Adaptive immunity and immune memory to SARS-CoV-2

Shane Crotty, Ph.D., is Professor the Centre for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology (LJI). His research focus is on understanding the immunobiology underlying vaccine function, with particular interest in the roles of these mechanisms in human viral vaccines and protection from infectious diseases. At University of California, San Francisco he discovered a mechanism of action of the antiviral drug ribavirin (Nat. Med. 2000, PNAS 2001), widely used to treat chronic hepatitis C infections. He completed postdoctoral work at the Emory University Vaccine Center with Dr. Rafi Ahmed, studying aspects of the generation and maintenance of immune memory after viral infections. Since 2003, his laboratory at LJI has focused on understanding mechanisms of immunological memory (Nature 2003, J. Exp Med. 2006, J. Immunology 2007), the immunological basis for the development of protective neutralizing antibodies to the smallpox vaccine (J. Virology 2005, 2008, 2009, and 2009. Immunity 2008, Vaccine 2009), the interactions of B cells and CD4 T cells (Immunity 2008, Science 2009, Immunity 2011), and the development of follicular helper CD4 T cells (Science 2009, Immunity 2011, Annual Review of Immunology 2011)

Prof Crotty his team study immunity against infectious diseases. They investigate how the immune system remembers infections and vaccines. By remembering infections and vaccines, the body is protected from becoming infected in the future. Vaccines are one of the most cost-effective medical treatments in modern civilization and are responsible for saving millions of lives. Yet, good vaccines are very difficult to design, and very few new vaccines have been made in the past 10 years. A better understanding of immune memory will facilitate the ability to make new vaccines. Dr. Tony Fauci, NIH, referred to some of the Crotty lab work as “exceedingly important to the field of immunogen design.”

Dr. Crotty is a member of the LJI Coronavirus Task Force. The Crotty Lab, in close collaboration with the lab of LJI Professor Alessandro Sette, Dr. Biol. Sci., was the first to publish a detailed analysis of the immune system’s response to SARS-CoV-2, the virus that causes COVID-19 (Cell, May 2020). The made a number of important findings. Most importantly, it showed that the immune system activates all three major branches of “adaptive immunity” (which learns to recognize specific viruses) to try to fight the virus: CD4 “helper” T cells , CD8 “killer” T cells, and antibodies. The LJI team found good immune responses to multiple different parts of SARS-CoV-2 (imagine the virus is made out of legos, and the immune system can recognize different individual legos), including the Spike protein, which is the main target of almost all COVID-19 vaccine efforts. This research helped dispel fears that the virus would elude efforts to create an effective vaccine. This scientific study had served as an important benchmark of immune responses for clinical studies and COVID-19 vaccine studies around the world, as evidenced by how extensively the study is being quoted (cited) in the scientific literature. It has also become the #1 most public attention getting Cell paper ever, according to Almetric.

Drs. Crotty and Sette also found that crossreactive immune memory appeared to exist in ~50% of unexposed, healthy people (Cell, May 2020). They inferred this might be due to previous infections with common cold coronaviruses. The LJI team went on to show that crossreactive memory T cells that recognize common cold coronaviruses also recognize matching sites on SARS-CoV-2 (Science, August 2020). The research may explain why some people have milder COVID-19 cases than others—though Crotty and Sette emphasize that this is speculation and much more data is needed (Nature Reviews Immunology, July 2020). Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, has shared this research with Congress, describing the study as “work we really need to pursue. We’re just at the cusp of really understanding the importance of this type of response in COVID.”

The Crotty Lab’s COVID-19 research has informed vaccine efforts worldwide. As highlighted by Voice of America, this work builds on what scientists have learned about past vaccines and the experimental approaches that may bring a COVID-19 vaccine to patients quickly. As Dr. Crotty has said, “I think there is good reason for optimism, but it’s not like in the movies. It takes a lot of people and a lot of time and effort to puzzle it out.”

Host: A/Prof Ian Cockburn, Immunology and Infectious Disease Department