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Helix Study Finds Tie Between HLA Allele, Side Effects of SARS-CoV-2 Vaccines

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Pfizer COVID vaccine

NEW YORK — A particular HLA allele may influence whether someone who receives a COVID-19 vaccine develops side effects that interfere with their daily routine, a new genome-wide association study from population genomics firm Helix has found.

In the US, SARS-CoV-2 vaccines from Pfizer and BioNTech, Moderna, and Johnson & Johnson are authorized for use in certain age groups. While the vaccines are safe and effective, some people have reported local and systemic reactions following inoculation, such as injection site pain, fever, or chills.

"Most of the science on vaccine side effects focuses on really, really serious adverse events," said co-author Will Lee, VP of science at Helix, noting that those are often the main concern during vaccine development.

But he added that more minor side effects can be common, and the COVID-19 pandemic and the associated mass vaccination drive have presented an opportunity to examine the genetic underpinnings of those more minor side effects and the biology of vaccine response.

Better understanding these reactions — which are often the ones that people are wary of when considering vaccination — could inform public health efforts as well as influence how vaccines are formulated. They could also point to ways to personalize vaccines in the future, noted Jacques Fellay, an associate professor at the Swiss Federal Institute of Technology who was not involved in the study.

The Helix team turned to two ongoing genetic research studies to conduct a genome-wide association study of vaccine side effects in more than 17,000 individuals. Through this, they homed in on an HLA allele linked with post-SARS-CoV-2 vaccine fatigue, chills, or other symptoms affecting daily life. Last month, the team posted a preprint of its findings to MedRxiv.

The researchers sent online surveys to Helix DNA Discovery Project and Healthy Nevada Project participants to ask about their vaccination status and any reactions they might have had following their shots. In particular, they asked about symptoms like injection site pain, fever, chills, and fatigue, and whether and to what degree these symptoms affected participants' ability to go about their daily lives. All participants had previously been analyzed with Helix's Exome+ assay.

Of the 17,440 respondents, 8,041 said they received the Pfizer/BioNTech and 7,085 the Moderna vaccine, while only 790 reported having received the Johnson & Johnson shot. Most respondents, 62.2 percent, reported vaccination had a mild or no effect on their day-to-day life.

However, 8.0 percent reported being unable, or only able with extreme difficulty, to perform their daily routines, while 9.6 percent said they had severe difficulties with going about their day.

In a genome-wide association study comparing participants with extreme or severe difficulties to those with mild or no difficulties, the researchers homed in on a link between HLA-A*03:01 and difficulties with daily routine after vaccination, though this effect was almost entirely driven by the Pfizer/BioNTech vaccine.

HLA is the most diverse region in the human genome and plays a crucial role in immunity, so a tie between variation there and a vaccine reaction isn't that surprising.

Senior author Liz Cirulli, a principal scientist with Helix, noted that when the human genetics community began researching COVID-19-related phenotypes, there was an expectation that there would be findings within the HLA region because of its importance to the immune system. But that, she added, had not been the case so far. "And so [this finding] was surprising because it had been elusive up until now," she said.

She added that this particular HLA-A allele does not yet appear strongly associated with other phenotypes.

Fellay noted, though, that the link between vaccine reactions and an HLA-A allele was a little unsuspected. HLA-A is a class I HLA allele, which is most involved with CD8+ lymphocytes, or killer T cells. By contrast, he noted that vaccines typically are associated with antibodies.

These results therefore provide a glimpse into the early immune response to vaccination, rather than antibody development, as that would take more time, he suggested. While Fellay was not involved in the study, he did discuss the findings with the researchers before the preprint was posted.

The response captured in the Helix study could be a general reaction to the lipid nanoparticle or mRNA of the mRNA-based vaccines, he said, but that would take additional study to figure out.

The Helix team further found that the link between HLA-A*03:01 and vaccine effects on daily life was more pronounced among the recipients of the Pfizer vaccine than of the Moderna vaccine, while the sample size for the J&J vaccine was too small to tell. Only among Pfizer recipients was the association statistically significant, while it was only trending that way for Moderna recipients, despite similar power to detect the association in both groups.

Cirulli noted that Moderna vaccine recipients tended to report higher levels of symptoms overall, likely due to the higher vaccine dose they receive. This could make it more difficult to tease out the effect, she said.

The effect was also largely observed in individuals of European and Hispanic ancestry, and the HLA-A*03:01 allele has a minor allele frequency of 15 percent among individuals of European ancestry, the researchers noted. Associations with other HLA alleles in other populations are also possible.

Findings like these could influence how vaccines are developed, Helix's Lee said, and could help design shots that mitigate reactions.

Knowing individuals' genetic backgrounds could help tailor vaccination to their particular propensity to respond to a vaccine or to experience side effects, Fellay suggested, though that would likely be for the next pandemic.

"Right now, it's obviously important to reach the largest number of people, and we don't have time or information to do personalization," Fellay said. "But the goal, as in other sectors of medicine, is to try and go in the direction of more stratification or personalization."

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