Study: Booster dose of mRNA COVID vaccine prompts strong T cell response in immunocompromised patients

People with an impaired immune system can achieve a relatively robust response against SARS-CoV-2 if they get a booster shot, scientists in Sweden have found in a clinical trial that administered extra mRNA shots to patients whose immunity was comprised by age, cancer, HIV and other conditions.

A team at the Karolinska Institutet in Stockholm tackled one of the larger questions in the global COVID vaccination effort: how efficacious are mRNA vaccinations in immunocompromised individuals. The question has persisted because of concerns that SARS-CoV-2 variants are not specifically targeted by vaccine-induced antibodies. And many immunocompromised individuals, scientists say, have impaired antibody responses.

In a clinical study published in Science Translational Medicine, Dr. Thomas R. Müller and colleagues say it isn’t antibodies that booster doses prompt into action—it’s the body’s T cells. By administering a third dose of mRNA vaccine, and in some special instances, a fourth dose, the Stockholm-based team was able to trigger a potent T cell response against SARS-CoV-2 in immunocompromised patients.

The research arrives amid a new stage in the SARS-CoV-2 challenge. Governments worldwide ended the COVID emergency phase several months ago. Yet no sooner had the emergency phase ended when public health agencies began ramping up for vaccinations to resume in the fall. SARS-CoV-2 is now prominent among wintertime viruses that pose a substantial threat. The virus’s emerging pattern of periodicity keeps concerns about vaccination—and booster doses—for immunocompromised people top of mind in the medical community.

The U.S. Centers for Disease Control and Prevention already recommends that people with impared immunity receive a third dose of COVID mRNA vaccine to reach a stronger level of immunity against the virus. The agency does not consider this a booster, but a necessary shot. Other countries, such as Sweden, deem the third, and even fourth mRNA shots, booster doses.

“Suboptimal immunity to SARS-CoV-2 mRNA vaccination has frequently been observed in individuals with various immunodeficiencies,” wrote Müller and the Karolinska team. “Given the increased antibody evasion properties of emerging SARS-CoV-2 subvariants, it is necessary to assess whether other components of adaptive immunity generate resilient and protective responses against infection.”

By adaptive immunity, Müller is referring to the body’s adaptive immune system (also defined as the acquired immune system). Although B cells, the source of antibodies are major components of adaptive immunity, a diverse and active component of adaptive immunity is the deep repertoire of T cells. And it is this vast army T cells that helps keep the virus at bay.

“We assessed T cell responses in 279 individuals, covering five different immunodeficiencies and healthy controls, before and after booster mRNA vaccination, as well as after omicron infection in a subset of patients,” Müller continued, underscoring that the team observed “robust and persistent omicron-reactive T cell responses that increased markedly upon booster vaccination and correlated directly with antibody titers across all patient groups.”

The team studied COVID booster responses in a range of patients whose immune systems were impaired for a variety of reasons: advanced age, organ transplantation, cancer, HIV and inflammatory conditions. Reactive T cells did not emerge after the first two mRNA shots in immunocompromised patients, but booster doses made a substantial difference, leading the team of researchers to underscore the importance of boosters for these patients.

By contrast, most healthy individuals with a robust immune system generate potent SARS-CoV-2–specific T cell responses after two vaccine doses comparable to levels observed after SARS-CoV-2 infection, Müller and the team in Stockholm said.

However, individuals across different immunodeficient states displayed impaired vaccine effectiveness and frequently generated low-to-nondetectable T cell responses after two SARS-CoV-2 mRNA vaccine doses, hence the importance of boosters for people with impaired immunity.

“Poor vaccination responsiveness in immunocompromised or elderly individuals was effectively counteracted by the administration of additional vaccine doses,” Müller, a postdoctoral researcher and immunologist at the Karolinska Institutet asserted in the study, which is titled, “Additive effects of booster mRNA vaccination and SARS-CoV-2 omicron infection on T cell immunity across immunocompromised states.”

The team compared T cell responses before and after boosters with the Pfizer/BioNtech mRNA vaccine, and then analyzed how well a subset of 78 vaccinated patients with exposure to the omicron variant fought off infection. Scientists found by administering an extra booster dose for these patients—a fourth dose—that they could make up for the poor initial response to the mutant strain.

The omicron-infected group displayed robust T cell responses against the variant and developed a more diverse arsenal of anti-SARS-CoV-2 T cells, suggesting that T cells can respond effectively to new variants.

In contrast to antibodies, T cells recognize intracellularly persistent antigens, a factor that helps generate a large and diverse T cell receptor repertoire. These T cells, in turn, work to quell the evolution of SARS-CoV-2’s escape mutations.

“Our findings highlight the importance of booster vaccination in immunocompromised individuals to sufficiently build up functional and long-living omicron-reactive CD8⁺ T cell responses that likely contribute to protection from severe disease,” Müller, lead author of the research said.

The Karolinska team acknowledged, however, that other researchers have found the exact opposite to their findings. For example, one study found no evidence of a significant T cell response after studying healthy triple-vaccinated, infection-naïve individuals. The same research also found significantly decreased omicron reactivity in triple-vaccinated individuals. The Karolinska scientists attribute their totally opposite finding of robust T cell responses to having conducted a much larger, more detailed study involving immunocompromised individuals.

“More detailed analyses revealed that poor responders after two doses particularly benefit from booster vaccination,” Müller wrote, noting that CD8⁺ T cell responses emerge after the third dose in immunocompromised patients. “Our data clearly underline the added benefit of booster vaccination for building up robust spike-specific T cell responses, especially in immunocompromised individuals and those who responded poorly to the first two doses.”

More information:
Thomas R. Müller et al, Additive effects of booster mRNA vaccination and SARS-CoV-2 Omicron infection on T cell immunity across immunocompromised states, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adg9452

Journal information:
Science Translational Medicine

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