SII’s Phase 2/3 bridging trial results finally out, says Covishield comparable to AstraZeneca vaccine
Central Drugs Standard Control Organisation asked SII in June 2021 to update the India-specific safety analysis on the website, but the company is yet to do so
Serum Institute of India’s Covishield has a ‘non-inferior’ immune response compared to the Oxford AstraZeneca vaccine, says the pre-print paper of the crucial Phase 2/3 immuno-bridging study trials. Covishield was manufactured in India after technology transfer from AstraZeneca.
Published more than seven months after the Indian government approved Covishield on January 3, 2021, the paper states that there were 34 cases of SARS-CoV-2 infections reported in the 1,600 participants during the study. The interim-results of the bridging study were first published by the Canada in July 2021.
When Covishield vaccine got the emergency use authorisation, the bridging study had not yet been completed. The last participant got the last dose on Dec 8, 2020, but SII had submitted emergency authorisation application on Dec 6, 2020 itself. The application was based on the safety data till November 14, 2020. The day 57 visit for the last participant was completed on January 15, 2021 and the study completed on June 6, 2021.
All India Drug Action Network (AIDAN) had sent repeated letters to the members in National Expert Group on Vaccine Administration for COVID-19 expressing concern about the timing of SII’s application for emergency approval because as per the timelines and criteria set out for interim analyses in the clinical trial protocol, the data for immunogenicity and safety was not available for Phase 3 participants before January 2, 2021. The Network had requested for specific data on the vaccine based on which the approval was granted in India.
The recently-released paper has not been peer reviewed and no public health experts have released any critiques of it. The main goal of this study was to compare the safety and immunogenicity of Covishield with AstraZeneca. Immunogenicity is the measurable immune response triggered by any vaccine.
The study, which was released on August 9, 2021, claimed that 98% of those who got both doses of Covishield developed immune response, while 98.9% of the participants who got two doses of AstraZeneca developed an immune response. The study observed anti-spike IgG geometric mean titres (GMTs) of 30 245·6 AU/mL (95% CI 26 794·0–34 141·8) for Covishield and 28 558·3 AU/mL (23 479·3–34 735·8) for AstraZeneca.
This assumes importance because Covishield has not yet been authorised by the European Medicines Agency or the new EU digital Covid certificate vaccine passport scheme, which facilitates travel for EU member states. As of August 30, 2021, India was still not on the list of countries from which non-essential travelers could fly to EU member states. EU member states still consider Covishield as not corresponding to AstraZeneca, which was granted authorisation for travel waiver
Phase 2/3 bridging study
In this observer-blind, randomised, controlled study, there were 1,600 participants, of which 401 were in the immunogenicity cohort, where they were randomly assigned in a 3:1 ratio to receive either Covishield or a placebo. The remaining 1,200 participants were randomly assigned in a 3:1 ratio to receive either Covishield or a placebo, respectively.
Of the 1,600 participants who enrolled and received at least one dose of vaccine/placebo, 21 withdrew consent, one was withdrawn from the Covishield group by the investigator due to an unrelated neurological severe adverse event of encephalopathy and one was withdrawn by the investigator from the placebo group due to an unrelated adverse event of hypertension.
The remaining 1,577 participants received the second dose. The day 57 visit for the last participant was completed on January 15, 2021. All participants completed study follow-up up to 180 days, stated the paper.
The study claims that one month after the first dose (day 29), antibody titres (amount of antibodies in the body) were greater than 6,600 AU/mL in both groups, and 1 month after the second dose, the GMTs were greater than 28,500 AU/mL in both groups. There was more than 325-fold rise in antibody titres in both groups. The ratio of two geometric mean titres for anti-S IgG antibodies between Covishield and AstraZeneca was 0·98 as against the expected 1. This means that Covishield was almost identical to AstraZeneca in performance.
In previous trials of AstraZeneca, the study stated, the vaccine showed substantial T-cell immune responses that peaked two weeks after the first dose. Similarly, the present study claimed that T-cell immune responses were seen in both the Covishield and AstraZeneca.
However, the study only stated in passing that Covishield triggers long-term cell memory, but it doesn’t show how much protection it offered, which is what is important, underscored an epidemiologist, who did not want to be named.
One of the facets of our immune system is antibody-protection, but there are several other cell lines involved in our immunological response to microbes. They include B-Cells and T-Cells, some with short memory and other with long-term memory (T-cell).
Severe adverse events
The study claimed that among all 1,600 participants who received a first dose, a total of 19 serious adverse events in 19 (1·2%) participants were reported. Of these, 15 had received Covishield, two had been administered AstraZeneca and two the placebo. The adverse events included fracture, malaria, megaloblastic anaemia, encephalopathy, cataract and vocal chord cyst.
According to the paper, there were no thromboembolic-associated or autoimmune-related SAEs. Overall, 330 (20·6%) participants reported a total of 493 AEs (464 mild, 26 moderate and 3 severe) after the first dose and 185 (11·7%) participants reported 238 AEs (228
mild, 9 moderate and 1 severe) after the second dose.
Among the 1200 participants in the safety cohort, 373 (31·1%) reported 630 unsolicited adverse events, including 301 (33·4%) participants reporting 529 events in the Covishield group, 72 participants reporting participants reporting 101 events in the placebo group.
Solicited AEs are pre-defined and systematic AEs that are known to be associated with immunisation. Unsolicited AEs are anything other than these pre-defined symptoms. The Covishield protocol stated that the solicited AEs were pain, redness, itch, fever, chills, malaise, fatigue, headache, nausea, and arthralgia (joint pains).
There were 34 cases of SARS-CoV-2 infections reported in the 1600 participants during the study period, of which 22 had been administered Covishield, two AstraZeneca and 10 in the placebo group.
Eighteen reportedly tested positive for Covis-19 after the first dose and 16 after the second dose. None of them were severe, and there were no deaths reported in the study.
Of these 34 Covid-19 cases, six occurred more than two weeks after the second dose and by day 57. Four of these participants were symptomatic and two were asymptomatic. Among these four symptomatic COVID-19 cases, one participant each in the Covishield and placebo groups had to be hospitalised at 21 and 41 days after the second dose respectively.
As of July 2021, more than 500 million doses of SII-ChAdOx1 nCoV-19 have been distributed globally. Together, including AstraZeneca and other sub-licence partners, more than 1 billion doses have been distributed to 170 countries.
However, SII has not released the trial protocol, which includes information about the bridging trial, plan to handle adverse events, regulatory requirements, objectives and endpoints of the study. It became public knowledge when US-based STAT news, which covers health, medicine, and the life sciences, disclosed the draft version of the trial protocol.
The interim-results of the bridging study have been available on the Canadian Health website since July 2021. It included the summary of the safety reports available for Covishield based on pharmacovigilance activities conducted by SII. The website had also put out the last safety and immunogenicity Report 5 dated April 1, 2021.
The Indian regulator - Central Drugs Standard Control Organisation (CDSCO) – is yet to put up the details of the bridging study. Even in the Subject Expert Committee (SEC) meeting held on June 22, 2021, the committee asked Serum Institute of India to update the India-specific safety analysis in separate section for further consideration. After detailed deliberation, the committee recommended revision of the factsheet of Covishield vaccine. More than two months after the meeting, the company is yet to do so.