Abstract
Introduction
Comirnaty® is an mRNA vaccine against COVID-19 which has been administered to millions of people since the end of 2020. Our aim was to study epidemiological and clinical factors influencing reactogenicity and functional limitation after the first two doses of the vaccine in health care workers (HCWs).
Material and methods
Prospective post-authorization cohort study to monitor safety and effectiveness of the vaccine.
Results
Local side effects were mild and presented both with first and second dose of Comirnaty. Systemic side effects were more frequent after 2nd dose. Nevertheless, previous SARS-CoV-2 infection was associated with systemic effects after the first dose of the vaccine (OR ranging from 2 to 6). No severe adverse effects were reported. According to multivariate analysis, the degree of self-reported functional limitation after the first dose increased with age, female sex, previous COVID-19 contact, previous SARSCoV-2 infection, and Charlson Comorbidity Index (CCI). After the second dose, the degree of functional limitation observed was lower in those with previous SARS-CoV-2 infection, and it was positively associated to the degree of functional limitation after the first dose.
Conclusion
Systemic adverse effects were more frequent after the second dose of Comirnaty. Previous SARS-CoV-2 infection was associated with systemic effects after the first dose. Age, female sex, previous COVID-19, previous isolation due to COVID-19 contact, and CCI showed to be independent predictors of the degree of functional limitation after the 1st dose of Comirnaty®. After the 2nd dose, the degree of functional limitation was lower in those who previously had SARS-CoV-2 infection.
Keywords: COVID-19, Vaccines, Comirnaty, reactogenicity
Abstract
Introducción
Comirnaty® es una vacuna de ARNm contra el COVID-19 que se ha administrado a millones de personas desde finales de 2020. Nuestro objetivo fue estudiar los factores epidemiológicos y clínicos que influyen en la reactogenicidad y la limitación funcional asociadas tras las dos primeras dosis de la vacuna en trabajadores de la salud.
Metodología
Estudio de cohorte prospectivo post-autorización para evaluar la seguridad y eficacia de la vacuna.
Resultados
Los efectos secundarios locales fueron leves y se presentaron tanto con la primera como con la segunda dosis de Comirnaty. Los efectos secundarios sistémicos fueron más frecuentes después de la segunda dosis. No obstante, la infección previa por SARS-CoV-2 se asoció con efectos sistémicos tras la primera dosis de la vacuna (OR de 2 a 6). No se informaron efectos adversos graves. El análisis multivariante demostró que el grado de limitación funcional tras la primera dosis aumentó con la edad, el sexo femenino, contacto previo con COVID-19, la infección previa por SARS CoV-2 y el índice de comorbilidad de Charlson (ICC). Tras la segunda dosis, el grado de limitación funcional observado fue menor en aquellos con infección previa por SARS-CoV-2, y se asoció positivamente al grado de limitación funcional tras la primera dosis.
Conclusión
Los efectos adversos sistémicos fueron más frecuentes después de la segunda dosis de Comirnaty. La infección previa por SARS-CoV-2 se asoció con efectos sistémicos después de la primera dosis. La edad, el sexo femenino, infección por COVID-19 previa, el aislamiento previo por contacto de COVID-19 y el ICC se mostraron como predictores inde- pendientes del grado de limitación funcional tras la 1ª dosis de Comirnaty®. Después de la 2.ª dosis, el grado de limitación funcional fue menor en los que previamente tenían infección por SARS-CoV-2.
Palabras clave: COVID-19, Vacunas, Comirnaty, reactogenicidad
INTRODUCTION
Since December 2019 more than 295 million COVID-19 cases and almost 5.5 million deaths have been reported worldwide [1]. The magnitude of the health problem has driven the focus of public health efforts to the development of effective and safe vaccines with an unprecedented celerity [2]. Comirnaty®, an mRNA BNT162b2 vaccine, developed by Pfizer-BIONTech, has been one of the first vaccines in being approved by EMA (European Medicines Agency) and FDA (USA Food and Drug Administration) [3,4]. This vaccine showed to be reasonable safe, and evidenced a high efficacy in preventing symptomatic (over 90%) and severe COVID-19 (over 95 %) in clinical trials conducted in adults, younger people (from 12-15 years old) and lately, in children (from 5 to 11 years) [5-8]. In different post-authorization studies conducted in Israel, the vaccine showed an effectiveness over 95% in preventing symptomatic COVID-19, and even higher in preventing severe illness or death [9,10]
In the different clinical trials conducted (adult people, adolescents, children), the safety profile of the vaccine showed to be acceptable, reporting mild to moderate side effects, such as injection site pain, fatigue, and headache, though some serious allergic reactions were observed [5,7,8]. In other post-authorization studies, less frequent side effects, (with around 1 per 10,000 incidence rate) such as myocarditis, and pericarditis, more common in young male people, have been reported [11,12]. Other possible less frequent side effects are under study. Further observational post-emergency use authorization studies are needed in order to more precisely define the safety profile of these new vaccines [13].
The COVIVAC-1 is a prospective cohort investigation on the safety and effectiveness of Comirnaty® vaccine in health care workers of a university teaching Spanish hospital who received two doses of the vaccine, taking into account epidemiological and clinical variables such as age, sex, ethnicity, blood group, comorbidities, previous COVID-19 infection, or previous exposure to COVID-19.
MATERIAL AND METHODS
COVIVAC-1 is a prospective cohort study about safety and effectiveness of mRNA BNT162b2 vaccine (Comirnaty®). This investigation was conducted in health care workers (HCW) of the HM Sanchinarro, a university teaching hospital in Madrid (Spain), who had received two doses of the vaccine. The first phase of the study, concerning safety, was carried out after reception of both doses of the vaccine. In this phase, which was focused on safety issues of the vaccine, the health care workers answered an online questionnaire about previous health conditions (including comorbidities, previous exposure to COVID-19 at home or at work, previous COVID-19 infection, or previous isolation due to COVID-19 contact), age, sex, ethnicity, blood group, date of administration of each dose, and possible adverse effects, from mild to severe. All participants agreed to enter the study (informed consent) at the time of receiving the second dose of vaccine. The study was approved by the Ethics Advisory Board of HM hospitals.
Quantitative data were presented with mean and standard deviation, or median and interquartile range in case of non-parametric data. Qualitative data were presented with proportions and percentages. Association was studied with Pearson coefficient for normal quantitative data, and chi square test in case of parametric qualitative data. In non-para-metric data, Spearman coefficient and Fisher’s exact test were applied, respectively. Logistic regression was applied to study the association of the different secondary effects to previous COVID-19 infection or exposure, and linear regression (multivariate) was used to study the association of clinical and epidemiological factors to the degree of functional limitation with each dose of the vaccine. Data analysis was performed with STATA software version 16.1.
RESULTS
Up to 278 HCW answered the questionnaire (85 male, 193 female). The mean age was 39.34 years in men, and 36.31 years in women (p<0.05). The complete description of the characteristics of participants is presented in Table 1.
Table 1.
Descriptive summary of Health Care Workers fully vaccinated with Comirnaty
| Sex n (%) | Men 85 (30.58) | Women 193 (69.42) | ||
|---|---|---|---|---|
| Age mean (IC 95%) | 39.34 (36.58-42.10) | 36.31 (34.93-37.70) | p = 0.031 | |
| BMI mean (IC 95%) | 25.37 (24.69-26.09) | 22.63 (22.10-23.17) | p < 0.0001 | |
| Ethnicity n (%) | Caucasian 76 (89.41) Asian 0 (0) Latin 9 (10.59) Black 0 (0) Other 0 (0) |
Caucasian 166 (86.01) Asian 2 (1.04) Latin 23 (11.92) Black 1 (0.52) Other 1 (0.52) |
||
|
p=0.749 |
||||
| Blood Group n (%) | 0- 8 (12.12) 0+ 23 (34.85) A+ 31 (46.97) B+ 4 (6.06) |
0- 12 (7.55) 0+ 53 (33.33) A+ 76 (47.80) B+ 18 (11.32) |
||
|
p=0.483 |
||||
| Comorbidities n (%) | ||||
| COPD- Asthma Acute Myocardial Infarction Cardiac Failure Vascular Peripheric Disease Stroke Dementia Rheumatologic Disease Ulcus Hepatic steatosis Hepatic Cirrhosis DM with target organ damage DM without target organ damage Hemiplegia Kidney Chronic Disease Tumour Leukaemia Lymphoma Metastasis AIDS |
3 (3.53) 0 (0) 0 (0) 4 (2.07) 0 (0) 0 (0) 4 (2.07) 0 (0) 0 (0) 0 (0) 0 (0) 4 (2.07) 0 (0) 0 (0) 3 (1.55) 0 (0) 0 (0) 0 (0) 0 (0) |
14 (7.25) 0 (0) 0 (0) 2 (1.18) 0 (0) 0 (0) 0 (0) 2 (2.35) 2 (2.35) 0 (0) 0 (0) 2 (2.35) 0 (0) 0 (0) 1 (1.18) 0 (0) 0 (0) 0 (0) 0 (0) |
p=0.234 p=0.606 p=0.182 p=0.0325 p=0.0325 p=0.883 p=0.808 |
|
| Charlson Index n (%) | 0 1 2 3 |
75 (88.24) 8 (9.41) 2 (2.35) 0 (0) |
167 (86.53) 21 (10.08) 4 (2.07) 1 (0.52) |
p=0.896 |
Regarding previous exposure to SARS-CoV-2, more than 60% of HCW reported previous exposure to COVID-19 patients without adequate protection in the laboral environment, around 15% at home, and around 15% had been isolated before the vaccination due to COVID-19 contact. 19 per cent of them reported previous SARS-CoV-2 infection The list of symptoms in those with previous COVID-19, as well as other more concrete data about previous exposure to COVID-19 might be consulted in Table 2.
Table 2.
Previous exposure to SARS-CoV2 in HCWs receptors of COVID-19 mRNA BNT162b2 (n =278)
| COVID-19 Laboral contact n (%) | 167 (60.07) | |
| COVID-19 Cohabiting Contact n (%) | 40 (14.39) | |
| Isolation due to COVID-19 contact n (%) | 42 (15.11) | |
| N. isolations due to COVID-19 contact |
29 (70.73) 9 (21.95) 3 (7.32) |
|
| 1 isolation n (%) 2.isolations n (%) 3.isolations n (%) | ||
| Previous COVID-19 diagnose n (%) | 53 (19.06) 31 (11.15) 3 (1.08) 19 (6.83) |
|
| PCR Ag test Serology |
n (%) n (%) n (%) |
|
| Hospitalization due to COVID-19 | 1 (0.36) | |
| ICU admission due to COVID-19 | 1 (0.36) | |
| Symptoms in previous COVID-19 cases in vaccinated health care workers n (%) Fever Cough Dyspnoea Diarrhoea Headache Dysgeusia Anosmia Asthenia Myalgia Odynophagia Chest tightness Extreme weakness Rash |
24 (45.28) 21 (39.62) 9 (16.98) 10 (18.87) 33 (62.26) 28 (52.83) 33 (62.26) 44 (83.02) 26 (49.06) 8 (15.09) 9 (16.98) 1 (1.89) 2 (3.77) |
|
The most frequent adverse effect was local pain, significantly slightly more common after first dose (83 vs 78%, p<0.05). On the other hand, systemic symptoms including fever (from mild to severe), dysthermia, use of antipyretic, headache, cough, vomiting, diarrhoea, adenopathy, myalgia, arthralgia, and work absenteeism, were significantly more frequent after the second dose of the vaccine (p<0.05). More concrete details might be consulted in Table 3. The degree of post-vaccine limitation was significatively higher after the second dose of the vaccine (Figure 1).
Table 3.
Adverse effects after 1st and 2nd dose of COVID-19 mRNA BNT162b2 vaccine (n =278)
| Adverse effect | 1st Dose n (%) | 2nd Dose n (%) | P | |
|---|---|---|---|---|
| None | 31 (11.15) | 27(9.71) | 0.48 | |
| Local erythema | 35 (12.59) | 30 (10.79) | 0.25 | |
| Local swelling | 51 (18.35) | 51 (18.35) | 1 | |
| Local pain | 232 (83.45) | 217 (78.06) | 0.025 | |
| Low grade fever (under 38ºC) | 18 (6.47) | 62 (22.30) | <0.0001 | |
| Fever >38ºC & < 39ºC | 6 (2.16) | 31 (11.15) | <0.0001 | |
| Fever >39ºC | 0 (0) | 7 (2.52) | <0.01 | |
| Asthenia | 72(25.90) | 72 (25.90) | 1 | |
| Headache | 60 (21.58) | 104 (37.41) | <0.0001 | |
| Dysthermia | 39 (14.03) | 97 (34.89) | <0.0001 | |
| Cough | 13 (4.68) | 46 (16.55) | <0.0001 | |
| Vomiting | 1 (0.36) | 16 (5.76) | <0.001 | |
| Diarrhoea | 6 (2.16) | 20 (7.19) | 0.002 | |
| Adenopathy | 11 (3.96) | 27 (9.71) | 0.002 | |
| Myalgia | 23 (8.27) | 80 (28.78) | <0.0001 | |
| Arthralgia | 16 (5.76) | 46 (16.55) | <0.0001 | |
| Antipyretic use | 44 (15.83) | 95 (34.17) | <0.0001 | |
| Urgent care need | 0 (0) | 0 (0) | ||
| Work absenteeism | 4 (1.44) | 16 (5.76) | 0.003 | |
| Post-vaccine limitation | ||||
| None (0) | 182 (65.70) | 122 (43.88) | < 0.001 | |
| Very Mild (1) | 45 (16.25) | 38 (13.67) | ||
| Mild (2) | 22 (7.94) | 34 (12.23) | ||
| Moderate (3) | 12 (4.33) | 38 (13.67) | ||
| Severe (4) | 13 (4.69) | 34 (12.23) | ||
| Very Severe (5) | 3 (1.08) | 12 (4.32) | ||
Figure 1.
Degree of functional limitation (0 to 5) in HCWs after 1st & 2nd dose of Comirnaty
Previous COVID-19 was significantly associated with higher incidence of low-grade fever (OR 2.96), asthenia (OR 2.48), headache (OR 2.8), dysthermia (OR 4.36), myalgia (OR 5.69), use of antipyretic (OR 3.46), and post-vaccine functional limitation, after the first dose of Comirnaty®. On the other hand, after the second dose of Comirnaty®, previous COVID-19 was associated with lower incidence of moderate fever (0R 0.13) and cough (OR 0.16), and, as with the first dose, with greater incidence of asthenia (OR 2.48). The rest of adverse effects studied did not show significative association with previous COVID-19 (Table 4).
Table 4.
OR of previous COVID-19 and adverse effects after mRNA BNT162b2 vaccine (n =278)
| Adverse effect* | Dose 1 OR (IC 95%) |
p | Dose 2 OR (IC 95%) |
p | |
|---|---|---|---|---|---|
| Low grade fever (<38ºC) | 2.96 (1.08-8.04) | 0.033 | 0.66 (0.30-1.45) | 0.303 | |
| Fever >38ºC & < 39ºC | 0.85 (0.10-7.40) | 0.880 | 0.13 (0.02-0.94) | 0.043 | |
| Asthenia | 2.48 (1.32-4.67) | 0.005 | 2.48 (1.32-4.67) | 0.005 | |
| Headache | 2.80 (1.46-5.38) | 0.002 | 0.83 (0.44-1.56) | 0.565 | |
| Dysthermia | 4.36 (2.11-9.00) | <0.0001 | 0.77 (0.40-1.47) | 0.425 | |
| Cough | 1.29 (0.34-4.86) | 0.71 | 0.16 (0.04-0.69) | 0.014 | |
| Myalgia | 5.69 (2.35-13.78) | <0.0001 | 0.97 (0.50-1.88) | 0.932 | |
| Arthralgia | 4.82 (1.72-13.52) | 0.003 | 1.04 (0.47-2.31) | 0.925 | |
| Antipyretic use | 3.46 (1.71-6.99) | 0.001 | 0.89 (0.47-1.69) | 0.721 | |
| Post-vaccine limitation | |||||
| None (0) Very Mild (1) Mild (2) Moderate (3) Severe (4) Very Severe (5) |
1 2.28 (1.04-5.01) 2.35 (0.84-6.59) 6.28 (1.88-21.01) 2.80 (0.80-9.75) |
0.039 0.103 0.003 0.108 |
1 0.63 (0.24-1.66) 0.45 (0.15-1.38) 1.20 (0.52-2.77) 0.32 (0.09-1.14) 0.67 (0.14-3.24) |
0.349 0.162 0.671 0.080 0.620 |
|
The rest of adverse effects did not show significant association (OR) with previous COVID-19, nor with 1st dose, neither with 2nd dose.
Finally, we employed linear regression analysis to study the predictive capacity of different factors and covariables in the degree of self-reported (from 0 to 5) functional limitation after each dose of the vaccine. Neither ethnicity, blood group, or body mass index revealed themselves as significant predictors of functional limitation after the first or second dose of Comirnaty®. After the first dose of Comirnaty®, in the multivariate model, we found a positive independent association between degree of functional limitation and age (years), female sex, previous SARS-CoV-2 infection, previous isolation due to COVID-19 contact, and Charlson Comorbidity Index Punctuation. By contrast, after the second dose of the vaccine, in the multivariate model, the degree of functional limitation was positively associated with the degree of functional limitation (0 to 5) after the first dose of vaccine (p<0.001), and it was significatively lower in people with previous COVID-19 (Table 5)
Table 5.
Multivariate Linear regression model of post-vaccine limitation after 1st & 2nd dose of Comirnaty®
| Model after 1st dose | ||||
|---|---|---|---|---|
| Coef. | CI 95% | P Wald | ||
| Age (each year) | 0.0016 | 0.001 to 0.002 | <0.001 | |
| Male Sex | -0.34 | -0.62 to - 0.05 | 0.021 | |
| Charlson Index | 0.35 | 0.05 to 0.65 | 0.020 | |
| Previous COVID-19 | 0.61 | 0.27 to 0.95 | <0.001 | |
| Isolation due to COVID-19 contact | 0.47 | 0.09 - 0.84 | 0.015 | |
| Model after 2nd dose | ||||
| Coef. | CI 95% | P Wald | ||
| Age (each year) | 0.00003 | -0.001 to 0.001 | 0.963 | |
| Male Sex | -0.20 | -0.60 to 0.20 | 0.332 | |
| Charlson Index | -0.04 | -0.45 to 0.38 | 0.859 | |
| Previous COVID-19 | -0.55 | -1.03 to -0.06 | 0.027 | |
| Isolation due to COVID-19 contact | -0.11 | -0.64 to 0.42 | 0.687 | |
| Functional limitation after 1st dose (0 to 5) | 0.48 | 0.31 to 0.64 | <0.001 | |
DISCUSSION
In our group of health care workers fully vaccinated with Comirnaty®, around 90% did experience at least one side effect. Most of the self-reported side effects were mild to moderate. The main adverse effect observed after the first and second dose of Comirnaty® was local pain. In general, systemic side effects were significatively more intense after the second dose of the vaccine. The degree of self-reported functional limitation (from 0 to 5) after vaccination was also significantly higher after the second dose of the vaccine (p<0.05).
This echoes the results of the clinical trial conducted by Polack [5], and the cohort study by Chapin-Bardales [14], with over three and half million participants, using the V-safe Active Surveillance System, in USA.
On the contrary, another evidence from our study was that in those with previous SARS-CoV-2 infection, systemic side effects were more intense after first dose of Comirnaty®. These findings were in congruence with those reported by Me-ni [15] in the British COVID Symptom Study and D’Arminio [16] on HCW in Italy.
A very rare adverse effect attributed to mRNA vaccines (Pfizer and Moderna) has been the development of myocarditis and/or pericarditis, mainly in the first week after the second dose, as reported by Kim [17], Montgomery [18], Marshall [19] or Boehmer [20]. No events of pericarditis or myocarditis post-vaccination with Comirnaty® were reported in our series of 278 HCW. No deaths or other serious adverse events were reported in our study.
A strength of our study is the attention paid to different epidemiological and clinical factors and their influence in the reactogenicity to Comirnaty®. In this way, in the multivariate linear regression analysis we found that age, female sex, Charlson Comorbidity Index Punctuation, previous SARS CoV-2 infection, and previous isolation due to COVID-19 contact were independent predictors of a higher degree of functional limitation after the first dose of Comirnaty®. After the second dose, previous COVID-19 was associated with a lower functional limitation, and only the degree of functional limitation after the first dose revealed itself as an independent predictor of greater impairment. Other evidences from our analyses not published in previous works include that no differences in functional limitation post-vaccination were observed according to body mass index, ethnicity, or blood group.
A limitation of our study was the limited number of participants, though this could be counterbalanced with the higher degree of precision in the answer to the questionnaire due to the fact that all of them were HCW. Although this limitation, we obtained results in congruence with much greater studies, such as the ones conducted by Chapin Bardales or Menni [14,15].
CONCLUSION
In conclusion, in the same way as other studies, globally we found a higher incidence of systemic side effects with the second dose of Comirnaty® than with the first dose, while in those previously infected by SARS-CoV-2 systemic adverse effects were more intense after the first dose. No events of myocarditis neither pericarditis were reported in our HCW population. No deaths or major severe adverse events were reported. The degree of functional limitation after the first dose was independently associated with age, female sex, previous COVID-19 isolation, previous SARS-CoV-2 infection, and punctuation in the Charlson Comorbidity Index. The degree of functional limitation after the first dose showed to be an independent predictor of a higher degree of functional limitation after the second dose, while previous SARS-CoV-2 infection was associated with a lower functional limitation after the second dose. Further post-emergency use authorization studies are still needed in order to define more precisely the safety profile of these new vaccines against COVID-19.
FUNDING
None to declare.
CONFLICT OF INTEREST
Authors declare no have conflict of interest
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