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Why People Might Respond to Vaccines Differently

Scientists have identified a signature in the blood that could help predict how well an individual will respond to vaccines. 

It had become clear during the COVID-19 pandemic that some patients were "better protected by vaccination than others", highlighted the authors of a new study, published in Nature Communications

"Many studies have shown that SARS-CoV-2 vaccines are less effective in people with weakened immune systems, but also that this effect is not uniform," they pointed out.

Despite the success of mRNA-lipid nanoparticle COVID-19 vaccines in reducing the risk of symptomatic infection, hospitalisation, and death, vaccinated patients with cancer "remained at increased risk" of severe outcomes following SARS-CoV-2 infection, highlighted the authors.

ABC – The Lexicon of Immunity

Vaccination involved stimulating the production of antibodies, produced by B cells, explained the authors. They added that one specific subset of B cells, known as age-associated B cells (ABCs), were a naturally occurring population of antigen-experienced B cells that in healthy individuals that "expands continuously with age". However, in people with certain immune dyscrasias, autoimmunity, and/or infectious diseases, ABCs accumulated prematurely. Therefore, whilst, on average, fewer than 1 in 20 of a healthy individual's B cells is an ABC, the proportion "gradually increases as we get older". 

The reasons for this increase were not yet fully understood, but might include previous infections, the authors suggested. "Certain people with weakened immune systems accumulate ABCs still faster," they underlined.

Dr Pehuén Pereyra Gerber, University of Cambridge, and co-author, explained that: "Looking at blood levels of ABCs could tell us that person A should respond well to a vaccine, while person B might need a stronger vaccine or to be prioritised to receive a booster."

Stratify Vulnerable Patients

For the study, a team from the Medical Research Council Toxicology Unit at the University of Cambridge examined ABCs from two very different patient groups – one comprised of people with an inherited condition that impaired the activity of their immune systems, and a second group comprised of cancer patients taking immunotherapy drugs – as well as from healthy individuals.

Emily Horner, University of Cambridge, and co-author, explained that: "By looking at patients' B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others."

After measuring the relative proportion of ABCs compared with healthy B cells, the researchers used single cell RNA sequencing to look at the activity of cells in detail. They also tested how these factors influenced the ability of a vaccinated individual's immune system to neutralise live SARS-CoV-2 virus.

Dr Juan Carlos Yam-Puc, University of Cambridge, and lead author, expressed "surprise" at the findings. "We found that the age-associated B cells in these very different groups looked the same," he said. "The key difference was in the amount of these cells – the greater the proportion of ABCs in an individual's blood, the less effective that individual was post-vaccination at neutralising the virus."

More ABCs - Reduced Vaccine Response

The authors said that immune check-point blockade (ICB) was a cancer therapy that observational studies had suggested could improve the efficacy of vaccines, and possibly "enhance antibody responses". 

However, complicating the positive potential of ICB for vaccine enhancement, ICB "induces the expansion" of ABCs, which may have a "confounding effect" on humoral vaccine responses, they cautioned.

The pathological consequence of expanded ABCs was likely related to their "increased frequency" rather than an inherent difference in these cells from patients with distinct diseases, emphasised the authors. "One of these consequences is a limitation of the humoral immune response to SARS-CoV-2 vaccination," they pointed out.

The discovery might explain why even among vulnerable patient groups, some individuals had better responses to vaccines than others. "People with fewer ABCs are likely to respond better to vaccines," the authors stressed.

Although the researchers examined ABCs in the context of responses to the SARS-CoV-2 vaccine, they believed that this phenomenon would apply more widely, for example to the annual influenza vaccine.

The authors acknowledged a number of limitations of the study, notably that the number of people studied was "modest", which limited the power to detect small differences in some comparisons and that precluded a formal multivariate analysis.

Despite the limitations the authors believed the finding that patients with increased ABC frequency had a reduced B cell vaccine response, leading to reduced neutralising capacity and reduced memory B cell formation was of "immediate clinical relevance". 

The study results placed ABC frequency as a predictive biomarker for reduced vaccine protection, which could guide booster vaccination schedules for patients at risk of breakthrough infection, they proposed.

"Ultimately, this research could lead to the development of a clinical test to predict vaccine efficacy for immunodeficient patients, and for the population more generally," said Dr James Thaventhiran, University of Cambridge, and senior author.

The study was funded by Medical Research Council, Medical Research Foundation, and The Evelyn Trust. The authors declared no competing interests.


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