key: cord-0772265-w1ttu8xr
authors: Kadali, Renuka A.K.; Janagama, Ravali; Peruru, Sharanya; Malayala, Srikrishna V.
title: Side effects of BNT162b2 mRNA COVID-19 vaccine: A randomized, cross-sectional study with detailed self-reported symptoms from healthcare workers
date: 2021-04-15
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.04.047
sha: d07024eecf67a5fcc3e674bb55ff051bcc3112c0
doc_id: 772265
cord_uid: w1ttu8xr

INTRODUCTION: Concerns are prevailing about the safety and side effects from BNT162b2 mRNA COVID-19 vaccine. METHODS: A randomized, cross-sectional study was performed to investigate the side effects of BNT162b2 vaccine using an independent online questionnaire gathering responses from healthcare workers (HCWs) with detailed review of organ systems. RESULTS: Of all HCWs, 87.98% (1245/1415) completed the survey. Of them, 64.5 % (803/1245) received BNT162b2 mRNA vaccine and reported at-least one or more symptoms (classified based on organ systems and occurrence rate) post-vaccination. Of these, 640/803 (79.7%) were able to continue activities of daily living (ADL), 103/803 (12.83%) were temporarily unable to perform ADL, 99/803 (12.33%) temporarily took off from work, only 20/803 (2.49%) required help from an outpatient provider, 5/803 (0.62%) required help from emergency department, and 2/803 (0.25%) required hospitalization. Despite, 97.61% had no intention to skip the second dose and 92.9% had already received it. CONCLUSIONS: The commonly reported symptoms (occurrence in the descending order) include soreness, fatigue, myalgia, headache, chills, fever, joint pain, nausea, muscle spasm, sweating, dizziness, flushing, feelings of relief, brain fogging, anorexia, localized swelling, decreased sleep quality, itching, tingling, diarrhea, nasal stuffiness, and palpitations. Despite, there is remarkable acceptance for the second dose among HCWs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented as a mysterious infection causing global pandemic in a short time, gaining world-wide attention, imposing challenges to medical field, researchers, epidemiologists, and policy makers about the nature of the virus, and posing challenges for a successful vaccine outcome (Umakanthan et al., 2020) .

SARS-CoV-2 is transmitted via respiratory droplets from face-to-face contact or contaminated surfaces. Although the role of aerosol spread in humans remains unclear, this mode of transmission is still a major concern (Ganyani et al., 2020) . SARS-CoV-2 infection causes fever, generalized weakness/fatigue, myalgia, dry cough, shortness of breath, nausea, vomiting or diarrhea, headache, anosmia, ageusia, and rhinorrhea . The common complications from this infection include pneumonia, acute respiratory distress syndrome, acute liver failure, cardiac abnormalities with troponin elevation, acute heart failure dysrhythmias, myocarditis, prothrombotic coagulopathy resulting in venous and arterial thromboembolic events, acute renal failure, neurologic manifestations, including impaired consciousness and acute cerebrovascular disease, and shock (Levi et al., 2020 , Long et al., 2020 , Middeldorp et al., 2020 , and Rodriguez-Morales et al., 2020 . The number of deaths related to SARS-CoV-2 infection in the United States within less than a year period (as of 02/22/2021) were 500,000 (CDC. COVID-19 Death Data and Resources, 2021) .

The Food and Drug Administration (FDA) in the United States authorized two mRNA vaccines to prevent SARS-CoV-2 infection (the Pfizer-BioNTech manufactured BNT162b2 mRNA COVID-19 vaccine on December 11, 2020, and the Moderna manufactured mRNA-1273 J o u r n a l P r e -p r o o f COVID-19 vaccine on December 18, 2020). On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for the use of a two-dose regimen of BNT162b2 mRNA vaccine (which was shown to have 95% efficacy in protection against COVID-19) in persons aged 16 years or older (Polack et al., 2020 , Oliver et al., 2020 .

The recommendation for a two-dose regimen of mRNA-1273 vaccine (which was shown to have 94.1% efficacy in preventing COVID-19 illness, including severe disease) was also issued by ACIP on December 19, 2020 (Baden et al., 2021) . The first phase of the vaccination program was primarily focused on healthcare workers (HCWs) nationwide (who are at the forefront and took the vaccine as a challenge) and on long-term care facility (LTCF) residents. The BNT162b2 vaccine consists of two doses (30 μg, 0.3 mL each) administered intramuscularly, 3 weeks apart (CDC. COVID-19 vaccination: clinical considerations, 2020) . A large population-based study described that allergic reactions to vaccines generally occur at a rate of 1.31 (95% CI, 0.90-1.84) cases per million vaccine doses, with no fatalities reported (McNeil et al., 2016) . Current reports from the Centers for Disease Control and Prevention (CDC) suggest that anaphylactic reactions to the BNT162b2 mRNA vaccine may occur more frequently than to other vaccines (CDC COVID-19 Response Team; Food and Drug Administration, 2020).

Overall, the COVID-19 mRNA-based vaccination program has generated many concerns, questions, and continuing arguments concerning the safety issues of both new mRNA vaccines among HCWs and the general population in the United States. A recent study on self reported side effects with mRNA-1273 vaccine among healthcare workers showed a broad spectrum of symptomatology with most of them being non-life threatening and having a high acceptance to that vaccine among healthcare workers (Kadali et al., 2021) . However, there are limited data and J o u r n a l P r e -p r o o f literature on the side effects of BNT162b2 mRNA vaccine that specifically focus on a detailed review of organ systems and the frequency with which the symptoms experienced after receipt of this vaccine. The objective of the present study was to analyze the safety and more detailed side effect profile of the BNT162b2 vaccine using a self-reported online survey questionnaire among HCWs. Therefore, we chose a random population of HCWs and investigated the side effects of these vaccines using responses from the survey questionnaire [consisting of a more detailed review of organ systems in comparison to what the CDC is collecting through the Vaccine Adverse Event Reporting System (VAERS)] (Gee et al., 2021) .

After obtaining institutional review board (IRB) approval for this research, we conducted a cross-sectional study by circulating an independent online survey questionnaire through an internet-based survey platform called 'Survey Monkey', which gathered anonymous responses from HCWs from verified healthcare communities representing various parts of the country during the early phase of COVID-19 vaccination. No personal identifications were obtained.

Survey Monkey web link was distributed to (1) coordinators of healthcare institutions and (2) verified communities of HCWs via social media, such as Facebook. Informed consent was obtained at the beginning of the survey. Participants who voluntarily agreed and consented to proceed and who chose to receive one of the two mRNA-based COVID-19 vaccines were automatically allowed to move forward to answer subsequent questions about the side effects and other variables. Those who chose 'None of them' were diverted to a disqualified page. The 

This study primarily focused on the BNT162b2 mRNA vaccine. Of the 1245 vaccine recipients who completed the survey, 803 (64.5%) received the BNT162b2 mRNA vaccine, and 35.5% (442) received the mRNA-1273 vaccine (Figure 1 ). Among the responses from BNT162b2 vaccine recipients, 7.1% belong to the age group between 18 to 30 years, 38.85% between 31 to 40 years, 29.51% between 41 to 50 years, 16.69% between 51 to 60 years, 7.2% between 61 to 70 years, 0.37% between 71 to 80 years, and 0.25% between 81 to 90 years. The average age of these participants is 43.09 years. Of the responses, 86.55% were from females and the remaining J o u r n a l P r e -p r o o f were from males. The majority of participants have a higher level of education, with either a doctoral or a professional medical degree or a master's degree (Table 1) .

A total of 92.9% of the HCWs who received the BNT162b2 mRNA vaccine took both doses, but the remaining 7.1% received only the first dose by the time of this study. Those who received BNT162b2 vaccine reported the following symptoms based on their complete review of organ systems. A detailed report of the event rate based on complete review of systems and in the descending order of occurrence is displayed in Endocrine symptoms: Decreased appetite*** was reported by 5.73% (46), heat or cold intolerance by 3.24% (26), increased thirst by 1.2% (9), increased appetite by 0.87% (7), and increased urine production by 0.25% (2) of the recipients (803).

Palpitations/racing heart was reported by 4.36% (35), chest pain by 1.12% (9), and blood pressure changes and syncope by 0.87% (7) of the recipients (803).

Respiratory symptoms: Shortness of breath was reported by 1.99% (16), coughing by 0.87% (7), and wheezing by 0.25% (2) of the recipients (803). We evaluated the extent of the impact of these symptoms on the vaccine recipients: 640/803 (79.7%) had no issues and were able to continue their daily routine activities, 103/803 (12.83%) were unable to perform regular daily activities temporarily and 99/803 (12.33%) required temporary time off from work. Only 20/803 (2.49%) required seeking help from an outpatient provider, 5/803 (0.62%) required seeking help from emergency department providers, and 2/803 (0.25%) required hospitalization and subsequent inpatient care (Table 2) 

A total of 2.14% (12) HCWs reported improvement or resolution of chronic symptoms after receiving the vaccination.

Specifically, two HCWs with a prior history of chronic psoriatic arthritis reported improvement in their psoriatic joint pains.

The present study aimed to analyze the safety and more detailed side effect profile of the BNT162b2 vaccine among HCWs in the United States. Based on the above results, vaccine recipients can primarily expect the following symptoms during the early phase of the postvaccination period. Among all the symptoms reported, localized soreness, generalized weakness, myalgia, headache, chills, fever, joint pain, and nausea were the most commonly reported symptoms, followed by muscle stiffness or spasm, sweating, dizziness, flushing, feelings of joy/relief/gratitude, brain fogging or reduced mental clarity/attention/concentration, decreased appetite, localized swelling at the injection site, decreased sleep quality, itching, tingling, diarrhea, nasal stuffiness, palpitations and/or high heart rate as other predominant symptoms. Of note, 97.61% of BNT162b2 vaccine recipients did not intend to skip the second dose of the vaccine irrespective of side effects, their conflicting schedules, and personal apprehensions.

Moreover, a total of 92.62% had already received the second dose of the vaccine by the time they responded to this survey.

At this point, the etiology of side effects or reactions to the BNT162b2 vaccine is still unclear.

The CDC estimates suggest that anaphylaxis (signs of trouble breathing, swelling of the face and throat, rash, and low blood pressure) occurs soon after vaccination in 11 cases per million doses among people receiving the BNT162b2 vaccine (CDC COVID-19 Response Team; Food and Drug Administration, 2020). A total of 16 deaths involving non-LTCF residents and 46 cases of anaphylaxis have been confirmed after the administration of Pfizer-BioNTech vaccine until January 13, 2021 based on VAERS report (Gee et al., 2021) . Furthermore, a report from Norway of 23 deaths among elderly BNT162b2 vaccine recipients raised understandable safety concerns;

however, further investigations are in progress to determine whether these deaths were related to J o u r n a l P r e -p r o o f the vaccines or represent an expected number of deaths among frail individuals who may already have had a limited life expectancy (Torjesen, 2021) . Thirteen of the deaths from this report have been investigated so far, and it was concluded that common adverse reactions to the mRNA vaccines, such as fever, nausea, and diarrhea, may have contributed to fatal outcomes in some of the frail patients (Torjesen, 2021) . The investigations are in progress, but the underlying conditions such as heart disease, cancer, stroke, probable pulmonary embolism, and otherwise frail health were considered as the causes of death in frail patients (Gee et al., 2021) . However, in our study, there were no reports of anaphylaxis or deaths due to the BNT162b2 vaccine. Therefore, we recommend following the CDC guidelines that everyone who is vaccinated should be observed for at least 15 min after receiving the vaccine, with epinephrine available at the vaccination site in case it is needed. It is the inactive ingredient or the excipient (including egg protein, gelatin, formaldehyde, thimerosal, or neomycin), but not the active ingredients, that are attributable for the allergic reactions. Avoidance of both mRNA COVID-19 vaccines in individuals with a history of anaphylaxis to polyethylene glycol (PEG), PEG derivatives, or polysorbate is recommended by the CDC. 14 Excipients (which are used in the vaccine to stimulate a stronger immune response, prevent bacterial contamination, and stabilize the potency of the vaccine during transportation and storage) are the major contributors to specific IgEmediated and immediate reactions associated with vaccines (Banerji et al., 2020) .

In our study, 10 HCWs (1.25%) reported that they tested positive for SARS-CoV-2 infection during the period between the first and second doses of BNT162b2 vaccine. There are concerns about whether COVID-19 can be caused by the vaccine, which is unlikely because these mRNA J o u r n a l P r e -p r o o f vaccines did not use live SARS-CoV-2 virus in their development. If SARS-CoV-2 infection is observed soon after vaccination, it is improbable that it is caused by the vaccine; instead, the infection might be caused by the failure of the vaccine (studies on this are in progress), preexisting infection before vaccine administration, or infection at the time of vaccination.

We recommend monitoring for further reports on the side effects of CDC as the vaccination program continues with its subsequent phases. About 6.35% vaccine recipients reported feelings of joy/relief/gratitude and only less than 2.5% of participants chose a rationale to skip their second dose. These can be taken as positive signs. At best, most of the vaccine recipients among HCWs took the challenge to end the deadly pandemic, irrespective of side effects. Nevertheless, before receiving the mRNA vaccine that acts against this deadly virus, which has caused millions of deaths worldwide within 1 year, vaccine recipients need to outweigh the risks of possible adverse events versus the potential benefit.

This study has several limitations. Since this was an independent study investigating for detailed self-reported symptoms through anonymous responses, the receipt of vaccine by the study participants and their reported symptoms were not verified or confirmed and recorded or documented officially by the study investigators. Most of the symptoms reported above were only in the early post-vaccination phase of the vaccine. The latent effects of this vaccine were not studied or included in this study. No specific data about the initial timing of the onset of symptoms after vaccine administration or the duration of symptoms were obtained in this study.

Some may incorrectly blame the vaccine for several systemic side effects that they develop soon after vaccination, although symptoms of their preexisting chronic medical problems may have J o u r n a l P r e -p r o o f contributed to these side effects, or they could be an unfortunate coincidence from new underlying medical problems that are not related to the vaccine. Chronic medical problems, such as heart attacks, blood disorders, cancer, stroke, and other rare illnesses, have occurred before the pandemic and will continue to occur. Acute and chronic health issues may be triggered after vaccine administration, as shown in this study, where two HCWs reported reactivation of herpes or shingle-like infection. The vaccine could be to blame if a thorough investigation is performed and if certain health problems occur at a higher-than-normal rate. If not, it is more likely to be an unfortunate coincidence that these effects are related to the vaccine (other examples including rare cases of Bell's palsy and other neurologic disease have been reported after COVID vaccination; however, so far, there is no clear suggestion that the vaccine played any role).

Similarly, it was reported that a physician in Florida developed a fatal blood disorder after receiving a COVID-19 vaccine, which raised concerns that it was triggered by the vaccine, although this condition did not occur among the tens of thousands of clinical trial subjects (Robert, 2021) .

A more detailed review of organ systems in comparison to what the CDC is collecting through the VAERS showed that symptoms of localized soreness, generalized weakness, myalgia, headache, chills, fever, joint pain, and nausea were the most commonly reported symptoms, followed by muscle stiffness or spasm, sweating, dizziness, flushing, feelings of joy/relief/gratitude, brain fogging or reduced mental clarity/attention/concentration, decreased appetite, localized swelling at the injection site, decreased sleep quality, itching, tingling, J o u r n a l P r e -p r o o f diarrhea, nasal stuffiness, palpitations and/or high heart rate as other predominant symptoms.

The majority (97.61%) of the vaccine recipients did not intend to skip the second dose of the vaccine, irrespective of side effects after the first dose, their conflicting schedules, and personal apprehensions. This indicates a remarkable acceptance rate for the second dose of this vaccine, which can be considered as a positive sign. At best, most of the vaccine recipients among HCWs took the challenge to end the deadly pandemic, irrespective of side effects. If SARS-CoV-2 infection is observed soon after vaccination (1.25% vaccine recipients in our study reported as tested positive for SARS-CoV-2 infection during the period between the first and second doses), it is unlikely to be caused by the vaccine; instead, the infection might be caused by the failure of the vaccine (studies on this are in progress), preexisting infection before vaccine administration, or infection at the time of vaccination. Our study design and methods may also provide direction to assess the detailed safety and side effect profile of mRNA based COVID-19 vaccines among pregnant women, lactating women and breast feeding infants to further add up to the existing literature related to this specific population.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

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