Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: A comparative study among healthcare professionals of Nepal.

BACKGROUND: Adverse events following immunization (AEFI) against SARS-CoV-2 are common as reported by clinical trials and contemporary evidence. The objective of the present study was to evaluate the local and systemic adverse events following vaccination with ChAdOx1 nCoV-19 and BBIBP-CorV among the healthcare professionals (HCPs) of Nepal.
METHODS: This cross-sectional study was conducted among 606 vaccinated HCPs of Kathmandu, Nepal. Data was collected from June 15 to 30, 2021 using a self-administered online survey tool. Multiple binary logistic regression models were used to predict the adverse events according to the vaccine types and doses after adjusting for age, sex, comorbidity and previous SARS-CoV-2 infection.
RESULTS: The mean (SD) age of the participants was 35.6 (13.2) years and 52% of them were female. Almost 59% of participants were vaccinated with two doses and around 54% of total of them took the ChAdOx1 nCoV-19 vaccine. At least one local and systemic adverse event was reported by 54% and 62% of participants after the first dose and 37% and 49% after the second dose of ChAdOx1 nCoV-19 and by 37% and 43% after the first dose and 42% and 36% after the second dose of BBIBP-CorV vaccine respectively. Injection site pain, swelling and tenderness at the injection site were the most frequently reported local AEFI while, fatigue, headache, fever and myalgia were the most frequently reported systemic AEFI. The logistic model demonstrated that the risk of both local and systemic adverse events was higher among the ChAdOx1 nCoV-19 vaccine recipients compared to the BBIBP-CorV vaccine. Almost 10% of individuals reported a post-vaccination SARS-CoV-2 infection and most of them occurred after taking the first dose of vaccine.
CONCLUSIONS: Recipients of both the ChAdOx1 nCoV-19 and BBIBP-CorV vaccine among the HCPs of Nepal reported only mild and constitutional symptoms including injection site pain and tenderness, headache, fever, fatigue, etc. after vaccination.

Introduction

The world is currently facing the largest pandemic of the century due to a newly emerged highly transmissible and pathogenic virus of the coronavirus family, the SARS-CoV-2 which causes an acute respiratory disease, named ’coronavirus disease 2019’ (COVID-19) [1]. This pandemic contributed to more than 205 million infections by the virus and four million deaths worldwide [2]. Vaccination against SARS-CoV-2 is recognized as a leading strategy to combat the pandemic and several vaccines have been promptly developed and approved by different health authorities for mass vaccination worldwide [3, 4].

In Nepal, almost 721 thousand COVID-19 cases were reported with almost 10000 deaths by June 2021 [2]. The government of Nepal started a public vaccination program in late January 2021 and administered more than 4.5 million doses of ChAdOx1 nCoV-19 and BBIBP-CorV vaccine by June 2021 covering 8% of their total population [5]. The ChAdOx1 nCoV-19 is an adenoviral vector vaccine manufactured by the Oxford-AstraZeneca, UK and BBIBP-CorV is an inactivated SARS-CoV-2 vaccine manufactured by the Sinopharm, China [3]. The large-scale clinical trials reported adequate safety profiles and antibody responses by both of the vaccines [6-9].

The clinical trials, as well as real-world evidence, reported some adverse events following immunization (AEFI) with these vaccines though most of these were mild constitutional symptoms. A population-based study from the UK conducted among more than half a million recipients of the BNT162b2 mRNA vaccine (Pfizer) or ChAdOx1 nCoV-19 recombinant vaccine (Oxford-AstraZeneca) reported that almost 22% of individuals after taking BNT162b2 vaccine, and 34% individuals after taking the ChAdOx1 nCoV-19 vaccine developed at least one systemic symptom, mostly mild headache, fatigue, and fever. Local symptoms like injection site pain, tenderness, and swelling were reported by almost half of the recipients [10]. Severe adverse events like anaphylaxis or thromboembolism were very rare after vaccination against SARS-CoV-2 [11-13].

Despite the facts, fear of side effects remains one of the major contributors to the COVID-19 vaccine hesitancy worldwide [14, 15]. Reports on vaccine side effects from own community could make the people confident about the vaccine. Moreover, there is hardly any data on the real-world side effects of ChAdOx1 nCoV-19 and BBIBP-CorV vaccine among the South-East Asian population. Healthcare professionals, especially physicians, nurses, and medical technicians can be a suitable group for reporting the side effects of vaccination due to their professional knowledge and trust in the population. Hence, the present study aims to report the local and systemic adverse events experienced following immunization with these two major vaccines deployed among the healthcare professionals (HCPs) of Nepal.

Methods

Study design and participants

This cross-sectional study was conducted among the HCPs working within the geographical area of Nepal and who took at least one dose of the ChAdOx1 nCoV-19 or BBIBP-CorV vaccine between February 15 and May 31, 2021, from different vaccination centers of Nepal. The sample size was calculated using the following formula:

, where, p = prevalence of side effects after vaccination, and d = precision of error. Menni et al. reported that 33·7% of the ChAdOx1 nCoV-19 vaccine recipients developed at least one side effect [10]. Using this information the calculated sample size was 343. The convenience sampling method was used to include participants. An online survey tool was used for data collection. Five physicians, three nurses, and three medical technologists were recruited to circulate the survey link among their professional networks through social media (Facebook). The survey link was also posted in different closed groups of these professionals with a description of the aims of the study and a request to fill it up. Finally, a total of 606 HCPs (386 physicians and 238 other staff such as nurses and medical technicians) filled up the form completely.

Data collection procedure: An online survey using Google Forms created with the guidance of previously published articles [10, 16, 17] was used for data collection. It had three parts: (i) the socio-demographic characteristics of the participants, (ii) self-reported side effects after vaccination, and (iii) history of SARS-CoV-2 infection before or after vaccination. If SARS-CoV-2 RNA or antigen was detected on a respiratory specimen collected ≥14 days after completing the primary series of the vaccines, it was defined as a vaccine breakthrough infection [18].

Ethical consideration

The ethical clearance of the research was obtained from the Nepal Health Research Council (NHRC) (Reference no. 351). Written consent was taken through email from the participants who agreed to participate in the study as explained on the first page of the survey form.

Statistical analysis

All statistical analyses were conducted using the STATA version 16.0. Frequency distribution with percentage was used to report the side effects experienced by the participants. The Chi-square test was used to determine the association between two categorical variables. Finally, multiple binary logistic regression adjusted for age, sex, comorbidity, and previous SARS-CoV-2 infection was used to predict the side effects according to the vaccine types and doses.

Results

A total of 606 HCPs (386 physicians and 238 supporting staff such as nurses and medical technicians) were considered as the sample in this study. The mean (SD) age of participants was 35.6 (13.2) years and almost 52% of them were female. More than 32% of the participants were infected by SARS-CoV-2 before vaccination. 17.66% of participants had comorbidity (such as type 2 diabetes mellitus, hypertension, chronic respiratory diseases like asthma and COPD, history of cardiovascular diseases, etc.). It was observed that around 54% of participants took the ChAdOx1 nCoV-19 vaccine and 46% took the BBIBP-CorV vaccine. The type of vaccine was decided by the government authority based on availability. Almost 59% of participants took both doses of vaccine (Table 1).

Table 1

Socio-demographic characteristics of the participants (n = 606).

Characteristics	Total, N(%)	Single dose, Total = 250; N(%)	Two dose, Total = 356; N(%)
Age (years) (mean 35.63, SD 13.17)
<55	515 (84.98)	188 (32.30)	327 (56.19)
≥55	91 (15.02)	62 (68.13)	29 (31.87)
Sex
Male	290 (47.85)	126 (39.25)	164 (51.09)
Female	316 (52.15)	124 (35.23)	192 (54.55)
Profession
Physician	386 (63.70)	115 (29.11)	253 (64.05)
Supporting stuffs	238 (39.27)	135 (48.56)	103 (37.05)
Comorbidity
Yes	107 (17.66)	62 (55.86)	45 (40.54)
No	499 (82.34)	188 (33.45)	311 (55.34)
Previous SARS-CoV-2 infection
Yes	194 (32.01)	74 (36.10)	120 (58.54)
No	412 (67.99)	176 (37.61)	236 (50.43)
Vaccine type
ChAdOx1 nCoV-19	328 (54.13)	101 (30.79)	227 (69.21)
BBIBP-CorV	278 (45.87)	149 (53.60)	129 (46.40)

The overall prevalence of local adverse events was 45% and 44% and the prevalence of systemic adverse events was 54% and 44% after the first and second dose respectively. It was observed that both local and systemic adverse events were more prevalent after both first and second doses of ChAdOx1 nCoV-19 compared to BBIBP-CorV (54% vs 37% and 62% vs 43% respectively after the first dose and 45% vs 42% and 49% vs 36% respectively after the second dose). Besides, these adverse events occurred more frequently after the first dose than the second dose of both vaccines. Pain, swelling and tenderness at the injection site were the most frequently reported local adverse events after both the first and second dose of the vaccines. On the other hand, fatigue, headache, fever and myalgia were the most frequently reported systemic adverse events (Table 2). No serious and life-threatening adverse event like anaphylaxis was reported.

Table 2

Adverse events reported by the participants after vaccination (n = 606).

Adverse events	ChAdOx1 nCoV-19				BBIBP-CorV
	First dose		Second dose		First dose		Second dose
	n	%	N	%	N	%	n	%
Local adverse events
Any local adverse event	178	54.3	102	44.9	102	36.7	54	41.9
Pain at injection site	130	39.6	64	28.2	76	27.3	32	24.8
Swelling	64	19.5	36	15.9	36	12.9	14	10.9
Tenderness	46	14.0	47	20.7	24	8.6	22	17.1
Itch	8	2.4	0	0.0	6	2.2	0	0.0
Swollen armpit gland	3	0.9	0	0.0	4	1.4	0	0.0
Redness	22	6.7	18	7.9	10	3.6	14	10.9
Warmth	29	8.8	22	9.7	8	2.9	2	1.6
Systemic adverse events
Any systemic adverse event	205	62.5	112	49.3	120	43.2	46	35.7
Headache	109	33.2	66	29.1	71	25.5	20	15.5
Fatigue	144	43.9	80	35.2	71	25.5	31	24.0
Chills and shivering	32	9.8	16	7.0	8	2.9	6	4.7
Diarrhea	10	3.0	4	1.8	5	1.8	0	0.0
Fever	108	32.9	80	35.2	55	19.8	23	17.8
Arthralgia	8	2.4	30	13.2	10	3.6	4	3.1
Myalgia	41	12.5	37	16.3	6	2.2	8	6.2
Nausea	22	6.7	14	6.2	14	5.0	2	1.6
Rash	0	0.0	4	1.8	0	0.0	0	0.0

Adverse events experienced by the participants after both vaccines were homogenous in different socio-demographic groups of participants. The logistic regression model showed that both local and systemic adverse events after the first dose of vaccination occurred at a comparatively higher rate in the case of the ChAdOx1 nCoV-19 vaccine (aOR 1.81, 95% CI 1.29–2.54 for local adverse events and aOR 2.32, 95% CI 1.65–3.26 for systemic adverse events) while this trend was observed for only systemic adverse events after the second dose (aOR 1.63, 95% CI 1.02–2.58). On the other hand, no significant difference was observed in the case of local adverse events of the ChAdOx1 nCoV-19 vaccine after the first and second dose, while systemic adverse events were more likely after the first dose of the vaccine (aOR 1.76, 95% CI 1.24–2.49). In the case of the BBIBP-CorV vaccine, both local and systemic adverse events were more likely after the first dose (aOR 2.61, 95% CI 1.57–4.35 for local and aOR 3.55, 95% CI 2.08–6.05 for systemic adverse events) (Fig 1).

Fig 1

Risk of adverse events according to vaccine type and doses (OR with 95% CI adjusted for age, sex, comorbidities, and previous SARS-CoV-2 infection).

A total of 61 participants were infected with SARS-CoV-2 after vaccination (infection rate 10%). Among them, 52 cases were reported after the first dose of vaccination (27 after the ChAdOx1 nCoV-19 vaccine and 25 after the BBIBP-CorV vaccine). On the other hand, all the 9 cases were reported after the second dose of the ChAdOx1 nCoV-19 vaccine. The median window period between vaccination and infection after the first dose was 13 days (range 3 to 43 days) and between vaccination and infection after the second dose was 6 days (range 3 to 12 days) (Fig 2). No vaccine breakthrough infection which is defined as infection by SARS-CoV-2 after at least 14 days of completion of two-dose vaccination was reported in the study.

Fig 2

SARS-CoV-2 infection among the participants up to 8 weeks after vaccination (n = 61).

Discussion

In this study, we investigated the adverse events experienced by the HCPs of Nepal following the administration of the two COVID-19 vaccines that are in use in Nepal. These two vaccines are being used by many South Asian countries so the findings are very relevant and important in this mass vaccination phase. According to our findings, more than half of the participants experienced mild (to moderate) local and systemic adverse events after vaccination.

At least one local and systemic adverse event was reported by almost 54% and 62% of participants after the first dose and 37% and 49% of participants after the second dose of ChAdOx1 nCoV-19 vaccine respectively in our study. A large-scale community-based study from the UK reported that local and systemic side effects occurred in 59% and 34% of participants respectively after the first dose of the same vaccine [10]. Though the prevalence of local adverse events was somewhat similar, that of systemic adverse events was comparatively higher in our study. However, it was lower than the expected rate of 88% as reported by a phase-3 trial of the vaccine [7]. Prevalence of common local and systemic adverse events like injection site pain and tenderness, headache, fever, fatigue, etc. were reported lower among the British population [10], and comparatively higher in Iraqi and Korean populations [16, 17] than in our study.

In the case of the BBIBP-CorV vaccine, local and systemic adverse events were reported by almost 37% and 43% respectively after the first dose and 42% and 36% respectively after the second dose. These findings were quite similar to the reports of the phase-2 trials of the vaccine, where almost one-third of the vaccine recipients experienced at least one adverse event [9, 19]. Injection site pain (22%) was the most common adverse event in the trial followed by fever (4%) and fatigue (3%) [19]. Though the prevalence of these adverse events was higher among our study participants compared to the trials, real-world evidence from Iraq reported a higher prevalence of these symptoms among the BBIBP-CorV vaccine recipients [16].

Our study revealed that the odds of both local and systemic adverse events were higher among the ChAdOx1 nCoV-19 vaccine recipients compared to the BBIBP-CorV vaccine. Evidence of comparative prevalence of adverse events of these two vaccines is scanty. One study conducted in Iraq supported our findings [16]. We could not establish any significant association between vaccine adverse events and the age or sex of the recipients, though prevalence was slightly higher among females. A higher prevalence of adverse events among females was also reported by some studies, though the role of age remained ambiguous [10, 16]. Besides, we found a slightly higher prevalence of adverse events among previously infected participants similar to a large-scale study [10]. It is hypothesized that this increased reactogenicity may be due to higher antibody titers and increased immunogenicity in previously infected individuals [20].

Among our participants, almost 10% reported a post-vaccination SARS-CoV-2 infection and most of them occurred after taking the first dose of the vaccine. However, no vaccine breakthrough COVID-19 was reported. A recent study among Indian health care workers reported that almost 36% of the total SARS-CoV-2 infection was post-vaccination infection and most of these occur after the first dose [18]. The Center for Disease Control of the USA (CDC), reported 3,729 vaccine breakthrough cases out of 144 million vaccinated people by June 2021 [21]. The emergence of newer variants of the vaccine might be responsible for these vaccine breakthrough cases which warrant further investigation [4]. Long-term follow-up is necessary to snap the actual picture of vaccine breakthrough infection among the population.

The main strength of this study lies in the fact that it provides a comparative picture of the side effects that occurred after taking the ChAdOx1 nCoV-19 and BBIBP-CorV vaccine among the HCPs of Nepal. Despite this fact, there are some limitations of the study. First of all, the study included only a small number of HCPs based on convenience sampling. This could potentially exclude a good number of individuals with severe side effects. Besides, we could not verify the membership of the participants as the HCWs. Moreover, the small sample size of the present study might not be representative of the large population of HCPs in Nepal. Moreover, information about the geographic location and ethnic characteristics of the participants were not collected. Hence, the prevalence of vaccine-related adverse events found in the present study might not be generalizable for the overall population of the country. Being a self-reported study, recall bias could not be rolled out. Besides, the post-vaccination infection may not be generalized to the overall population as we know that healthcare workers are tested more frequently even if they are asymptomatic. Finally, we could investigate only the short-term side effects of the vaccine. A sustainable and long-term surveillance method in the general population is necessary to evaluate possible future adverse events and remedies.

Conclusions

Adverse events of both vaccines deployed in Nepal are mostly constitutional symptoms like injection site pain and tenderness, headache, fever, and fatigue, and are mild in severity. The ChAdOx1 nCoV-19 vaccine recipients reported a slightly higher rate of adverse events compared to the BBIBP-CorV vaccine recipients. The finding should be widely disseminated among mass people to make them more confident in vaccine uptake and reduce vaccine hesitancy in general.

(XLSX)

Click here for additional data file.

14 Apr 2022

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Subish Palaian

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf.

2. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

3. Please amend your current ethics statement to address the following concerns:

a) Did participants provide their written or verbal informed consent to participate in this study?

b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure.

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

5. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Additional Editor Comments:

Dear author,

Regards.

The manuscript has been reviewed by two reviewers and the comments are available below. The comments are mainly related to the methodology and data analysis. Kindly revise the manuscript based on the comments.

Best wishes

Subish Palaian

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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: No

Reviewer #2: Yes

**********

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

PLOS ONE 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: No

**********

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: Thank you for the invitation to review this manuscript. The manuscript is mostly well-written and presented. The study is interesting and relevant. A few corrections to language may be required at certain places.

My concerns are related to the Methodology of the study. The population of health care professionals in Nepal is large and a sample of 606 health care professionals (HCPs) may not adequately represent this population. The sampling method in this study was a convenience one as stated by the authors. I am not sure that this sample can adequately provide data from the population of HCPs in Nepal. The authors have provided no information about the geographical distribution of the respondents within the country. Does the sample correspond to the population of HCPs in Nepal regarding demographic characteristics? I am not sure that the conclusions as mentioned in the abstract follow from the study results. The conclusions in the main manuscript seem OK. As the denominator is small I am not sure prevalence of adverse effects can be calculated. The findings will be only the prevalence among the study sample, and it will be difficult to generalize it to the general population of HCPs in Nepal.

In the Results can the authors explain why they mention no vaccine breakthrough infection was noted. The authors have not mentioned about IRB approval and obtaining written, informed consent from the participants in this study. I would recommend specialised statistical review of this manuscript.

The authors should deposit the de-identified data in a publicly available repository.

Reviewer #2: The findings from this study will be of importance to advocate the public on vaccination and reduce their anxiety regarding the side effects.

Overall, please check the grammatical errors and paraphrasing needs to be done as per recommendation.

Results

1) The first Chi-square analysis seems unnecessary as the parameters are not associated with the dosing completion since the vaccination is dependent upon availability and the set duration between first and second dose.

2) The graphs need legends and appropriate choice of graph type is imperative.

Conclusion

This article has been clearly written however the conclusion about the anaphylaxis being rare is a bit of a stretch as this has not been evaluated in this study.

**********

6. 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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: PONE-D-21-28369_HZ.pdf

Click here for additional data file.

12 May 2022

Response to Reviewers Date: April 30, 2022

Paper Title: Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a real-world, comparative study among healthcare professionals of Nepal

Journal Name: PLOS ONE

Paper ID: PONE-D-21-28369

Dear Editor

Thank you very much for providing reviewers’ insightful remarks on our manuscript. We have made the necessary changes and revised the manuscript accordingly, and detailed point–by–point corrections are given below:

Review Reports:

Reviewer #1:

Thank you for the invitation to review this manuscript. The manuscript is mostly well-written and presented. The study is interesting and relevant. A few corrections to language may be required at certain places.

Authors reply: We would like to thank the reviewer for the kind words. We have revised the grammatical errors according to your suggestion.

My concerns are related to the Methodology of the study. The population of health care professionals in Nepal is large and a sample of 606 health care professionals (HCPs) may not adequately represent this population. The sampling method in this study was a convenience one as stated by the authors. I am not sure that this sample can adequately provide data from the population of HCPs in Nepal. The authors have provided no information about the geographical distribution of the respondents within the country. Does the sample correspond to the population of HCPs in Nepal regarding demographic characteristics? I am not sure that the conclusions as mentioned in the abstract follow from the study results. The conclusions in the main manuscript seem OK. As the denominator is small I am not sure prevalence of adverse effects can be calculated. The findings will be only the prevalence among the study sample, and it will be difficult to generalize it to the general population of HCPs in Nepal.

Authors reply: We have calculated the sample size for the present study from a previously published article. However, we agree with you that, the sample size included in the present study might not be representative of the large population of the HCPs in Nepal. Moreover, geographic and ethnic variety was also not considered in the present study which limits the generalizability of the findings. We have mentioned these issues in the limitation section of the manuscript (Page 13, Line 223-227).

“Moreover, the small sample size of the present study might not be representative of the large population of HCPs in Nepal. Moreover, information about the geographic location and ethnic characteristics of the participants were not collected. Hence, the prevalence of vaccine-related adverse events found in the present study might not be generalizable for the overall population of the country.”

In the Results can the authors explain why they mention no vaccine breakthrough infection was noted.

Authors reply: Thanks for mentioning the issue. We have added the definition of vaccine breakthrough infection as an explanation of the statement which was missing in the previous version (Page 10, Line 174-175).

“No vaccine breakthrough infection which is defined as infection by SARS-CoV-2 after at least 14 days of completion of two-dose vaccination was reported in the study.”

The authors have not mentioned about IRB approval and obtaining written, informed consent from the participants in this study. I would recommend specialised statistical review of this manuscript.

Authors reply: Thanks for mentioning the issue. The statement regarding ethical considerations is now mentioned in the manuscript (Page 6. Line 122-125).

“The ethical clearance of the research proposal was obtained from the Nepal Health Research Council (NHRC) (Reference no. 351). Informed written consent was obtained through email from the participants who agreed to participate in the study as explained on the first page of the survey form.”

The authors should deposit the de-identified data in a publicly available repository.

Authors reply: Thanks for your suggestion. The data will be made publicly available.

Reviewer #2:

The findings from this study will be of importance to advocate the public on vaccination and reduce their anxiety regarding the side effects.

Overall, please check the grammatical errors and paraphrasing needs to be done as per recommendation.

Authors reply: We would like to thank the reviewer for the kind words. We have revised the grammatical errors according to your suggestion.

Results

1) The first Chi-square analysis seems unnecessary as the parameters are not associated with the dosing completion since the vaccination is dependent upon availability and the set duration between first and second dose.

Authors reply: Thanks for your suggestion. We have omitted the Chi-square analysis from Table 1.

2) The graphs need legends and appropriate choice of graph type is imperative.

Authors reply: Thanks for your suggestion. We have added legends in the graphs.

Conclusion

This article has been clearly written however the conclusion about the anaphylaxis being rare is a bit of a stretch as this has not been evaluated in this study.

Authors reply: Thanks for your valuable comment. We agree with you and deleted the statement from the conclusion (Page 13, Line 235).

We would like to thank the reviewers for the valuable comments. We have revised the documents to the best of our ability, but we will definitely be happy to provide further improvement if there are further clarifications required.

With best regards

Dr. Md. Golam Hossain

Professor of Health Research Group

Department of Statistics, University of Rajshahi

Rajshahi-6205, Bangladesh

E-mail: hossain95@yahoo.com

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

20 Jul 2022

23 Jul 2022

Response to Reviewers Date: July 23, 2022

Paper Title (old): “Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a real-world, comparative study among healthcare professionals of Nepal”

Paper title (New): “Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a comparative study among healthcare professionals of Nepal”

Journal Name: PLOS ONE

Paper ID: PONE-D-21-28369R1

Dear Editor

Thank you very much for providing reviewers’ insightful remarks on our manuscript. We have made the necessary changes and revised the manuscript accordingly, and detailed point–by–point corrections are given below:

Review Reports:

Reviewer #1:

Kindly deposit the data associated with the study in a public repository. Otherwise the authors have addressed the comments.

Authors’ reply: Thank you for your comment. We have already submitted the dataset to the Journal repository during manuscript submission.

Reviewer #3:

Title:

I suggest removing the title of "Real world". The instrument in this case was designed specifically for this study.

Authors’ reply: Thank you for your suggestion. According to your suggestion, we have removed “Real world” from the title. The new title is, “Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a comparative study among healthcare professionals of Nepal”

Summary:

Avoiding the term "fully", currently there are people with 3 or even 4 doses of vaccination.

Authors’ reply: We have avoided the term “fully” [Line: 46].

Introduction:

I suggest considering an additional base bibliography. https://doi.org/10.54034/mic.e1262

Authors’ reply: We have added the suggested bibliography [reference 4].

Methods:

There was some way to confirm that the respondents were health personnel. The instrument was online, so how could membership in the group of HCWs be verified?

Authors’ reply: Thank you for your comment. We have circulated the online questionnaire within the professional social media groups of the HCWs. However, we did not take any specific measure to verify their identity as HCWs which we have mentioned in the limitation section [Page 13, line 234-235].

Results.

Avoid the use of "partially" and "Fully". Indicate 1 or two doses.

Were there subjects with a heterologous vaccine schedule?

Authors’ reply: Thank you for the suggestion. We have corrected the manuscript accordingly [Table 1, Page, 7; Line:138-141].

Discussion.

Add a paragraph about the possible presence of variants during the study period. https://doi.org/10.54034/mic.e1256

Authors’ reply: Thank you for the suggestion. We have added the statement in the discussion [Page 12, line 215-216]

We would like to thank the reviewers for the valuable comments. We have revised the documents to the best of our ability, but we will definitely be happy to provide further improvement if there are further clarifications required.

With best regards

Dr. Md. Golam Hossain

Professor of Health Research Group

Department of Statistics, University of Rajshahi

Rajshahi-6205, Bangladesh

E-mail: hossain95@yahoo.com

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

26 Jul 2022

Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a comparative study among healthcare professionals of Nepal

PONE-D-21-28369R2

Dear Dr. Hossain,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Kovy Arteaga-Livias

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

2 Aug 2022

PONE-D-21-28369R2

Adverse events following immunization with ChAdOx1 nCoV-19 and BBIBP-CorV vaccine: a comparative study among healthcare professionals of Nepal

Dear Dr. Hossain:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Kovy Arteaga-Livias

Academic Editor

PLOS ONE