Since the emergence of severe acute respiratory syndrome coronavirus−2 (SARS-CoV-2) and its subsequent coronavirus disease (COVID-19), it had been clear that we can only overcome such a pandemic through individual acquired immunity (1). This can be reached either by previous infection or immunization through vaccines (1). Uncontrolled spread of the disease to achieve indirect immunity (herd immunity) is associated with high morbidity and mortality rates and overwhelmed healthcare systems and personnel (1, 2). Therefore, reaching herd immunity through mass vaccination is the only appealing and effective intervention amid this pandemic (2–4). Since the authorization of first COVID-19 vaccine (BNT162b2) by the European Medicines Agency (EMA) in December 2020, a cascade of milestones in the road toward herd immunity had been achieved by the European Union (EU) member states including the Federal Republic of Germany (Germany) (5). Nevertheless, after almost 1 year of mass vaccination, the pandemic remains on march and there is no predictive data about how long we still need to overcome this catastrophe.

Several variants of concern (VoC) had been identified throughout the previous months, and they were associated with breakthrough infections and novel epidemic waves (6, 7). Omicron (B.1.1.529) is the most recent VoC reported to and declared by the World Health Organization (WHO) on November 26^th, 2021 (7, 8). Phylogenetic studies showed that Omicron arose independently of the currently dominant Delta variant (B.1.617.2), and it has an unprecedently high number of amino acid changes in the spike protein compared to the original SARS-CoV-2 detected in Wuhan (9). Few of the 30 changes brought by the Omicron variant have phenotypic impact, e.g., increased transmissibility and immune evasion, while many changes have unclear significance (9, 10). Omicron has been spreading rapidly and detected in several countries globally including Germany, where Robert Koch Institute (RKI; Berlin, Germany) reported a total of 16,748 Omicron cases by December 30^th, 2021 with +3,619 new cases (28%) reported since the previous day (11). Therefore, RKI recommended that the persons who have not received their primer doses of COVID-19 vaccines should be vaccinated immediately and VB doses should be available to all age groups unrestrictedly (12).

Vaccine hesitancy (VH) is defined by the WHO as “delay in acceptance or refusal of vaccines despite availability of vaccine services” and depicted as one of the top 10 threats for global health since 2019 (13, 14). In Germany, Holzmann-Littig et al. (2) found that 8.3% of German healthcare workers were hesitant to accept COVID-19 vaccination in February 2021 (2). The young age was associated with lower COVID-19 vaccine acceptance, and the acceptance levels were not different across genders (2). Vaccine booster hesitancy (VBH), waning of vaccine-elicited immunity, and emerging of SARS-CoV-2 mutations act simultaneously to prolong the pandemic interval (15, 16). Therefore, tackling vaccine hesitancy through evidence-based interventions and rapid development of COVID-19 vaccine boosters (VB) that are capable of controlling the emerging mutations are the most urgent interventions which should be approached by health systems globally nowadays (15, 17–19).

This study aimed to evaluate COVID-19 VBH among a highly educated subset of the German population, i.e., university students and employees, and to explore the potential drivers of COVID-19 VBH. The primary objective was to measure the prevalence of COVID-19 VBH among German university students and employees. The secondary objectives were: (i) to evaluate the associations between COVID-19 VB acceptance and demographic and anamnestic characteristics of the target population, (ii) to evaluate the association between COVID-19 VB acceptance and its psychosocial predictors, e.g., perceived effectiveness, perceived safety, risk-benefit ratio, and ethical barriers.

The overall COVID-19 VB acceptance among German university students and employees was satisfactory (87.8%) and induced by various altruistic promoters, e.g., family health protection, community health protection, and patients' health protection. Compared to our findings, Rzymski et al. (32, 33) and Klugar et al. (15) revealed lower COVID-19 VB acceptance levels among Polish (71%) and Czech (71.3%) populations in September 2021 and November 2021, respectively (15, 32). Additionally, Alhasan et al. (34) found that only 55.3% of the Saudi healthcare workers indicated their acceptance to receive COVID-19 VB when they were surveyed in August 2021 (34). Similarly, Yadete et al. (35) found that about 62% of a representative sample of the American adult population accepted COVID-19 VB in July 2021 (35). On the other hand, 84.8% of the Chinese adults were willing to receive COVID-19 VB in June 2021, and 88.9% of the American medical students were in favor of receiving COVID-19 VB in Spring 2021 (36, 37).

By December 20^th, 2021, there had been 6,991,381 confirmed COVID-19 cases in Germany representing 8.3% of the total German population, which is larger than the proportion of the previously infected participants (5.9%) in our sample (38). This difference can be attributed to the age structure of our sample which was younger than the age structure of confirmed cases in the general population, with bearing in mind that younger age groups are associated with asymptomatic and mild infections which tend to be undetected/missed (39). According to RKI, the largest age group of confirmed COVID-19 cases in Germany is 35–59 years, while the mean age of our participants was 29.08 ± 10.93 years with an interquartile range of 22–31 years (40).

In our sample, the most administered COVID-19 vaccine type was BNT162b2 (78.1%), followed by mRNA-1273 (12.2%), AZD1222 (7.5%), and Ad26.COV2.S (2.1%). The same order was found among the general German population; by December 26^th, 2021, there had been 164.3 million doses of COVID-19 vaccines in Germany with BNT162b2 being the most commonly administered type (72.1%), followed by mRNA-1273 (15.9%), AZD1222 (8.8%), and Ad26.COV2.S (3.2%) (41). While the crude vaccination rate, i.e., receiving at least one vaccine shot, in Germany was 74.1%, the crude vaccination rate in our sample was 95.7%, thus suggesting that our sample may represent an above-average subset of the German population in terms of vaccine acceptance that could be attributed to their supposedly high level of health literacy (41).

One of the public health challenges that happened amid 2021 and portrayed by our findings is the dramatic decline of public demand for AZD1222 vaccine (commonly known as AstraZeneca-Oxford COVID-19 vaccine), which had been received by 125 participants for the first dose and only 24 participants for the second dose with 80.8% of decline. The “AstraZeneca catastrophe” had been triggered by the initial decision of the German Standing Committee on Vaccination (STIKO) to deliver AZD1222 for those below 65 years of age due to incomplete data of pre-authorization trials (42). Few weeks later, the situation was further complicated by the emergence of few thrombotic events among the individuals who received AZD1222 that made the European Medicines Agency (EMA) recommends temporary suspension of AZD1222 mass administration until those reports were reviewed (43). However, the EMA's safety committee recommended the continuation of AZD1222 use for mass inoculation as its benefits were found to weigh its risks, the public demand continued to fall in western Europe including Germany to the point that the Federal Government of Germany donated all remaining AZD1222 doses to COVAX consortium in August 2021 (44).

Living with an immunocompromised family member was significantly associated with increased likelihood of COVID-19 VB acceptance among American adults (35). El-Mohandes et al. (45) concluded that protection of one's own health, protection of family health, and help ending the pandemic were the major reasons for accepting COVID-19 vaccines among American adults (45). Another study of social media users in the US revealed that having a large family was associated with higher odds of COVID-19 vaccine acceptance; however, vaccine hesitancy remained existent in large families that did not have confidence in pharmaceutical industry (46). Similarly, our study revealed that protection of one's own health was the most commonly cited promoter for COVID-19 VB acceptance (95.6%), followed by protection of community health (91.6%) and protection of family health (91.2%). Moreover, our findings are in complete agreement with the results of Schernhammer et al. (47) who found that protection of one's own health and protection of family health were the most common reasons for Austrian adults to accept COVID-19 vaccines (47). Given that evidence-based communication strategies are crucial for the fight against COVID-19 vaccine hesitancy, our results underline the importance of positive emotions in enhancing vaccine uptake by highlighting the role of indirect immunity in protecting family members and beloved ones (15, 48).

COVID-19 vaccine hesitancy had decreased significantly during the lockdown period among Italian residents; therefore, Caserotti et al. (49) proposed that lockdown and the anti-pandemic restrictions can be contextual factors that induce vaccine acceptance (49). On the other hand, Fernandes et al. (50) could not find any correlation between the number of days in lockdown and vaccination intention, thus suggesting that anti-pandemic restrictions could have caused a sense of protection due to the associated decline of cases during lockdown, which may have made the people believe that vaccination was no longer necessary (50). Having easier social life with less restrictions on mobility and gatherings was one of the key promoters for COVID-19 VB acceptance (57.9%) in our sample, and avoidance of frequent testing (22.5%) was also an important promoter. These findings suggest that vaccine messaging may benefit from highlighting the social benefits of mass vaccination that can help reduce anti-pandemic restrictions dramatically.

In April 2021, the WHO issued a policy paper discussing the ethical concerns of COVID-19 mandatory vaccination and adopted no position with or against COVID-19 vaccine mandates (51). According to the WHO, vaccine mandates should not be approached as the first option for achieving public health goals, e.g., reaching herd immunity and protection of the vulnerable population, as they do compromise individual liberties and adversely affect the public trust in vaccines (51, 52). However, vaccine mandates are ideally applied when they are necessary, and when there is sufficient evidence on vaccine safety and effectiveness, private employers-imposed vaccine mandates can be counterproductive especially in western societies (51–54). The employer's endorsement was only reported by 3.7% of our participants as the promoter for COVID-19 VB acceptance, thus suggesting that vaccine mandates might not be the best option for enhancing vaccine uptake in Germany currently.

A recent cross-sectional survey from Portugal found that the perceived risk of severe COVID-19 infection was associated with increased odds of vaccine acceptance (55). This finding can be understood within the context of the 3-C model for vaccine hesitancy which implies that vaccine compliance as one of the three key elements of vaccine decision is influenced by perceived risk of disease severity (56, 57). In our sample, the belief that COVID-19 VB can prevent severe illness was a strong predictor of COVID-19 VB acceptance. Moreover, the capacity of COVID-19 VB to reduce community transmission and symptomatic infection were also strong predictors of COVID-19 VB acceptance. The growing evidence on COVID-19 vaccines effectiveness against community transmission and symptomatic infection had supported the rationale of administering booster doses for tackling two synergistically occurring phenomena; the decline of vaccine-elicited immunity and the emerging variants (33, 58–60).

Klugar et al. (15, 61) found that the perceived effectiveness of COVID-19 VB against the emerging variants of SARS-CoV-2 was not a significant predictor for COVID-19 VB acceptance among Czech healthcare workers (15). One the other hand, more than half (55.3%) of Saudi healthcare workers indicated their interest in receiving mRNA-based vaccine which is specifically developed for the Delta variant (34). In our sample, the perceived effectiveness against the emerging variants was a strong predictor for COVID-19 VB acceptance, thus underlining the importance of promoting the emerging evidence on COVID-19 VB capacity against the variants (17, 18, 62).

Safety of COVID-19 vaccines had been one of the debates that were specifically targeted by the anti-vaccination campaigns for undermining the mass vaccination efforts; therefore, the WHO called for timely and transparent dissemination of safety data of COVID-19 vaccine trials (63–66). The healthcare students who exhibited less concerns regarding COVID-19 vaccines side effects were more inclined to accept vaccination (67–69). Independent (non-sponsored) studies that are designed to monitor the self-reported side effects of COVID-19 vaccines constitute a crucial resource for active surveillance of COVID-19 vaccines safety (61, 70–76). Even minor post-vaccination side effects may cause anxiety and social burden for the recently vaccinated individuals that may hinder them from continuing their vaccination regimen; therefore, vaccine messaging should normalize the post-vaccination side effects and describe their postulated onset, duration, and severity in order to reassure the vaccinees (50, 77). The high severity of side effects following the primer doses was a key predictor for COVID-19 VB refusal among the Polish population as reported by Rzymski et al. (32). Our findings are consistent with the Polish results, as the participants who required hospital admission or sought medical care/treatment were more likely to be hesitant about receiving COVID-19 VB. These results are echoed by the finding that beliefs of equal safety and non-inferior safety were strong predictors of COVID-19 VB among our participants.

The ethical dilemma of vaccine justice has been found to be a prominent a barrier for COVID-19 VB acceptance among Czech healthcare workers as well as our sample (15). Such dilemma is triggered by the WHO stance against dissemination of booster doses in high-income countries while frontline healthcare workers in some developing countries are still queuing to receive their first dose (78–80). Dr. Ghebreyesus, the Director-General of WHO, has recently proposed a roadmap of five steps to tackle the crisis of vaccine inequity; (i) firstly, the countries which purchased enormous numbers of doses that exceed their actual populations' needs should donate those doses to the poorest countries through COVAX and the African Vaccine Acquisition Trust (AVAT), (ii) secondly, vaccine manufactures should prioritize and fulfill their contracts with COVAX and AVAT, (iii) thirdly, G7 and other vaccine-donating countries should fulfill their commitments urgently, (iv) trade barriers and export restrictions on COVID-19 vaccines should eliminated, and (v) all these recommendations need to be fulfilled simultaneously (80).

Our LGBTQ+ participants had lower levels of COVID-19 VB acceptance, which is similar to what was recently reported by Riad et al. (70, 72–74, 76, 81–83) who found that LGBTQ+ university students in the Czech Republic were less willing to receive COVID-19 vaccines (81). The recent systematic review of Garg et al. (84) on COVID-19 vaccine hesitancy among LGBTQ+ communities revealed that the common reasons for vaccine hesitancy were vaccine safety concerns, previous negative experiences with healthcare providers, and lack of inclusion of LGBTQ+ individuals in vaccine trials (84). The differences between males and females in terms of COVID-19 VB acceptance were not statistically significant among our participants. Holzmann-Littig et al. (2) found no statistically significant difference between female and male German healthcare workers in terms of COVID-19 vaccine acceptance (2). While some national and multinational studies found that males were more likely to accept COVID-19 vaccines, other studies found that females were more pro vaccination (82, 85–89).

Recent studies found that younger age was associated with lower odds of COVID-19 vaccine acceptance, which could be the main reason for why German university students had lower levels of COVID-19 VB acceptance compared to Germany university employees. Young age is associated with decreased likelihood of severe illness and disease complications, lower perceived risk of COVID-19, and delayed vaccine uptake due to the prioritization schemes of vaccine dissemination (76, 83).

The overall COVID-19 VB acceptance among German university students and employees was satisfactory (87.8%) and induced by various altruistic promoters, e.g., family health protection, community health protection, and patients' health protection. The students (86.3%), the previously infected participants (76.4%), the participants who did not receive primer doses of COVID-19 vaccines (2.5 %), and those who were hospitalized (40%) and sought medical care/treatment after receiving primer doses (86.8%) were less likely to accept COVID-19 VB compared to the employees (90.7%), the participants who were not previously infected (88.6%) and those who received primer dose (91.7%), and the participants who were not hospitalized (92%) nor sought medical care/treatment after primer doses (92.9%), respectively. The perceived effectiveness of COVID-19 VB against severe illness, symptomatic infection, community transmission and emerging variants was a key promoter for COVID-19 VB acceptance; therefore, it needs to be highlighted in vaccine messaging. In addition, the perceived safety of COVID-19 VB and ethical dilemmas of vaccine justice need to be addressed publicly.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee of the Faculty of Medicine at Justus Liebig University Giessen (Ref. 259/21). The patients/participants provided their written informed consent to participate in this study.

SA and AR: conceptualization and writing—original draft preparation. KM, MK, and AR: methodology. AR: software, formal analysis, and supervision. SA and KM: validation. SA and H-PH: investigation and funding acquisition. MK and H-PH: writing—review and editing. SA: project administration. All authors have read and agreed to the published version of the manuscript.

This work of AR was supported by Masaryk University grants number MUNI/IGA/1104/2021 and MUNI/A/1402/2021.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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