Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial not Allowed)

PA-20-184 - NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-196 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Purpose

Purpose and Rationale

As of October 14 2021, 6,177,946 SARS-CoV-2 positive pediatric cases (0-18 years) have been reported in the USA since the pandemic began. 925,000 children were SARS CoV-2 positive in August 2021, representing an almost six-fold increase since July 2021. 850,000 new cases have been reported in September and October 2021. Severe respiratory illness with COVID-19 remains less common in children than in adults. However, during September and October 2021, pediatric hospitalizations for COVID-19 related respiratory illness (1.4 % of pediatric COVID-19 cases in states that reported) have increased five-fold. Hospitalization for COVID-19 in younger children (0- 4 years) and unvaccinated adolescents has increased ten-fold. While there is Emergency Use Authorization (EUA) of the COVID-19 vaccine in children who are 5 years of age or older, children younger than 5 years of age continue to be unvaccinated and hence vulnerable to infection, particularly during the coming winter months, when most respiratory viruses also peak in incidence and severity, particularly in younger, unvaccinated children.

People with SARS-CoV-2 infection tend to be more predisposed to co- infection with other respiratory microbes than those who are not SARS-CoV-2 positive . A higher incidence of viral co-infection in SARS-CoV-2 infected children (12%) compared to SARS-CoV-2 infected adults has also been reported. Earlier in the pandemic, non-pharmacological interventions (NPI), such as masking and physical distancing, resulted in dramatic reduction in illness and hospitalization from other respiratory viruses, such as the respiratory syncytial virus (RSV). Relaxation of lockdown measures/NPI has led to co-emergence of respiratory viruses and SARS-CoV-2 (particularly the Delta variant), the latter predominantly in children who are not vaccinated yet. Further, an unseasonal increase in RSV infections has been reported, with a documented surge in infections in the summer months from May 2021 that is significantly increased compared to previous years. Co-infection with respiratory viruses, particularly RSV with SARS-CoV-2 is resulting, in preliminary surveys, in severe respiratory disease in children and young adults, with a few reports of evidence of chronic ongoing lung damage in babies.

A survey of weekly pediatric intensive care unit (PICU) admissions of children (0-18 years of age) with COVID-19 in the USA and worldwide during September and October 2021 suggests that severe disease from COVID-19 with respiratory manifestations may be becoming more common, with the majority of patients in the PICU being unvaccinated, and greater than 50% of admissions being severely critically ill. A significant percentage of patients admitted to intensive care units demonstrate co-infection predominantly with Rhinovirus or RSV, and also enteroviruses and influenzas.

Viral co-infections may influence the trajectory of the virus as it makes its way around the globe. However, the impact of co-infection with COVID-19 and other viruses (e.g., RSV, Influenza, Rhinovirus, Parainfluenza and Metapneumovirus) in children, and whether co-infections increase vulnerability to SARS-CoV-2 disease or vice versa remains unknown. The pathobiology of innate and adaptive immunity in the setting of co-infection and the impact of co-infections to vaccines (e.g., primary vaccinations, COVID-19 and/or the influenza vaccine) and vice versa need elucidation. The increased severity of RSV may also provide an opportunity to study severe RSV in existing cohorts enriched for genetic susceptibility to severe disease.

This NOSI is intended to support projects that will employ existing and new clinical trial cohorts/observational cohorts to screen for co-infection, phenotype and collect biospecimens to answer some of these questions and to encourage investigator-initiated applications for basic, translational and human subject research (not clinical trials) in this space.

Selected Research Examples:

• Does past or concurrent SARS-CoV-2 infection impact susceptibility to and increased severity from infections caused by RSV and other viruses in children?
• Does co-infection with RSV and other respiratory viruses increase severity of SARS CoV-2 in the lower respiratory tract in children?
• What is the pathobiology of SARS-COV-2 co-infection with RSV and/or other respiratory viruses?
• What predisposes some children to severe respiratory COVID-19, with a focus on under-represented minorities, childhood obesity and social determinants such as overcrowding?
• Does COVID-19 (including infection with Delta variants, and other mutant forms) favor co-infection with RSV and other respiratory viruses? If so, what is the clinical presentation and pathobiology?
• Does co-infection with RSV, rhinoviruses and other respiratory viruses impact SARS-CoV-2 entry into nasal epithelial cells?
• Does co-infection with RSV, rhinoviruses and other respiratory viruses affect systemic and local (upper airway mucosal) pediatric immune responses leading to increased susceptibility to SARS-CoV-2?
• Does the lymphopenia ubiquitously associated with SARS-CoV-2 infection increase vulnerability to severe lower respiratory tract disease from other viruses in childhood?
• Does SARS-CoV-2 infection affect systemic and local (upper airway mucosal) pediatric immune responses leading to increased susceptibility to other respiration tract infections?
• What is the immune response to co-infections at different ages?
• What is the impact of respiratory viral co-infections with SARS-COV-2 on special populations- such as premature babies, children with recurrent wheezing, chronic rhinitis, asthma, obesity, Down Syndrome, cystic fibrosis, sickle cell disease and other chronically critically ill children?
• What is the effect of respiratory viral co-infections and Influenza and/or COVID-19 vaccination on clinical presentation and outcomes?
• How does COVID-19 vaccination in children impact the epidemiology of co-infections?
• Can existing in vitro or animal models of viral infections help elucidate the pathobiology of co-infection and guide data and sample collection in existing pediatric cohorts?
• Which demographic and clinical factors predispose some children to severe respiratory SARS-CoV-2/other respiratory virus co-infectivity with emphasis on less represented populations, childhood obesity and social determinants such as poverty and overcrowding?
• How does co-infection with SARS-CoV-2 and other respiratory viruses impact pediatric development, including immune system development and function?

Application and Submission Information

This notice applies to due dates on or after February 5, 2022 and subsequent receipt dates through September 8, 2025.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice:

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-HL-22-004 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Scientific/Research Contact(s)

Aruna Natarajan, MD, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Division of Lung Diseases
Telephone: 301-827 -0180
Email: aruna.natarajan@nih.gov

Tessie October, MD, MPH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-6757
Email: tessie.october@nih.gov

Sonnie Kim, MS
National Institute of Allergy and Infectious Diseases (NIAID)
Division of Microbiology and Infectious Diseases
Telephone:240-627-3287
Email: sonnie.kim@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8014
Email: agrestia@nhlbi.nih.gov

Maggie Young
Eunice Kennedy Shriver NICHD National Institute of Child Health and Human Development (NICHD)
Telephone: (301) 642-4552
Email: Margaret.young@nih.gov

Dhana Khurana
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2966
Email: vandhana.khurana@nih.gov