Study looks at long-term response to COVID vaccine in immunocompromised

“I think it’s going to provide evidence for continued, regular vaccination, especially in this [immunocompromised] group of individuals,” said Emily Ricotta, Ph.D., M.Sc., on how she predicts the NIH PERSIST study she’s leading will impact COVID-19 preventative care.

Ricotta is a research fellow in the Laboratory of Clinical Immunology and Microbiology at the National Institute of Allergy and Infectious Disease (NIAID). PERSIST is “studying the immune response to COVID vaccines in people with immune disorders,” she said, noting that this population was excluded from COVID-19 vaccine clinical trials. 

To answer questions about vaccine response in the immunocompromised, Ricotta and her colleagues are carefully following each study participant for at least two years after their last dose of COVID-19 vaccine (both primary series shots and boosters count as a dose). The study is collecting data on three overall indicators: antibodies made by B cells, T cell antigen receptors, and post-vaccination COVID-19 infections. 

PERSIST began recruiting in April 2021 and remains open for enrollment. Ricotta hopes to recruit 400 people with immune disorders and 100 non-immunocompromised controls when the study is fully enrolled.

Enrollees are split roughly half and half right now between those with primary immunodeficiency or inborn errors of immunity versus those with secondary immunodeficiency. With that number of enrollees, PERSIST may also be able to tease apart vaccine response differences between populations that are immunocompromised for different reasons.

In people who are not immunocompromised, studies show that COVID-19 vaccines trigger B cells to produce antibodies that recognize and block the SARS-CoV-2 spike protein. These neutralizing antibodies are the first line of protection and prevent someone from becoming infected by the virus. Short-term studies show that most people with primary and secondary immunodeficiencies produce an initial antibody response to COVID-19 vaccination, with some notable exceptions (for example, solid organ transplant recipients, some people with common variable immunodeficiency (CVID), those with X-linked agammaglobulinemia (XLA)). 

The PERSIST study will extend knowledge of that response by looking at the amount and quality of antibodies against SARS-CoV-2 six, 12, and 24 months after vaccination. It may pick up differences in how robust the vaccine-induced antibody response is over time, either in the immunocompromised population as a whole or in subgroups.

Another aspect of vaccine response that study investigators are looking at is T cells. After vaccination, people who are not immunocompromised develop T cells with T cell antigen receptor (TCR) proteins on their surfaces that specifically recognize the SARS-CoV-2 spike protein. T cells that recognize and bind to different parts of the spike protein help clear the virus by killing off infected cells.

Sequencing the DNA for the ‘repertoire’ of TCRs in a given person after vaccination predicts what parts of the spike protein that person’s T cells will recognize and how strongly. For PERSIST, analyzing the TCR repertoire of those who are immunocompromised versus those who aren’t could answer questions about the strength and diversity of this important part of the adaptive immune response. And, as with antibodies, there may be long-term differences that haven’t been captured by other studies.

Finally, PERSIST enrollees send in saliva samples for SARS-CoV-2 PCR testing every other week for six months after their last vaccine dose. Any sample that tests positive is sequenced to get a full picture of the virus. 

Since the rise of the Omicron variant, Ricotta and her colleagues have seen a significant difference in the number of post-vaccination COVID-19 infections in those who are immunocompromised compared to those who aren’t. The good news is that the majority have been mild. But Ricotta said these preliminary results show that people who are immunocompromised remain at higher risk of infection.

Ricotta hopes to publish initial results from PERSIST in spring 2022 and will continue publishing throughout the study as various analyses are completed. Referencing people who are immunocompromised amid loosening pandemic restrictions, she said “So sorry, everyone else thinks we’re done, but you need to continue to be protected.”

Interested in helping Ricotta and her colleagues understand vaccine response in people who are immunocompromised? NIH PERSIST is still recruiting people 12+ years old with primary and secondary immunodeficiencies!

Read about eligibility and sample timeline.

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