Researchers are discovering that people with weakened immune systems respond very differently to COVID-19 vaccines than the general population, and they may need ongoing protection strategies that differ from what works for others. A long-term study called PERSIST is following hundreds of immunocompromised individuals to understand how their bodies mount immune defenses after vaccination, with preliminary findings already showing they remain at significantly higher risk of infection even after being vaccinated.

What Happens When COVID Vaccines Meet a Weakened Immune System?

When most people receive a COVID-19 vaccine, their immune system springs into action in a predictable way. B cells produce antibodies that recognize and block the SARS-CoV-2 spike protein, creating a first line of defense against infection. T cells develop specialized receptors that help identify and destroy virus-infected cells. But for people with primary immunodeficiency (inborn immune disorders) or secondary immunodeficiency (acquired conditions like those following organ transplants), this process doesn't always work the same way.

The PERSIST study, led by researchers at the National Institute of Allergy and Infectious Disease (NIAID), was designed specifically to answer questions that couldn't be addressed during the original COVID-19 vaccine trials. "This population was excluded from COVID-19 vaccine clinical trials," explained Emily Ricotta, Ph.D., M.Sc., a research fellow in the Laboratory of Clinical Immunology and Microbiology at NIAID, who is leading the study. The study aims to recruit 400 people with immune disorders and 100 non-immunocompromised controls to understand how vaccine protection develops and persists over time.

"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.

Emily Ricotta, Ph.D., M.Sc., Research Fellow, Laboratory of Clinical Immunology and Microbiology at NIAID

How Are Researchers Measuring Immune Response in This Population?

The PERSIST study is taking a comprehensive approach to understanding vaccine response by tracking three key indicators over at least two years after each vaccine dose:

• Antibody Production: Researchers measure the amount and quality of antibodies against SARS-CoV-2 at six, 12, and 24 months after vaccination to see how robust and durable the immune response is over time.
• T Cell Response: Scientists analyze the diversity and strength of T cell antigen receptors (TCR), which help predict what parts of the spike protein a person's T cells will recognize and how effectively they'll fight infection.
• Real-World Infection Rates: Study participants send in saliva samples every other week for six months after their last vaccine dose, with any positive tests sequenced to understand what virus variants are circulating.

The study began recruiting participants in April 2021 and remains open for enrollment. Roughly half of current participants have primary immunodeficiency or inborn errors of immunity, while the other half have secondary immunodeficiency. This split allows researchers to identify whether vaccine response differs depending on why someone's immune system is weakened.

What Do Early Results Reveal About Infection Risk?

Short-term studies had already shown that most people with primary and secondary immunodeficiencies do produce an initial antibody response to COVID-19 vaccination, though some groups respond poorly. These include solid organ transplant recipients, some people with common variable immunodeficiency (CVID), and those with X-linked agammaglobulinemia (XLA).

But the PERSIST study's preliminary findings paint a more sobering picture when looking at actual infection rates. Since the rise of the Omicron variant, researchers have observed a significant difference in post-vaccination COVID-19 infections between immunocompromised and non-immunocompromised people. The encouraging news is that most infections in vaccinated immunocompromised individuals have been mild. However, these results demonstrate that people who are immunocompromised remain at higher risk of infection even after vaccination.

"So sorry, everyone else thinks we're done, but you need to continue to be protected," Ricotta noted, referencing the broader public's shift away from pandemic precautions while immunocompromised individuals face ongoing vulnerability.

How Might These Findings Change Vaccination Recommendations?

The PERSIST study's long-term data could fundamentally reshape how doctors approach COVID-19 prevention in immunocompromised populations. Rather than a one-time vaccination series, the evidence emerging from this research suggests that regular, continued vaccination may be necessary for people with immune disorders to maintain protection.

Ricotta and her team hope to publish initial results from PERSIST in spring 2022 and will continue releasing findings as various analyses are completed. The study is still recruiting people ages 12 and older with primary and secondary immunodeficiencies, meaning the final dataset could be even more comprehensive than current preliminary analyses.

For the roughly 400 million people worldwide living with primary immunodeficiency alone, understanding how vaccines work in their bodies isn't just an academic question. It's about ensuring they have access to the same level of protection that vaccination provides to the general population. The PERSIST study represents a critical step toward answering that need with real, long-term data.