PLOS Glob Public Health plos plosgph PLOS Global Public Health 2767-3375 Public Library of Science San Francisco, CA USA 10.1371/journal.pgph.0001053 PGPH-D-22-01340 Research Article Medicine and health sciencesMedical conditionsInfectious diseasesViral diseasesCOVID 19 Medicine and health sciencesMedical conditionsInfectious diseasesInfectious disease controlVaccines Medicine and health sciencesMedical conditionsInfectious diseasesViral diseasesInfluenza Medicine and health sciencesMedical conditionsInfectious diseasesInfectious disease controlVaccinesBooster doses Biology and life sciencesImmunologyVaccination and immunization Medicine and health sciencesImmunologyVaccination and immunization Medicine and health sciencesPublic and occupational healthPreventive medicineVaccination and immunization Biology and life sciencesImmunologyVaccination and immunizationVaccine development Medicine and health sciencesImmunologyVaccination and immunizationVaccine development Medicine and health sciencesPublic and occupational healthPreventive medicineVaccination and immunizationVaccine development Medicine and health sciencesClinical medicineSigns and symptomsPainMyalgia Medicine and health sciencesClinical medicineSigns and symptomsHeadaches Increased adverse events following third dose of BNT162b2/Pfizer vaccine in those with previous COVID-19, but not with concurrent influenza vaccine Adverse events associated with the booster dose of BNT162b2/Pfizer vaccine https://orcid.org/0000-0001-7593-3436 Raw Rachael K. Conceptualization Data curation Investigation Methodology Project administration Writing – original draft Writing – review & editing 1 * https://orcid.org/0000-0002-3295-244X Rees Jon Conceptualization Data curation Formal analysis Validation Writing – review & editing 2 Chadwick David R. Conceptualization Funding acquisition Investigation Methodology Resources Supervision Writing – review & editing 3 School of Medicine and Health, Newcastle University, Newcastle upon Tyne, United Kingdom The School of Psychology, University of Sunderland, Sunderland, United Kingdom Centre for Clinical Infection, James Cook University Hospital, Middlesbrough, United Kingdom Wagner Abram L. Editor University of Michigan, UNITED STATES

The authors have declared that no competing interests exist.

 * E-mail: Rachael.raw3@nhs.net 17 2 2023 2023 3 2 e0001053 17 8 2022 23 1 2023 2023 Raw et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Prior studies suggest that adverse events (AEs) following doses one and two of BNT162b2/Pfizer vaccine are worse in those with a prior history of COVID-19. To establish whether this outcome applies to a third/booster dose, we conducted a survey with 534 healthcare workers (HCW) in Northeast England, who reported AEs following all three doses of BNT162b2/Pfizer vaccine. We also explored AEs associated with concurrent seasonal influenza immunisation, in a subset of 492 HCWs. For all doses of BNT162b2/Pfizer vaccine there was a cluster of systemic AEs that were consistently worse in HCWs with a prior history of COVID-19. AEs were no worse in HCWs who received their third/booster dose within 7 days of the influenza jab, rather than further apart. Gender and the presence of ongoing COVID-19 symptoms (OCS) had no effect on AEs associated with COVID-19 or influenza vaccination, though younger HCWs experienced more AEs overall. Our findings have implications for vaccine hesitancy and immunisation protocols.

 North East and North Cumbria Academic Health Sciences Network (AHSN) Chadwick David R. The CHOIS study was supported by the North East and North Cumbria Academic Health Sciences Network (AHSN; fund awarded to co-author DRC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability Data is uploaded as supplementary information. Outbreaks COVID-19 1. Introduction

Global vaccination efforts against SARS-CoV-2 began in late 2020, with BNT162b2/Pfizer [1], mRNA-1273/Moderna [2], and ChAdOx1/AstraZeneca [3] vaccines applied predominantly in the UK population. Healthcare Workers (HCWs) have been a priority target group. Phase three trials demonstrated general safety of these vaccines, but adverse events (AEs) have been widely reported, albeit mostly mild-to-moderate in nature and short in duration [4–10]. We have previously demonstrated an association between prior COVID-19 infection and increased AEs following administration of dose one of BNT162b2/Pfizer vaccine, but not after dose two [9, 10]. The presence of "ongoing COVID-19 symptoms" (OCS; symptoms persisting from 4–12 weeks) [11] was also associated with increased AEs after the second dose of BNT162b2/Pfizer vaccine [9, 10].

In late 2021, a ‘booster’ dose of COVID-19 vaccine was recommended, and as of May 2022, just under 40 million UK citizens had received this third dose [12]. To our knowledge, it is unknown whether the previously observed effects of factors such as COVID-19 history carry over to the booster dose. Furthermore, due to the timing of booster vaccinations, many eligible individuals, particularly HCWs, were invited to receive their COVID-19 booster at the same time as their seasonal influenza jab, which raises the question of whether concomitant influenza/COVID-19 vaccination may enhance AEs. Large trials have shown that co-administration of influenza vaccine with the second dose of a COVID-19 vaccination (including NVX-CoV2373 [13], ChAdOx1 [14] or BNT162b2 [14]) did not yield any worse AEs than when the COVID-19 vaccine was delivered on its own. No study has yet looked at concomitant administration in the context of the COVID-19 third/booster dose.

The primary aim of our present study was to explore the impact of risk factors for vaccine-associated AEs following the third/booster dose of BNT162b2/Pfizer vaccine in HCWs. This included prior COVID-19 history, the presence of OCS, and HCWs’ age/gender. We also examined whether prior COVID-19 history would lead to worse AEs following the influenza jab. As a secondary aim, in a small subgroup, we also compared AEs between those who received their BNT162b2/Pfizer booster around the time of their Influenza jab, and HCWs who had their vaccinations > 7 days apart.

 2. Method 2.1. Ethics statement

All participants gave their written informed consent, and Cambridge East Research Ethics Committee approved this study (Ethics Ref: 20/EE/0161), which was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

 2.2. Participants

HCWs recruited from three Northeast England hospitals, formed an opportunistic sample for this retrospective observational and descriptive study. HCWs were invited via email, to complete an anonymous online survey, which captured their experience of AEs following first, second and third/booster doses of the BNT162b2/Pfizer vaccine using structured and multiple-choice questions The email was sent out to all HCWs, both clinical and non-clinical, using the weekly Hospital Communications service. Those who had received all three doses of BNT162b2/Pfizer vaccine were eligible to partake.

 2.3. Materials and procedure

AEs were documented using a modified version of the FDA Toxicity Grading Scale. [15] as previously described [9, 10]. HCWs indicated whether they had received influenza vaccine within 7 days of the COVID-19 booster dose. If HCWs did not receive both vaccinations within this time interval, they were also asked to describe AEs following the influenza vaccine. Prior COVID-19 history was classed as positive for HCWs with self-reported positive PCR and/or COVID-19 test(s). The number of moderate-to-severe AEs persisting >24hr were calculated for doses one, two and three of BNT162b2/Pfizer, and for influenza where it was not administered concomitantly. For BNT162b2/Pfizer doses one and two, AEs were only counted as moderate/severe if they were rated as “similar or worse than my current symptoms”. Effects of age, gender, presence of OCS, and whether influenza vaccine was administered concomitantly were also considered.

 2.4. Statistical analysis

Statistical analysis was conducted using JASPv0.16.3.0 [16]. Frequencies of categorical variables and the occurrence of any moderate-to-severe AEs were examined using the chi-square test. Scores were compared using 2-way ANOVA and ANCOVA where age and gender were relevant. Multivariable logistic regressions were applied to identify the relationship between COVID-19 status and moderate-to-severe AEs, and the Bonferroni correction applied to the resulting significance/confidence intervals. Correlation/tests of difference explored associations between AEs and age/gender.

 3. Results

Five-hundred and thirty-four HCWs responded to the questionnaires (15% male, mean age 49.6yr [SD-10.6]. Looking at prior COVID-19 history, 147/454 (32.3%) self-reported previous COVID-19. 492 (92.1%) had received influenza vaccine: 56 HCWs (11.4%) had it within 7 days of their third BNT162b2/Pfizer dose, 292 HCWs (59.4%) had their doses >7 days apart. 144 HCWs (29.3%) did not indicate time interval. Raw data is available to view as supplementary information (see S1 Data).

Initial analyses revealed a significant negative relationship between age and the number of moderate-to-severe AEs following third BNT162b2/Pfizer and influenza vaccines (BNT162b2/Pfizer Kendall’s-tau = -0.16; influenza Kendall’s-tau = -0.14;both p<0.001). However, for BNT162b2/Pfizer there was no significant relationship between age and number of AEs reported following doses one and two. There was a significant strong positive relationship between number of AEs reported for doses one and two (Kendall’s-tau = 0.46;p<0.001), a negative relationship between AEs following doses one and three (Kendall’s-tau = -0.13;p<0.001), but no relationship between number of AEs for doses two or three, or between each of doses two and three, and the number of influenza AEs reported. There were no significant differences in number of AEs reported by male versus female HCWs, as shown in Table 1.

10.1371/journal.pgph.0001053.t001 Number of AEs by participant gender and vaccine dose: Mean (S.D) number of AEs reported by male versus female HCWs for all three BNT162b2/Pfizer doses and the seasonal Influenza vaccine.
Male (n = 80) Female (n = 454) p d [95% C.I.]
Age 48.7 (11.5) 49.6 (10.7) - -
BNT162b2/Pfizer Dose 1 2.84 (2.85) 2.86 (2.75) 0.95 0.008 [-0.23–0.25]
BNT162b2/Pfizer Dose 2 2.44 (2.90) 2.55 (2.80) 0.74 0.04 [-0.2–0.28]
BNT162b2/Pfizer Dose 3 0.99 (1.97) 1.43 (2.01) 0.07 0.22 [-0.02–0.46]
Influenza 0.78 (1.79) 0.76 (1.48) 0.90 - 0.02 [-0.26–0.23]

For occurrence of one or more moderate/severe AEs, there was a significant association with previous COVID-19 and BNT162b2/Pfizer dose one (O.R.-1.64[1.13–2.38];p = 0.011), dose two (O.R.-1.63[1.12–2.35];p = 0.011), dose three (O.R.-2.44[1.67–3.55];p<0.001), and between previous history of COVID-19 and occurrence of AEs following the influenza vaccine (O.R.-1.88[1.25–2.82];p = 0.002). To investigate the effect of prior COVID-19 on number of AEs following all three BNT162b2/Pfizer vaccines, a two-by-three (AEs x vaccine dose) ANOVA was performed. Age and gender were not used as covariates here given the non-significance of relationships identified with doses one and two, as described above. There was an overall main effect of prior COVID-19 (F(1.8, 957.7) = 48.63;p<0.001), whereby HCWs with prior COVID-19 reported 2.59 [2.39–2.79] versus 1.91[1.71–2.12] AEs (Fig 1A). There was a significant difference in number of AEs reported following dose one (F(1,527) = 19.93;p<0.001), with post-hoc testing (Bonferroni-p<0.05) demonstrating that the number of AEs reported for dose three (1.36 [1.14–1.59]) was significantly lower than reported for dose one (2.84[2.61–3.07]), and dose two (2.55[2.32–2.78]. There was no interaction between vaccine dose and COVID-19 history (Fig 1A).

10.1371/journal.pgph.0001053.g001 Frequency of AEs by vaccine type, prior COVID-19 status and interval between doses.

A. Number of AEs according to previous COVID-19 history, for all three BNT162b2/Pfizer doses. B. Number of AEs according to previous COVID-19 history for BNT162b2/Pfizer third/booster dose and the seasonal influenza vaccine. C. Number of AEs according associated with the influenza vaccine versus BNT162b2/Pfizer third/booster dose for those HCWs who had these vaccines ≤ or > 7 days apart.

To investigate the difference in number of AEs between BNT162b2/Pfizer dose three and the influenza vaccine, together with the role of interval between each vaccine, a two-by-two-way ANCOVA (vaccine x dosage interval), with age and gender as covariates (given the significant relationships here with dose three), was performed. Overall, there were significantly more AEs following BNT162b2/Pfizer dose three (1.28[1.07–1.49]), compared to the influenza vaccine (0.81[0.60–1.02]; Fig 1B); AEs F(1,331) = 3.86;d = 0.28[0.19–0.37];p<0.001), but there was no significant effect of interval between vaccines (F(1,331) = 0.02;p = 0.88), and no interaction between these variables (F(1,311) = 0.61;p = 0.44; Fig 1C).

Given the association between occurrence of any influenza AEs and prior COVID-19, we investigated this further. A two-by-two-way ANCOVA (vaccine-type x prior COVID-19) was performed, with age and gender as covariates. The overall significant difference in number of AEs between prior COVID-19 and influenza was maintained (F(1,470) = 1.06;p<0.001), but there was also a significant overall effect of prior COVID-19 with those previously symptomatic reporting more AEs across both types of vaccine (F(1,470) = 11.73,p<0.001), but crucially a significant interaction between vaccine type and COVID-19 history F(1,470) = 4.16;p = 0.04). A simple effects analysis revealed this interaction was due to significantly larger numbers of AEs to BNT162b2/Pfizer vaccine in those with prior COVID-19 (t(527) = 3.61,p<0.001;d = 0.34[0.15–0.52]), whilst the difference in number of AEs following influenza vaccine was not significant (t (488) = 1.78;p = 0.08;d = 0.17[-0.02–0.36]).

A similar pattern of results was found for prolonged AEs, which were scored as total number of vaccine-associated AEs rated as moderate/severe, lasting >24 hours. In this instance, an ANCOVA found significantly higher numbers of prolonged AEs associated with BNT162b2/Pfizer vaccine compared to influenza (1.09[0.96–1.23] v 0.32[0.19–0.45]; AEs F(1,511) = 15.24;p<0.001), a higher number of prolonged AEs in those with prior COVID-19, than without (0.84[0.69–1.00] v 0.57[0.42–0.72]; AEs (F(1,511) = 4.09;p = 0.044), and a significant interaction between these variables (F(1,511)–7.13;p = 0.008). A simple effects analysis showed that the number of prolonged moderate-to-severe AEs was again only significantly higher following BNT162b2/Pfizer vaccine (t(528) = 3.03;d = 0.28[0.10–0.47];p = 0.003), with no significant difference in prolonged AEs for the influenza vaccine (t(532) = 0.44;d = 0.04[-0.14–0.22];p = 0.66).

Incidence of each type of AE following BNT162b2/Pfizer dose three for those with and without prior COVID-19, is shown in Table 2. As in our previous work, the cluster of headache, fatigue, myalgia and arthralgia were most common in HCWs with prior COVID-19. Overall, the incidence of AEs to dose three were remarkably like those following the first two doses. Looking at the types of AEs most frequently reported, headache, fatigue, and myalgia were associated with prior COVID-19 for the third/booster dose of BNT162b2/Pfizer, after correcting for multiple comparisons, age and gender (Fig 2; Table 2). The effect for arthralgia was very nearly significant (p = 0.06). A similar analysis for time interval between influenza and BNT162b2/Pfizer dose three, found no significant relationship for occurrence of any of the vaccine-associated AEs (all p>0.9).

10.1371/journal.pgph.0001053.g002 Moderate and severe AEs by COVID-19 status: Percentage of cases reporting moderate or severe AEs (95% CI) following BNT162b2/Pfizer third/booster dose in those with and without a history of COVID-19.

N & V: nausea and vomiting.

 10.1371/journal.pgph.0001053.t002 Moderate and severe AEs by COVID-19 status: Percentage of cases reporting moderate or severe AEs following BNT162b2/Pfizer third/booster dose (95% CI) in those with and without a history of COVID-19 (the former including OSC).
Dose 3
Odds Ratio (95% C.I.) p
Fever 1.44 (0.55 3.81) >.99
Fatigue 2.37 (1.32 4.27) < .001
Myalgia 2.25 (1.18 4.28) 0.001
Arthralgia 2.10 (0.98 4.46) 0.06
Lymphadenopathy 0.79 (0.79 1.40) >.99
Local Pain 1.43 (0.77 2.65) >.99
Local Redness 2.56 (0.77 8.53) 0.33
Local Swelling 3.15 (0.82 12.11) 0.18
Nausia & Vomiting 0.51 (0.12 2.12) >.99
Diarrhoea 1.49 (0.23 9.47) >.99
Headache 2.03 (1.10 3.77) 0.011

Comparing the subset of HCWs with OCS (n = 32), with those without OCS, there was a similar reduction in number of AEs to BNT162b2/Pfizer dose three, compared to doses one and two (F(1.82,957.8) = 11.89;p<0.001; dose one 2.91[2.41–3.4]; dose two 2.48[1.97–2.98]; dose three 1.44[1.08–1.80]; Bonferroni-corrected post-hoc for dose three being significantly different [p<0.05] to doses one and two. There was no significant overall difference in number of AEs between groups (F(1,527) = 0.03;p = 0.86 (OCS mean 2.30[1.73–2.87]; control mean 2.25[2.10–2.39]), and no significant interaction (F(1.82, 957.8) = 0.15;p = 0.84). This suggests that OCS had no effect on number of AEs reported at each BNT162b2/Pfizer dose interval. Furthermore, there was no significant difference in number of AEs experienced following the influenza jab, between those with versus without OCS (without = 0.70;SD-1.5; with = 0.56,SD-1.4; AEs d = 0.09[-0.30–0.56];p = 0.54).

 4. Discussion

Our previous work highlighted risk factors for increased BNT162b2/Pfizer vaccine-associated AEs, specifically females, younger age, prior COVID-19, and OCS were associated with increased AEs reported following doses one and/or two [9, 10]. The main findings of our present study were firstly, that frequency of AEs to BNT162b2/Pfizer vaccination progressively reduced across all doses. Nevertheless, moderate-to-severe AEs were markedly more common in our cohort compared to the COV-BOOST trial that used the same AE grading system following third/booster doses of BNT162b2/Pfizer (AEs<5%;n = 96) [17]. Our finding of progressive reductions in AEs across successive doses contrasts with both our prior work (showing AEs increased between doses one and two [10]) and a recent Israeli stud showing the opposite effect [18]. This might have occurred because either the present work involved a new sample of HCWs (hence individual differences) or HCWs becoming more accustomed to vaccine-associated AEs over time. Similarly, another surprising result was that gender did not appear to influence AEs, whereas our past studies have consistently shown females to report more AEs following doses one and two of BNT162b2/Pfizer vaccination [9, 10]. Younger participants in the present study reported more AEs following the third/booster BNT162b2/Pfizer dose, and the influenza vaccine, the former finding being consistent with our and other’s prior work [9, 10].

Our second key finding was that the effect of prior COVID-19 on vaccine-associated AEs, was again carried over to the third/booster BNT162b2/Pfizer dose in terms of increased AEs. Nevertheless, the presence of self-reported OCS did not seem to impact AEs to BNT162b2/Pfizer vaccination at any of the dosage timepoints, although our sample of HCWs with OCS was notably small.

Regarding the effect of influenza vaccination on AEs experienced around the time of the third/booster BNT162b2/Pfizer dose, our analysis was somewhat limited by the small number of HCWs that received their influenza vaccine within 7 days of t BNT162b2/Pfizer vaccination (n = 56). Analyses did however show that HCWs in this subgroup reported similar numbers/levels of AEs compared to individuals who received vaccines more than 7 days apart. This supports previous safety data, which found no worse AEs reported following concomitant administration of influenza with doses one or two of COVID-19 vaccines [13, 14].

Limitations of the present work include the large sample imbalance for participant gender (85% female), and the retrospective recall (up to 12 months) of AEs in the present study. Given that vaccine safety plays a central role in people’s decision to accept a vaccination, our present work has implications for vaccine hesitancy [19, 20]. We found that BNT162b2/Pfizer-related AEs diminished with each successive dose and were no worse than the AEs reported by HCWs following influenza vaccine, which has been widely accepted for many years. Our present work also provides preliminary data to support concomitant administration of the third/booster BNT162b2/Pfizer vaccination alongside the influenza vaccine. These findings of relatively mild AEs, even when given alongside influenza vaccine, should be used to bolster public confidence in immunisation programmes.

 5. Conclusion

Prior history of COVID-19 was associated with increased AEs to BNT162b2/Pfizer vaccination at all three dosage points. The presence of OCS and female gender had no impact on AEs to BNT162b2/Pfizer or influenza vaccination, though younger HCWs experienced more AEs. Lastly, AEs were no worse in HCWs who received concomitant booster BNT162b2/Pfizer and influenza vaccines.

 Supporting information Raw data for all participants who received 3 doses of BNT162b2/Pfizer vaccine.

(CSV)

We would like to thank the CHOIS research team, John Rouse and the North East and North Cumbria NIHR for assistance with the survey.

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6 Dec 2022

PGPH-D-22-01340

Increased adverse events following third dose of BNT162b2/Pfizer vaccine in those with previous COVID-19, but not with concurrent influenza vaccine.

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Comments to the Author

1. Does this manuscript meet PLOS Global Public Health’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Global Public Health does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Reviewer Comments:

The authors have a grandiose study, very important to health, as it tries to shade light on the implication for covid-19 vaccine uptake and immunization protocols. The study is very promising, but some minor points must be reviewed before possible publication.

Abstract:

The authors in the present study had a sample size of 534 HCW who were enrolled in the study:

The authors should be specific how many individuals were analysed separately for AEs following all three doses of BNT162b2/Pfizer vaccine and those were involved in the concurrent seasonal influenza immunisation.

Methods:

The authors needs to provide ethical approval number for this study

The authors should clearly demonstrate how they arrived at sample size of 534 (show sample size calculation)

Results

In line 156-157 the authors states that “A similar pattern of results was found for prolonged AEs, which were scored as total number of vaccine-associated AEs rated as moderate/severe, lasting >24 hours”. In the subsequent studies they could have performed correlation analysis between the adverse events within less than 24hrs and after prolonged period in order to paint a clear picture as to whether the development and increase in AEs is observed after long period of vaccination.

Conclusion

Since the large sample size that was analyzed constituted 85% female, can we conclusively state that AEs witnessed during covid-19 vaccination programs may be gender specific?

Reviewer #2: Reviewer’s comment

Introduction

(1)Line 41: Authors should indicate the exact AEs that were frequently reported

(2)Lines 43/46: It would be appropriate if authors differentiate or state the specific AEs reported following a single dose of BNT162b2/Pfizer vaccine and the events reported during ongoing COVID-19 symptoms vaccination with BNT162b2/Pfizer 47 vaccine after second dose.

Methods

(1)Lines 78-80: Provide the ethics approval reference number

(2)The methodology employed in this students has some gaps that need to be addressed or filled.

a.Authors employed the use of email to invite responses. However, it was not clear how the respondents were selected, no clear inclusion and exclusion criteria were stated.

b.Sample size was not predetermined.

c.The use of emails did not allow authors to verify the AEs being described. How were you able to verify these events?

d.Was the questions structured or unstructured?

e.Were there avenue for follow up, if you required further information

f.The use of emails did not allow anonymity. In this case, how did you ensured anonymity?

Results

(1)Lines 99/101: Avoid beginning a sentence with a number. Please revise

(2)Line 101: 144 HCWs (29.3%) did not indicate time interval. This seems a flaw in the design of the questionnaire. Authors should have envisaged this, even at the design stage.

Discussion

(1)Line 204: stud---study

(2)Our findings have implications for vaccine hesitancy and immunisation protocols. This was the concluding part of the abstract. The discussion section only has this on vaccine hesitancy ‘Given that vaccine safety plays a central role in people’s decision to accept a vaccination, our present work has implications for vaccine hesitancy’ It makes it very difficult to understand how this study could have implications on vaccine hesitancy and immunization protocols, in general. Please discuss the study to take care of this.

Reviewer #3: The authors are advised to include a statement about the type of study design that was employed.

Page4 line 88: The authors should provide citation for the software JASPv0.16.3.0.

Authors should avoid starting a sentence with abbreviations.

There are also a couple of spelling errors in the discussion aspect of the manuscript, the authors are advised to revise for punctuation and spelling.

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Reviewer #1: Yes: JAMES NYABUGA NYARIKI (PhD)

Reviewer #2: No

Reviewer #3: No

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 10.1371/journal.pgph.0001053.r002 Author response to Decision Letter 0 Submission Version 1

14 Dec 2022

Submitted filename: Rebuttal.docx

 10.1371/journal.pgph.0001053.r003 Decision Letter 1 Wagner Abram L. Academic Editor 2023 Abram L. Wagner This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

25 Jan 2023

Increased adverse events following third dose of BNT162b2/Pfizer vaccine in those with previous COVID-19, but not with concurrent influenza vaccine.

PGPH-D-22-01340R1

Dear Dr Raw,

We are pleased to inform you that your manuscript 'Increased adverse events following third dose of BNT162b2/Pfizer vaccine in those with previous COVID-19, but not with concurrent influenza vaccine.' has been provisionally accepted for publication in PLOS Global Public Health.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Global Public Health.

Best regards,

Abram L. Wagner, PhD, MPH

Academic Editor

PLOS Global Public Health

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Reviewer Comments (if any, and for reference):

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Does this manuscript meet PLOS Global Public Health’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Global Public Health does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All the issues I raised in the manuscript has been addressed to my satisfaction

Reviewer #2: All comments have been adequately addressed

Reviewer #3: The authors have satisfied all my concerns, the manuscript can now be accepted for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

Do you want your identity to be public for this peer review? If you choose “no”, your identity will remain anonymous but your review may still be made public.

For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dr. JAMES NYABUGA NYARIKI

Reviewer #2: Yes: Enoch Aninagyei

Reviewer #3: No

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