Thread by @Neurophysik

My analysis of the paper released by #BharatBiotech researchers & the Press Statement by the Drugs Controller General of India (DCGI) on Restricted Emergency approval of 1out of 3 COVID-19 virus vaccine from Bharat Biotech: A thread...

1. PIB "The Phase III efficacy trial was initiated in India in 25,800 volunteers & till date, ~22,500 participants have been vaccinated across the country"

Fact check "A total of 25,800 subjects will be enrolled & randomized in a 1:1 ratio to receive BBV152B vaccine and control"

1. Fact check contd...

A 1:1 ratio means half of 25800 will be enrolled, of which only (almost) 12900 will be given BBV152B vaccine and the other 12900 will be given a placebo, i.e. Phosphate buffered saline PBS with Alum gel (without antigen)

Source: CTRI

In the preprint dated 22 December 2020, data suggests 380 randomised participants out of which one half received 3 µg doses & the other half, 6 µg doses.

Over 921 were screened but eliminated due to exclusion criterion. Thus, 190 per dosage group with additional placebo subjects

2. PIB: "...and the vaccine has been found to be safe as per the data available till date"

Fact check: Safety from Phase 1 trials

Local adverse reactions resolved in 24h:

After 1st dose 4·7% in 3 µg & 4·2% in 6 µg groups
After 2nd dose 2·6% in 3 µg & 3·2% in 6 µg groups

2. contd...

Safety from Phase 1 human trials:

Total adverse reactions including systemic reactions: 9·7% in 3 µg & 10.3% in 6 µg groups.

A total of 6 (28·6%) out of 21 unsolicited adverse events were reported to be related to the vaccine, out of which 1 was in placebo.

Safety from Phase 2 human trials:

TH-1 mediated Cytokines like interleukins, interferons, TNF alpha increase on day 56, 2 weeks after the 2nd dose. This is cell-mediated immunity & proinflammatory.

Last day accounted for: 104 days (3 mons) after the 2nd dose in Phase 1

Safety from Phase 2 human trials (contd.):

TH1 was largely TNF alpha + INF gamma, reported as the ration of TH1: TH2, i.e. cell-mediated: antibody-mediated. A balanced ratio suggests optimum vaccine efficacy. An imbalance may lead to autoimmune/allergy-like conditions.

Safety from Phase 2 human trials (contd.):

This does not mean there was an imbalance in the results. It means that TH1 was higher than TH2. Also, these cell-mediated responses were found similar to the studies conducted by Karolinska, Sweden

sciencedirect.com/science/articl…

So does this mean the #BharatBiotech vaccine demonstrates efficacy:

Efficacy is not just a serology test but also determined after exposure. There is no data to suggest efficacy as of 22 Dec based on phase 1 & 2 human trials in a total of 380 people who received vaccine doses.

Interesting to note that in Bharat Biotech data, serum (Human convalescent sera) reported higher neutralising antibodies in symptomatic patients as compared to asymptomatic. Serum taken after 30-60 days after diagnosis of COVID-19.

Also, no difference across age groups

More details on the news here by @sandygrains

https://twitter.com/sandygrains/status/1345387762464169984?s=20

Part 2.1: #Covishield vaccine tech transfer from AstraZeneca/Oxford vaccine (Oxford/AZ-ChAdOx1 nCoV-19)

PIB 1: "As 23,745 participant data from the overseas clinical study shows efficacy, SII granted permission to conduct Phase-II/III clinical trial on 1600 subjects in India"

Part 2.2: #Covishield FACT CHECK 1:

The 'overseas' data as listed by PIB was a combination of Brazil, South Africa & UK - recruited 23,848 in total. However, data from only 11,636 was included in the interim primary efficacy analysis.

@TheLancet review thelancet.com/journals/lance…

Part 2.3: Efficacy

PIB 2: Oxford vaccine has efficacy of 70.42%

Fact Check 2: After 2 std. doses, efficacy was 62·1% & those who received low dose after a standard dose, efficacy was 90·0%. Thus, overall efficacy across groups was 70·4% which can be tweaked to a high 90%

Part 2.4 How does #Covishield compare with AZ/ Oxford ?

PIB: SSI was granted permission to conduct Phase-II/III clinical trial on 1600 participants in India. The interim safety & immunogenicity data in this trial matched with the data from the overseas Oxford vaccine studies.

Part 2.4 contd..

CTRI updated on 8th & 26th Dec reported approval received for Phase II/III trials. However, ongoing recruitment for immunogenicity will be tested in only 400 participants randomly assigned in a 3:1
300 in COVISHIELD & 100 in AZ/ Oxford vaccine. (NOT 1600)

Part 2.5: What about the remaining 1200 in the #Covishield trial?

In 3:1 ratio, 1200 recruited in a safety study.
900 receiving Covishield & 300 receiving placebo.

Thus, 300 (comparison immunogenicity study) + 900 (from the safety study)= 1200 in total Covishield subjects

Part 2.6 Comparison of 1200 people vaccinated with Covishield (SII) with 4 months of follow-up in 11 636 participants is negligible. Especially, the immunogenicity comparison with a total of only 400 people.

More on AztraZeneca / Oxford efficacy here on @TheLancet

thelancet.com/journals/lance…

Vaccine number 3 by Cadila Healthcare: ZyCov-D

Permission for Phase-III clinical trial in 26,000 Indians granted to ZyCov-D vaccine based on DNA. They are also researching pegylated Interferon-alpha & heat-killed TB bacteria in COVID-19 patients

Thread # 3...

Part 3.1 #cadila

Based only on 1048 participant data of phase 1+2, Cadila got the permission to conduct Phase-III clinical trial in 26000 Indian participants.

If phase I & II had 1048 people & half were in placebo, only about 524 people would have received the vaccine.

3.2 Cadila vaccine is based on a different intradermal administration of the recombinant DNA, unlike the other vaccines. No data is available for safety, efficacy or immunogenicity for this vaccine.

The question remains how does data from <1k get approved for phase III.

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More on 'news' around the three vaccines by @AnooBhu

https://twitter.com/AnooBhu/status/1345606299438837760?s=20