that those who had breakthrough infections had T cells with a greater ability to recognize and attack the SARS-CoV-2 virus, including its Omicron and Delta variants. This enhanced immune response is being likened to a “wall of immunity” by the researchers. This suggests that individuals who have had breakthrough infections may have a more robust defense against future infections. The study was conducted by scientists at La Jolla Institute for Immunology (LJI).The study found that individuals who had symptomatic breakthrough infections develop T cells that are more effective at identifying and attacking SARS-CoV-2, including the Omicron and Delta variants. The researchers refer to this enhanced protection as an “immunity wall.”
“The virus may change, but so does the immune system. T cells don’t remain inactive. Instead, they adapt to recognize the mutated parts of the virus,” says LJI Professor Alessandro Sette, Dr.Biol.Sci., who co-led the Cell Reports Medicine study with LJI Professor Shane Crotty, Ph.D., and LJI Research Assistant Professor Alba Grifoni, Ph.D.
Key findings Â
- Participants in the study who had symptomatic breakthrough infections generated T cells that were able to identify various segments of the SARS-CoV-2 virus, including both the “Spike” and non-Spike epitopes.
- These infections resulted in the production of T cells that were capable of recognizing mutated regions on new variants of SARS-CoV-2.
- Even asymptomatic breakthrough infections enhanced T cell responses, although the impact was not as significant.
- Breakthrough infections also stimulated B cells to create antibodies that could react to different strains of SARS-CoV-2. Many of these antibodies targeted the new viral variants as well as the original.vaccine antigens.
- Upon further examination, the study’s researchers concluded that individuals who had undergone multiple COVID-19 vaccinations and SARS-CoV-2 infections did not exhibit harmful “T cell exhaustion.”
T cells increase their fighting ability
Various research studies have demonstrated that immunization against SARS-CoV-2, the virus responsible for COVID-19, offers individuals substantial immune defense against severe illness. Multiple studies led by LJI have indicated that this immune defense is enduring and can even provide protection against new viral “variants of concern.”
In this recent study, LJI scientists delved into the specific ways in which significant advances in immune protection against COVID-19 are achieved.The immune system is affected by breakthrough infections that impact T cells and B cells. A large group of study volunteers who had received the SARS-CoV-2 vaccine were monitored over time, and many of them experienced breakthrough infections. The LJI researchers then followed up with these volunteers to collect new blood samples after the infections occurred.
“We had a unique opportunity with this study volunteer cohort to observe the changes in the immune system before and after a breakthrough infection,” said Grifoni.
Alison Tarke, Ph.D., a co-first author of the study and Postdoctoral Researcher at LJI, led the research efforts.The study found that breakthrough infections caused T cells to increase their “repertoires,” allowing them to recognize multiple features, or antigens, on SARS-CoV-2.
These T cells developed their broad repertoires as a result of both vaccination and breakthrough infection. COVID-19 vaccines trained the T cells to recognize a crucial part of SARS-CoV-2 known as the “Spike” protein. At the same time, SARS-CoV-2 infection caused T cells to identify Spike, as well as several other viral proteins.
As a result of the breakthrough infection, the study participants had T cells that could recognize and attack SARS-CoV-2, even if part of the virus had changed.The virus underwent a mutation.
Increased protection
The emergence of the Omicron and Delta variants led to B cells producing a wider range of antibodies. These antibodies were able to target specific parts of the virus that were common between the vaccine and the infecting SARS-CoV-2 variant.
Most of these new antibodies were effective at attacking the parts of the virus that were common between the vaccine and the variants. According to Dr. Parham Ramezani-Rad, co-first author of the study and Instructor at LJI, new B cell responses that were specific only to the infecting variant and not the vaccine were uncommon.
The research indicated that the majority of the new antibodies targeted shared epitopes between the vaccine and the variants, providing enhanced protection.The researchers have discovered an interesting pattern in individuals who have experienced breakthrough infections. COVID-19 vaccines are typically administered in the upper arm, resulting in the production of anti-SARS-CoV-2 immune cells that are distant from the upper respiratory system. Since SARS-CoV-2 typically infects the upper respiratory tract first, there may be a delay in the arrival of the appropriate immune cells to the site of infection. Grifoni suggests that a breakthrough infection could potentially provide an additional layer of protection on top of the vaccine.
The scientists also identified markers of previous SARS-CoV-2 infection in approximately30% of participants in the study had never experienced symptoms of COVID-19, indicating that they may have had asymptomatic cases of the virus at some point during the pandemic. According to Grifoni, the study suggests that many people who were unaware of having contracted the virus may have actually had a breakthrough infection. The majority of the population seems to have been affected by a combination of vaccination and one or more breakthrough infections. The study also found no evidence of T cell exhaustion from repeated infection or COVID-19 vaccination.The researchers found that breakthrough infections caused T cells to increase the production of different types of cytokines, which are molecules that help fight infection. Before a breakthrough infection, T cells may only produce one or two types of cytokines. However, after a breakthrough infection, the same cells produce multiple types of cytokines, making them more effective in fighting off the pathogen. This means that T cells are not exhausted but rather improving their capabilities. It appears that there are limits to the “immunity wall,” as T cell.The study found that the production of neutralizing antibodies by B cells decreased after a subsequent symptomatic infection, without a significant increase in antibody levels. As SARS-CoV-2 continues to evolve and can still cause severe illness in those with weakened immune systems, the researchers recommend following current CDC guidelines on receiving booster vaccines. This discovery may help guide future vaccine efforts.also involved in the development of new vaccines for potential future SARS-CoV-2 variants and other viruses with pandemic potential. Ramezani-Rad mentioned that their study addresses important questions about how breakthrough infections impact antibody responses. He is interested in how upcoming SARS-CoV-2 variants or new vaccine designs might further impact the immune system. Ramezani-Rad also emphasized the importance of studying local B cell responses in the upper airway to understand how B cell responses are induced, especially after breakthrough infections. Sette and Grifoni are also actively involved in this research.The focus of the research is on training T cells to identify various types of coronaviruses simultaneously, with the goal of developing a vaccine that can combat multiple coronaviruses. A study conducted in 2023, in collaboration with scientists from the University of Genoa, revealed that certain T cells have the ability to recognize multiple coronaviruses simultaneously. This study also examines how breakthrough infections can impact T cell responses to combat new SARS-CoV-2 variants. Sette, one of the researchers, expresses interest in exploring the potential of leveraging this phenomenon to prepare for other potential pandemic threats. This research represents a significant step towards developing protection against viral infections.Infections and possible global epidemics.”
Other contributors to the research, “SARS-CoV-2 breakthrough infections enhance T cell response magnitude, breadth, and epitope repertoire,” are Tertuliano Alves Pereira Neto, Yeji Lee, Vanessa Silva-Moraes, Benjamin Goodwin, Nathaniel Bloom, Leila Siddiqui, Liliana Avalos, April Frazier, Zeli Zhang, Ricardo da Silva Antunes, and Jennifer Dan.
This investigation received funding from the National Institutes of Health (NIH; T32AI125179), the NIH National Institute of Allergy and Infectious Diseases (75N93021C00016, 75N9301900065, and AI142742.)
