Even though mRNA-based COVID-19 vaccines are very effective against SARS-CoV-2, they can cause side effects like fatigue. How can this be avoided?

In a new study published on May 31 in the open-access journal PLOS Biology, Ayesa Syenina of the Duke–NUS Medical School in Singapore and her colleagues say that a new analysis of blood samples from people who were vaccinated for COVID-19 has found specific molecular characteristics that are linked to a higher risk of feeling tired after the vaccination.

Experiments on mice also suggest that changing the vaccination administration approach could help alleviate these side effects.

People’s willingness to get vaccinated or obtain a booster dose may be influenced by adverse post-vaccination effects, limiting efforts to minimize COVID-19’s spread and severity. However, the molecular mechanisms underlying unfavorable post-vaccination effects remain unknown.

Syenina and colleagues investigated blood samples from 175 healthcare workers who got BNT162b2, the Pfizer-BioNTech COVID-19 vaccination, to gain a better understanding. They used the blood samples to examine a snapshot of each participant’s gene expression, or which genes are active or inactive.

This study discovered that those who had moderately severe fatigue after vaccination had increased baseline expression of genes related to T cell and natural killer cell activity, two important cell types in the human immune system.

In addition, the researchers used mice to test two distinct immunization injection techniques. BNT162b2 was given to some mice via intramuscular injection, which is the current way for administering the vaccine to human patients. Other mice were given a subcutaneous injection, which involves injecting the vaccine into tissue right beneath the skin.

Compared to mice who got intramuscular immunization, mice who underwent subcutaneous vaccination exhibited immune-system responses that were consistent with a lower risk of side effects including fatigue. The protective effects of immunization did not appear to be harmed by subcutaneous injection.

More research is needed to build on these findings and investigate their therapeutic implications. Nonetheless, they contribute to a better understanding of post-vaccination fatigue and suggest an approach for reducing its occurrence.

“This study provides a first insight into the molecular basis of a side effect that many have experienced following mRNA vaccination,” says coauthor Eng Eong Ooi. “We hope that this finding would spur more studies to fully understand the underpinning mechanisms behind vaccine-associated side effects and collectively contribute to developing even more tolerable vaccines.”

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