key: cord-0821936-am7olu9z
authors: Ramasamy, Maheshi N; Jessop, Lucy J
title: CoronaVac: more data for regulators and policy makers
date: 2021-07-08
journal: Lancet
DOI: 10.1016/s0140-6736(21)01543-9
sha: 8810f745566deacbcc0a3b0234046cab56c54a59
doc_id: 821936
cord_uid: am7olu9z

nan

CoronaVac: more data for regulators and policy makers As of July, 2021, almost 3 billion doses of COVID-19 vaccines have been administered globally. 1 However, there remains an urgent need to broaden access to safe and effective COVID-19 vaccines, especially in low-income and middle-income countries experiencing surges in SARS-CoV-2 infections. Inactivated viral vaccines are an established technology and have several advantages for large-scale roll-out, including their stability at normal refrigeration temperatures and their long shelf-life. 2 Several inactivated SARS-CoV-2 candidate vaccines are in phase 3/4 trials, and two have received WHO emergency use authorisation: CoronaVac (developed by Sinovac Life Sciences, Beijing, China) and BBIBP-CorV (Sinopharm, Beijing, China). 3 In The Lancet, Mine Durusu Tanriover and colleagues 4 present the interim results of a double-blind, randomised, controlled trial of CoronaVac versus placebo in Turkey. Adults aged 18-59 years who were seronegative and RT-PCR-negative for SARS-CoV-2 infection received two doses of CoronaVac (3 μg β-propiolactoneinactivated SARS-CoV-2 in 0·5 mL aqueous suspension with 0·45 mg/mL aluminium) or placebo (containing all the ingredients except the inactivated virus) with a 14-day interval between doses. The intention-to-treat population (n=10 214) consisted of 5907 (57·8%) men, 4307 (42·2%) women, 3675 (36·0%) health-care workers, and 1463 (15·6%) participants with a body-mass index of greater than or equal to 30 kg/m², with an overall median age of 45 years (IQR 37-51).

The primary, per protocol analysis of vaccine efficacy included 10 029 participants who received two doses of vaccine (n=6559) or placebo (n=3470). The primary outcome was the incidence rate of PCR-confirmed symptomatic COVID-19 occurring later than 14 days after the second dose, of which 41 cases were reported. Nine of these cases were in the CoronaVac group (incidence rate 31·7 cases [95% CI 14·6-59·3] per 1000 person-years) and 32 were in the placebo group (192·3 cases [135·7-261·1] per 1000 person-years), giving a vaccine efficacy of 83·5% (95% CI 65·4-92·1; p<0·0001). Six participants were hospitalised with COVID-19, all in the placebo group.

Adverse events (analysed in the intention-to-treat population) were reported in 1259 (18·9%) CoronaVac recipients and 603 (16·9%) placebo recipients. Injection site pain and fatigue were the most commonly reported local and systemic adverse events, respectively, and both were more common in the vaccine group and were mostly of grade 2 severity or less. 11 participants (six [0·1%] in the vaccine group and five [0·1%] in the placebo group) had serious adverse events, of which one event (a severe allergic reaction) was judged to be related to the vaccine.

Immunogenicity analyses were done in a subset of participants (n=1413) at 14 days after the second dose. Seroconversion was measured with use of a commercial ELISA-based assay to detect IgG and IgM antibodies specific for the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, and was observed in 880 (89·7%) of 981 vaccine recipients and 19 (4·4%) of 432 placebo recipients (with seropositivity in the placebo group presumed to be due to SARS-CoV-2 infection). An in-house, live virus neutralisation assay showed that 356 (92·0%) of 387 seropositive participants had also developed detectable levels of neutralising antibodies (mean antibody titres of ≥1/15).

Tanriover and colleagues' findings suggest that two doses of CoronaVac have robust efficacy (within the WHO target product profile for SARS-CoV-2 vaccines) 5 and acceptable tolerability when administered with a 14-day interval. CoronaVac is also available as singledose vials, which improves ease of administration and reduces wastage.

Strengths of the study include the large sample, robust mechanisms of capturing symptomatic COVID-19 outcomes using weekly automated telephone questionnaires, and the double-blind design. One limitation of the study was the early censoring of the efficacy analysis due to the emergency use authorisation of the vaccine in Turkey, granted as a result of rising local case numbers. In addition, the median followup period was short, at only 43 days (IQR 36-48). Participants in the study were relatively young and had few comorbidities, limiting the ability to infer vaccine efficacy in people more susceptible to severe COVID-19. However, previous published data suggest that immune responses elicited by CoronaVac are similar in adults aged 18-59 years and 60 years and older. 6 No viral sequencing data were presented and, although it can be assumed that a proportion of the cases in the study timeframe (September, 2020, to January, 2021) were caused by SARS-CoV-2 lineage B.1.1.7 (the alpha variant of concern), no conclusions can be drawn about the efficacy of CoronaVac against different SARS-CoV-2 lineages. Notably, the preliminary results of the CoronaVac phase 3 trial in Brazil showed vaccine efficacy of 50·7% (95% CI 35·9 to 62·0%) against symptomatic disease when SARS-CoV-2 lineage P.2 (the zeta variant) was the predominant circulating lineage, 7 and a test-negative case-control study done during a period of SARS-CoV-2 lineage P.1 (gamma variant) dominance estimated vaccine effectiveness at 36·8% (-54·9 to 74·2). 8 The anti-RBD antibody results presented by Tanriover and colleagues 4 were non-quantitative. Although an immune correlate of protection for COVID-19 remains to be determined, absolute antibody titres at multiple timepoints alongside a benchmark of convalescent serum or WHO serum standard would have allowed the comparison of immunogenicity with other vaccine candidates. A phase 1/2 study of CoronaVac 9 showed lower antibody titres after a single dose than after two doses, which could explain the low efficacy of 46·4% (95% CI 0·4-71·2) observed 14-27 days after the first dose of vaccine in the current study. These data reinforce the need for two doses of CoronaVac for adequate protection.

During the COVID-19 pandemic, clinical trials have been done at pace with rolling regulatory reviews as manufacturers strive to produce safe and effective vaccines. Competent authorities face the dilemma between waiting for phase 3 efficacy data to support regulatory approval and the urgent need to vaccinate vulnerable populations, as occurred in Turkey during this trial. Reduction in disease prevalence through vaccine deployment coupled with non-pharmacological interventions can itself impair the assessment of vaccine efficacy. China is reported to have approved CoronaVac for vaccination of high-risk groups in June, 2020, 9 after phase 1/2 data showed that the vaccine was well tolerated and immunogenic; 10 however, few local effectiveness data are available because of the low incidence of COVID-19. 11 Countries with a high incidence of disease, including Indonesia, Brazil, and Chile, authorised CoronaVac for emergency use in early 2021 and have subsequently generated interim efficacy data from phase 3 trials 7,8 as well as post-authorisation passive safety surveillance data, which have contributed to the WHO authorisation. 12 Peerreviewed publication of phase 3 results such as these are vital to strengthen public confidence and inform policy decisions on the introduction and use of novel vaccines.

As countries open their economies and restart international travel, digital proof of vaccination and mutual recognition of vaccines will become increasingly important. Open access to data on vaccines yet to be adopted locally will help to inform countries on whether to accept travellers who have received these vaccines. 13, 14 The recent WHO recommendation for use of CoronaVac, 3 which is currently approved in 32 countries, could also facilitate free, safe movement of vaccinated individuals.

Tanriover and colleagues' study 4 suggests that CoronaVac is another useful tool in the global fight against COVID-19, although more data are needed on its efficacy against emerging SARS-CoV-2 variants and on its duration of protection across different age groups and geographical settings and in the presence of comorbidities. The results of ongoing effectiveness studies (NCT04747821 and NCT04789356) and immunogenicity studies (NCT04756830 and NCT04775069) are keenly awaited.

MNR is a principal investigator on the AstraZeneca COVID-19 vaccine trials at the Oxford Vaccine Group but does not receive any personal fees or grants from any pharmaceutical companies. LJJ is the director of public health for the National Immunisation Office in the Health Service Executive, Dublin, Ireland, and is responsible for the coordination of national immunisation programmes. The views expressed are those of the authors and do not necessarily represent the views of the University of Oxford or the Health Service Executive. 

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