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Review 2: "The More Symptoms the Better? Covid-19 Vaccine Side Effects and Long-term Neutralizing Antibody Response"

Reviewers found this preprint potentially informative to strong, in particular praising the statistical methods used in the analysis.

Published onNov 09, 2023
Review 2: "The More Symptoms the Better? Covid-19 Vaccine Side Effects and Long-term Neutralizing Antibody Response"
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key-enterThis Pub is a Review of
The more symptoms the better? Covid-19 vaccine side effects and long-term neutralizing antibody response
The more symptoms the better? Covid-19 vaccine side effects and long-term neutralizing antibody response

Protection against SARS-CoV-2 wanes over time, and booster uptake has been low, in part because of concern about side effects. We examined the relationships between local and systemic symptoms, biometric changes, and neutralizing antibodies (nAB) after mRNA vaccination. Data were collected from adults (n = 364) who received two doses of either BNT162b2 or mRNA-1273. Serum nAB concentration was measured at 1 and 6 months post-vaccination. Daily symptom surveys were completed for six days starting on the day of each dose. Concurrently, objective biometric measurements, including skin temperature, heart rate, heart rate variability, and respiratory rate, were collected. We found that certain symptoms (chills, tiredness, feeling unwell, and headache) after the second dose were associated with increases in nAB at 1 and 6 months post-vaccination, to roughly 140-160% the level of individuals without each symptom. Each additional symptom predicted a 1.1-fold nAB increase. Greater increases in skin temperature and heart rate after the second dose predicted higher nAB levels at both time points, but skin temperature change was more predictive of durable (6 month) nAB response than of short-term (1 month) nAB response. In the context of low ongoing vaccine uptake, our convergent symptom and biometric findings suggest that public health messaging could seek to reframe systemic symptoms after vaccination as desirable.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The authors of this manuscript find that several systemic symptoms (chills, headache, feeling unwell and tiredness) and two biometric measures (change in max skin temp and min heart rate) following the 2nd COVID-19 dose correlate with neutralizing antibodies (nAB) measured 6 months following vaccination. The majority of the aforementioned variables also correlated with higher nAB measured 1 month following vaccination. The authors suggest that public health messaging reframing systemic side effects as beneficial could improve vaccine uptake. 

The authors have conducted a thoughtful and thorough analysis of their study data. I suggest including more detail on the Type II F-tests conducted in the methods section; currently the methods indicate 4 hypothesis tests conducted on each exposure (systemic side effect and biometric measure) but does not explicitly define these tests. In my experience, unless a reader is very familiar with Type II F-tests, typically requiring extensive statistical training, most readers will not understand what hypothesis tests / models are being compared. The authors use the word "predict" instead of "associated with" in many places in the paper; the analysis conducted is one to determine association not to evaluate the quality of systemic side effect and biometric measures as predictors for nAB at 1- and 6-months following vaccination. Aside from mislabeling association as prediction, the results are interpreted accurately. However, I challenge the author's conclusion that their study's findings support reframing systemic side effects as beneficial (to increase vaccine uptake). Although the authors found statistically significant differences in nAB when comparing presence or absence of systemic side effects, they need to subsequently argue that the size of the differences observed would translate to better protection by the vaccine. The nAB levels are all very high and I don’t believe there are studies to support a threshold for nAB to designate protection vs. not (or even to define what constitutes protection). In addition, the authors should acknowledge the potential downside to the suggested messaging, e.g. persons who don't experience side effects after initial vaccination may NOT seek boosters since they may assume no systemic side effects indicate poor vaccine response (which is certainly NOT supported by any studies) so no reason to continue to get boosters if they aren’t offering protection. 

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