Defining the risk of SARS-CoV-2 variants on immune protection.

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures.

Systematic discovery of TLR signaling components delineates viral-sensing circuits.

Deciphering the signaling networks that underlie normal and disease processes remains a major challenge. Here, we report the discovery of signaling components involved in the Toll-like receptor (TLR) response of immune dendritic cells (DCs), including a previously unkown pathway shared across mammalian antiviral responses. By combining transcriptional profiling, genetic and small-molecule perturbations, and phosphoproteomics, we uncover 35 signaling regulators, including 16 known regulators, involved in TLR signaling. In particular, we find that Polo-like kinases (Plk) 2 and 4 are essential components of antiviral pathways in vitro and in vivo and activate a signaling branch involving a dozen proteins, among which is Tnfaip2, a gene associated with autoimmune diseases but whose role was unknown. Our study illustrates the power of combining systematic measurements and perturbations to elucidate complex signaling circuits and discover potential therapeutic targets.

US National Institutes of Health Prioritization of SARS-CoV-2 Variants.

Since late 2020, SARS-CoV-2 variants have regularly emerged with competitive and phenotypic differences from previously circulating strains, sometimes with the potential to escape from immunity produced by prior exposure and infection. The Early Detection group is one of the constituent groups of the US National Institutes of Health National Institute of Allergy and Infectious Diseases SARS-CoV-2 Assessment of Viral Evolution program. The group uses bioinformatic methods to monitor the emergence, spread, and potential phenotypic properties of emerging and circulating strains to identify the most relevant variants for experimental groups within the program to phenotypically characterize. Since April 2021, the group has prioritized variants monthly. Prioritization successes include rapidly identifying most major variants of SARS-CoV-2 and providing experimental groups within the National Institutes of Health program easy access to regularly updated information on the recent evolution and epidemiology of SARS-CoV-2 that can be used to guide phenotypic investigations.

The Landscape of NIAID-funded Observational COVID-19 Cohort Studies.

The spread of SARS-CoV-2 since late 2019 represented an unprecedented public health emergency, which included a need to fully understand COVID-19 disease across all ages and populations. In response, the US National Institute of Allergy and Infectious Diseases (NIAID) rapidly funded epidemiology studies that monitored COVID-19. However, the diversity and breadth of the populations studied in NIAID-funded COVID-19 observational cohorts were not easy to extrapolate because of siloed approaches to collect and report data within NIAID. Here, we describe the effort to develop a harmonized cohort study reporting tool that includes common epidemiological data elements as well as NIAID priorities. We report its implementation to analyze metadata from 58 COVID-19 cohort studies funded February 2020 to June 2021, visualize key metadata including geographic distribution, study duration, participant demographics, sample types collected, and scientific priorities addressed. A bibliographic analysis highlights the scientific publications and citations across these funded studies and demonstrates their enormous impact on the COVID-19 field. These analyses highlight how common data elements and reporting tools can assist funding agencies to capture the landscape and potential gaps during public health responses and how they can assist in decision making.

The neutralizing antibody response against West Nile virus in naturally infected horses.

A major neutralizing epitope (here referred to as the T332 epitope) located on the lateral surface of domain III (DIII) of the West Nile virus (WNV) envelope protein has been identified based on the analysis of murine monoclonal antibodies. However, little is known about the humoral immune response against WNV in a natural host or whether DIII in general or the T332 epitope in particular are important targets of neutralizing antibodies in vivo. To characterize the types of antibodies produced during infection with WNV, we studied a group of naturally infected horses. Using immune adsorption assays coupled with the use of virus particles bearing mutations in the T332 epitope, we found that in some animals neutralizing activity against DIII and the T332 epitope was below the limit of detection. In contrast, some animals generated a significant fraction of neutralizing activity to DIII and the T332 epitope. Thus, while antibodies to the T332 epitope did not represent a significant fraction of the total antibody response in the infected animals studied, in some horses, they comprised a significant fraction of neutralizing activity, making this an important but far from dominant neutralizing epitope. Rather, the neutralizing response to WNV generated in infected horses is both variable and polyclonal in nature, with epitopes within and outside of DIII playing important roles.