https://orcid.org/0000-0001-9565-4389
ABSTRACT
This study- a secondary analysis of data from a randomized, observer-blinded, non-inferiority study among volunteers between 18–55 y old in Türkiye- evaluated the impact of previous SARS-CoV-2 infection before the first dose of inactive TURKOVAC on post-vaccine local and systemic adverse events (AEs) comparing with CoronaVac. Of 1266 participants analyzed, 27.7% had a previous COVID-19 history. Local and systemic AEs were observed in 37.3% and 39% of the participants. The frequency of AEs was slightly higher in the first 30 minutes and 24 hours among participants with a COVID-19 history; none were severe. 1203 participants had a second dose vaccination, and 27.3% had a history of COVID-19. The frequencies of local and systemic AEs after the second dose were similar between those with and without a COVID-19 history. The TURKOVAC and CoronaVac showed similar frequencies of local and systemic AEs in the first 30 minutes after vaccination.
Introduction
As of May 2023, the coronavirus disease 2019 (COVID-19) pandemic has resulted in more than 765 million confirmed cases and almost 7 million deaths, as the World Health Organization (WHO) reported.Citation1 Today, the most effective strategies to prevent individuals from the disease and its spread in the population include vaccination and applying personal preventive measures. According to the WHO COVID-19 vaccine tracker, there are 50 approved vaccines worldwide, and 11 of them were granted emergency use listing by the WHO by the end of 2022.Citation2 During the pandemic period, four vaccines have received conditional approval for clinical use in Türkiye: the mRNA vaccine Comirnaty, adenovirus vector-based vaccine Sputnik V (Gamaleya), CoronaVac, and the TURKOVAC, a whole virion inactivated vaccine developed with the SARS-CoV-2 strain isolated from a patient in Türkiye with confirmed COVID-19.Citation3
Following the successful results from preclinical studies, the safety and immunogenicity of TURKOVAC were evaluated in phase I and II trials. The results of the phase I trial showed that neutralizing antibodies were determined in 84%, and anti-SARS-CoV-2 specific antibodies were present at Day 43 in the sera of all vaccinated individuals.Citation4 The subsequent phase II study showed that total immunoglobulin G responses against SARS-CoV-2 were significantly higher in the 6 μg dose group than in the 3 μg dose group, without no significant difference between neutralizing antibody titers and T cell responseCitation4 Most recently, the phase III trial evaluating the efficacy, immunogenicity, and safety of the two-dose schedules of TURKOVAC versus CoronaVac (Sinovac Life Sciences Co., Ltd., Beijing, China) reported that TURKOVAC was non-inferior to CoronaVac in terms of efficacy and demonstrated a good safety and tolerability profile.Citation5
In addition to these favorable outcomes from the safety and efficacy trials, addressing the outcomes in vulnerable populations is important since these groups are excluded from clinical trials.Citation6 Individuals with prior COVID-19 are one of the special subpopulations, and assessment of the vaccine outcomes in this group is crucial, given the prevalence of the disease. Nevertheless, the rapid accumulation of data from these individuals revealed insights into the risk-benefit profiles of vaccines and drove the implementation policies during the pandemic.Citation7 Current evidence suggests that the immune response to vaccination improves as the time between a prior infection and the vaccination increases,Citation8 and health authorities, including the Centers for Disease Control and the WHO, recommend vaccination after COVID-19 but consider delaying for a 3-month period.Citation9,Citation10 Previous studies reported increased systemic adverse events in individuals with prior COVID-19 after mRNA or vector-based vaccines, which was considered to occur due to immune priming.Citation11,Citation12 The first vaccine dose after COVID-19 induced antibody responses similar to the levels after the second dose in individuals without prior COVID-19 history.Citation13
Given the importance of evaluating the effects of COVID-19 on subsequent vaccination and the lack of data regarding TURKOVAC on this subject, this study was conducted as a secondary analysis of the phase III trial of TURKOVAC, in which the local and systemic adverse events were evaluated in demographic subgroups, after administration of the first and second vaccinations, comparatively between patients with and without a COVID-19 diagnosis before initial vaccine application.
Materials and methods
The original phase III study is a randomized, observer-blinded, non-inferiority phase III clinical trial to assess the efficacy, immunogenicity, and safety of the two-dose TURKOVAC versus the two-dose CoronaVac among volunteers between 18–55 y old in Türkiye (Registered at ClinicalTrials.gov, NCT04942405). Participants were randomly assigned in a ratio of 1:1 to one of the two arms to receive either 0.5 mL of the inactivated study vaccine TURKOVAC or 0.5 mL of CoronaVac in two doses 28 d apart. The dosage of TURKOVAC and CoronaVac vaccines for this study was 3 μg/0.5 mL for each. The study protocol was published elsewhereCitation5 and approved by the Clinical Research Ethics Board of Hacettepe University (No: KA-21070 and Date: 21 June 2021). Informed consent was obtained from all volunteers involved in the study.
The history of past COVID-19 infection was evaluated and confirmed from the medical histories, patient records, and anti-spike antibody positivity results.
The SARS-CoV-2 IgG spike assessments were done using Abbott SARS-CoV-2 IgG II Quant analysis, a chemiluminescence microparticle immunological assay (CMIA) that detects IgG antibodies against SARS-CoV-2 in human serum and plasma qualitatively and quantitatively on an ARCHITECT i System. This assay is also used to evaluate the immunity of individuals by determining the IgG antibodies against the spike receptor-binding domain (RBD) of SARS-CoV-2 quantitatively. The cutoff for this test is 50.0 AU/mL, and values lower than this threshold are considered negative, whereas values equal to or higher than this limit are considered positive results.
The primary outcome of this study was evaluating the impact of previous COVID-19 disease before the first dose of inactive COVID-19 vaccines on post-vaccine local and systemic adverse effects. Secondary outcomes evaluated the progression and the type of adverse events in demographic subgroups after the second vaccination dose. Since this is a secondary analysis of the original phase III study, all data were included in the current analyses. The adverse event assessment was a secondary objective, and the related endpoint was the incidence of adverse reactions within 7 d after each vaccination dose in that study.Citation5 Thus, our study evaluated the adverse events that progressed in the first 7 d after vaccine doses. An Interactive Voice Response System (IVRS) was used to monitor the adverse events at every visit, and both predefined symptoms (solicited events) and other patient-reported unspecified symptoms (unsolicited events) were recorded and analyzed.Citation5
Statistical analyses
Descriptive data for adverse events in subcategories were presented using frequency and percentages. Categorical data were compared between independent groups (adverse event positive vs. negative, and local vs. systemic adverse events) using the Chi-square test, or the Fisher’s exact test if assumptions for a Chi-square test were not met. A two-sided p-value <.05 (type-I error level of 5%) was considered statistically significant. All analyses were performed using the PASW Statistics for Windows, Version 18.0 (SPSS Inc., Chicago, IL, USA).
Results
A total of 1266 participants, 341 (27%) females and 925 (73%) males, were included in this study. Age distribution showed that 238 (18.8%) participants were between 18–29 y, 487 (38.5%) were between 30–39 y, and 541 (42.7%) were between 40–55 y. About 351 (27.7%) participants had a history of COVID-19 disease before the vaccine application. Local and systemic adverse events were observed in 37.3% and 39% of the study group, respectively. The rate of adverse events between the participants with and without a history of COVID-19 disease before vaccine application was similar (76.4%, both groups). When the adverse events were evaluated in sex groups, 48.4% and 49.5% of females and 33.5% and 35.4% of males with a positive COVID-19 history had local and systemic adverse events. Adverse event progression was significantly higher among females with previous COVID-19 (p = .043), but not in males (p = .58). When the adverse event progression was compared separately in patients with and without COVID-19 history, females had a significantly higher proportion of adverse events in both groups (p < .001) than males.
The proportions of local and systemic adverse events in age groups were 50.5% and 45.1% in 18–29 y, 38% and 48.8% in 30–39 y, and 27.5% and 25.2% in 40–55 y groups, respectively. In the 30–39-year-old age group, adverse events were significantly higher among individuals with a COVID-19 history (p = .013), but individuals without a COVID-19 history in the 40–55-year-old age group had significantly more adverse events (p < .001). When adverse event progression was evaluated in COVID-19 history subgroups, the 18–29-year-old age group had the highest adverse event proportions (p < .01, both groups). The distribution of adverse events in the study groups according to demographic characteristics is presented in .
Table 1. Adverse events in demographic subgroups of participants with and without COVID-19 disease history before the vaccine application.
The timing of adverse events in the study groups is summarized in . Although the proportion of local and systemic events was slightly higher in the first 30 minutes and 24 hours among the patients with a COVID-19 history, none were classified as severe adverse events. After the first 24 hours, local adverse events were slightly higher, and systemic adverse events were slightly lower in the patients with positive COVID-19 history in the first 3- and 7-d following vaccination; also, none were classified as severe adverse events.
Table 2. Timing of adverse events after first dose of TURKOVAC in participants with and without COVID-19 disease history.
1203 participants had a second dose of TURKOVAC or CoronaVac application, and 329 (27.3%) of them had a history of COVID-19. Among them, local and systemic adverse events were observed in 0.3% and 17.3%, respectively, which was also similar among participants without a COVID-19 history ().
Table 3. Adverse events after the second dose of COVID-19 vaccination in participants with and without COVID-19 disease history.
Local and systemic adverse events were similar in TURKOVAC and CoronaVac in the first 30 minutes after vaccine application (p = 1.0). After 30 minutes, the participants in the TURKOVAC group with a COVID-19 history had higher proportions of local and systemic adverse events (p < .001). However, participants without a COVID-19 history had more local adverse events after TURKOVAC (p < .001), whereas systemic adverse events were more observed after CoronaVac injection (p < .001). These differences were observed in the first 24 hours, 3 d, and 7 d after the applications of both vaccines. After the second dose of vaccine applications, local and systemic adverse events were similar between the TURKOVAC and CoronaVac groups regardless of the history ().
Table 4. Timing of adverse events in the TURKOVAC and CoronaVac groups with and without COVID-19 disease history.
Discussion
This study showed that confirmed COVID-19 infection before COVID-19 vaccination had no significant impact on the incidence and severity of the post-vaccine local and systemic adverse events associated with the TURKOVAC vaccine. The comparisons between participants with and without COVID-19 history revealed that 76.4% of both groups had any adverse events after vaccination. Additionally, local adverse events occurred 3.6% more, and systemic adverse events were 3.7% less in the positive COVID-19 history group, but the differences were not significant, and none were severe adverse events. The analyses in demographic subgroups also revealed similar outcomes in sex and age groups and between the comparative vaccine CoronaVac.
The recently published study by Tanriover et al.Citation5 reporting the interim results of the randomized, observer-blinded, non-inferiority phase III study for efficacy, immunogenicity, and safety of the two-dose schedules of TURKOVAC versus CoronaVac showed the safety and non-inferiority of the TURKOVAC and a relative risk reduction of 41.03% (95% CI 12.95–60.06) after 14 d of the second dose administration among healthy volunteers between 18–55 y old. The interim safety analyses were conducted in the modified intention-to-treat group including 915 participants who received at least one dose of the study vaccine, and total adverse events were higher in the TURKOVAC arm (58.8% vs. 49.7%, p = .004), which none of them were grade IV adverse events or deaths, 1 patient in the TURKOVAC arm had grade III and the remaining were either grade I or II adverse events.Citation5 The current study included the entire study population of 1266 participants and showed an equal proportion of adverse events in both study arms without a difference. On the other hand, the COVID-19 positivity before the second dose of COVID-19 vaccination was 27.3% in the present study. The previous phase III study by Tanriover et al.Citation5 reported that 375 cases had antibody positivity at baseline and were excluded from the study, and 59 patients out of 915 (modified intent-to-treat group) were diagnosed with COVID-19 before the second dose of vaccination. Although these patients were excluded from the modified per-protocol group, they were comparatively lower than that in the present study (6.5% vs. 27.3%) regarding the COVID-19 positivity before the second dose of COVID-19 vaccination.
Another recently published study by Omma et al.Citation14 evaluated the safety and immunogenicity of CoronaVac and TURKOVAC vaccines used as homologous booster dose after the second dose of CoronaVac primary vaccination. Authors reported that two vaccines were similar regarding the frequency of adverse events, which were 34.3% in the TURKOVAC arm and 24.6% in the CoronaVac arm (p = .11), and local and systemic adverse events were also similar in both booster vaccine groups. When our results regarding the similarity of adverse events after the second dose of vaccine administrations are considered, those results suggest that the safety profile of TURKOVAC is consistent over time after the post-booster administration of the vaccine.
The question about the impact of past COVID-19 history on the post-vaccine adverse events was raised during the development and administration of various vaccines. A literature search revealed that the majority of the studies that evaluated this concern was conducted for mRNA and viral vector vaccines. A previous cross-sectional study by Parés-Badell et al.Citation15 evaluated the local and systemic adverse events after administration of two mRNA vaccine types in 2879 healthcare workers and reported that adverse events were significantly higher for individuals with a history of COVID-19. Authors reported that 96% of participants with a history of COVID-19 related hospitalization, and 86% of participants with mild or moderate symptomatic COVID-19 had adverse events, whereas only 67% of individuals without a COVID-19 history had adverse events after two doses of mRNA vaccines. Another recent study by Bettinger et al.Citation16 evaluated the short-term safety of COVID-19 viral vector (Vaxzevria) and mRNA (Comirnaty, Spikevax) vaccines on 684,988 adults with a prior history of SARS-CoV-2 infection in the Canadian National Vaccine Safety Network, and reported that adverse events that impact daily activities or require medical assessment within 7 d after each vaccine dose were more likely in the presence of a previous COVID-19 history. Another nation-wide retrospective cohort study by Li et al.Citation17 evaluated the impact of previous microbiologically confirmed SAR-CoV-2 infection on hospitalization after mRNA vaccination and found an absolute risk increase about 1:1000 in individuals with a prior infection, but the risk was transient, hospitalizations were for a median of 2 d and patients returned to baseline health rapidly. A real-world safety and reactogenicity study by Mathioudakis et al.Citation11 also reported that prior COVID-19 infection was associated with increased risk of local or systemic adverse events after the first dose of mRNA or viral vector-based vaccine administrations and increased severity of any adverse events. This increased risk after the first-dose administration was also reported by Raw et al.Citation13 The difference between the first and second vaccine doses were evaluated in different studies and reported to be likely associated with the antibody response differences between seropositive and seronegative patients, in which IgG responses were significantly higher among seropositive patients at baseline.Citation18
Despite the mRNA or vector-based vaccines, there is a paucity of studies that evaluated the impact of the previous history of a SARS-CoV-2 infection on the adverse events after inactivated COVID-19 vaccines. The only study identified through a comprehensive literature search was by Lai et al.Citation19Authors evaluated the post-vaccination adverse events of special interest that were adapted from the WHO’s Global Advisory Committee on Vaccine Safety among individuals with or without previous SARS-CoV-2 infection and compared the outcomes between CoronaVac and Comirnaty recipients. Their results showed no significant difference in adverse events, emergency visits or hospitalization rates between patients with and without a previous COVID-19 infection in both CoronaVac and Comirnaty groups. The result of that study was similar to our results showing no significant impact of previous SARS-CoV-2 infection on the post-vaccination adverse events associated with inactivated COVID-19 vaccines.
In conclusion, this is the first study that evaluated the impact of previous COVID-19 infection on adverse events after vaccination with inactivated virus vaccine – TURKOVAC comparing with CoronaVac, which showed no significant impact of previous infection on the incidence and severity of the post-vaccine local and systemic adverse events associated with the TURKOVAC vaccine.
Author contributions
MDT, IA, and AK contributed to the conceptualization and methodology of the study. MDT, OAA, RG, OY, IC, SK, SA, EHA, SU, IA, AK, and the TURKOVAC Study Group contributed to the investigation of the study. MDT and SU contributed to the data curation. All in-line authors and the TURKOVAC Study Group contributed to the writing – review & editing of the Manuscript. MDT and SU conducted the project administration. All authors have read and agreed to the published version of the manuscript.
Acknowledgments
We are grateful to all the participants who have volunteered to be a part of this study and to all of the members of the clinical research teams of the participating sites. We thank the Health Institutes of Türkiye for funding the study and also the members of the DSMB for their contributions to the execution of this study safety.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
Proposals should be submitted to the sponsor, Health Institutes of Türkiye, who holds all the financial and intellectual rights of the study and the study vaccine TURKOVAC.
Additional information
Funding
References
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