MHRA's (UK drug regulator) 57-page Public Assessment Report on Oxford/AstraZeneca vax is out:… Like Oxford's publication, does not mention phase 3 trials in US & India (& so its serious adverse event), so not clear this is a selective trial report... 1/n
...Quality assessment of the drug & manufacturing facilities based on manufacturer reports & certifications, not MHRA inspections. Presumably as with Tozinameran (BNT/Pfizer vax), this would be done by the European Medicines Agency (EMA)...2/n
...Independent Batch Testing for the vaccine is undertaken UK National Institute for Biological Standards and Control (NIBSC). Temperature requirements confirmed (does not need super-freezing) ...3/n
...A reproductive toxicology assessment is underway, results not yet available. Otherwise, they conclude there is enough pharmacological/preclinical data on this vaccine...4/n
...There is an unpublished study with "a finding of hepatitis in ferrets" but no further details are reported. (That doesn't mean it would happen in humans & the doses in animal studies are far higher than used in humans) ...5/n
...From the pooled data on immunogenicity, the MHRA concludes "these data suggest that the higher levels of immunogenicity engendered in the LDSD group are
influenced more by interval than by dose level"...6/n
... Primary efficacy analysis was symptomatic Covid-19 ("event") at least 15 days after the 2nd dose (same as for Moderna's vaccine; for Tozinameran (BNT/Pfizer) it was 7 days). There were 98 events for 2 "standard" doses (131 if you also count "low"-dose-first) ...7/n
...People were: 88% between 18 & 55 years; 83% white (4% Asian, 4% Black); 61% female; 36% had co-morbidities (20% rate of obesity). Overall vaccine efficacy: 70% (CI:55-81%), similar for people with co-morbidities - 73% (CI:49-86%). 62% for 2 standard doses (CI:40-76%) ...8/n
..."There is limited information available on efficacy in participants aged 65 or over, although there is nothing to suggest lack of protection." They say there was "a wide confidence interval" for this group but don't report it ...9/n
...Only 1 person with severe Covid-19: in the control group. (So again, not enough data - as with other trials, this wasn't a primary outcome.) Hospitalization: 5 people, control group only. Counting from dose 1, efficacy against hospitalization was 88% (CI:46-97%)...10/n
...In the UK study, they could also identify people with asymptomatic Covid-19 who had been negative for signs of previous infection at the start of the study. Counting both asymptomatic & symptomatic, vaccine efficacy was 57% (CI: 39-69%)(for 2 standard doses not reported)..11/n
... Vaccine efficacy from 1st dose was 73% (CI:49-86%) (2 standard doses not reported).

Subgroup analyses of dosing interval: they didn't report less than 8 wks. Confidence intervals wide for the ones they did report: 8-11 wks & over 11 wks. 8-11 wks similar to overall...12/n
...They basically bury the "low"-dose-first hypothesis ...13/n
...They pooled adverse events data across phase 1 to phase 3 trials, but 1 trial (South Africa) solicited fewer adverse events, did so for 6 days not 7, & didn't offer a "severe" grading option (grade 4)...14/n
...73% reported a systemic adverse event; 8.3% severe (vs 2.5% in control, which was usually another vaccine). The 1st doses had more & more severe adverse events (opposite to mRNA). Higher rate of severe systemic events than 18-65 yr-olds with the Moderna vaccine (3.2%)...15/n
...Rate of serious adverse events (SAE) <1%. 1 onset of MS most lesions probably pre-vax, 1 likely "short segment inflammatory myelitis": "presence or the absence of a causative association between the AZD1222 vaccine and these two cases cannot be concluded with
...They report that 2 SAEs were considered related by the investigator: fever of 40.5 (resolved in a day with acetaminophen), transverse myelitis (the same myelitis referred to above)... 17/n
...On balance: my concerns on trial quality not allayed. Vaccine efficacy for standard doses 60-70% depending on dosing interval in predominantly white 18-55 year olds, with wide confidence intervals. Apparently more & more severe adverse events than the mRNA vaccines. 18/18
...PS (always seems to be at least 1!): And there's still the proviso that the safety assessment for this vaccine excluded the completed Indian phase 3 trial & so it's not comprehensive for the vaccine.

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More from @hildabast

7 Jan
Some results from Brazilian phase 3 trial for Sinovac's inactivated Covid vaccine CoronaVac released at a press conference. Vaccine efficacy for mild symptomatic Covid-19: 78%, similar in people under & over 60 years. 0 moderate/severe/hospitalized... 1/n…
...For background: it's a trial in healthcare workers. The protocol was published here:… Collection of records on this vaccine here:… ....2/n
...Currently buying it from China, US$10 a dose: more than the Oxford vaccine ($3), half of Tozinameran (BNT/Pfizer). However supply of Oxford vax uncertain, whereas they already have drug regulator clearance for local manufacture of CoronaVac... 3/n…
Read 9 tweets
31 Dec 20
Statement from the UK Joint Committee on Vaccination & Immunisation (JCVI) on why they believe their strategy will achieve maximum impact:… 1/n
...They point out that most of the people who got sick with Covid-19 between 1st & 2nd doses of Tozinameran (BNT/Pfizer vax) did so in the 1st 2 weeks, so the efficacy after 2 weeks was 89% (95% CI 52-97%). But Pfizer stresses... 2/n
...that's only known for people who got their booster shot at 3 weeks, so it's unknown if it stays high for up to 3 months… For the Oxford/AstraZeneca vax, they rely on a subgroup analysis - but the data isn't provided...3/n
Read 5 tweets
30 Dec 20
#tbt This is the amazing Anna Wessels Williams (1863-1954) in the early 1900s. Her sister nearly died in childbirth in 1887: distressed by her treatment, she entered medical school. She moved to lab work in 1894: her 1st major breakthrough came fast ...1/4…
...While her boss was on vacation, she solved the barrier to high-yield diphtheria vaccines. She followed that with a 2-year sabbatical at the Pasteur Institute, creating a rabies vaccine that would be mass-produced in the US. Next was a rabies test in 1905 used for decades...2/4
...She was on the frontlines of the 1918 influenza pandemic, developed a more accurate diagnostic test for trachoma, & co-published a major textbook as well as one of the early successful science books for the public in 1937 ... 3/4
Read 4 tweets
29 Dec 20
Well, dear readers, my take on "the winning formula" for Oxford/AstraZeneca did not age well. According to the Indian manufacturing partner, it isn't the "low"-dose-1st subgroup. It's another subgroup, perhaps a subgroup of a subgroup...… HT @wogboy11 ..1/6
..The sweet spot he says is "a 2-to-3 months’ gap between dose 1 & dose 2". First let's recap their original data. They said intervals didn't make a difference. For the "standard"-"standard" group >8 wks apart vaccine efficacy was 65·6% (24·5 to 84·4). Ditto 6 weeks cutoff ..2/6
...The protocol doesn't limit the possible exploratory subgroup analyses ⬇️: so many ways they could have found a subgroup that hit this mark. Eg half the already-small "low"-dose-1st group had >12 wks apart: sliced off those perhaps? But I don't think that's the main point ..3/6
Read 6 tweets
28 Dec 20
MHRA verdict reportedly coming any day for the Oxford/AstraZeneca vaccine. I've been asked if I think their process is comparable to FDA's. Good question, post-Brexit. So I looked at 3 regulator reports for Tozinameran (BNT/Pfizer): FDA, MHRA, EMA (Europe) ...1/6
...2 agencies have unequivocal advantages:

1) Only the EMA did manufacturing inspections, which is a very big deal;

2) FDA had greater transparency: they're the only 1 releasing manufacturer briefing, released reports pre-committee, live-streamed committee discussion ...2/6
... FDA assessment report: 92 pages, almost all clinical data/issues, extensive data analysis - released days before their decision;

MHRA: 51 pages, not as much analysis - released 2 weeks after decision;

EMA: 140 pages, extensive data analysis, wide coverage ...3/6
Read 7 tweets
27 Dec 20
The AstraZeneca boss says they have new data for "the winning formula" that shows as good a result as Tozinameran (BNT/Pfizer) & Moderna. Based on what we know so far, is that likely? Well, yes...and no... 1/6…
...Protocol for their pooled analysis of trials had 2 analyses, dependent on reaching set events (people sick with Covid-19 more than 2 weeks after 2nd dose) in the standard-standard dose group: 53 events for the 1st analysis, 105 for the "final"... 2/6…
..We've seen 1st analysis: 98 events in that group. So they only needed a few more events to get to final of 105. Vaccine efficacy in that group was 62·1% (95% CI 41·0–75·7): with upper bound 75.7%, small data increase unlikely to get them over 90% ...3/6…
Read 7 tweets

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