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Review 4: "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 14, 2023
Review 4: "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:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



The preprint by Dutcher et al. - “The more symptoms the better? COVID-19 vaccine side effects and long-term neutralizing antibody responses” - reports on the results of a comprehensive and well-designed investigation of symptoms and biometric changes after COVID-19 mRNA vaccination and their correlation with the development of anti-SARS-CoV-2 neutralizing antibodies. The authors report that certain self-reported symptoms (including chills, feeling unwell, tiredness, and headache) as well as objective biometric data (such as increases in skin temperature and heart rate) after the second mRNA vaccine dose were associated with the development of significantly more neutralizing antibodies measured at 1 and 6 months post-vaccination. 

In the study by Dutcher et al, convincing data are presented that indicate that certain symptoms experienced by mRNA vaccinees after their second vaccine dose may be associated with the development of higher levels of neutralizing antibodies. Interestingly, neutralizing antibody levels were also positively associated with the number of self-reported symptoms. These data are further supported by objective biometric changes such as greater increases in skin temperature and heart rate measured after the second vaccine dose in study participants with higher levels of neutralizing antibodies. The authors use lentivirus-based pseudovirus neutralization assays that they describe in a separate study by Prather et al. Some more background information on these assays should also be added to this manuscript (plasmids used, type of pseudoviruses). Similarly, anti-SARS-CoV-2 antibody binding assays that were used for participant inclusion/exclusion criteria should be mentioned and briefly described in the methods section. The Oura ring applied for biometric measurements in this study is a smart wearable device that has been used in several recent health and physical activity monitoring studies. The authors could add some discussion on the accuracy of the Oura device for the measured variables. The statistical measurements conducted in this study are appropriate and comprehensive in particular for the biometric measurements, for which three candidate methods of summarizing each set of nightly measurements (heart rate, heart rate variability, and skin temperature) including the 1st percentile, the mean, and the 99th percentile were evaluated. 

Neutralizing antibodies have been found to be good correlates of protection against symptomatic COVID-19, although efforts to define thresholds of antibody levels required for protection are complicated by differences between individuals in their virus exposure and host factors that impact susceptibility to symptomatic COVID-19. It is therefore unclear if the detected differences in antibody responses between individuals who did or did not experience certain vaccine side effects also translate into different levels of protection as this study did not report on “breakthrough” cases of SARS-CoV-2 infection after vaccination. Very cautious information of the general public is therefore required. The authors suggest that public health messages should be reframed to emphasize that some post-vaccination symptoms may be positive indicators for an effective response to vaccination. In my opinion this needs very careful phrasing to avoid unsettling those who may not experience symptoms after vaccination and I therefore suggest that authors elaborate a bit more on this concern. It is known that the vast majority of individuals irrespective of their reported symptoms produce high neutralizing antibody concentrations after their second vaccine dose. 

Key strengths of this study over previously published investigations on correlations of neutralizing antibodies and vaccine side effects are i) careful inclusion and exclusion criteria (e.g. only individuals without anti-Spike antibodies before vaccination and anti-Nucleocapsid antibodies at the 6-month time point were included to avoid confounding data with those from individuals previously infected with SARS-CoV-2), ii) analysis of neutralizing antibodies at later time points (6 months after the 2nd dose) to avoid the ceiling effect of detecting large amounts of antibodies that are produced in the first month after vaccination, iii) inclusion of objective biometric measurements. The authors are aware and discuss the limitations of their study. 

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