Thread by @das_seed

A short note on dosing regimen of COVISHIELD for complete vaccination.

We've 3 different set of trials:

1. UK/Brazil trials
This trial was open-label, w/ scandalous error in dosing regimen ("half-dose" error), had multiple major amendments in protocol when trial was undergoing

w/ minimum gap b/w 2 doses set to be 4 weeks.

COVISHIELD was initially supposed to be a single dose vaccine, but in middle of trial they realized that booster dose was required for higher efficacy compared to just single dose.

In the process, due to mfg/supply delay, intended

interval of 4 weeks was not achieved & got prolonged.

Attached are intended & extrapolated sub-group analysis that was carried out by PIs as part of protocol, w/ different dosing levels & intervals.

*extrapolated analyses were not part of protocol hypothesis but in response to

the editors/referees.

Extrapolatory analysis can often be statistical gymnastics where you beat the data to extent that it gives inferences confirming your bias.

No one bought half & full dose combo despite it showing better efficacy since it was not part of actual hypothesis.

The median interval between doses for the SD/SD group in COV002 was 69 days, i.e., 9.85 weeks (CI: 50–86, i.e, approx b/w 7 weeks to 12 weeks). Conversely, the majority of participants in COV003 in the SD/SD group (2493 (61·0%) of 4088) received a 2nd dose w/in 6 weeks of 1st.

Efficacy estimates from EMA, EU Commission for assessment of COVISHIELD was done with standard dosing regimen w/ 4 to 12 weeks as interval b/w 2 full doses.

2. India trial: This was bridging studies for safety & immunogenicity among Indian population

and to compare equivalence of COVISHIELD w/ Vaxzevria.

Condition for regulatory authorization/approval is based on efficacy analysis from large RCTs abroad, while also taking consideration of safety signals from these trials.

Dosing schedule for Indian trial was two full doses

w/ interval of 4 weeks.

However, immunogenicity analysis was done at prematurely (against description of protocol). Even safety analysis have issues. Timeline & details of some important events regarding this are mentioned in thread attached.

3. US trial: Double-blind, large RCT w/ two standard doses at gap of fixed 4 weeks (28 days).

Trial results announced via press release was 76% efficacy against symptomatic COVID19 disease. It's more than efficacy from UK/Brazil trial for 2 std doses.

It's CRITICAL to note that proper verification on efficacy of a vaccine initially comes from a well-blinded sufficiently large-sized randomized control trials. Real-world data acts as supporting evidences.

Real-world data have limitations because there can be number of factors

that could have major role compared to vaccine in outcomes we see from real-world data. [RECOVERY trials are great example to know why RCTs are important than assertions based on real-world data].

Now we can turn around discussion to current dosing interval in India.

We have revised interval (gap) b/w 2 doses of COVISHIELD to 12 to 16 weeks based on extrapolatory sub-group analysis of UK/Brazil trial data, results published online on 8 December 2020 (last year).

Pics of recommendation from @WHO during Feb '21.

There's no proper real-world data from UK/India/EEA for dosing interval greater than 12 weeks (12-16 weeks) yet, because authorizations were w/ gap between 4 to 12 weeks in these nations. Only India extended the gap to 12 to 16 weeks, while UK reduced the gap to 4 to 8 weeks for

priority groups (50+ years and clinically vulnerable) amid real-world data showing concerning decrease in effectiveness against B.1.167.2 strains, 1st identified in India.

India will have to collect it's own real-world data for 12 to 16 weeks to perform

statistical gymnastics.

COVID19 vaccines does provide some level of protection. What NTAGI COVID19 vaccine committee & NEGVAC should do is to prioritize two doses at interval of minimum 4 weeks for priority group (based on risk factor: age, clinical, occupation) so that they get

better protection than just from single dose (which seems to be too low against B.1.167.2 strains).

For non-vulnerable group w/ comparatively low risk factors, it would be better if all these vaccines are for now diverted to those w/ high risks.

NEGAV should consider

differential dosing intervals based on risk/vulnerability of group.

There needs to be complete transparency over assessment & rationale behind decisions. We cannot hype or underplay efficacy & safety factors of vaccines. Need balance w/ facts.