The COVID-19 pandemic has revealed a frightening reality; the course of infection with this disease is highly variable. Some young patients have died from the virus, whereas some elderly people have survived without experiencing respiratory symptoms at all. Researchers are left wondering: why?
For illuminating factors that underlie these varied susceptibilities — through efforts that began with biking through eerily quiet Parisian streets in the earliest pandemic days to collect blood samples — Paul Bastard is the grand prize winner of the inaugural Michelson Philanthropies & Science Prize for Immunology.
Bastard's hope is that his findings about the impairment of specific immune mechanisms in those who have suffered most from COVID-19 will pave the way for the adoption of precision medicine approaches for this disease, and for infectious diseases more broadly.
"The precision medicine approach would let us give the patient the treatment that would help the most with the least side effects," said Bastard, a researcher at the Imagine Institute (INSERM, University of Paris) in Paris, France, and the Rockefeller University in New York, New York. It would also enable researchers to target particularly vulnerable patients, to help them avoid severe disease.
Bastard has been interested in the question of why infection with SARS-CoV-2 (the virus that causes COVID-19) is fatal in only some people — and how to treat this group — since the earliest days of the pandemic.
"As COVID-19 emerged in France, I went to help for a few weeks in the hospital where my wife worked," Bastard said. "I was a pediatrician suddenly taking care of elderly patients with an unknown disease. The whole building was now exclusively for COVID-19 patients. It was quite terrible as people who were previously healthy would need oxygen and treatment in the intensive care unit, and unfortunately often died. It was a huge motivation for me to try to understand why this was happening in order to be able to help."
Sampling During Lockdown
Through a consortium established in February 2020 to understand varied COVID-19 outcomes — the COVID Human Genetic Effort (CHGE) — Bastard and many colleagues across the world were able to recruit patients with varying degrees of clinical outcome. CHGE was established by Jean-Laurent Casanova of Rockefeller University and Helen Su of the National Institute of Allergy and Infectious Diseases.
"When the CHGE was initiated," Bastard said, "the aim was to recruit as many people as possible — with either life-threatening COVID-19 or very mild or asymptomatic infection." The researchers sequenced these patients' genome components that code information for protein-making to test their hypothesis that some individuals with life-threatening COVID-19 had underlying errors in their immune systems.
Working in the laboratory of human genetics of infectious diseases of Jean-Laurent Casanova and Laurent Abel and being affiliated with the consortium allowed Bastard and colleagues to swiftly recruit samples from a large number of patients, for their genetic and immunological studies.
"In France I remember starting the recruitment during the first lockdown. It was early March 2020, and I went on my bike all around the hospitals in Paris and nearby suburbs to collect blood samples from patients. The city was completely empty, and all delivery services were shut down, so I was assigned a special authorization to collect these COVID-19 samples. Initially, we would recruit a few patients a day, but we soon received many more."
The results of the sequencing studies from this large pool revealed something consistent in some of the hospitalized patients suffering from severe COVID-19: a glitch in type I interferon (IFN) signaling.
Type I IFNs, secreted by cells when they are infected, normally help fight viruses. In some individuals, however, the body had previously developed an autoimmune response with autoantibodies attacking type I IFNs and blocking their antiviral effect, as Bastard was observing. This abnormal reaction can then exacerbate harmful inflammation and disease.
Identifying autoantibodies against IFN as a driver of severe COVID-19, especially in older patients but also in many younger patients presenting with life-threatening COVID-19, provided clues to the reasons why COVID-19 is fatal for some individuals. The pattern suggested to Bastard that screens could help identify patients at the highest risk of life-threatening complications from SARS-CoV-2 infection.
"These patients would really benefit from being identified as early as possible — even before SARS-CoV-2 infection — getting vaccinated, and being treated at onset of disease to prevent severe disease," he said.
Bastard explained that screening for autoantibodies against type I IFNs could be relatively easily done using a technique called "ELISA" routinely used in biology labs. "There are already several labs and hospitals in France and abroad that have implemented it … which is absolutely thrilling for me to hear."
As part of their study of autoantibodies against IFNs in COVID-19 patients, Bastard and colleagues uncovered that they appear to increase in prevalence with age in the general population, though the researchers don't know why. "It could be because the aging of the immune system becomes more 'permissive' to these autoantibodies," he said. He writes in his prize-winning essay that there may be a role for autoantibodies against type I IFNs in many other viral diseases (like influenza) that also increase in severity with age.
Bastard helped other colleagues identify a second factor underlying severe COVID-19 outcomes: rare mutations in genes controlling type I IFNs, for example the gene which encodes the receptor TLR7 that is involved in initiating type I IFN responses. Screening for these mutations, while a little more difficult, could also be implemented, he said.
"Having information [about the presence of these mutations] before patients contracted COVID-19 would give the physicians the opportunity to administer the missing interferons to the patients in order to avoid severe disease," said Bastard.
Collectively, data from the efforts of Bastard and his colleagues stands to help physicians formulate the best course of treatment for at-risk patients.
"This research stood out to the Science editors and judges for its exceptionally important identification of factors that can contribute to COVID-19 severity, and which can be recognized prior to infection allowing people with particular vulnerabilities to protect themselves. More broadly, this work may also help explain some of the variability seen in immune responses to other viruses and help inform clinical practice in the years to come," said Seth Thomas Scanlon, associate editor at Science.
The Michelson Philanthropies & Science Prize for Immunology focuses on transformative research in human immunology, with trans-disease applications to accelerate vaccine and immunotherapeutic discovery. This international prize is intended to encourage and support young investigators from a wide range of disciplines. It is awarded annually to one young scientist based on work done in the past three years.
"It is really a huge honor for me to receive such an important prize," said Bastard. "Although I am receiving it, the work that was done here is that of a very large team of people in our lab and outside — led by Qian Zhang and Jean-Laurent Casanova — without whom none of it would have been possible. Winning this prize is really a recognition of all of this work and of our field."
"This is the kind of brilliant and disruptive thinking that will change the trajectory of immunology," said Gary Michelson, founder and co-chair of Michelson Philanthropies. "We are proud, through this partnership with Science, to support the next generation of innovators and provide a renowned platform for their research. Early career investigators with bold concepts do not receive traditional funding. This award shines a spotlight on the problem of not funding the people who are at the ideal intersection of intellect, knowledge, imagination, daring and perseverance."
Lisa Wagar is a finalist for her research deciphering immune responses to viruses and vaccines using human tonsil organoids. Wagar received a BSc from the University of Ontario Institute of Technology and a Ph.D. from the University of Toronto. After completing her postdoctoral fellowship at Stanford University, Wagar started her lab in 2020 in the department of physiology and biophysics at the University of California, Irvine where she is currently an assistant professor. Her research focuses on translational human immunology and the use of organoids to understand the complex interactions that occur between immune cells upon vaccination and infection in humans.
Scott B. Biering is a finalist for his research revealing how a conserved flavivirus protein holds potential as a target for versatile vaccines and therapies. Biering received undergraduate degrees from the University of California, Los Angeles and a Ph.D. in microbiology from the University of Chicago. He is currently a postdoctoral scholar at the University of California, Berkeley in the laboratory of Eva Harris. His present research investigates the role of viral proteins in inducing viral pathogenesis and promoting viral dissemination.