Adverse effects of COVID-19 vaccines in university students

Introduction

The coronavirus disease 2019 (COVID-19) pandemic is one of the greatest global threats, with manifestations of acute respiratory syndrome caused by the SARS-CoV-2 virus.¹ This has led to hospitalizations and deaths since early 2020, with a mortality rate of 1% and a total of more than 6.8 million deaths as of 25 March 2023.² Vaccination has proven to be an effective preventive measure against COVID-19, reducing its spread and severity.³ In Thailand, there are three major types of vaccine: (1) inactivated vaccines, including CoronaVac and BBIBP-CorV, (2) viral vector (VV) vaccine, including ChAdOx1 nCoV-19, and (3) mRNA vaccines, including BNT162b2 and mRNA-1273.^4,5 In February 2021, CoronaVac was implemented as the first official COVID-19 vaccination regimen for populations at risk of COVID-19 and for healthcare workers. Subsequently, VV and mRNA vaccines became available. However, due to the limited supply of the vaccines, alternative primary vaccine regimens of heterologous COVID-19 vaccines including CoronaVac-ChAdOx1 nCoV-19, CoronaVac-BNT162b2, and ChAdOx1 nCoV-19-BNT162b2 have been used since late 2021.^6–9 These heterologous COVID-19 vaccine regimens have gained significant interest among the Thai population because there is less evidence of serious adverse events and because they are more accessible.^7,10

While university students have less symptomatic COVID-19 infection than other populations, their social interaction increases the possibility of asymptomatic transmission, leading to higher rates of community infections.^11,12 COVID-19 vaccination is essential to control the spread of the virus and achieve herd immunity. Especially for adolescents, the vaccines help prevent asymptomatic infection and therefore play an important role in disease control in the community.^13,14 However, vaccine hesitancy among university students is a concerning issue, as it may lead to prolonged community transmission and increased chances of infection. Some students may be skeptical about the safety, efficacy, and adverse effects of the vaccine, which may discourage them from getting vaccinated.^5,15,16

The adverse effects of COVID-19 vaccines may vary depending on the type of vaccine administered. Some of the most common adverse effects associated with COVID-19 vaccines include soreness or redness at the injection site, fever, headaches, fatigue, and muscle pain.^17–19 In rare cases, more serious adverse effects, such as myopericarditis and thrombotic events, may occur in adolescents and young adults but usually with a favorable prognosis.^20,21 While studies show that the overall adverse effects among the global population are mild and self-limited,²² there is limited research specifically focused on type, intensity, onset, difference between each dose, and natural history of the adverse effects among university students.

This study aimed to investigate the characteristics of adverse effects that may arise from administering COVID-19 vaccines to university students in Thailand. The results will provide valuable information and guide strategies to implement mass COVID-19 vaccination among university students.

Methods

Results

Discussion

Adverse effects originate from natural reactions to exogenous substances, such as vaccines. When these substances are detected by innate immune lineages, specifically neutrophils and macrophages, cytokines are released to trigger an immune response. This can result in systemic adverse effects, such as fever, muscle pain, headache, and nausea.²⁴ The introduction of an inactivated COVID-19 vaccine in a population aged over 18 years has shown a significant induction of T-cell response secreting IFN-gamma.²⁵ This mechanism may explain why young adults are more likely to experience vaccine-related systemic adverse effects than other age groups, as they have lower spike-specific IFN-gamma+CD4+ T cells, leading to more widespread T-cell activation and cytokine secretion.²⁶ In our study, we found high rates of adverse reactions among university students (49.9% and 49.8% for the first and second doses, respectively). These results were consistent with high prevalence of adverse effects after COVID-19 vaccination among young adults reported from previous studies.^27–31

Regarding the COVID-19 vaccines’ adverse effects, muscle pain, fever, and injection site pain were common among all three types of vaccines, which was similar to other studies.^{14,18,27–29,31–33} Injection site pain was common because of local responses induced by the injection and the high concentration of vaccine at the affected tissue.^14,31 In contrast, muscle pain and fatigue are systemic reactions which commonly occur as a result of changes in pro-inflammatory cytokine levels in response to vaccine. These include a rise in interleukin-6 (IL-6) (causing fever) and increase in autoimmune activities that impair self-tolerance, disrupt the balance of muscle metabolism and cause cell damage and muscle pain.^26,34

The frequency of each adverse effect varied based on the number of doses and the vaccine types. Overall, regardless of the dose, the group receiving the inactivated vaccines reported a lower prevalence of adverse effects compared to those receiving the VV and mRNA vaccines, which was similar to a report by Al Khames Aga et al.¹⁸ According to a review of COVID-19 vaccine effectiveness and adverse effects, inactivated vaccines elicit lower antibody responses compared to mRNA or viral vector vaccines because of their lower reactogenicity.³⁵ The adverse effects of VV and mRNA vaccines can vary depending on the number of doses. In particular, VV vaccines had more adverse effects after the first dose compared to the second dose, while mRNA vaccines had more after the second dose compared to the first dose. These findings were consistent with those described in previous studies.^19,30,36 Although the underlying mechanism of the different AE intensity between two doses is currently unknown, we hypothesize that it may be due to the body’s adaptation to the VV vaccine component leading to less adverse effect intensity in the second dose, while the increased immune response for the second dose of mRNA vaccine explains the more intense adverse effects in the second dose.

Some students experienced minor adverse effects like loss of appetite, vomiting, and diarrhea after receiving one of the three vaccine types, which were also reported in some studies.^18,27,32 Rare adverse events like thrombosis and myocarditis have been reported following VV and mRNA COVID-19 vaccination,^27,37,38 but were not reported in this study. Gastrointestinal symptoms and other minor effects were not frequently reported in this study compared to other studies.^28,33,39 The VV vaccine was reported by some of our study participants to have caused coughing in addition to other common adverse effects. This was possibly due to an immune response to the vaccine that led to respiratory tract inflammation and triggered the cough reflex arc.⁴⁰ For the mRNA vaccines, the prevalence of minor adverse effects, such as loss of appetite, vomiting, diarrhea and rashes was higher after the second dose compared to the first dose. This finding was consistent with the result from a previous study and might be explained by the increased immunogenicity and reactogenicity induced by the second dose.³²

Most adverse effects from the first dose of the COVID-19 vaccines typically occurred within 48 hours. The onset of these side effects matched the reports of mRNA vaccines stating that systemic adverse effects are usually observed within the first or second day.^31,36 However, our study showed that adverse effects from the second dose may be delayed and can occur up to 96 hours post vaccination. While some studies have compared the severity of effects after the first and second doses,¹⁸ few have discussed the management of adverse effects from COVID-19 vaccines. Our study found that symptomatic treatment was typically required for the adverse effects caused by the VV vaccine, which accounted for the highest proportion of such cases among the three major types of vaccines. This may be explained by the higher intensity of adverse effects experienced by students than with the other types of vaccines. However, overall adverse effects were non-severe, and only a small number of cases required hospital treatment. These findings are consistent with those reported in a previous study.²⁷

There were recognizable limitations of this study. First, the single-center study may limit generalizability to other students in different settings. Second, because the survey was anonymous and self-administered, some questions may have been misunderstood. Third, the survey was conducted in a short period of time, and the respondents may have been affected by time limitations and by influences from recent social media and/or news. Lastly, there were inherent limitations, such as recall bias and confounding factors. Therefore, further research is necessary to determine the causal relationship between types and number of vaccine doses and adverse effects, especially among university students.

In conclusion, this study highlights the adverse effects that university students experienced after receiving the three major types of COVID-19 vaccines. Muscle pain, injection site pain, fever, headaches, and fatigue were commonly reported adverse effects while gastrointestinal symptoms and cough were reported less commonly. Overall, inactivated vaccines and the VV vaccine had the lowest and highest incidence of adverse effects, respectively. The majority of adverse effects occurred 24-48 hours after vaccination, were more severe with the first dose compared to the second dose, and resolved spontaneously without any treatment at a hospital. The study findings can be informative for university students and stakeholders in their institutions. Our findings can also help those involved in public health policies to improve vaccine acceptance and to improve management and monitoring of COVID-19 vaccines’ adverse effects among university students.