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Review 2: "Adverse effects and antibody titers in response to the BNT162b2 mRNA COVID-19 vaccine in a prospective study of healthcare workers"

This preprint investigates antibody titer and whether titer correlates with a variety of parameters, including age, weight, sex, and post-vaccine symptom severity. Reviewers deem date reliable with only minor revision to data analysis.

Published onAug 04, 2021
Review 2: "Adverse effects and antibody titers in response to the BNT162b2 mRNA COVID-19 vaccine in a prospective study of healthcare workers"
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key-enterThis Pub is a Review of
Adverse effects and antibody titers in response to the BNT162b2 mRNA COVID-19 vaccine in a prospective study of healthcare workers

AbstractBackgroundmRNA COVID-19 vaccines are playing a key role in controlling the COVID-19 pandemic. The relationship between post-vaccination symptoms and strength of antibody responses is unclear.ObjectiveTo determine whether adverse effects caused by vaccination with the Pfizer/BioNTech BNT162b2 vaccine are associated with the magnitude of vaccine-induced antibody levels.DesignSingle center, prospective, observational cohort study.SettingParticipants worked at Walter Reed National Military Medical Center and were seen monthly at the Naval Medical Research Center Clinical Trials Center.ParticipantsGenerally healthy adults that were not severely immunocompromised, had no history of COVID-19, and were seronegative for SARS-CoV-2 spike protein prior to vaccination.MeasuresSeverity of vaccine-associated symptoms was obtained through participant completed questionnaires. Testing for IgG antibodies against SARS-CoV-2 spike protein and receptor binding domain was conducted using microsphere-based multiplex immunoassays.Results206 participants were evaluated (69.4% female, median age 41.5 years old). We found no correlation between vaccine-associated symptom severity scores and vaccine-induced antibody titers one month after vaccination. We also observed that 1) post-vaccination symptoms were inversely correlated with age and weight and more common in women, 2) systemic symptoms were more frequent after the second vaccination, 3) high symptom scores after first vaccination were predictive of high symptom scores after second vaccination, and 4) older age was associated with lower titers.LimitationsStudy only observes antibody responses and consists of healthy participants.ConclusionsLack of post-vaccination symptoms following receipt of the BNT162b2 vaccine does not equate to lack of vaccine-induced antibodies one month after vaccination. This study also suggests that it may be possible to design future mRNA vaccines that confer robust antibody responses with lower frequencies of vaccine-associated symptoms.FundingThis study was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded by the Defense Health Program, U.S. DoD, under award HU00012120067. Project funding for JHP was in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The funding bodies have had no role in the study design or the decision to submit the manuscript for publication.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



  • This article is well-written and structured, but some fundamental information needs to be provided. For example, two important pieces of information regarding when, on average, participants received the two vaccine doses and when, after the vaccination, the determination of the antibody titers was performed should be clarified in the text. Is this period of time relatively homogeneous or are there large ranges of dates?

  • The findings of the article are interesting even if their interpretation may be limited by the small sample size.

  • The authors state that the study is prospective, which it is not. The study reported here is an observational study (retrospective for the data on vaccinations and perhaps for the data on antibody titers, and cross-sectional considering the symptoms’ investigation).

  • Seventy percent of the study’s sample is made up of women and some symptoms are, not unexpectedly, more frequent in women.

  • The study reports in the abstract and conclusions sections a result which is not supported by the study’s findings: “This study also suggests that it may be possible to design future mRNA vaccines that confer robust antibody responses with lower frequencies of vaccine-associated symptoms. Indeed, emerging studies suggest the balance between vaccine immunogenicity and reactogenicity can be better tuned for COVID-19 mRNA-based vaccines as well (32)”. I would suggest deleting this sentence.

  • The results of the study are reliable and generally justified according to the methodology and data presented. Even considering the possible limitations, the data is in line with current scientific literature (i.e. a large variety of symptoms reported after COVID-19 vaccines are relatively frequent, there are no severe effects for the vast majority, and symptoms are more common after the second dose). I am not sure about the finding related to a higher reporting of symptoms after vaccination in younger individuals, because, in this case, this result is a bit contradictory with the finding of no relations with antibody titers; we would expect a stronger immune response in younger adults compared to older subjects.

  • Accordingly, the manuscript confirms previous work and contributes to the collection of evidence on COVID-19 mRNA vaccine-related adverse effects and antibody titers induced.

  • Some recent and relevant papers already published on the topic are not considered; I suggest citing some of them and considering them in the discussion section of the results:

1)     Hall VJ, Foulkes S, Saei A, Andrews N, Oguti B, Charlett A, Wellington E, Stowe J, Gillson N, Atti A, Islam J, Karagiannis I, Munro K, Khawam J, Chand MA, Brown CS, Ramsay M, Lopez-Bernal J, Hopkins S; SIREN Study Group. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021 May 8;397(10286):1725-1735. doi: 10.1016/S0140-6736(21)00790-X.

2)     Chapin-Bardales J, Gee J, Myers T. Reactogenicity Following Receipt of mRNA-Based COVID-19 Vaccines. JAMA. 2021 Jun 1;325(21):2201-2202. doi: 10.1001/jama.2021.5374.

3)     Favresse J, Bayart JL, Mullier F, Dogné JM, Closset M, Douxfils J. Early antibody response in health-care professionals after two doses of SARS-CoV-2 mRNA vaccine (BNT162b2). Clin Microbiol Infect. 2021 May 8:S1198-743X(21)00224-X. doi: 10.1016/j.cmi.2021.05.004. Epub ahead of print.

4)     Modenese, A.; Paduano, S.; Bargellini, A.; Bellucci, R.; Marchetti, S.; Bruno, F.; Grazioli, P.; Vivoli, R.; Gobba, F. Neutralizing Anti-SARS-CoV-2 Antibody Titer and Reported Adverse Effects, in a Sample of Italian Nursing Home Personnel after Two Doses of the BNT162b2 Vaccine Administered Four Weeks Apart. Vaccines 2021, 9, 652.

5)     Tré-Hardy M, Cupaiolo R, Papleux E, et al. Reactogenicity, safety and antibody response, after one and two doses of mRNA-1273 in seronegative and seropositive healthcare workers [published online ahead of print, 2021 Apr 1]. J Infect. 2021;S0163-4453(21)00158-4. doi:10.1016/j.jinf.2021.03.025

6)     Padoan A, Dall'Olmo L, Rocca FD, Barbaro F, Cosma C, Basso D, Cattelan A, Cianci V, Plebani M. Antibody response to first and second dose of BNT162b2 in a cohort of characterized healthcare workers. Clin Chim Acta. 2021 Aug;519:60-63. doi: 10.1016/j.cca.2021.04.006.

7)     Manisty C, Otter AD, Treibel TA, McKnight Á, Altmann DM, Brooks T, Noursadeghi M, Boyton RJ, Semper A, Moon JC. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet. 2021 Mar 20;397(10279):1057-1058. doi: 10.1016/S0140-6736(21)00501-8.

8)     Meo SA, Bukhari IA, Akram J, Meo AS, Klonoff DC. COVID-19 vaccines: comparison of biological, pharmacological characteristics and adverse effects of Pfizer/BioNTech and Moderna Vaccines. Eur Rev Med Pharmacol Sci. 2021 Feb;25(3):1663-1669. doi: 10.26355/eurrev_202102_24877.


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