Researchers have long known that individuals who are immunosuppressed can potentially have a different or suboptimal response to vaccines. But how this basic immunology concept would apply to the COVID-19 pandemic was unknown when the first vaccines rolled out worldwide in late 2020.

“No one who was immunocompromised had ever received an mRNA vaccine — these were completely new platforms,” says Johns Hopkins transplant surgeon Dorry Segev. “It was very important for us to understand their impact on our patients as soon as we could.”

Toward that end, Segev and his colleagues have produced a wealth of data over the past year on how transplant recipients responded to first, second and additional doses of COVID-19 vaccines. In August 2021, the National Institute of Allergy and Infectious Diseases awarded the team $40 million to study the impact of third and additional doses on people who have had a kidney transplant. The research team includes site principal investigator William Werbel, an infectious diseases specialist. Segev is overall principal investigator.

“We were in a unique position,” Werbel says, “to work with the NIH and its excellent partners to study the COVID-19 vaccines, having spent months tracking and reporting responses among thousands of immunocompromised people through a national observational cohort.”

As with other drugs, safety and efficacy are the primary concerns for researchers studying COVID-19 vaccines in transplant patients, says Segev. Initial data on safety was promising — neither mRNA vaccine appeared to cause extraordinary side effects, nor did they seem to affect the health of donor organs. However, efficacy data was troubling: In an observational study, only 17% of people who had received an organ transplant appeared to produce detectable anti-COVID-19 antibodies after the first dose, compared with nearly 100% of individuals with healthy immune systems. After a second dose, that number rose to just 54%. Even among those with antibodies present, their abundance was much lower than levels in individuals who were not immunocompromised.

This lack of vaccine efficacy for the first two doses among individuals who are immunosuppressed has had real-world consequences, Segev says. Subsequent studies by the team show the risk of breakthrough COVID-19 infection was 82 times higher in fully vaccinated transplant patients than the general population, and associated hospitalization rates were 485 times higher. Mortality rates were at 9%, compared with nearly zero in vaccinated patients who are immunocompetent.

“This level of protection was clearly inadequate for people with organ transplants,” Segev says.

In September 2021, the team published a case series of 30 transplant patients showing that a third vaccine dose could significantly boost the number of patients who produced antibodies. However, 67% of the 24 patients who had negative antibody titers before their third dose continued to lack protective antibodies afterward, suggesting considerable room for improvement.

In the new study, Segev, Werbel and their team plan to look deeper within the immune system to better understand why some transplant patients respond better to COVID-19 vaccines than others, examining levels of B and T cells and other immune components and activity. They will also investigate the safety and efficacy of reducing immunosuppression in raising the response of these vaccines and whether mixing or matching the third dose with previous dose types can make a difference. “Understanding how to maximize vaccine response,” says Segev, “will be critical for our current pandemic, and for those to come.”

Werbel adds: “This is a race to protect the most vulnerable people against COVID-19. We need to use carefully conducted clinical trials conducted on an aggressive schedule to study promising strategies to improve protection.”