In the present survey we sought to better understand the safety, tolerability and immunogenicity of the ChAdOx1 nCoV-19 vaccine among Polish teachers. Interestingly, two out of three teachers reported they would change the product for another vaccine – mostly a mRNA vaccine - if there was such an opportunity; this clearly highlights the necessity of this study.
The vast majority of teachers receiving ChAdOx1 nCoV-19 experienced more than one side effect at the same time. Adverse events were significantly more common after the first dose and were mild in severity. Injection site pain was the most common type of local side effects. Common systemic symptoms were: feverishness, followed by headache, malaise fatigue and chills. Reactions were significantly less common in males and in older teachers.
In this cohort of teachers, predominantly healthy adults of working age, all developed a positive anti-spike IgG antibody test by ≥ 8 weeks post vaccination. Mean GMTs remained relatively high in all age groups. Previous infection with SARS-CoV-2 and longer dose interval were both positive predictors of higher immunologic response.
Median dosing interval
Median dosing interval in this study was 69 days, with the range of 25-111 days; only two teachers reported a shortened interval between ChAdOx1 doses. This means that the vast majority of the study participants did not follow the Polish government recommendation, announced on May 17th 2021, which endorsed 35 days as a between-doses interval . It is worth emphasizing that this regulation was in opposite to the United Kingdom (UK) and several other countries policy to employ an ‘extended interval’ vaccine regimen in which the booster dose of ChAdOx1 vaccine is delayed for 10 to 12 weeks following the first dose [6,24].
Frequencies and intensity of adverse reactions
We found that any systemic adverse effects affected almost three in four participants and local side effects – more than every second teacher. Very similar results regarding systemic solicited adverse events (71.6%) were reported in the double-blind, randomized, placebo-controlled, phase 3 clinical trial on ChAdOx1 nCoV-19 vaccine, conducted in the United States, Chile, and Peru . However, more participants in the RCT group than in our study had local solicited adverse events (74.1%). The reactogenicity of the ChAdOx1 nCoV-19 vaccine in teachers up to 67 years of age was also comparable to that reported in other RCTs [7,13-15] and listed in the product characteristics , as well as to observed by some other authors who conducted research outside clinical trials [17,18].
Furthermore, adverse effects observed in this study were similar in nature to those previously reported (feeling feverish, headache, malaise, chills, injection-site tenderness and pain) [13,16,17]. Severe systemic allergic reactions following immunization, such as anaphylactic shock, were not reported by study participants, however, the small sample size reduced the chance to detect such adverse events. Recent data imply an incidence of anaphylactic shock as very infrequent (1 per 200,000 -1 per million doses) .
We found fewer adverse events among the studied teachers after the boost vaccination than after the prime vaccination. Similar results have been seen in other studies which assessed the ChAdOx1 nCoV-19 vaccine safety [13,16,17]. Of note, some other studies found that individuals vaccinated with the ChAdOx1 nCoV-19 vaccine were more likely to experience systemic side-effects than those who had been given the BNT162b2 vaccine .
Side-effects were more prevalent in teachers aged <50 years than older teachers. Our results provide evidence to support other studies, both the RCTs and conducted in the community, of lower occurrence of side-effects in older than in younger individuals [13,16,17,26]. We also found that adverse effects were less common in men than women which is consistent with previous studies .
Local and systemic side effects were reported to be higher in individuals previously infected with SARS-CoV-2 than in those without known past infection for BNT162b2 and ChAdOx1 nCoV-19 COVID-19 vaccines [17,27-29]. Given evidence from these studies, we investigated the extent to which previous SARS-CoV-2 infection was associated with reports of adverse effects. No consistent difference in occurrence of systemic/local adverse effects between individuals who reported a previous infection and those who did not might be due to the small sample size, as well as to the information bias; although in 55% of teachers SARS-CoV-2 infection was confirmed by an adequate test, in the rest of cases the analyses relied on participants reports regarding previous infection.
Anti-spike antibody titres
We found 100% seroconversion rate among the study population after receiving two doses of ChAdOx1 vaccine, however, 4.2% of participants were low responders. As such, these findings show that vaccination is highly effective for induction of spike-specific immune responses in the working-age population, such as teachers. Some other studies reported similar rates of low responses among participants, however, in contrast with our results, this was independently associated with several long-term health conditions .
Antibody levels after two vaccine doses were significantly higher in individuals with prior SARS-CoV-2 infection compared to those achieved by teachers without infection. Previous infection with SARS-CoV-2 was the biggest positive predictor of the magnitude of quantitative antibody response post second vaccine dose, with median readings 2.6-fold higher with previous infection compared to without infection. This was also reported by other authors who explored this trend regarding ChAdOx1 nCoV-19 vaccine [7,18], as well as other vaccines [18,30-32]. For instance, a study conducted among Israeli healthcare workers (21 days post-dose 1 of the BNT162b2 mRNA COVID-19 vaccine) found that those with prior infection had antibody titres one magnitude order higher than naïve individuals . These findings may suggest prioritization on uninfected persons in regions where COVID-19 vaccine-sparing strategies are required [31,32]; such prioritization may also refer to the third vaccination in previously infected healthy individuals.
Concerning our second main finding, longer dose interval led to a greater immune response to ChAdOx1 nCoV-19 vaccine. Other studies confirmed that dosing interval is one of the most significant factor in determining the efficacy of this vaccine [7,8]. For instance, an analysis of four RCTs, conducted in South Africa, Brazil and the UK, found that efficacy was higher if the booster ChAdOx1 nCoV-19 vaccine dose was received 8-11 weeks after the first; furthermore, it was increased if participants received the booster dose more than 11 weeks after the first . This incremental VE with increasing prime-boost intervals positively correlated with GMTs of anti-SARS-CoV2 spike IgG binding antibody. A similar boost to antibody responses was seen with a longer duration in some other studies on the BNT162b2 COVID-19 vaccine [21,33].
Among demographic factors, older age has been repeatedly reported to associate with reduced antibody responses after COVID-19 vaccination due to age-related decline in immune functions [18, 34]. No statistically significant differences in the antibody response between age groups were found in this survey, possibly due to a defined study population, i.e. teachers in a relatively young age (median of 50.5 years). However, a relatively low correlation was found between age (r 0.144, p=0.046) with anti-S antibody titres. Some studies found [7,13,21] that two vaccine doses achieved high responses across all age groups, which supports our findings. By contrast, another two-dose mRNA vaccine candidates have shown immunogenicity in older adults, but absolute neutralizing antibody responses in adults aged 65–85 years were lower than in those aged 18–55 years . A two-dose inactivated virus vaccine has also shown lower absolute neutralizing antibody titres in adults aged 60 years and older than in adults aged 18–59 years . Additional studies on post-vaccination antibody responses in different age groups would be of value.
In our survey of teachers no association was found between female gender and better ChAdOx1 vaccine antibody response. This may be due to the small sample size and relatively small representation of males in the sample, as well as to the fact that the study population consisted of the middle-age individuals. Some previous studies found that between-gender differences in antibody responses become more marked above 60 years of age . Our findings are consistent with some previous observations , however, other authors which conducted larger population studies reported that females generate stronger humoral immunity than males [18,37].
Although many long-term health conditions, such as rheumatoid arthritis, chronic liver disease, type 2 diabetes, obesity, asthma, hypertension, as well as taking corticosteroids and immunosuppressants were independently associated with low responses [18,38], we did not detect any significant differences in antibody responses regarding teachers with comorbidities and healthy individuals. This may be attributable to the relatively low fraction of teachers reporting any long-term health conditions.
Potential limitations did exist in this study. The sample size of our study population was relatively small, which could possibly hinder some of the associations. Second, our cohort was predominately females. This echoes the demographic profile of Polish teachers with males comprising only 17.8% . However, for the gender-discrepancy reason, the cohort may not be representative for the entire population of working adults. Third, self-reported data were used for variables such as BMI and comorbidities, as well as (in 45% of participants) regarding the previous SARS-CoV-2 infection. This can introduce information bias, together with misclassification. The time of evaluation ranged between 1 and 4 weeks following the second immunization, introducing time as a possible bias. However, when the evaluations were controlled for this factor, they still yielded the same results. Furthermore, we assessed the intensity of the overall side-effects following the ChAdOx1 nCoV-19 immunization, no matter which dose had been taken. Although the vast majority of participants reported adverse events as more intense after the first vaccination than after the second one, the frequency assessed in this study could have been slightly higher than while assessed separately for each dose of the vaccine. Furthermore, T-cell response was not assessed in this study. Although the correlation between antibody response and vaccine efficacy is high, which suggests that the neutralizing antibody response is important, T-cell responses may contribute to protection from COVID-19 even in the presence of lower neutralizing antibody titers . Finally, the study design (a cross-sectional study) does not allow an inference of causality .