Developing the Covid-19 vaccine

[PeteB]

Another quick sense check

https://twitter.com/cheianov/status/1330851286254833672

[shpalman]

Another quick sense check

https://twitter.com/cheianov/status/1330851286254833672

He goes for 2 cases in the half-dose group and 28 in the full-dose group, which would give me 93.3% and 60.6%, whereas 3 and 27 would give me 90.0% and 62.0%.

[sTeamTraen]

A problem here is that the standard errors are driven by the number of cases (people who developed the disease), not the number of participants (people who got the vaccine). So with only 2 and 28 cases there are going to be some big confidence intervals.

The Oxford group really need to get their data out in a preprint quickly, in order to avoid the impression that they are just playing PR catch-up.

[AMS]

I don't think people generally use preprint servers for clinical trial data, but I would hope there's a paper ready to come out in a proper journal, possibly waiting under a publication embargo.

[shpalman]

Reports that the Oxford vaccine reduces asymptomatic transmission and also I think they did regularly test the trial participants in this one.

[Woodchopper]

Here’s a link to the Oxford vaccine press release https://www.astrazeneca.com/media-centr ... 22hlr.html

Some info in there

[Woodchopper]

Reports that the Oxford vaccine reduces asymptomatic transmission and also I think they did regularly test the trial participants in this one.

Yes, they swabbed the participants every week.

[lpm]

Good! Glad someone thought to test weekly.

If there's merely partial reduction in transmission then our little Covid companion is facing a severe loss of habitat.

[sTeamTraen]

There were a total of 131 COVID-19 cases in the interim analysis.

One dosing regimen (n=2,741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8,895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001).

With those numbers and proportionate numbers of cases, there would be 31 cases with the half dose first and 100 with the full dose first. 90% (62%) efficiency suggests to me that the treatment group had 10% (38%) of the number of cases of the control group. That would mean (3 Tx, 28 control) cases in the half-dose trial and (27 Tx, 73 control) in the full-dose trial, and that would also give the expected (30 Tx, 101 control) in the overall score, for an average efficacy of 70% (i.e., the vaccine prevented 71 out of 101 cases in the treatment group). Assuming equal sample sizes in each group:

Code: Select all

> chisq.test(matrix(c(3,1368,28,1342),ncol=2))
X-squared = 18.811, df = 1, p-value = 1.443e-05

> chisq.test(matrix(c(27,5791,73,5745),ncol=2))
X-squared = 20.426, df = 1, p-value = 6.2e-06

Those are pretty convincing test statistics. But the null hypothesis being tested here is that the vaccine is entirely ineffective. I'm concerned, in particular, that the better results for the half-dose group may be just a fluke (amusingly, it was apparently caused by an error, which at least helps with blinding, I suppose), so that the overall efficacy might be only, say, 65% --- at which point you have to wonder (a) if it's useful, given the takeup levels you'd need to reach herd immunity with an R0 of 3.0, and (b) whether people will be prepared to accept a "product" that, in poorly-informed layperson's terms, "only works two times out of three".

[Woodchopper]

Oxford/AZ Vaccine Efficacy Data
https://blogs.sciencemag.org/pipeline/a ... icacy-data

[jdc]

Reports that the Oxford vaccine reduces asymptomatic transmission and also I think they did regularly test the trial participants in this one.

Yeah, statnews saying:

The Oxford researchers suggested the vaccine may reduce transmission of the virus, because they saw fewer asymptomatic cases in their trial. One of the challenges of controlling spread of the SARS-CoV-2 virus is that some people who become infected have no symptoms but can still transmit the virus.

The press release chops posted says this on testing:

Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR. In addition, weekly swabbing are done for detection of infection and assessment of vaccine efficacy against infection. [UK trial]

Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR. [Brazil trial]

[jdc]

Those are pretty convincing test statistics. But the null hypothesis being tested here is that the vaccine is entirely ineffective. I'm concerned, in particular, that the better results for the half-dose group may be just a fluke (amusingly, it was apparently caused by an error, which at least helps with blinding, I suppose), so that the overall efficacy might be only, say, 65% --- at which point you have to wonder (a) if it's useful, given the takeup levels you'd need to reach herd immunity with an R0 of 3.0, and (b) whether people will be prepared to accept a "product" that, in poorly-informed layperson's terms, "only works two times out of three".

It's not useful for Americans:

“If it’s 70%, then we’ve got a dilemma,” said Fauci. “Because what are you going to do with the 70% when you’ve got two [vaccines] that are 95%? Who are you going to give a vaccine like that to?”

The problem was also flagged in an analysis by Geoffrey Porges of the investment bank Leerink. “We believe that this product will never be licensed in the US,” Porges wrote.

Poor countries, though:

AstraZeneca said in a release that it intends to seek emergency use authorizations in countries around the world that have a regulatory framework that allows for conditional or early approval of medical products, and will seek an emergency use listing from the World Health Organization, a pathway to rapid approval for low-income countries.

The vaccine can be stored at normal refrigeration temperatures for up to six months, which will make it easier to deploy in more settings than the vaccines from Pfizer and Moderna, which must be stored at ultra-low temperatures. The Pfizer vaccine must be stored at -94 degrees Fahrenheit, while the Moderna must be stored at -4 F. Once thawed, Moderna’s vaccine can be stored at fridge temperature for a month.

“The vaccine’s simple supply chain and our no-profit pledge and commitment to broad, equitable and timely access means it will be affordable and globally available,” AstraZeneca CEO Pascal Soriot said in a statement.

[shpalman]

... the null hypothesis being tested here is that the vaccine is entirely ineffective. I'm concerned, in particular, that the better results for the half-dose group may be just a fluke (amusingly, it was apparently caused by an error, which at least helps with blinding, I suppose), so that the overall efficacy might be only, say, 65%...

Yes, the whole question is indeed whether the ~90% result in the smaller subgroup who accidentally got a half-dose is meaningful.

If, say, 7-8 of the covid cases (instead of 3 cases) in the vaccinated subjects had been in the half-dose subgroup instead of the full-dose subgroup then both groups would have had efficacies closer to the 70% average. You'd obviously need even more covids among the half-dose subgroup to bring the average down to 65%.

[FredM]

On a lighter note (from @ivograham):

Pfizer vaccine: effective, protective and safe
Modena vaccine: effective, protective and safe
Oxford vaccine: effective, protective, and safe

[Gfamily]

On a lighter note (from @ivograham):

Pfizer vaccine: effective, protective and safe
Modena vaccine: effective, protective and safe
Oxford vaccine: effective, protective, and safe

Very good

[PeteB]

Those are pretty convincing test statistics. But the null hypothesis being tested here is that the vaccine is entirely ineffective. I'm concerned, in particular, that the better results for the half-dose group may be just a fluke ..

Somebody else has tried that too based on 2 or 3 in the half dose group

with 2

https://twitter.com/cheianov/status/1330851286254833672

"The overall probability that regimen 1 performs better than regimen 2 is slightly over 98%"

with 3

https://twitter.com/cheianov/status/1331006287627382784

" For these numbers I find that Regimen 1 performs better than Regimen 2 with 94.5% confidence. "

I'm interested in this

amusingly, it was apparently caused by an error

Have you got a source for that - I had assumed they had a prior belief the half first dose might be more effective, that made it rather more convincing to me

edited - found it https://www.theguardian.com/uk-news/202 ... sing-error

[shpalman]

On a lighter note (from @ivograham):

Pfizer vaccine: effective, protective and safe
Modena vaccine: effective, protective and safe
Oxford vaccine: effective, protective, and safe

When the Oxford vaccine runs out there'll always be the Durham one.

[shpalman]

amusingly, it was apparently caused by an error

Have you got a source for that - I had assumed they had a prior belief the half first dose might be more effective, that made it rather more convincing to me

https://www.theguardian.com/uk-news/202 ... sing-error

“The reason we had the half dose is serendipity,” said Mene Pangalos, executive vice-president of biopharmaceuticals research and development at AstraZeneca.

When university researchers were distributing the vaccine at the end of April, around the start of Oxford and AstraZeneca’s partnership, they noticed expected side effects such as fatigue, headaches or arm aches were milder than expected.

“So we went back and checked … and we found out that they had underpredicted the dose of the vaccine by half,” said Pangalos.

Instead of restarting the trial, he said researchers decided to continue with the half dose and administer the full dose booster shot at the scheduled time.

[PeteB]

Thanks

[JQH]

How long before some quack starts shouting that if reducing the dose improves effectiveness that proves homeopathy works !!!111!!!!

On a serious note, starting with a reduced dose and building up might generally be more effective. My elder brother used to work for big Pharma and he mentioned one drug that had greatly reduced side effects if you started with a small dose and built up. His experience was that doctors did not prescribe it correctly.

[Stephanie]

That seems reasonable put like that. I'm just anticipating unexpected stumbling blocks to emerge.

I'll take your bet - either we get a vaccine, or I get some money. 2021 is looking up.

Consolation betting - same thinking my dad used when he went to the bookies to put £200 on the UK voting for Brexit.

I think stumbling blocks have already been a factor in delaying the progress so far (not sure how unexpected they've been), in terms of things like Novavax having trouble scaling up or J&J/AZ pausing their trials. I suppose we could see more things cropping up but I'd have thought most of the opportunity for stumbling blocks would be past by now?

They've got through phase 1 and 2 trials, and are well on with phase 3 so various hurdles like problems finding enough recruits or not getting the hoped-for phase 1/2 results have already not cropped up. We've already been through some of the others (as above). What's left? Disappointing phase 3 results comes to mind (please no), or more of the adverse events that have briefly paused trials. After that isn't it mostly about passing regulatory checks? I don't know much about this element of vaccines, I'm usually reading about alleged problems with existing vaccines rather than the approval process for new jabs. Shame tomp isn't here, I bet he'd know.

I asked tomp, he has come back with the following:

Normally it takes months to approve a new medicine cos the company sends all the data from pre-clinical to the latest phase 3 results, via manufacturing and packaging and everything to us and then the assessors go through it all slowly and methodically and then things like risk might plans are discussed and agreed.

For a seasonal vaccine, it's often done as a variation to the license, which is a far shorter process and they pretty much just need to demonstrate human safety and efficacy equivalent to previous vaccines.

For the covid vaccines, we have been doing two things to speed stuff up. 1st we assessed, agreed and pre-approved packaging and labelling as much as possible. Then we have been doing a rolling review of data so the pre-clinical, phase 1 and 2 studies will already have been assessed and GMP compliance at proposed sites is being done too.

We also agreed to checkpoints throughout the studies when certain numbers of patients had been vaccinated/placeboed and certain numbers had caught COVID. So, depending on the apparent efficacy, we will know whether we can, in theory grant conditional approval with the studies still ongoing.

So when they send us the data, the review process will be far shorter. And, of course, since the whole world is desperate for this and there's silly national pride at stake, every regulator will be dedicating the max useful number of resources to this to speed up the decision-making process further still to beat the others.

Normally we have a CHMP meeting at routine intervals (the next is 7-10 December) and documents need submitting well in advance. This time, I expect an ad-hoc extraordinary CHMP for no more than 1 week after the rapporteur has finished their assessment.

The agency closes for Christmas on 23 December this year so maybe in the 2 weeks between then or perhaps twixt Xmas and New year. Since nobody will be doing much at Christmas and we are now used to virtual meetings and we'd all like to know we were doing our bit to help the world, it is very possible.

[Herainestold]

Sputnik V vaccine has 91% efficacy.

Joining the flood of press releases announcing positive results from COVID-19 vaccine trials, developers of Russia’s Sputnik V vaccine today reported 91.4% efficacy from a second interim analysis of more than 18,000 people, bolstering a claim the team made on 11 November with scant evidence.

Whereas the initial report rested on a mere 20 cases of COVID-19, with no details on how they were split between vaccinated and placebo groups, the new analysis is based on 39 cases total, eight among the vaccinated group versus 31 in the much smaller placebo arm. “This is great news not just for Russia, but the world,” Kirill Dmitriev, CEO of the Russian Direct Investment Fund that is bankrolling the development of the candidate, announced at a virtual press conference this morning.

“One thing seems to be clear, that this platform works,” Alexey Chumakov, a researcher at the Russian Academy of Medical Science’s Chumakov Institute of Poliomyelitis and Viral Encephalitides in Moscow, wrote in an email. “Of course, with any vaccine, and especially with the ones that have such potential for future revenue flow, as well as political impact, one must be careful in any type of pronouncement, only time and testing will tell.”

Dmitriev said partners in India, South Korea, China, and Brazil are producing the vaccine, which could cost less than $10 a shot. Current agreements would allow for the production of 1 billion doses in 2021, with first doses delivered internationally in January.

https://www.sciencemag.org/news/2020/11 ... ce-success

[Bird on a Fire]

Good news. Another cheaper vaccine, and one that will probably be available to countries that have trouble accessing medication because of US sanctions, like Iran and Venezuela, which have both been badly hit. And more for the rest of us, I guess.

[Herainestold]

Not just the Russian vaccine for developing countries, but the Chinese have offered vaccine help.

BEIJING (Reuters) - President Xi Jinping said on Saturday that China is ready to step up global COVID-19 vaccine cooperation, and called for better international coordination on policies to facilitate movement of people.

Pharmaceutical companies and research centres around the world are working on potential COVID-19 vaccines, with large global trials of several of the candidates involving tens of thousands of participants underway. China has five home-grown candidates undergoing Phase III trials.

“China is willing to strengthen cooperation with other countries in the research and development, production, and distribution of vaccines,” Xi told the G20 Riyadh Summit via video link.

“We will fulfill our commitments, offer help and support to other developing countries, and work hard to make vaccines a public good that citizens of all countries can use and can afford,” he said.

He also called for stronger international policy coordination to establish travel “fast tracks” that would facilitate orderly global movement.

With that in mind, Xi said China would propose the creation of a mechanism by which travellers’ coronavirus test results were recognised internationally through digital health codes.

https://uk.reuters.com/article/uk-g20-s ... KKBN2810M1

[PeteB]

Was the UK given the half first dose and Brazil the full first dose ? If so could the different % success be due to something to do with the countries ?