RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
The authors used the term “post rapid approval,” which is technically incorrect. The accepted term is Emergency Use Authorization (EUA).
The authors’ mention of rapid mass vaccination with an effective vaccine as the only lasting solution is not entirely correct. Along with vaccination, COVID-19 appropriate behavior such as hand hygiene, masks, and social distancing are detrimental factors in controlling the pandemic. The efficacy of vaccines granted EUL by WHO varies from 51 – 95 % against the original Wuhan strain of SARS-CoV-2. The efficacy of the vaccines has reduced further with the emergence of newer highly variants like Alpha, Beta, and Delta variants. Hence COVID-19 appropriate behavior and vaccination remains the most effective measure to control the pandemic.
Covishield is a non-replicating viral vector-based vaccine and has not been developed by Serum Institute of India (SII). SII only produces the vaccine developed by Oxford University in Collaboration with AstraZeneca firm.
The authors arrive at the efficacy of vaccines by analyzing the number of symptomatic RTPCR cases in the vaccine arm compared to the placebo arm during phase 3 clinical trials. The efficacy of Oxford vaccine and Covaxin is 70.4 % and 77.8 % based on the analysis of data from Phase 3 clinical trials1,2 The seroconversion rate of Covishield (first dose - 91% and second dose - 100%) and Covaxin (98.3% after 56 days post-vaccination) is not same as the efficacy of the vaccines. Likely, recipients of vaccines with seroconversion may still not be protected if titers of antibodies are low or Neutralizing antibodies (Nabs) have not developed at titers that are required to be protective against COVID-19.
The authors’ claim of this article being the first study of the Clinical profile of COVID-19 illness in post-vaccinated individuals is not entirely correct7.
Material and methods
There is no mention of approval of the ethics committee taken by the authors for this study.
The period of study is mentioned from April 2021 to May 2021. It is advisable to mention the exact dates of the start and end time points.
The inclusion criteria are very vague. Breakthrough infections post-vaccination are defined as two weeks after administration of the second dose3. The interval between the first and second doses of Covishield has been modified multiple times (from 4 weeks to 16 weeks), whereas the interval for Covaxin has remained 4 weeks. This data has not been provided/collected in the study, which is a limitation of the study.
Rapid antigen test (RAT) has very high specificity but poor sensitivity4. Therefore, the use of RAT to diagnose SARS-CoV-2 is likely to miss a considerable number of cases which is a limitation of the study.
It is not clear that The study participants did oxygen saturation by pulse oximeter at home or in a health care facility. Suppose it was carried out at home by the participants. In that case, it introduces a major bias because of the validation/standardization of the pulse oximeter and technique used, as this will introduce a bias in the study.
The criteria defined by the authors for post-vaccination COVID-19 infection (confirmed COVID-19 positive who has taken at least one dose of the vaccine four weeks before having covid-19 infection) is arbitrary. The defined criteria for breakthrough infection post-vaccination is individuals developing infection two weeks after full immunization (completing both doses)3.
The inclusion of subjects who developed COVID-19 less than four weeks after the first dose of vaccination in the comparative arm is fallacious. Some degree of protection is offered by even one dose of vaccination. The comparative arm should have been age-matched unvaccinated subjects who developed COVID-19 infection during the study period.
The reason for dividing the study population into five groups is not understood.
The authors have mentioned that 33 (19.6%) in the study population and 16 (38.1%) subjects in the comparative group had at least one comorbid condition. No details of the comorbid condition have been provided in table 1. The type of comorbid condition is important as the risk of infection and severity of the disease increases in certain conditions.5
In table 2, ten (6%) of the study population developed Covid-19 after the first dose. As mentioned earlier, infections occurring less than two weeks after the second dose cannot be considered breakthrough cases.
The percentage of symptomatic subjects in the study population was (76.8%) whereas it was 69% in the comparative group. This higher incidence of symptomatic patients in the fully vaccinated group compared to the comparative group who were not fully vaccinated is contrary to the studies that demonstrate fewer symptomatic patients in the fully vaccinated group.6
The significance of classifying coughs as dry and productive is not understood. The respiratory rate, which is a better marker of the disease severity in COVID-19, has not been included in the clinical profile of subjects.
The recommended cut-off values of Spo2 for classification of disease severity are >94%, 90 to < 93%, and < 90%; however, authors in Table 3 have defined Spo2 levels not as per the recommended guidelines.
The spectrum of gastrointestinal symptoms has not been mentioned in table 3.
It is advisable that authors have at least assayed the antibody levels in the subjects to get a more realistic picture and strengthen the study.
The authors have mentioned that mass vaccination, the only viable strategy to mitigate viral pandemics, is not entirely true. The surveillance measures, contact tracing, appropriate behavioral changes in society, and development of antivirals are adjuncts to mitigate viral pandemics rather than just relying on mass vaccination.
It is a well-known fact that fully vaccinated subjects (two doses) more commonly have mild/asymptomatic COVID-19 infections than partially vaccinated (one dose) subjects who have higher chances of developing moderate/severe disease6. This is due to the level of humoral and CMI response generated by the vaccines.
The authors need to mention the limitations of the study in the manuscript.
Raches Ella, Siddarth Reddy, William Blackwelder, Varsha Potdar,
Pragya Yadav, et al. Efficacy, safety, and lot to lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): a double-blind, randomised, controlled phase 3 trial. medRxiv 2021.06.30.21259439;
Voysey M, Clemens SAC, Madhi SA et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99-111. doi: 10.1016/S0140-6736(20)32661-1. Epub 2020 Dec 8. Erratum in: Lancet. 2021 Jan 9;397(10269):98. PMID: 33306989; PMCID: PMC7723445.
A. Fernandez-Montero et al., Validation of a rapid antigen test as a screening tool for SARS-CoV-2 infection in asymptomatic populations. Sensitivity, specificity and predictive values, EClinicalMedicine (2021), https://doi.org/10.1016/j. eclinm.2021.100954
M.G. Thompson, J.L. Burgess, A.L. Naleway, H. Tyner, et al. Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines. June 30, 2021 NEJM. DOI: 10.1056/NEJMoa2107058
V K M Niyas, R Arjun, Breakthrough COVID-19 infections among health care workers after two doses of ChAdOx1 nCoV-19 vaccine, QJM: An International Journal of Medicine, 2021;, hcab167, DOI: https://doi.org/10.1093/qjmed/hcab167