COVID-19 breakthrough infections build an 'immunity wall'

COVID-19 breakthrough infections in vaccinated individuals may offer an unexpected benefit: heightened immunity against future SARS-CoV-2 infections.

Research from La Jolla Institute for Immunology (LJI) reveals that those who experience breakthrough infections develop a more robust immune response, particularly through improved T cell recognition and targeting of the virus.

COVID-19 breakthrough infections

The LJI scientists analyzed blood samples from vaccinated volunteers who had breakthrough infections.

The team discovered that these individuals developed T cells capable of recognizing multiple parts of the SARS-CoV-2 virus, including its variants like Omicron and Delta. This enhanced ability is referred to as an “immunity wall.”

“The virus evolves, but, importantly, so does the immune system. T cells do not sit idle. Instead, they learn to recognize the parts of the virus that mutate,” explained Professor Alessandro Sette, who co-led the study.

Key Findings

• Symptomatic Breakthrough Infections: Volunteers who experienced these infections developed T cells that recognized various targets on the SARS-CoV-2 virus.
• Improved T Cell Recognition: These T cells were better equipped to identify and respond to mutated regions on new variants.
• Asymptomatic Breakthrough Infections: Even without symptoms, these infections boosted T cell responses, though less significantly.
• B Cell Response: Breakthrough infections led to the production of cross-reactive antibodies, targeting both the new variants and the original vaccine antigens.
• No T Cell Exhaustion: There was no evidence that repeated vaccinations and infections caused harmful T cell exhaustion.

T cells gain fighting power

Vaccination against SARS-CoV-2 provides significant protection against severe disease. LJI studies show that this protection is long-lasting and effective against new viral variants.

The researchers focused on how breakthrough infections impact T and B cells by tracking a group of vaccinated volunteers who later contracted COVID-19.

“With this study volunteer cohort, we were in a unique position to see how the immune system looked before and after a breakthrough infection,” noted Professor Alba Grifoni.

Breakthrough infections prompted T cells to expand their repertoires, meaning they could recognize multiple features of SARS-CoV-2. This broadening was due to the combination of vaccination and infection.

Vaccines taught T cells to recognize the spike protein, while infections helped them recognize additional viral proteins. As a result, T cells could target SARS-CoV-2 even if it mutated.

Breakthrough infections and B cell responses

Breakthrough infections also stimulated B cells to produce diverse antibodies targeting common epitopes between the vaccine and the infecting variant. These new antibodies were effective against both the vaccine’s antigens and the viral variants.

“New B cell responses that are only specific to the infecting variant, but not the vaccine, are very rare,” said study co-author Parham Ramezani-Rad.

Another significant finding was the location of immune cell development. COVID-19 vaccines are typically administered in the upper arm, while SARS-CoV-2 infects the upper respiratory tract. This discrepancy can delay the immune response. A breakthrough infection can add an extra layer of protection by initiating immune cells closer to the infection site.

The impact of asymptomatic infections

The experts identified markers of previous SARS-CoV-2 infection in about 30% of volunteers who never showed symptoms, suggesting they had asymptomatic infections.

“Our study suggests most people who never thought they got a breakthrough infection actually did,” explained Professor Grifoni. “The majority of the population appears to be affected by a combination of vaccination and one or more breakthrough infections.”

No evidence of T cell exhaustion

The research also dispels concerns about T cell exhaustion from repeated vaccinations and infections. Instead, breakthrough infections prompted T cells to produce more cytokines, enhancing their infection-fighting capabilities.

“After the breakthrough infection, the same cells produce multiple types of cytokines, making them more efficacious,” noted Professor Grifoni. “Not only are our T cells not exhausted, but they are actually improving their capabilities.”

However, the “immunity wall” has its limits. Following an asymptomatic breakthrough infection, T cell abilities were found to plateau with subsequent symptomatic infections, although B cells continued producing neutralizing antibodies.

The importance of booster vaccines

Despite the benefits of breakthrough infections, the researchers emphasize the importance of following current CDC guidelines for booster vaccines. SARS-CoV-2 continues to evolve, and COVID-19 can still cause serious illness, especially in immunocompromised individuals.

This research provides crucial insights for developing new vaccines against future SARS-CoV-2 variants and other potential pandemic viruses. Researchers are keen to explore how future variants or new vaccine designs might further enhance the immune response.

“Studies of local B cell responses in the upper airway – where the infection occurs – will also be informative on how B cells responses are induced, particularly after breakthrough infection,” said Ramezani-Rad.

The ultimate goal is to train T cells to recognize multiple types of coronaviruses simultaneously, potentially leading to a “pan-coronavirus” vaccine. This breakthrough study marks a significant step in understanding how to protect against viral infections and future pandemics.

“We’re very interested to see if this phenomenon could be exploited in general to prepare against other potential pandemic threats,” said Sette. “This is a step in a journey to help us protect against viral infections and potential pandemics.”

The study is published in the journal Cell Reports Medicine.

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