguma D, Fredregill C, Connelly R. Independent evaluation of Wolbachia infected male mosquito releases for control of Aedes aegypti in Harris County, Texas, using a Bayesian abundance estimator. PLoS Negl Trop Dis. 2022 Nov 14;16(11):e0010907. doi: 10.1371/journal.pntd.0010907.

• Beebe NW, Pagendam D, Trewin BJ, Boomer A, Bradford M, Ford A, Liddington C, Bondarenco A, De Barro PJ, Gilchrist J, Paton C, Staunton KM, Johnson B, Maynard AJ, Devine GJ, Hugo LE, Rasic G, Cook H, Massaro P, Snoad N, Crawford JE, White BJ, Xi Z, Ritchie SA. Releasing incompatible males drives strong suppression across populations of wild and Wolbachia-carrying Aedes aegypti in Australia. Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2106828118. doi: 10.1073/pnas.2106828118.

• Ogunlade ST, Meehan MT, Adekunle AI, Rojas DP, Adegboye OA, McBryde ES. A Review: Aedes-Borne Arboviral Infections, Controls and Wolbachia-Based Strategies.

Vaccines (Basel). 2021 Jan 8;9(1):32. doi: 10.3390/vaccines9010032.

• Crawford JE, Clarke DW, Criswell V, Desnoyer M, Cornel D, Deegan B, Gong K, Hopkins KC, Howell P, Hyde JS, Livni J, Behling C, Benza R, Chen W, Dobson KL, Eldershaw C, Greeley D, Han Y, Hughes B, Kakani E, Karbowski J, Kitchell A, Lee E, Lin T, Liu J, Lozano M, MacDonald W, Mains JW, Metlitz M, Mitchell SN, Moore D, Ohm JR, Parkes K, Porshnikoff A, Robuck C, Sheridan M, Sobecki R, Smith P, Stevenson J, Sullivan J, Wasson B, Weakley AM, Wilhelm M, Won J, Yasunaga A, Chan WC, Holeman J, Snoad N, Upson L, Zha T, Dobson SL, Mulligan FS, Massaro P, White BJ. Efficient production of male Wolbachia-infected Aedes aegypti mosquitoes enables large-scale suppression of wild populations. Nat Biotechnol. 2020 Apr;38(4):482-492.

doi: 10.1038/s41587-020-0471-x.

• Sippy R, Rivera GE, Sanchez V, Heras F, Morejón B, Beltrán E, Hikida RS, López- Latorre MA, Aguirre A, Stewart-Ibarra AM, Larsen DA, Neira M. Ingested insecticide to control Aedes aegypti: developing a novel dried attractive toxic sugar bait device for intra-domiciliary control. Parasit Vectors. 2020 Feb 17;13(1):78. doi: 10.1186/s13071- 020-3930-9.

• Aldridge RL, Gibson S, Linthicum KJ. Aedes aegypti Controls AE. Aegypti: SIT and IIT-An Overview. J Am Mosq Control Assoc. 2024 Mar 1;40(1):32-49. doi: 10.2987/23- 7154.

• Jones RT, Ant TH, Cameron MM, Logan JG. Novel control strategies for mosquito-borne diseases. Philos Trans R Soc Lond B Biol Sci. 2021 Feb 15;376(1818):20190802. doi:

10.1098/rstb.2019.0802.

2. Approach The application should describe project implementation for surveillance and community engagement activities to promote project interest and cohort retention throughout the study period. These activities should include regular communication with participants, as well as community education about arboviral disease prevention strategies. Findings from this project can be used to identify and scale successful strategies for dengue prevention and control in Puerto Rico and other endemic areas. The applicant should respond to this NOFO with a full application that includes a proposal and budget for these objectives.

The application should address the following information:

• Describe how this work addresses the public health challenge of dengue and other arboviruses, and how previous work has been used to improve prevention, detection, management, and/or response to AFIs and arboviral diseases in patients or populations.

• Describe how previous research results provided high quality outputs and contributed to improvements in public health practice and population health.

• Summarize any previous collaborations with the project team and in vector-borne disease research; and the type, quality, and use of outputs from that work for informed decision making.

• Describe if the project team has or plans to have staff with sufficient skills in epidemiology and biostatistics to: 1) rapidly and accurately manage, clean, and analyze datasets from surveillance and community cohorts; and 2) create products to disseminate information through presentations, reports, and publications.

• Explain if evidence-based interventions or strategies will be used in the research plan.

• Propose strategies to maximize recruitment and retention of eligible participants so hospital and community cohorts are representative of the population, including groups more likely to be underrepresented such as people who are pregnant, children, and non- English speaking.

• Describe plans to assess if clinical management of dengue and arbovirus patients adheres to WHO guidelines or other evidence-based best practices (such as methods that will be used for medical record review, etc.).

• Describe plans for determining effectiveness and reliability of a dengue rapid diagnostic test, and how standards for evaluating new diagnostics will be adapted to the local situation.

• Describe whether the project uses any existing critical partnerships or collaborations, and how you plan to create new partnerships to implement the project successfully.

• Describe how the project team will maximize and measure community engagement and uptake of information campaigns related to mosquito control and arboviral disease prevention.

• Describe plans to implement nested clinical studies to assess interventions and management approaches, and to better understand short-, medium-, and long-term clinical outcomes of dengue and other arboviruses, particularly in children and pregnant women.

Objectives/Outcomes Objective 1: Strengthen hospital surveillance of acute febrile illness (AFI) to ensure early detection of emerging arboviruses and other pathogens, enabling timely intervention and containment of outbreaks.

Outcomes for Objective 1:

• Each year, approximately 4,000 cases of AFI in the clinical setting are enrolled.

• At least 30% of eligible participants are recruited each year and all required specimens are collected in >95% of recruited participants.

• All (100%) of specimens and their required study forms are prepared for transportation to

CDC for diagnostic testing.

• Epidemiological trends and characteristics of identified pathogens routinely assessed, and relevant interest holders are notified.

• The surveillance system quickly identifies new cases of AFIs and VBDs to improve our ability to respond to both known and unknown threats as a continuation of the Sentinel Enhanced Dengue Surveillance Site (SEDSS) funded by RFA-CK-20-001.

Objective 2: Use the AFI surveillance platform established in Objective 1 to conduct clinical research on dengue and other arboviral diseases, including among special populations such as women and children.

Outcomes for Objective 2:

• Clinical management of dengue patients is evaluated for alignment with WHO 2009 guidelines, ensuring adherence to best practices.

• Collaborative nested clinical studies are implemented with internal and external interest holders to assess interventions and management approaches, and to better understand short-, medium-, and long-term clinical outcomes, particularly in children and pregnant women.

• A comprehensive evaluation of a dengue rapid diagnostic test is conducted to determine its efficacy and reliability.

• Research results contribute to improvements in recommendations and public health practice.

Objective 3: Maintain and enhance the community cohort to assess incidence and prevalence of arboviral infection as well as other AFIs, while also evaluating vector control strategies in selected communities.

Outcomes for Objective 3:

• The sample size for the ongoing community of approximately 3,200 participants cohort is reached. Each year, approximately 250 cases of AFI among the community cohort are enrolled.

• Annual interviews with all cohort participants are conducted to capture information about arboviral illness, vector control, mobility, and other topics relevant to study goals.

• Community engagement activities are implemented to disseminate information on mosquito control and arboviral disease prevention.

• At least 80% of participants are retained each year, including successful collection of specimens for arboviral testing, by using social media and other communications to increase participant engagement, ensure accurate contact information, and minimize loss to follow-up.

• New participants are recruited as necessary to maintain the required study sample size and meet research goals.

• A tracking system (e.g., phone call, SMS, phone app, or other methods) is maintained to contact participating households weekly, identify cases of acute febrile illness, and schedule follow-up visits for those reporting illness within the past 7 days.

• Scheduled visits to households are successfully completed (>90%), with questionnaires administered on illness, care-seeking behavior, including serum and other relevant specimens collected from all household members.

• Specimens are stored and sent to CDC or designated laboratories for diagnostic testing to identify the causes of acute febrile illnesses.

• Diagnostic test results are provided to participants electronically or by mail, ensuring timely communication of health information.

• Epidemiologic trends of arboviral disease and other acute febrile illnesses among participating households and communities are analyzed regularly and reported monthly.

• A robust cohort is maintained to detect shifts in disease patterns, especially with the potential arrival of new threats like the Oropouche virus as established by the Communities Organized for the Prevention of Arboviruses (COPA) supplement to RFA-

CK-20-001.

Objective 4: Strengthen and modernize infrastructure for data management and analysis, ensuring that the surveillance platform is capable of handling large, complex datasets in real-time.

Outcomes for Objective 4:

• Staff are hired or trained on essential data management and analysis skills for the full scope of activities in this funding announcement. This includes, but is not limited to:

using software for data collection and analysis, data management, data quality assessments, troubleshooting problems with data systems and data collection equipment, data analysis, statistical methods, data visualization, output interpretation, and reporting.

• Data are managed using the established data infrastructure, including tracking recruitment and ensuring the quality of questionnaire and clinical data. This includes cleaning data to correct errors or missing information and generating weekly status reports on participant recruitment and questionnaire responses.

• Lab test results are accurately matched to participants, with monthly status reports generated to track specimens and lab results efficiently.

• Cleaned and ready-to-use datasets are generated quarterly for analysis, ensuring consistency and readiness for research activities.

• Descriptive analyses of demographic, clinical, laboratory, and other questionnaire data are routinely performed, and findings are shared with interest holders in quarterly reports and presentations.

• Dedicated staff with expertise in descriptive and analytic epidemiology and/or biostatistics analyze study data to share important findings in presentations, reports, and publications.

• Data from hospital and community cohorts about high-risk and vulnerable populations are used to inform development of strategies to reduce health disparities among people living in Puerto Rico.

• Faster, more accurate epidemiological analyses are performed to support timely decision-making in response to emerging health threats.

Objective 5: Strengthen collaborations with the local government, community leaders, and other interest holders to ensure the continuity of the established program, and foster an environment of rapid communication and cooperation to ensure long-term support for clinical- and community-based surveillance and research platforms.

Outcomes for Objective 5:

• Novel vector control interventions are selected and implemented in collaboration with existing and new partners to combat arboviral diseases in the community cohort.

• Additional interest holders are identified to support clinical- and community-based acute febrile illness surveillance, introduction of novel vector methods, and other key aspects of the surveillance and research platforms.

• Research findings are disseminated through partnerships, encouraging joint efforts and promoting new collaborative research projects.

The key outcome measured from the objectives will be the annual burden of arboviral infection and disease in the community and health care settings. The burden should be assessed by measuring incidence of arboviral disease among patients seeking care in a clinical setting, as well as by measuring incidence of symptomatic arboviral infection and annual prevalence of arboviral infection among households in selected communities in a prospective cohort study. The awardee will be responsible for specimen collection and shipment to laboratories supporting the project. Participants recruited in the clinical setting should be interviewed about risk factors and symptoms at the acute visit and have one follow-up assessment 7 to 10 days after illness onset to collect a convalescent serum specimen and determine severity of illness. Participants in the community cohort should have specimens collected annually for arbovirus testing and should be interviewed to assess community knowledge and practices regarding mosquito bite and arbovirus prevention and the implementation of vector control strategies. Participants in the community cohort should also be engaged in an active surveillance program to identify episodes of acute febrile illness and to test for arboviral infection.

Population of Focus

This NOFO targets populations at risk of infection from arboviruses, such as dengue, Zika, chikungunya, and emerging threats like Oropouche, specifically focusing on residents of Puerto Rico. The tropical climate, high urban density, and limited healthcare access make Puerto Rican communities particularly vulnerable to these mosquito-borne illnesses. Socio-economic challenges and environmental factors further exacerbate these risks, leading to disproportionately higher rates of arboviral diseases.

The application should focus on identifying the most at-risk populations within the project area, using relevant data including social determinants of health, to pinpoint communities disproportionately affected by these public health threats. These populations may include individuals from racial or ethnic minority groups, those with lower socioeconomic status, those with limited health literacy, and non-English-speaking populations. The applicant is encouraged to design and implement strategies that reduce these disparities.

To ensure inclusivity, project activities should be conducted in both Spanish and English, and efforts should be made to recruit trusted local staff to engage directly with communities. CDC requires the applicant to clearly identify the population characteristics of those included in NOFO activities, as this information is critical for evaluating the effectiveness and applicability of public health interventions across different groups. Additionally, the applicant should ensure that the program is accessible to all populations and strive to reach people and communities that may otherwise not have been included without intentional public health efforts.

Collaboration/Partnerships The application should explain how the project team will maintain long-term partnerships with key collaborators to increase project feasibility and sustainability. Potential collaborations are expected with the following groups:

• Local hospital systems, academic institutions, and the Puerto Rico Department of Health (PRDH) to achieve the desired outcomes at the hospital-based surveillance of acute febrile illness sites.

• Community partners and interest holders for the community-based longitudinal cohort to monitor arboviral disease. These partnerships may include local government (e.g., PRDH, Department of Education, Department of Agriculture, and Department of Natural Resources), community leaders, community representatives, private schools, health care providers, and other service providers. The award recipient may convene community advisory boards to assist with planning activities; these boards are not advisory boards to

CDC.

• Vector control programs, arboviral disease surveillance staff, and other surveillance or prevention program staff, as appropriate, for the successful implementation of the projects.

• Academic and public health partners with expertise in qualitative and quantitative methods to conduct research activities and project evaluation.

• Collaborating laboratories to conduct specimen preparation, shipment, and testing.

Evaluation/Performance Measurement The application should include measurable goals and aims based on 5-year research period of performance. The application should describe specific, measurable, achievable, realistic, and time-phased (SMART) project objectives for each activity described in the application’s project plan and describe the development and implementation of project performance measures based on specific programmatic objectives.

The applicant is required to develop a comprehensive evaluation plan that aligns with the objectives and outcomes outlined in this NOFO. The evaluation plan should describe how the applicant will measure the effectiveness and impact of activities, ensuring continuous improvement and successful achievement of program goals. The applicant must allocate sufficient staffing, resources, and expertise to support the evaluation activities, with specific attention to the following components:

Surveillance and Cohort Maintenance: The applicant must track recruitment efforts (minimum 30% of eligible participants), participant retention (minimum 80% annually), specimen collection (at least 95% of recruited participants during initial visit and 30% of convalescent visits in SEDSS), and diagnostic result matching (minimum 100%) to ensure complete and timely data collection. Performance will be measured by the successful conduct of community and clinic-based surveillance, annual interviews of community cohort participants (>90%), participant retention (minimum of 80% for community cohort), replacement, specimen collection and submission to CDC, notifications of results to participants, compliance with convalescent visit, implementation of clinical studies, completion of scheduled interviews and visits to households, and the regular reporting of epidemiologic trends.

Data Management and Analysis: Evaluation should include monthly assessments of data quality (timeliness, completeness, and errors), including data cleaning, specimen tracking, and lab result reporting. The recipient will be required to demonstrate the following: 1) annual improvements in the number and expertise of staff involved in data management; 2) quality assurance, database troubleshooting and maintenance; and 3) reporting of findings conducted from descriptive and advanced data analyses to interest holders. Data quality indicators of timeliness, completeness, and number of errors should improve over time.

Interest holders Engagement: The applicant must evaluate the success of interest holders’ collaboration, including the implementation of vector control interventions (combined with efforts to build community buy-in), dissemination of research findings, and engagement with new and existing partners. Performance indicators will include the number of collaborative studies initiated (particularly in pregnant women and children) and the integration of interest holders feedback into project activities. Additional indicators include uptake of findings and recommendations by interest holder groups (e.g., policy changes, etc.), and number and types of target interest holders who participate in meetings.

Impact of Interventions: Assessments of the effectiveness of clinical management and vector control interventions will be conducted using both clinical and community data, with regular monitoring of incidence trends and health outcomes. Research results should provide high quality outputs that contribute to public health recommendations and improvements in public health practice. Performance for information campaigns about mosquito control and arboviral disease prevention can be measured by setting and reaching targets for community engagement during outreach (e.g., number of webpage visits, etc.).

Diagnostics: Global standards for assessing effectiveness and reliability for a new dengue rapid diagnostic test are identified, adapted for the local situation, and implemented.

The applicant is expected to provide monthly and quarterly reports on key performance indicators, ensuring timely feedback for adaptive management of the project. All evaluation activities should be designed to assess the applicant’s ability to: 1) conduct this project independently; 2) adequately provide community and clinical follow-up; 3) measure impact of the program on reducing disease burden; 4) improve public health response; and 5) ensure program sustainability.

Translation Plan The application should describe how research findings will be disseminated through presentations to interest holders, reports, and peer-reviewed publications to develop strategies and guidelines for control and prevention of tropical arboviral diseases. For surveillance findings, the applicant should describe how they will be used in Puerto Rico to raise awareness and improve clinical management of dengue and other acute febrile illnesses for which delays in clinical diagnosis and initiation of appropriate management can result in increased morbidity and mortality. In addition, knowledge of the epidemiology, seasonality and incidence of tropical arboviruses and other AFI can be used by the Puerto Rico Department of Health and other public health agencies to direct limited resources, plan interventions, and inform educational campaigns.

The application should include communication strategies such as regular interest holder meetings, seminars, trainings, and national and international…