key: cord-0796198-c5bw6tgs authors: Izak, Marina; Stoyanov, Evgeniy; Dezuraev, Keren; Shinar, Eilat title: Correlation of Anti-SARS-CoV-2 S1-specific IgG antibody levels and adverse events following vaccination with BNT162b2 mRNA COVID-19 Vaccine in healthcare workers date: 2021-12-03 journal: Vaccine DOI: 10.1016/j.vaccine.2021.11.082 sha: 6bf7c1b40e03e4e2890ffd6b007225fd1eb8c749 doc_id: 796198 cord_uid: c5bw6tgs Currently approved anti-COVID-19 vaccines have been found to be safe and effective and almost 60% of Israeli residents are already vaccinated by BNT162b2 vaccine. This observational study was designed to evaluate the adverse events of vaccine reported by 61 healthcare workers at least 7 days after the 2(nd) vaccination, and to investigate the correlation of adverse events and anti-SARS-CoV-2 IgG antibody levels. The median participant's age was 51.25 years, 16 men and 45 women; 77% (44% of male and 84.5% of female participants) reported adverse events. Injection site pain, fatigue and fever were the most common symptoms, and significantly higher antibody levels (average 19,387 AU/mL) were found in participants who had fever compared to those who did not experience fever (average antibody levels of 9,977 AU/mL, p<0.001). This finding corresponds to previous observations of higher anti-SARS-CoV-2 IgG antibody levels in COVID-19 patients presented with fever. In Israel, more than 5.5 million people (59.97% of the 9.3 million population)have already been vaccinated with two doses of BNT162b2 mRNA vaccine (1) , and the efficacy and safety were lately reported (2) . Israel's experience in responding to large-scale national emergencies played an important role in rapid planning and implementation of the vaccination process. Some concerns were raised regarding the vaccines, including the frequency and severity of adverse events. We have conducted an analysis of adverse events after vaccination with BNT162b2 mRNA Covid-19 Vaccine of Magen David Adom (MDA) healthcare workers and the correlation between adverse events and level of the anti-Spike protein (anti-S1) IgG antibodies. None of the participants were diagnosed with COVID-19 prior to vaccination. Clinical symptoms and anti-S1 anti-SARS-CoV-2 IgG antibodies were investigated in sixty-one MDA healthcare workers: laboratory technicians, phlebotomists and administration personnel, vaccinated between December 21 st , 2020 and February 28 th , 2021. All clinical symptoms, appeared from the day of injection of the first dose of spike messenger RNA (mRNA) BNT162b2 Covid-19 Vaccine (Pfizer-BioNTech) till day 21 after the second dose were considered adverse events after vaccination. The work was conducted according to the Code of Ethics of the World Medical Association (Declaration of Helsinki). Participants younger than 18 years old and those who diagnosed as COVID-19 prior to vaccination or post vaccination were excluded from the study. All participants gave consent to report adverse events and to have Participants were divided to groups by age ("younger" individuals, aged 30-49 and "older" aged 50-71) and by sex. Antibody levels were calculated in asymptomatic participants and in those who had adverse events after vaccination. Symptomatic participants divided to subgroups by symptoms. Antibody levels between groups of participants were compared using Chisquare test. Sixty-one vaccinated individuals, who got two doses of BNT162b2 mRNA Covid-1 vaccine at least 21 days apart, participated in the study. Sixty received the second dose within 28 days from first dose and one -46 days after the first dose. Venous blood samples were drawn once, at least 7 days after the second vaccine dose (average 15 days, 7-27 days). The median age of participants was 51.25 years, 16 men and 45 women. Seventy seven percent of participants (47/61) reported at least one symptom that was attributed to the vaccination; 14/61 (23%) did not have any symptoms. Adverse events presented in Table 1 . Frequently reported adverse event in "younger" group was fever ≥37.8°C (38.5% of participants), in "older" group this symptom was less frequent (20%). Nobody reported fever>39°C. No severe adverse events (Grade 3 or 4) were reported (5). IgG anti-S antibodies were detected in blood samples of all participants. Average level of IgG was 12,599 AU/mL (range 229-37,840 AU/mL), no significant difference was found between both sexes: men had an average level of 11,854 AU/mL and women -12,865 AU/mL Twenty six "younger" individuals had similar average antibody level than 35 "older": 12,903 AU/mL versus 12,374 AU/mL, respectively. The average antibody level among individuals who reported adverse events after vaccination was not significantly different from the average level of antibodies in asymptomatic persons -13,177 AU/mL versus 10,663 AU/mL, respectively (p=0.39). Participants who had fever as an adverse event had higher levels of antibodies (average 19,387 AU/mL) compared to those who did not have fever (average 9,977 AU/mL), p<0.005 (Fig.1) . Participants reporting fatigue, pain at injection site, headache, muscle aches, nausea, chills and sleepiness had similar levels of antibodies compared to those who did not complain on these symptoms. March 17, 2021. We found that two doses of mRNA vaccine drawn immune responses in all participants, with post-vaccination antibody titers ranged from 229 to 37,840 AU/mL. Most participants (77%) experienced some symptoms after vaccination, and the most common symptoms were pain in injection site, fatigue and fever. We found that female participants experienced more subjective symptoms than men. Similar rate of objective symptoms (e.g., fever) was found in both sexes. Antibody levels were similar between "younger" and "older" age groups. No serious adverse events were observed. In general, vaccinated individuals who reported adverse events had similar antibody levels, comparing to those who did not have any symptoms. The only exclusion was fever (≥37.8°C): persons experienced fever as an adverse event after vaccination had significantly higher antibody levels. The same phenomenon was described in recipients of other vaccines, e.g., young children, received measlescontaining vaccines (6) . In COVID-19 patients: who suffered from fever during the course of the disease, the antibody levels in plasma were higher than in those patients who did not have fever (7) (8) . The suggestion that a febrile temperature can boost the innate and adaptive immune and drive more prominent immune reactions was made years ago and the evidence from previous studies reviewed by Evans et al (9) . There is a controversy among medical professionals about the role of antipyretic drugs in prevention and treatment of post-vaccination febrile reactions. According to the observation of Prymula et al, antibody responses to some vaccines decreased due to use of prophylactic paracetamol in children, however, conclusions of another studies did not support this finding (10) . This conclusion is controversial, as in another trials it was shown that paracetamol given to children after influenza vaccine did not decrease an immune response (11) . It could be concluded that release of endogenous pyrogens, and, as a result post-vaccination febrile reaction, is associated with enhanced antibody production. Our study had several limitations. We evaluated adverse events and antibody This small observation study examined the possible correlation of anti-SARS-CoV-2 S1-specific IgG antibody levels after vaccination with BNT162b2 mRNA COVID-19 vaccine with adverse events following vaccination in sixtyone healthcare workers. Recently, antibody responses to single dose of BNT162b2 vaccine were investigated (12) and IgG antibodies were found in most participants of the study. In our study, all recipients of two doses of BNT162b2 vaccine produced IgG anti-S antibodies, with average level of 12,599 AU/mL (range 229-37,840 AU/mL). Adverse events after BNT162b2 vaccine (1) and after first dose of ChAdOx1 nCoV-19 or BNT162b2 mRNA COVID-19 vaccines were reported recently (13) and were similar to adverse events experienced by healthcare workers participated in our study: injectionsite pain, myalgia, fatigue, headache and fever. Younger individuals experienced fewer side effects in contrast to findings of Kim et al (13) ; women reported more adverse events. Most of sixty-one participants reported mild adverse events, and fever ≥ 37.8°C was an only significant predictor of higher IgG levels. The current experience with reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2 was recently summarized in systematic review and meta-analysis (14) Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting Abbott Alinity i SARS-CoV-2 IgG II Quant Reagent Instructions for Use Establishment of the WHO International Standard and Reference Panel for anti-SARS-CoV-2 antibody Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Post-immunisation fever and the antibody response to measles containing vaccines Characteristics and serological patterns of COVID-19 convalescent plasma donors: optimal donors and timing of donation Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections Fever and the thermal regulation of immunity: the immune system feels the heat Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials The effect of antipyretics on immune response and fever following receipt of inactivated influenza vaccine in young children Antibody Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine Adverse Events in Healthcare Workers after the First Dose of ChAdOx1 nCoV-19 or BNT162b2 mRNA COVID-19 Vaccination: a Single Center Experience Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2 ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work