Discussion
This interim analysis indicated that, in a population aged 18–59 years, CoronaVac had high efficacy for preventing symptomatic COVID-19 (83·5% relative to placebo) and COVID-19-related hospitalisation (100%) at least 14 days after the second dose. Efficacy in subgroups was not a secondary outcome and the trial was not designed or powered to analyse the efficacy of the vaccine with regard to demographic variables and risk factors. Such analyses will require further trials designed accordingly. Anti-RBD antibodies developed in 89·7% of volunteers in a subset of our study sample, and 92·0% of those who were seropositive also produced protective levels of neutralising antibodies at least 14 days after the second dose of vaccine.
Inactivated SARS-CoV-2 vaccine candidates have shown promising results in preclinical trials.
13,
14,
15Gao and colleagues
13showed that, in mice, rats, and rhesus monkeys, 6 μg CoronaVac induced SARS-CoV-2-specific neutralising antibodies that effectively neutralised ten representative SARS-CoV-2 strains and provided complete protection against SARS-CoV-2 challenge in non-human primates. BBV152 (manufactured by Bharat Biotech), another inactivated vaccine, generated a quick and robust immune response with no histopathological changes in the lungs upon SARS-CoV-2 challenge in animal studies, provided adequate protection against SARS-CoV-2 infection in rhesus monkeys, induced T-helper-1 cell-skewed immune responses with elevated IgG2a/IgG1 ratios, and increased levels of SARS-CoV-2-specific IFNγ+CD4+ T-lymphocyte responses.
15,
16A phase 1 trial also revealed moderate seroconversion rates that persisted for up to 3 months after the second dose.
17,
18The immune response elucidated with inactivated vaccines is not confined just to the spike protein but rather to other SARS-CoV-2 proteins—the matrix proteins, envelope proteins, and nucleoprotein—which theoretically could be reflected as a vast array of immunogenic responses.
6,
7Voss and colleagues
19 showed that, in people previously infected with SARS-CoV-2, the plasma IgG response against SARS-CoV-2 was oligoclonal and more than 80% of spike protein IgG antibodies were directed towards non-RBD epitopes in the spike protein. This finding indicates that non-RBD-directed antibodies might have a role in protection against SARS-CoV-2 infection.
Phase 1/2 trials of CoronaVac in volunteers aged 18–59 years and older than 60 years showed that the vaccine doses and schedules investigated (3 μg or 6 μg, applied 14 days or 28 days apart) all had similar safety and immunogenicity profiles.
20,
21Considering the production capacity and emergent need for vaccines, the 3 μg dose of CoronaVac has been suggested for efficacy assessment.
20Palacios and colleagues
22reported an overall efficacy of CoronaVac against symptomatic COVID-19 of 50·7% (95% CI 36·0–62·0) 14 days or more after the second dose; however, the efficacy in preventing the need for assistance (defined as a score ≥3 on the WHO Clinical Progression Scale) was 83·7% (58·0–93·7) and efficacy against moderate and severe cases was 100% (56·4–100·0). In a subset of participants, neutralising antibody assays showed that there were no significant differences in the frequency of seroconversion or geometric mean titres of neutralising antibodies against the B.1.128 variant compared with those against the P.1 and P.2 variants. The study cohort only included health-care workers actively working with COVID-19 patients, and a PCR-positive case with local symptoms (such as sore throat, nasal congestion, or rhinorrhoea) was considered as a failure of the vaccine, thus indicating that the vaccine might confer lower protection against asymptomatic or mildly symptomatic cases. The interim report of the phase 3 trial in Chile with a subset of 434 health-care workers, including those aged 60 years or older, revealed high seroconversion rates for specific anti-S1-RBD IgG and neutralising antibodies, along with a robust T-cell response.
23The interim phase 3 results of other COVID-19 vaccines have shown efficacies ranging from 62·1% to 95%.
24,
25,
26,
27,
28Higher and more rapidly established efficacies were observed with mRNA-based vaccines.
25,
26 Considering the immunogenic mechanisms of inactivated vaccines, because one dose is not expected to be as efficacious as two doses, we did not expect to and could not show an early protective effect after the first dose, in contrast to findings with mRNA vaccines.
The tolerability of CoronaVac in this study was excellent and the incidence of adverse events, most of which were solicited systemic events, was low. The majority of the adverse events were grade 1 and occurred within 7 days after the injection. No grade 4 adverse events were observed and there was only one adverse event (an allergic reaction) that required hospitalisation.
The targeted sample size could not be reached because CoronaVac was granted emergency use authorisation by the Turkish Ministry of Health while the study recruitment was ongoing, and an immediate vaccination programme was initiated for health-care workers and later for the general public in Turkey. To comply with ethical standards, recruitment was closed earlier than planned and the placebo recipients were offered vaccines, depending on their vaccination priority.
The strengths of this study include the low dropout rate, reflecting the good tolerability of the vaccine. Additionally, the participants were from different risk groups and occupations, rendering the results of the study more generalisable to the real-world context. Additionally, active symptom surveillance was pursued to detect COVID-19 cases.
This study also has several limitations. First, the median follow-up period after randomisation to the date of unmasking was 43 days (IQR 36–48), which is a very short duration of follow-up. It is not possible to comment on the long-term protective effects of the two-dose immunisation schedule with this interim analysis.
Second, one should bear in mind that the study population consisted of relatively young (median age 45 years [37–51]) and healthy individuals with a low prevalence of chronic diseases, and the overall event rate was very low. Therefore, the generalisability of the findings of this interim analysis needs to be evaluated cautiously. In particular, the number of patients hospitalised with COVID-19 was quite low and the study population consisted of individuals at relatively low risk of severe or critical COVID-19, restricting our ability to make generalised conclusions about severe disease.
Third, the study used a 14-day interval immunisation scheme, whereas the community immunisation was with a 28-day interval. It has been claimed that, although 28-day immunisation schemes elucidated better immunogenicity after the second dose, longer intervals between the two doses are correlated with a higher probability of contracting COVID-19 before getting fully immunised and a great chance of emergence of mutant variants that can replicate in the setting of suboptimal levels of neutralising antibodies.
29As our results pertain to the data before the emergence of variants of concern, we cannot comment on the efficacy of CoronaVac on the prevention of infection with mutant viruses. Although one of the prespecified outcomes was seroconversion, we have avoided using this term in our reporting of the results because the immunoassay we used was a semiquantitative assay. In fact, all of the participants were seronegative at the time of screening; therefore, the seropositivity 14 days after the second dose of vaccine would indicate seroconversion. However, we could not exclude the possibility that some samples with antibody levels below a sample-to-cutoff ratio of 1 might have very low concentrations of established antibodies. The current report neither involves data on the sequential serum neutralising antibody titres nor the magnitude of T-cell responses or the duration of protectivity. However, a study setting has been established to analyse the proliferation and functional capacity of CD4+ and CD8+ T cells, and the results of an initial study in a group of COVID-19 survivors have been reported by Tavukcuoglu and colleagues.
30 This setting is now being used to analyse the samples from selected participants of this trial to show the functional capacity of T cells induced by CoronaVac to reinvigorate antiviral immunity against SARS-CoV-2.
In summary, our results show that CoronaVac has good efficacy against symptomatic SARS-CoV-2 infection and severe COVID-19 (ie, that requiring hospitalisation), along with a very good safety profile in a population aged 18–59 years. Because this analysis included a very short follow-up period before the emergence of viral variants and included a young and low-risk population, further data are needed on the performance of CoronaVac to demonstrate the efficacy of the vaccine against the variants of concern and the duration of protection, and to assess the safety and efficacy in older adult populations, adolescents, and children, and individuals with specific chronic diseases.
Contributors
The principal investigators, SU and MA, conceptualised and coordinated the study. SU, MA, MDT, and HLD drafted the manuscript. SU, MA, MDT, and HLD accessed and verified the data and contributed to the analysis and interpretation of the data. SU, MA, MDT, and HLD edited the manuscript. All authors were involved in organisation, coordination, conduct, and technical support of the study; collected data; critically reviewed the manuscript and approved the final version; had full access to all data in the studies, and had final responsibility for the decision to submit for publication.
Data sharing
Anonymous participant data will be available upon completion of the clinical trial and publication of the completed study results upon request to the corresponding author. Proposals will be reviewed and approved by the sponsor, researchers, and staff, on the basis of scientific merit and absence of competing interests. Once the proposal has been approved, data can be transferred through a secure online platform after signing a data access agreement and a confidentiality agreement.
Declaration of interests
We declare no competing interests.
Acknowledgments
We are grateful to all participants who volunteered to be part of this study and to all members of the clinical research teams of the participating sites. We thank TUSEB for funding the study and Omega-CRO for the statistical analyses and production of figures, and providing the study protocol. We also thank the members of the data and safety monitoring board for their contributions in the safe execution of this study.