Unlocking the secrets of immune imprinting: how past infections affect future COVID-19 risk

Disease and treatment 14. nov 2023 3 min Clinical Professor Peter Garred Written by Morten Busch

Researchers have uncovered how our immune system responds to COVID-19 vaccination and virus variants. The results show that the immune response varies depending on factors such as previous infections and the timing of vaccination – and that some individuals have a greater risk of becoming infected again and again. The research sheds light on the complexity of our immune system and emphasises the need to adapt vaccination strategies to protect against future virus variants. Understanding these mechanisms is crucial for our response to future pandemics.

The ongoing battle against the ever-evolving SARS-CoV-2 has raised perplexing questions. Despite widespread vaccination efforts, the emergence of the Omicron variant has revealed a puzzling twist – why do some individuals remain more vulnerable than others to infection, even after vaccination? One answer lies in the enigmatic concept of immune imprinting.

“In the face of the constant challenge of new emerging variants of SARS-CoV-2, we have uncovered a profound puzzle. Despite vaccination, some individuals show heightened susceptibility to reinfection, hinting at the enduring influence of past encounters with the virus. We believe that this phenomenon, known as immune imprinting, holds the key to understanding our diverse responses to SARS-CoV-2. Understanding this phenomenon in depth is essential for addressing future pandemics,” explains Peter Garred, Senior Consultant and Professor at the Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen and Department of Clinical Medicine, University of Copenhagen.

More complex over time

The battle between the human immune system and SARS-CoV-2 has been a central focus throughout the COVID-19 pandemic, including a discussion on what protects you best: infection or vaccination. The researchers from Rigshospitalet and Herlev and Gentofte Hospital in Denmark hoped to paint a more detailed portrait of how the immune system responds to the virus, also possibly offering vital clues for future pandemics.

“Our results reveal that certain individuals have a greater risk of infection or reinfection. Participants with low levels of antibodies after vaccination had a significantly higher risk of SARS-CoV-2 infection.”

Their data derived from about 3,000 hospital employees who volunteered for regular blood sample collections during the pandemic, enabling researchers to monitor their immune responses to SARS-CoV-2 infections and vaccinations over time.

“We specifically examined the risk of infection with the Omicron variant, but the variation in immune responses has become considerably more complex over time, since people have encountered different SARS-CoV-2 variants with varying intervals between vaccinations.”

Participants previously infected had higher antibodies

The study carefully measured two types of antibodies, immunoglobulin G (IgG) and IgA, along with the ability of T cells to respond to SARS-CoV-2. IgG is primarily present in the bloodstream and plays a crucial role in neutralising SARS-CoV-2. IgA, in contrast, is primarily present in mucous membranes such as the nose and lungs, and its levels typically rise after infection.

“Although both IgG and IgA levels significantly affect the risk of repeated infections, we did not find the same correlation between T-cell responses and infection risk. T cells are vital in fighting infections and have been shown in other studies to protect against severe COVID-19, whereas antibodies play a more substantial role in viral transmission and, consequently, infection.”

T cells identify and destroy infected cells, coordinate immune responses and form memory to combat future threats, providing long-lasting protection against numerous pathogens. The study also sheds light on the duration of T-cell immunity after vaccination, suggesting that T-cell responses are less affected than antibodies by the mutations of SARS-CoV-2 over time.

“Our research indicates that the responses of both antibodies and T cells after vaccination were generally higher among participants who had previously been infected with SARS-CoV-2. Although we have previously shown that antibody levels decline significantly over time, we also found that a booster vaccination can increase antibody levels to the same levels as before or higher.”

Some are more vulnerable

One of the most intriguing findings in the study related to the connection between the initial Wuhan variant infection and reinfection with the Omicron variant. Individuals who had previously been infected with the Wuhan variant and then later with Omicron had a weaker immune response than those who had only been infected with Omicron.

“This phenomenon is known as immune imprinting and has been observed previously during influenza pandemics. Think of your immune system as a kind of camera with memory. When it sees a virus, it takes a picture and stores it. The next time you encounter the same virus or a variant of it, your immune system looks in its photo album to determine how to react.”

The challenge with immune imprinting is that the immune system can become so fixated on the initial “picture” that it struggles to recognise and effectively respond to a new version. This insight is vital for understanding why individuals can become infected and fall ill when new SARS-CoV-2 variants emerge.

“It underscores the importance of carefully selecting which virus variants are included in future vaccines to ensure optimal protection.”

Denmark is experiencing a significant increase in COVID-19 cases, especially as new SARS-CoV-2 variants emerge.

“However, Denmark’s population has relatively good immunity because of vaccination and previous infections, which currently overshadows immune imprinting. Unfortunately, some people are more vulnerable to severe and hospital-requiring illness, especially older and immunocompromised individuals. These individuals will greatly benefit from a booster vaccination that is balanced between the original Wuhan type and the new Omicron variants.”

New virus variants continue to emerge

The new research emphasises the need for continually examining and adapting vaccination strategies, especially given the new virus variants.

“Our study paints a complex picture of COVID-19 immunity, highlighting the importance of antibody responses and immune imprinting. It reinforces the significance of evolving vaccination strategies to combat ever-changing SARS-CoV-2 variants and protect populations worldwide.”

The concept of immune imprinting is a pivotal discovery, showing that previous exposure to one virus variant can affect how the immune system responds to new variants. This memory effect can lead to suboptimal responses, creating difficulty for the immune system in recognising and fighting off new versions of the virus.

“In a world in which new virus variants continue to emerge, our research underscores the need for ongoing evaluation and adaptation of vaccination strategies. By understanding how the timing of infections and vaccinations influences our immune responses, we can better prepare for future pandemic threats and ensure more effective protection for all.”

Peter Garred leads a research group at Rigshospitalet and the University of Copenhagen. He tries to understand the structure, molecular genetics and c...

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