A study in Annals of Internal Medicine in June 2024 suggests that short-term systemic side effects of SARS-CoV-2 mRNA vaccination “are associated with greater long-lasting [neutralising antibody] responses”. The paper, from researchers at University of California San Francisco (UCSF), uses symptom reports and antibody responses from 363 people who had the Pfizer-BioNTech or Moderna mRNA vaccines when they were introduced. UCSF states that “fewer than 1 in 4 people in the US” have taken last year’s updated COVID-19 vaccine; it is suggested that “one of the most common reasons for bypassing the COVID vaccine is concern about side effects”.
The authors suggest that vaccine protection against SARS-CoV-2 wanes “considerably” and uptake of boosters has been “low”. The most commonly reported reasons for not having a booster among people who received at least 1 dose of a COVID-19 vaccine were a “perception of low added benefit in protection from illness” and “worry about side effects”. However, recent evidence indicates that greater systemic symptoms after SARS-CoV-2 vaccination “may reflect a more potent immune response”.
“A deeper understanding of this relationship may help to address low rates of vaccine uptake. Specifically, public health messaging might aid uptake by reframing short-term postvaccination symptoms as positive indications that the vaccine is likely to be working rather than as undesirable side effects.”
Previous research has linked SARS-CoV-2 vaccine reactogenicity to a “higher subsequent anti-spike immunoglobulin level”, but only a few studies have measured neutralising antibodies (nABs).
“Quantifying functional antibody activity (that is, nAB) is important because, although they are correlated, the effects of SARS-CoV-2 vaccines on nAB and absolute anti-spike immunoglobulin G (IgG) are dissociable, and nABs specifically seem critical in coferring protection from COVID-19.”
The study
The researchers state that they used “convergent self-reported symptom and objective biometric measurements to identify predictors of subsequent serum nAB concentration” at 1 and 6 months after vaccination in a cohort of adults who had received an initial 2-dose series of BNT126b2 or mRNA-1273. The self-reported variables included the presence or absence of 13 individual symptoms and total systemic count; biometric variables included measures of vaccination-induced change in skin temperature (ST), heart rate (HR), heart rate variability (HRV), and respiratory rate (RR).
The results suggest “no statistically significant associations” between the presence or absence of any symptom at dose 1 and subsequent nABs. For dose 2, nABs were higher for participants reporting versus not reporting the following symptoms:
- Chills
- Feeling unwell
- Tiredness
- Headache
These people had “1.4 to 1.6 times the nAB level of people who did not report each symptom, at 1 month and 6 months later”. Furthermore, each additional symptom experienced after dose 2 “predicted a 1.1-fold increase in subsequent nABs”. Thus, participants who reported 7 total symptoms subsequently had “roughly double” the nAB level of participants reporting 0 symptoms. From the objective biometric data, it emerges that “greater vaccination-induced change in ST and HR, specifically at dose 2, predicts greater nAB at both 1 month and 6 months later”. Indeed, effect sizes were “large”, with every 1 °C of vaccination-induced ST change associated with a “tripling” of the nAB level 6 months later.
The paper warns against “inferences about any given person’s level of nABs or protection from SARS-CoV-2 infection”. For example, while participants who reported tiredness had an average nAB level 1.5 times the level of those who didn’t report tiredness, not everyone who reported tiredness had higher nABs than every person without tiredness. Therefore, “tiredness should not be taken to mean something definitive about a given person’s nAB level”. Furthermore, although nAB level “has been shown to have a strong relative association with risk for COVID-19″, the authors highlight that the relationship with absolute risk “will be variable and dependent on base infection rates”.
This is emphasised by first author Dr Ethan Dutcher, postdoctoral researcher in the UCSF Department of Psychiatry and Behavioural Sciences and the Weill Institute for Neurosciences.
“Generally, we found that the higher the number of side effects, the higher the level of antibodies. But this wasn’t a hard rule: some people without side effects had better antibodies than some people with side effects.”
Co-senior author, Dr Elissa Epel, a vice chair in UCSF’s Department of Psychiatry and Behavioural Sciences, acknowledges that “the toll of COVID is still high for some – sickness, lost work, lasting fatigue, and the dreaded long COVID”.
“While the symptoms from vaccination can be very unpleasant, it’s important to remember that they don’t come close to the disease’s potential complications.”
Co-senior author Dr Aric Prather, professor in the UCSF Department of Psychiatry and Behavioural Sciences, says that “with COVID-19 vaccines likely here to stay, identifying what predicts a strong antibody response will remain important”.
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