When you choose to publish with PLOS, your research makes an impact. Make your work accessible to all, without restrictions, and accelerate scientific discovery with options like preprints and published peer review that make your work more Open.

PLOS BLOGS Absolutely Maybe

Across the Vaccine Efficacy Line, and a Late-Breaking Safety Episode: Covid-19 Vaccine Race, Month 11

We’re now into the 11th month since sequencing of the genome of SARS-Cov-2, the virus that causes Covid-19. This is the fifth of my month-by-month posts about the vaccine race – and it’s a whopping post for an eventful and complicated month!

This month, we found out at least 2 Covid-19 vaccines definitely work well. We kept hearing a vaccine might be possible in a year to 18 months at best. “Best” happened! Those particular vaccines make this cartoon I drew a few months ago true: The virus’ spikes are going to be at least part of their downfall.

Cartoon dreaming of coronavirus spikes

By my estimate, over a quarter of a million people have been recruited into the phase 3 trials that are already running or at the starting gate – a giant thank you to them all! – and the ones that aren’t finished recruiting will need another quarter of a million people. But before we get to specific vaccines, let’s start with some background.

Protocols, event-driven trials, and “readouts”

Protocols have been described as trial blueprints. A good protocol contains a lot of detail about trial design, including the processes and measurements that will be used, and the way data will be analyzed.

Botttom line: Except for the actual final numbers, a good 100-page protocol is far more informative than a few pages of a medical journal article. Protocols have been released publicly for 6 of the 12 Covid-19 vaccines in phase 3 trials, although they vary in quality and usefulness. I gather them here. (There are notes on this collection and how to use it at the bottom of this post.)

These protocols show these are event-driven trials. This means the trial is getting its key answer based, not on when it reaches a target sample size, but when it reaches a target number of events (people with Covid-19).

But because we’re encouraged to think of trials by their sample size – “there were 78,000 participants” – when we hear about the number of events that’s the goal of these trials, it might sound worryingly small. There are safeguards, though.

We have to factor in how much certainty we want to see in the data. That’s why the FDA has not only set a minimum vaccine efficacy – 50% – but a lower bound for the confidence interval calculated around it to gauge uncertainty. For FDA authorization, that lower bound must be at least 30%. That way, they determined, we can be reasonably sure that even if efficacy were to drop as more people got Covid-19, the odds are it wouldn’t drop so low that the vaccine couldn’t make a meaningful dent in the pandemic. (The European equivalent, the EMA, has said although they would prefer a 30% minimum, they would consider lowering the bar to 20%.)

There are careful rules for determining every step of this process, and a group of independent experts run the analyses. The data they provide is being called a “readout”. 

If the protocol is detailed enough, and the readout clearly sets out what the protocol had specified, then we can judge how reliable the result is for a central question – is the vaccine likely to work at least that well in another group of people?

BioNTech/Pfizer and NIH/Moderna crossed the phase 3 results efficacy line decisively

First BNT/Pfizer released details of their first analysis (along with an updated protocol) – I wrote about it at WIRED. Then Moderna did. Then BNT/Pfizer released their “final” analysis on November 18, and applied for FDA authorization: Their hearing will be on December 10, with the data and documentation to be released 2 days prior. Then Moderna released their “final”, on November 30. Their FDA hearing will be on December 17, and again, documentation to be released 2 days prior.

Both are reporting on similar outcomes: People who got ill from Covid-19, long enough after their second injection to be considered vaccinated. (Which means we still don’t know what happened in between, and how many people didn’t get a second injection, for example.) The BNT/Pfizer analysis had 170, and the Moderna analysis was 196.

We can be confident they both vaccines work really well at reducing the risk of getting symptomatic Covid-19 – in the short-term at least. Around 94% overall vaccine efficacy after completing the course is at the high end for vaccines – and they both landed there. And both reduced the risk of severe Covid-19 as well, putting to rest the fear this risk could theoretically increase. As if that’s not enough good news, both vaccines are effective for older people and across a range of groups (although we don’t know how strong that evidence is yet).

From here on, though, there are points of difference. Let’s start with what’s hard-wired into the two vaccines. We’ve heard a lot about the challenge of the BionTech-Pfizer vaccine needing to be frozen at extreme temperatures, and then used within five days of getting into normal refrigerators. Workarounds are possible. It’s been done with Ebola vaccine. And with vaccines in high demand and short supply in the near future, it doesn’t seem likely that consignments of vaccine will be hanging around longer than five days after arriving. But both these vaccines are prohibitively resource-intensive. If vaccines were cars, these would both be high-end luxury vehicles.

Moderna’s two shots are four weeks apart – the BNT-Pfizer interval is three weeks, so people achieve immunity substantially more quickly: That’s a big deal in a pandemic. The BNT-Pfizer trial is far bigger – over 43,000 compared to Moderna’s 30,000. They will have a lot more data on older people – around 18,000 people in the trial are 55 or older.

Then there is a big advantage within the vaccine itself. That difficult-to-manufacture mRNA component causes quite a lot of adverse reactions along with the immunity it can trigger. The BNT-Pfizer vaccine’s dose in each injection is 30 µg while the Moderna one is 100 µg. And although these are different vaccines and you couldn’t safely assume this would translate into a lower rate of adverse events for the BNT-Pfizer vaccine, that is how it seems to be shaping up. There will be a laser focus on safety when the full results are available – especially since mRNA vaccines are new, and so don’t have the advantage of being “tried and tested” ways of vaccinating vast numbers of people.

Phase 3 readouts with question marks:

Sputnik V

Sputnik V, from Russia, has not released a protocol, so there are too many unanswerable questions to rely on the press releases alone. The first, on November 11, analyzed only 20 events, with no statistical information or justification for that analysis. They said the efficacy rate was 92%.

Their second analysis, released on November 24, analyzed 39 events. Their protocol, they said, allowed for 3 such analyses: at 20 events, 39, and a final at 78. That seems low, and they don’t share the statistical methods they used. However, the second release did report the number of people analyzed, and how many in vaccine and placebo groups became sick with Covid-19. The efficacy rate was 91%, which would clear the bar if it continued – but we’re mostly in the dark.

The readout doesn’t mention age or gender, or severe Covid-19. As I wrote about their earlier stage results, they had managed there to have an extraordinarily young group of healthy people (average age of 26), with some groups 100% male. So watch out for that, as well as data on adverse events.

Oxford/AstraZeneca

The second vaccine I’ve placed in this group is the Oxford/AstraZeneca one. The developers did have a protocol published – but it was undated, released only the week before, was thin on details, and contained a controversial proposal. There wouldn’t be an analysis of a standardized, adequately powered phase 3 trial, as specified by regulators – and as their protocol for a trial of theirs just like that underway in the US did.

Instead, they would do a meta-analysis of 4 trials, only half of which were phase 3 – and which did not include their phase 3 trial from India. They set the lower boundary for efficacy at 20%, which makes it easier to clear the bar and call efficacy. They didn’t explain the statistical techniques they would use, and didn’t reveal the detail on what number of events would trigger analyses.

The interim analysis they released on November 23, differed from the analysis described in the protocol. Unlike all the other readouts, this one didn’t include basic data like how many people in which group got Covid-19. And it was based on a meta-analysis of 2 subgroups from 2 phase 3 trials: one in the UK, and one in Brazil. I wrote a critique about this at WIRED, supported by a timeline and sources here. They also didn’t mention age, but the protocol for the UK trial and trial registry report for the one in Brazil suggest there aren’t many older people in these trials.

The efficacy rate they reported for the standard vaccination course was 62% – and they didn’t provide the numbers of people with Covid-19 in that and the only other subgroup they reported. They got a lot of criticism about their claim of high efficacy – 90% – for a relatively small group of people no older than 55 who were given half a dose followed by a standard dose. It was originally accidental. They have acknowledged the need for a new trial to test the hypothesis. That leaves an unknown proportion of the 131 events to support 62% efficacy – and we don’t know the range of uncertainty.

They reported there were no severe Covid-19 illnesses in the group getting the vaccine. People in the trial had home self-swab tests to use each month, and we’ll need to see how that affects the Covid diagnoses.

The UK government has requested the Medical and Healthcare products Regulatory Agency (MHRA) to assess the vaccine for emergency use authorization, based on this analysis.

This is the vaccine that needed to pause trials for 2 serious neurological events, 1 in July, which was deemed unrelated to the vaccine, and the other in September, where they concluded there wasn’t enough evidence to say if it related to the vaccine or not. And this weekend, another was reported…

The late-breaking safety episode

In mid-October, a 40-year-old trial participant in the Indian phase 3 trial of the Oxford/AstraZeneca vaccine had a serious neurological adverse event, requiring intensive care. The vaccine developers’ partner, the Serum Institute of India (SII), deemed the event unrelated to the vaccine – but it was clearly a serious adverse event in the trial. (Any episode of intensive care would be classed as a serious adverse event.) The drug regulator’s investigation is not complete.

Despite this, the head of SII has recently stated that there were no hospitalizations in the Indian trial, and no serious adverse events. The trial participant’s lawyer made the situation public, as they have asked for compensation, indicating they would shortly lodge a court claim, and calling for the trial to be halted.

In an appalling turn of events, the SII has said it will sue the trial participant for damage to the SII’s reputation. Maybe there’s a worse way to handle this, but I find it hard to imagine one. And it’s clear that determination of whether or not this event is vaccine-related has financial implications for the manufacturer.

What now? We don’t know if regulators in other countries with ongoing trials of the Oxford/AstraZeneca vaccine have been notified. It’s been about a month since the event. Many of us have been calling for radical transparency in these trials. It’s obviously urgently needed here, along with reassurance that this event has been properly investigated. The handling of this at many levels raises a lot of questions.

[Update December 2] Other trial participants expressed concern about the way this man was being treated by the vaccine manufacturer. They have contacted the drug regulator, concerned that they were given injections after the serious adverse event without being informed of it, and some are reportedly considering legal action. Fortunately, the trial participant has almost completely recovered: he was in the intensive care unit for 10 days.

[Update December 3] Media report that the drug regulator in India convened a panel this week to assess the event, concluding that the event was not vaccine-related. No further details.

Since my last round-up post, there was one other serious adverse event in a Covid-19 vaccine trial that was made public. The trial in Brazil for Sinovac’s inactivated vaccine, CoronaVac, was temporarily put on hold to investigate. It was reportedly a suicide, but whether the participant was in a vaccine or placebo group hasn’t been made public.

Keep in mind, serious adverse events are inevitable in any group of a quarter of a million people over a few months. There should be case-by-case investigations – and then consideration of whether there are any other signals to consider, and any possible patterns (like a surprisingly high rate of a type of adverse event).

Next wave of phase 3 readouts?

Any of the vaccines already mentioned could have subsequent or final readouts. And unless there’s been a major disappointment, expect results from Chinese inactivated vaccines soon – possibly in the first week of December:

  • Sinovac’s Coronavac has reached its number of events for their first efficacy analysis for the trial in healthcare workers – 74 events. According to the published protocol, the minimum they needed was 61. (This trial includes some children and pregnant women.)
  • From media reports, it sounds as though the interim analysis for one or both of the Sinopharm (China National Biotec Group) vaccines could already have been done. No protocols have been publicly released for these 2 vaccines. The 31,000 people in the UAE in their big 45,000-participant trial have reportedly been getting Covid-19 tests every 2 weeks.

Novavax and Janssen/J&J have been very quiet, but it’s possible either or both could have readouts in December. [Update Dec 1: Novavax issued a progress report on their trials and I’ve updated figures below.] It’s hard to know for sure what’s happening with the viral vector vaccine from China’s CanSino, but it’s possible they are near to readout stage, too.

Overview of phase 3 trials

There are now 12 vaccines in at least 1 phase 3 trial, including 1 which has got to the starting gate since the last round-up post. It’s a protein subunit vaccine: That’s a more traditional form of vaccine – like hepatitis vaccines, for example. It was developed under the auspices of the Chinese Academy of Medical Sciences, and it’s the fifth Covid-19 vaccine from China to reach phase 3 trial. I could find only scant and vague details of the trial, but I don’t speak Chinese, so might not have found valuable information.

There are also some major new phase 3 trials for vaccines that were already on the list. Johnson & Johnson now has the biggest trial program, for their viral vector vaccine. They started a 30,000-person trial of 2 shots of their vaccine. They already have a 60,000-person trial underway for a single shot – it is the only major candidate for a single shot vaccine to get to this stage so far.

Novavax has a 30,000-person US trial starting soon, adding to their 15,000-participant trial in the UK. That’s another protein subunit vaccine. And Sinovac started a small 1,040-person trial in China, to check if their mass-produced inactivated vaccine, CoronaVac, gets the same results as the one they produced for the trials. That’s called a non-inferiority trial.

Note: I don’t include phase 2/3 trials that are beginning as small phase 2 trials, but have not yet progressed to phase 3. They would, unfairly, look ridiculously under-powered – and progressing on is never guaranteed. There are trials in that category for Inovio and Medicago vaccines, so they may be joining this “club” soon. [Update – Medicago did, the day after this post was published!]

To give you an overview of the phase trials, I have 2 tables, listing them in alphabetical order by vaccine name, with the inactivated viruses as a separate group. The first blue table estimates how far along the trials are. The green table that follows shows how many earlier stage trials and results each has had, and maps out a few more details of the phase 3 trials.

Phase 3 trials: recruitment progress

VaccineTarget or final sizeSingle or similar trials?Reaching target? (November 30)
Ad26.COV2-S
Johnson & Johnson
USA
90,0002 large trials1 with 60,000, unknown recruitment status (began late September).
The other is months away.
Ad5-nCoV
CanSino
China
40,500Mostly single trialMajor trial reportedly close to fully recruited.
BNT162b2
BioNTech/Pfizer
Germany
43,931Single trialFully recruited.
ChAdOx1 nCov-19/AZD1222
AstraZeneca
UK (Oxford Uni)
64,9413 very different large trials (plus some small)2 major trials 10,000+ each (UK and Brazil) close to or fully recruited.
Major trial in US and some other countries months way (10,000 out of 40,051).
Small trial in India fully recruited.
Other small ones, unknown.
mRNA-1273
Moderna
USA (NIH)
33,0001 large, 1 smallTrial of 30,000 fully recruited. Trial of 3,000 young people months away.
NVX-CoV2373
Novavax
USA
45,0002 trials (1 not yet underway)Trial of 15,000 in UK fully recruited.
Sputnik V (Gam-COVID-Vac)
Russia
42,260Mostly single trialTrial of 40,000 over half recruited (began late August).
(Unnamed subunit vaccine)
Chinese Academy of Sciences
29,000Single trialMonths away.
Inactivated virus vaccines
2 BBIBP-CorV vaccines
Sinopharm
China
60,300+2 large trials, several smallTrial with 45,000 fully recruited.
Others: months away.
CoronaVac
Sinovac
China
27,980+2 large trials, 2 smallTrial with 13,060 healthcare workers in Brazil fully recruited.
Trial for 13,300 in Turkey close to fully recruited.
1 small trial fully recruited.
Covaxin
Bharat Biotech, Indian Medical Research Council
India
28,500Single trialMonths away.
Total participantsOver 500,000
planned
Over 250,000 likely to be already recruited
(Further details on trials in next table.)

Overview of phase 3 trials, and the preclinical and early stage results they have reported


Vaccine

Company
Country
Preclinical Phase 1
results

 

People

Phase 1/2
results

 

People

Phase 2
results

 

People

Phase 3

Total people
By trial (countries)

Ad26.COV2-S
Johnson & Johnson
USA
Primate, non-primate n.a. 1,045 (partial report) n.a.

90,000:

60,000 (single shot) (Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, USA)

30,000 (2 shots) (Planned: Belgium, Colombia, France, Germany, Philippines, South Africa, Spain, UK, USA)

Ad5-nCoV
CanSino
China
Non-primate only 108 n.a. 508

40,500:

40,000 
(Pakistan – reportedly also Mexico and Saudi Arabia)

500
(Russia)

BNT162b1-b3
BioNTech/Pfizer
Germany
Primate, non-primate (b2 only) b1:

45
(USA)

b1:

60
(Germany)

b1 & b2:

195
(USA – incl 45 above)

n.a.

Unpublished

43,991 (b2)
(Argentina, Brazil, Germany, South Africa, Turkey, USA)

ChAdOx1 nCov-19/AZD1222
AstraZeneca
UK (Oxford Uni)
Primate, non-primate n.a. 1,077 560 (from the phase 2/3 trial)

64,941:

12,390**
(UK)

40,051
(USA)

10,300
(Brazil)

1,600
(India)

400
(Kenya)

100***
(Russia)

mRNA-1273
Moderna/NIH
USA
Primate, non-primate 85 n.a. Unpublished (600)

33,000

30,000 adults
(USA)

3,000 young people
(USA)

NVX-CoV2373
Novavax
USA
Primate, non-primate n.a. 83 n.a.

45,000:

15,000
(UK)

30,000
(Mexico, Puerto Rico, USA)

Sputnik V (Gam-COVID-Vac)
Gamaleya Institute
Russia

Unpublished n.a. 76 n.a.

42,100+

40,000
(Russia)

100
(Belarus)

2,000
(Venezuela)

1,600**
(India)

(Unnamed subunit vaccine)
Chinese Academy of Sciences

Unpublished Unpublished (2 of 50 each) n.a. Unpublished (900)

29,000
(Uzbekistan, other sites to follow are Ecuador, Indonesia, Pakistan)

 

Inactivated vaccines:          
BBIBP-CorV x 2 (1 Wuhan, 1 Beijing)
Sinopharm
China

Unpublished (Wuhan)

 

Primate, non-primate
(Beijing)

n.a. 320 (Wuhan)

 

640
(Beijing)

n.a.

60,300+:

45,000 (both vaccines)
(Bahrain, Egypt, Jordan, UAE)

3,000 (Beijing only)
(Argentina)

300 (Wuhan only)
(Morocco)

Apparently additional:

12,000 (both vaccines) (originally 6,000)
(Peru)

? (both vaccines)
(Serbia)

? (Beijing only)
(Pakistan)

CoronaVac (PicoVacc)
Sinovac
China
Primate, non-primate 144 n.a. 600

27,980+:

13,060 (originally 9,000)
(Brazil)

 

13,300
(Turkey)

1,620
(Indonesia)


(Philippines)

1,040 (non-inferiority)
(China)

Covaxin (BBV152)
Bharat Biotech/Indian Medical Research Council
India
Non-primate n.a. Unpublished
(755)
n.a.

28,500 (India)

Vaccines with published or preprint results (and/or Phase 3 trial register entry)
* a combined phase 1/2/3 trialwith 2,000 phase 1/2
** a combined phase 2/3 trial
*** an unrandomized phase 3 trial

n.a. = not applicable
Sources: unless otherwise linked, the sources are from my tagged public Zotero collection (detailed below this post)

Early to mid-stage clinical trial results since the last round-up

  • Medicago’s CoVLP plant-based vaccine with Glaxo-Smith-Kline adjuvant: Phase 1 results released as a preprint on medRxiv on November 6. Included 180 people, and most of the effect coming from the adjuvant (including quite high adverse effects, for example, up to 40% of people had fevers). (This is the Canadian one based on a tobacco plant relative, with tobacco industry financial involvement.)

  • Curevac’s CVnCoV mRNA nanoparticle vaccine: Phase 1 results released as a preprint on medRxiv on November 9. There were 248 people. This is “the other” famous German vaccine candidate.

  • Chinese Academy of Sciences’ inactivated vaccine (unnamed): Phase 2 trial results were published in Clinical Infectious Diseases on November 9. This was the first report for this vaccine, with 750 people. No word yet on a phase 3 trial for this vaccine.

  • Sinovac’s inactivated vaccine, Coronavac: Phase 1/2 trial results were published in The Lancet on November 17. This included the first report for 144 people in phase 1, and the second report on 600 people in phase 2.

  • Oxford/AstraZeneca’s viral vector vaccine: Phase 2 results were published in The Lancet on November 18. This reported on 560 people enrolled into their phase 2/3 trial. Participants will generally have progressed into phase 3 trial of the trial.

And in other recent news …

  • No word yet from the World Health Organisation (WHO) on when the international SOLIDARITY trial to compare vaccines head-to-head will start, but a government minister in the Philippines said it will start in December, with a local target participation of 4,000 people. No word yet on which vaccines.

  • The Gates Foundation committed its largest individual grant to develop Covid-19 vaccine to Icosovax – first-in-human trials next year if all goes well.

  • After intensely politicizing the vaccine debate in Brazil, adamantly insisting he’d resist any Chinese vaccine on political grounds, Brazil’s president backed off, saying any vaccine approved by Anvisa, the nation’s drug regulatory agency, would be accepted.

  • Another little crack in the big secrecy wall of government contracts with drug companies for Covid-19 vaccines: Novavax released its Operation Warp Speed contract with the US government in its Securities and Exchange Commission (SEC) filings.

  • Thought about what will happen to the people in the placebo groups of trials after vaccines have been shown to work? Good story on that by Matthew Herper at STAT News.

~~~~

Cartoon of facing off coronavirus

All my Covid-10 vaccine race posts

All previous Covid-19 posts

My op-ed about Covid-19 vaccine adverse effects at WIRED

Disclosures: My only interest in Covid-19 trials is as a person worried about the virus, as one of my sons is immunocompromised. I have worked for an institute of the NIH in the past, but not the one working on the vaccine (NIAID). More about me.

Update [Nov 30]: Removed a statement about the serious adverse event in India qualified by “if the participant was vaccinated” – an interview with the local lead investigator subsequently confirmed the participant received the vaccine.

Updates [Dec 1]: Added Medicago’s newly registered phase 2/3 trial. Added details from Novavax’s progress report – my thanks to Ben Pollinger, who alerted me to this on Twitter.

Updates [Dec 3]: Updated BNT/Pfizer’s trial participants – although trial reported ended, a small increase in the number of participants was reported (currently almost the target registered). Update on SAE in India. Added new Moderna trial in young people, and Sputnik V trial in India.

Update [Dec 10]: Correction to table – BNT/Pfizer results formerly listed as phase 1/2 moved to phase 1. Although titled phase 1/2, no phase 2 results were included. (Grateful to Julia Belluz from Vox, who pointed out this.)

The cartoons are my own (CC BY-NC-ND license). (More cartoons at Statistically Funny and on Tumblr.)

Background note: The timing for these roundup posts is based on the January 2020 sequencing of the genome for SARS-Cov-2. The sequencing was submitted for release on January 5, and published on January 12.

Sources for the table are included among the records in my public Zotero collection of Covid-19 vaccines with any published results (or preprints), or that are in phase 3 trial (more details below). Please let me know if I’m missing any! On November 30, the collection included 203 entries (up from 150 last monthly roundup):

  • 71 vaccine groups with published or posted results;
  • 85 preclinical reports;
  • 6 phase 1 trial reports;
  • 10 phase 1/2 reports;
  • 4 phase 2 reports;
  • 7 trial efficacy readouts for phase 3 (press releases), for 4 vaccines
  • 9 protocols for trials, for 6 vaccines, including 1 vaccine with an original and updated protocol;
  • 2 author replies to letters to the editor about their publications;
  • 80 trial registry entries associated with these vaccines.*

May not include all entries where a trial is registered in multiple registers.

Notes on the collection 

This is a publicly accessible collection I update regularly. It includes any Covid-19 vaccine with published preclinical, clinical trial results, or trial protocols. If a phase 3 trial starts (or is about to) without any prior publications, that trial would also be included. Once a vaccine is in the collection, clinical trial register entries for that vaccine are also added.

When trials are registered in more than clinical trials registry, the multiple records may or may not be in the collection: If I have located a record in ClinicalTrials.gov, I do not hunt for additional registrations. For my own convenience in keeping an overview of vaccine progress, when preprints appear later in journals, I over-write the original record with the journal article.

The entries are tagged by vaccine and what type of record it is – phase 2 results, or a trial protocol, for example. Those tags are bottom left: clicking on any of the record types will narrow down the list of records to those types of records and/or specific vaccines. Double-click on any of the actual records, and it will take you to it. Clicking off a specific vaccine’s tag will get you into the full collection for all vaccines with published results and/or phase 3 trials. For example, this link shows all the protocols I know of.

You can notify me of anything missing either via Twitter or via a comment on this post. (I moderate comments at the blog, so if you want your message to stay private, just say so.)

Leave a Reply

Your email address will not be published. Required fields are marked *


Add your ORCID here. (e.g. 0000-0002-7299-680X)

Related Posts
Back to top