From the Deputy Director for Intramural Research

How the NIH Intramural Program Is Fighting the COVID-19 Pandemic

Michael Gottesman

Given the constant presence of NIH leaders such as NIH Director Francis Collins and National Institute of Allergy and Infectious Diseases (NIAID) Director Anthony Fauci in the popular press, on TV and radio and in print, and in commentaries in academic journals, it is clear that the NIH has played a major role in strategic planning, communication of public-health requirements, and development of strategies to prevent, detect, and treat infection caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), the virus responsible for COVID-19. What may not be as clear to many intramural staff are the major contributions that have been made over the past year by intramural—and extramural—scientists, working in teams and as independent contributors, to the science underlying our current understanding of the diagnosis, prevention, therapy, and pathophysiology of COVID-19.

Early in the COVID-19 pandemic, we sought to document the contributions of our intramural scientists to the antipandemic effort by creating a dashboard in collaboration with Christine Cutillo (National Center for Advancing Translational Sciences, NCATS) listing all of the projects being carried out in the intramural research program (IRP). Currently, there are 23 institutes and centers involved in COVID research with about 400 active projects—ranging from basic science to preclinical research to clinical trials—and 313 distinct PIs. The research areas are equally divided between immunology–host response and therapeutic (drugs and biologics) at 14%; 10% in pathogenesis; 8% in genetics and genomics; and 7% in structural biology. Bioinformatics, virology, computational and systems biology, diagnostics, epidemiology, and vaccines are all in the 6% range. Natural history, clinical trial, and mental and behavioral health are in the 2–5% range. There are 63 reagents available in the registry. When the IRP dashboard was being developed, a resource center collating NIH COVID-19 related resources and tools was also created to enhance sharing and coordination; both the dashboard and the resource center can be accessed via the NCATS COVID-19 Resource Center (NIH PIV card required).

Many of these research activities were highlighted in the October 29–30, 2021, workshop organized by the NIH COVID-19 Scientific Interest Group (chaired by Pam Schwartzberg, NIAID) and colleagues at the FDA. In addition, the Office of Intramural Research, with funding by NIAID, provided grant support for intramural scientists as part of the Intramural Targeted Anti-COVID-19, a competition overseen by Ted Pierson in NIAID. Of 159 applications, 40 were funded.

There have been so many important intramural contributions to the COVID-19 effort that it is difficult to choose just a few to highlight in this essay, but I will do my best (and I hope that the architects of the equally important work that is not cited do not feel slighted).

The most obvious is the contribution of the dedicated team at NIAID’s Vaccine Research Center (VRC) to the development of a structure-based vaccine. Since the SARS outbreak in 2002–2004, VRC Deputy Director Barney Graham and his many talented associates and colleagues, including Kizzmekia Corbett, (NIAID), have been working on the general principles for creating vaccines to counteract significant coronavirus epidemics. Targeting the coronavirus spike (S) protein, they discovered (with their collaborator Jason McLellan, an alumnus of the VRC and now at the University of Texas at Austin), that substitutions of two prolines between two key areas would stabilize the S protein in its native functional conformation. This engineered structure has become the basis for many of the vaccines under current development, all of which have proven to be exceptionally effective in preventing SARS-CoV-2 symptomatic infections. Specifically, this variant is encoded by the messenger RNA present in the Pfizer and Moderna vaccines. It is also encoded by the adenovirus type 26 vaccine vector in the Johnson and Johnson–Janssen vaccine.

In the area of therapeutics, NCATS has done extensive work to screen existing drugs to be repurposed for treatment of SARS-CoV-2 infection. In addition, the team of Emmie de Wit and Vincent Munster at NIAID’s Rocky Mountain Laboratories (Hamilton, Montana) was one of the first to demonstrate the efficacy of the antiviral agent remdesivir in rodents and nonhuman primates. Their work accelerated the development of this agent for treatment of hospitalized patients with moderate to severe COVID-19; remdesivir remains a standard of care.

There have been many contributions to understanding the structure of the virus and how it enters and leaves cells. In addition to the pioneering and elegant structural work from the Graham group, NIH structural biologists throughout the IRP have explored the structure of the S protein–angiotensin-converting enzyme 2 receptor complex, providing a much better understanding of the early steps in viral entry.

Also relevant to viral entry, the team led by Kelly Ten Hagen (National Institute of Dental and Craniofacial Research) showed that furin cleavage in SARS-CoV-2 is modulated by mucin type O glycosylation, which possibly explains why the UK B.1.1.7 variant is more transmissible than the other variants, because some of the mutations in this variant are close to this site. At the other end of the viral replication cycle, Nihal Altan-Bonnet (National Heart, Lung, and Blood Institute) demonstrated that SARS-CoV-2 uses a lysosomal pathway to leave cells, an unexpected finding that could have important therapeutic implications.

Considerable progress has also been made in understanding what host factors predispose someone to severe disease. Helen Su and Luigi Notarangelo, NIAID, in collaboration with the laboratory of Jean-Laurent Casanova at Rockefeller University (New York), showed that in up to 15% of persons severely ill with COVID-19, defects in the pathways involved in the action of type 1 interferons (interferons alpha and omega), caused either by mutations or neutralizing autoantibodies, played a significant role. This work reinforces the role that even subtle defects in the immune system play in susceptibility to severe viral infection and may lead to potential therapies for severely ill patients who have such defects.

Although these examples don’t begin to touch the tip of the coronavirus iceberg at NIH, I think they are pretty “cool” science. We can expect much more to come.