A group of nearly 70 academic scientists, doctors, and biotech leaders sent a letter with an unusual request to the US Food and Drug Administration on Thursday: Please pay more attention to T cells, an overlooked part of the immune system that helps clear up viral infections.
For much of the pandemic, COVID-19 vaccine developers and researchers have largely focused on studying antibodies induced by the shots. Neutralizing antibodies, which many labs are skilled at measuring, are essential for preventing the coronavirus from infecting our cells in the first place.
Earlier in the pandemic, the Pfizer and Moderna shots triggered high levels of antibodies that prevented 95 percent of infections. But as new variants emerged, fewer of those antibodies were able to recognize the changing virus. Booster shots can help raise the level of helpful antibodies, but protection against infection is short-lived.
“Short-term neutralizing antibody responses are certainly important but not the entire picture, and they may not always be the most relevant immune parameter in protection against COVID-19,” said Dr. Dan Barouch, one of the scientists who signed the letter to the FDA, and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center.
Some studies published over the past few months, including ones from Barouch’s lab, suggest that T cells can still recognize and clear up Omicron infections. “T cell responses are also likely important for long-term durable protection against severe disease, particularly with viral variants that largely escape antibodies,” he said.
“I’d like for the FDA and scientists to better appreciate the valuable role T cell immunity plays in saving lives and the importance of collecting T cell data in vaccine clinical trials and including these data in vaccine reviews,” said Dr. Rick Bright, chief executive of the Pandemic Prevention Institute, who also signed the letter.
“By developing and standardizing assays to measure and monitor T cell responses, we will be much better informed about existing and future vaccine development and optimization options,” Bright added.
The durability of immune responses is particularly important since many experts say it is unreasonable to expect people to continue getting booster shots to raise antibody levels every three to six months. Doctors were split on their reactions to the FDA’s recent authorization of second booster shots for people age 50 and older.
E. John Wherry, an immunologist at the University of Pennsylvania who helped draft and organize the letter to the FDA, said that the durability of T cell immunity may partially explain why the vaccines are still able to protect most people from severe disease, hospitalizations, and death, even though mild infections are still common with Omicron.
“Although some trials and studies do include analysis of T cell responses, this is typically not asked for by the FDA and T cell data is often not part of the decision-making discussion,” Wherry said. He hopes the letter to the FDA will spur the agency to actively encourage more research on T cell responses in vaccine trials. Understanding all types of immunity, and not just antibodies, is important for having better definitions of what it means to be “protected” going forward, Wherry said.
The letter, which was addressed to FDA commissioner Dr. Robert Califf and vaccine chief Dr. Peter Marks, pointed out that the single-minded focus on neutralizing antibodies is particularly evident in the FDA’s review of COVID vaccine trials in teens, children, and infants. Because people in these age groups are less likely to develop severe coronavirus infections, the FDA authorized COVID vaccines for children based on studies showing that the shots induce antibody levels similar to those seen in adults.
The FDA delayed review of Pfizer’s vaccine for children under 5 because the antibody levels were not high enough, but the group wrote that a better understanding of T cell responses in the young children “may have informed decisions regarding potential authorization of the vaccines in this population.”
“A number of us in our private conversations were growing frustrated by the heavy emphasis on antibodies and, in contrast, the ignoring of cellular immunity,” said Dr. Lance Baldo, who helped draft and organize the letter, and is chief medical officer of the cancer blood-testing startup Freenome.
Until recently, Baldo was chief medical officer of Seattle-based Adaptive Biotechnologies, which makes tests to measure T cell responses to past COVID infections. He helped draft the letter to the FDA, and the firm’s current chief executive and chief scientific officer signed it.
The letter pointed to studies of Omicron in South Africa as evidence of the importance of T cells. Many people in the country who had two doses of the Johnson & Johnson or Pfizer vaccines did not have high enough levels of neutralizing antibodies to prevent Omicron infections. But the vaccines still protected most people from developing severe disease that required hospitalization, likely thanks to their T cells.
Part of the reason for the focus on antibodies is that they are easier to collect and study than T cells. Dr. William Morice, a blood cancer researcher and president of Mayo Clinic Labs in Rochester, Minn., said that although T cells “are inherently more difficult to assess” than antibody responses, tests exist to study them. He hopes the letter will spur the agency to “promote the use of these tests for the public good.”
Other people who signed the letter include executives at biotech firms developing next-generation COVID-19 vaccines designed to elicit better T cell immunity. Dr. Andrew Allen, chief executive of Gritstone Bio, which is developing one of those shots, hopes that a focus on T cells will lead to “variant-proof immunity, better than what we typically have today.”