key: cord-0991275-554jy15c
authors: Paran, Yael; Saiag, Esther; Spitzer, Avishay; Angel, Yoel; Yakubovsky, Michal; Padova, Hagit; Ben-Ami, Ronen; Goldinger, Ilana; Gamzu, Ronni; Sprecher, Eli; Zeltser, David; Henig, Oryan
title: Short term safety of booster immunization with BNT162b2 mRNA COVID-19 vaccine in healthcare workers
date: 2021-12-31
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab656
sha: d73b98987f97fd305e15b330fc23a2533a02d63c
doc_id: 991275
cord_uid: 554jy15c

This study demonstrated good short-term safety profile after a third dose of BNT162b2 vaccine among HCWs. There were more frequent local reactions and less systemic reactions compared to the second dose. HCW's who reported reactions had higher pre-booster titer of anti-S1 antibodies compared to those reported no reactions.

A 2-dose series of the BNT162b2 mRNA vaccine was shown to prevent symptomatic and asymptomatic SARS-CoV-2 infection, [1] [2] [3] [4] with an acceptable safety profile. [1] [2] [3] [4] [5] Waning vaccine effectiveness, coupled with a surge of infections due to the Delta SARS-CoV-2 variant, prompted the Israeli ministry of health to recommend a third (booster) dose of the vaccine for adults aged 60 years and above as well as HCWs above the age of 30 years. 6 However, the safety of repeat of BNT162b2 dosing in immunocompetent individuals has not been systematically assessed. Here, we report on the short-term incidence of adverse events following BNT162b2 booster vaccination among HCWs.

This study was conducted at the Tel Aviv Sourasky Medical Center, a tertiary medical center in Tel Aviv Israel. HCWs aged 30 years or older were included in this study if they had previously completed a 2-dose BNT162b2 vaccination series, had no documented previous infection with SARS-CoV-2, and were not immunocompromised. Informed consent was obtained by means of an electronic form. The BNT162b2 dose (30 mcg in 0.3 ml delivered to the deltoid muscle) was identical to primary series doses. Adverse events were monitored using a structured 13-item questionnaire administered after the second and third doses of the vaccine. The questionnaire was sent to participants 3-7 days after vaccination.

Anti-spike receptor binding domain (S1 RBD) IgG antibodies titer ("pre-booster antibody titer") was measured up to 7 days prior to immunization using indirect chemiluminescent microparticle immunoassay on the ADVIA Centaur XP system (Siemens, Tarrytown, New 

For comparison with reported rates of local and systemic reactions after the second dose, we relied on historical anonymous records from our institution of similar questionnaires screening for adverse events.

All statistical analyses were performed using R software version 4.0.3.

Statistical significance for continuous variables was determined using Wilcoxon's rank sum test (one-tailed) and for categorical variables using a Hypergeometric test (one-tailed). P values were corrected for multiple testing where applicable using Holm's method.

Between August 1, 2021, and August 21, 2021, 9292 HCWs received a third BNT162b2 dose as part of the hospital's vaccination campaign. Median participant age was 52 years (IQR 42-62). Overall, 890 HCWs (30%) responded to the adverse event questionnaire and contributed to the safety cohort. The median age in the safety cohort was 47 years (IQR 92-55), 204 (22.9%) were older than 55 years, and 588 (66%) were female. In 97.2% of participants the time interval between second and third vaccine dose was at least 5 months. Pre-booster anti S1 IgG titers were available for 536 HCWs (60%).

The historical safety cohort included 2256 HCWs who responded to the adverse event questionnaire following the second vaccine dose. (Supplemental Table 1 ).

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Local injection site reactions were reported by 778 HCWs (87.4%) (Supplemental Table 2 ).

The most common local reaction was pain at the injection site reported by 461 HCWs (52%).

Local reactions were significantly more frequent among persons aged 55 years or younger than among persons older than 55 years: 92.7% versus 81.9%, P <0.001 (Figure 1a) . reported similar degree of reactions. Eighteen participants (2%) responded that they did not recall and could not compare their experience. (Figure 1b) .

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Compared with local reactions reported after the second vaccine dose, reactions were more frequent after the third dose: 92.7% versus 89.6% for persons aged 55 years or younger (P = 0.039) and 81.9% versus 75.3% for persons older than 55 years (P = 0.058) (Figure 9 ). Systemic symptoms were less frequent after the third vaccine dose compared to the second dose: 61.3% versus 71.8% for persons aged 55 years and younger (P <0.001) and 42.2% versus 48.6% for persons older than 55 years (P = 0.06) (Fig. 9) .

The median pre-booster titer of anti-S1 IgG antibodies was significantly higher for participants who reported local and systemic reactions compared with those who reported no reactions after the booster dose (4.61 [IQR 2.89-8.24] vs 3.35 [IQR 1.79-5.12], p<0.0001) supplemental figure S1 and Supplemental table S3). There was no significant difference in the anti-S1 IgG antibody titers between the age groups with a median titer of 4.24 (IQR 2.72-7.63) in persons 55 years or younger and 4.42 (IQR 1.89-8.33) in persons older than 55 years

In this observational study of immunocompetent HCWs who received a third (booster) vaccine dose BNT162b2, the local and systemic reactions within a week after vaccination were mild and were similar to those observed in previous studies that evaluated the safety of the BNT162b2 primary series. 1, 7 There were no severe adverse events. As noted for the primary BNT162b2 series, local reactions and systemic symptoms were more frequent in persons 55 years or younger than in older individuals. 1, 7 M a n u s c r i p t Significantly, more local but fewer systemic reactions were reported following the third versus the second vaccine dose. The median pre-booster anti-S1 IgG titers were higher in persons who reported local and systemic reactions than for those who reported no symptoms, as was also reported recently by Rechavi et al. 8 This finding suggests that humoral immune priming is associated with local and systemic symptoms after booster vaccination. Previous studies have shown that the humoral response to an mRNA vaccine persisted longer in the regional lymph nodes than in peripheral blood. Turner et al. 9 found that while circulating IgG and IgA-secreting plasmablasts in peripheral blood that target the S protein declined and became undetectable three weeks after the second immunization, S-binding B cells and plasmablasts persisted in the germinal centers of draining lymph nodes on the side of immunization for at least 12 weeks after immunization.

There are several limitations to our study. First, the study was questionnaire based with relatively low response rate, and therefore subjected to recall and report bias. However, the questionnaire was sent to participants up to one week after receiving the booster dose to minimize this effect. Second, only short-term reactions occurring up to 7 days after vaccination were assessed. Third, the cohort size was small with predominance of young participants, as expected from a cohort of HCWs. and was not powered to detect rare adverse events such as myocarditis and anaphylaxis.

In conclusion, a third dose of BNT162b2 was associated with generally mild short-term local and systemic reactions, which were more frequent among younger vaccine recipients. 

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data

BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting

Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers

2021. 6. Indications for third mRNA vaccine aggaint COVID-19, 4th update

Vaccine sideeffects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study

None of the authors have any conflicts of interest to declare. The study was not funded.

The study was approved by the Tel Aviv Sourasky Medical Center institutional review board (approval numbers 0565-21-TLV and 0530-21-TLV).The Helsinky committee has exempted us from obtaining written informed consent of the patients involved in our manuscript.

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