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

The First Phase 3 Safety Picture & the Rise of Emergency Use: Covid-19 Vaccine Race, Month 10

Cartoon of virus versus vaccine researcher with fingers crossed

NOTE: A lot has happened in the couple of weeks since I last updated this post. New monthly roundup coming soon!

We’re now into the 10th month since sequencing of the genome of SARS-Cov-2, the virus that causes Covid-19. We were told, over and over, “a year to 18 months” is the soonest there could be a vaccine, and that would be ambitious. And we are here, on tenterhooks for results of big phase 3 trials, in less than a year – a testament to what can be achieved when vast amounts of money, brains, and time are hurled at an existential threat.

This is the fifth of my month-by-month posts about the vaccine race. A couple more vaccines have reached phase 3 trials since the last post – and several of the trials have either fully recruited, or passed their original targets and set new larger ones. As you’ll see below, by my count there are now over 150,000 people in phase 3 trials for Covid-19 vaccines, pushing towards a current target of over 430,000 people. The other big themes of the month, it seems to me, were vaccine safety and emergency use – including signs of cold feet about it from the US. We’ll start with good news on safety.

First announcement of safety results from a phase 3 trial: CoronaVac

There’s no publication for this. But it was an announcement by the head of the public research institute running the trial. The results are also consistent with the vaccine’s earlier results, and in line with what would be expected from an inactivated virus vaccine. Coronavac is produced by Sinovac, a pharmaceutical company from Beijing. The course is 2 injections, 2 weeks apart, and the vaccine has an aluminum hydroxide adjuvant (booster).

It’s a phase 3 trial in healthcare workers in Brazil, with an original target size of 9,000, but now expanded to 13,060. The protocol for the trial was recently published in the journal, Trials. And the results are for that first 9,000. There were no serious or severe adverse events, and 35% had less serious reactions – apparently including moderate as well as mild ones, but that’s not clear. For Covid-19 vaccines, that’s a low rate of adverse effects.

The results are similar to the experience with the vaccine in the phase 2 trial in China. They didn’t publish phase 1 results, because the vaccine they produced early on was less potent, but the data are being provided to drug regulators. The phase 2 trial was randomized, with 480 people getting either the same dose that’s gone to phase trial or a dose that was twice as high. Plus there were 120 people in a placebo group. They were split between getting their second injections after 2 weeks or 4 weeks. There were no severe reactions. There were 3 serious adverse events, none of which were judged to be vaccine-related.

There were 120 people in that trial getting the same dose and timing as the phase 3 trial. Altogether, 33% of those people had adverse events (compared to 22% in the placebo injection group and 35% for the higher dose). The rate of fever was 3.3% at each dose (compared to 1.7% in the placebo group). Having the injections at a 2-week interval instead of 4 weeks increased the rate of adverse events.

Now it’s all down to whether the encouraging level of immune response from earlier studies translates into protection against Covid-19. The primary effectiveness outcome for the trial in Brazil, as with almost all of the vaccines, is symptomatic and confirmed Covid-19 (2 weeks after the last injection – so that pre-existing infection doesn’t count). The number needed to trigger an interim analysis is 61 illnesses – and 151 would be enough for a final verdict. They’ve expanded the number of hospitals recruiting healthcare workers to reach their expanded size more quickly, and hope for an answer on effectiveness in November or December – just weeks away. And there’s another 13,300-participant trial, too, with the same 2-week interval, in Turkey. That is for 1,300 healthcare workers, and the general population for the rest. That trial only started about a month ago. There are also 2 small trials, one in Indonesia (which is fully recruited) and the other in the Philippines.

It’s not all plain sailing, though. Sinovac had planned a trial in Bangladesh, but those plans crashed on the issue of funding. And Brazil’s president is opposed to national purchase of a vaccine from China on political grounds. Nevertheless, the government of São Paulo state has applied to the drug regulatory authority (Anvisa) for emergency use authorization of CoronaVac. On October 23, Anvisa authorized the import of 6 million doses of CoronaVac, although it can’t be distributed yet. Other countries are also counting on CoronaVac. For example, Indonesia hopes to have enough CoronaVac for 40% of its population – at around $14 per dose. Turkey’s Minister of Health reportedly indicated that 5 million doses of CoronaVac were likely to be available there in December.

The confidence in safety of this and other Chinese vaccines has underpinned emergency use determinations. Whatever you think of emergency use before effectiveness results are in, if there’s good surveillance and those outcomes are reassuring, it’s an important supplement to randomized trials. Successful widespread use would be a major driver of confidence about a Covid-19 vaccine’s safety. As we’re about to see, the scale of emergency use now far exceeds the rate of use in clinical trials.

Number of countries already authorizing vaccines growing – and signs of cold feet in the US

Several drug regulatory agencies have established rules specifically for authorizing emergency use, including the new guidance issued this month by the US Food and Drug Administration (FDA), Brazil, and reportedly the UK’s agency (MHRA). However, while the European Medicines Agency (EMA) is accelerating their approval procedures for Covid-19 vaccines, they are maintaining full marketing approval only.

On October 1, the WHO invited manufacturers with vaccines in phase 2 and phase 3 trials to indicate interest in being assessed for pre-qualification for their Emergency Use List (EUL). EUL pre-qualification means UN agencies can consider purchasing those vaccines, and, they said, evaluation would take place “within the next 6 months”. The process covers both results data and the quality of manufacture. That pre-qualification is going to be a critical flag to fly for many countries.

Here are the countries I can find that already have emergency use vaccination programs (or are about to have them), in chronological order from first authorization or announcement:

  • China: CanSino’s vaccine was authorized for use in the military (June 29), followed by wider emergency use authorization for it and 3 other vaccines – Sinopharm’s 2 and CoronaVac (July 22).
  • Russia: Sputnik V was registered for limited use (August). Another local vaccine, EpiVacCorona, will reportedly be registered in October, too.
  • UAE: The Sinopharm vaccines were authorized for emergency use there. Those vaccines are being tested in the UAE’s #4Humanity phase 3 trial, and the trial’s academic lead, Nawal Al Kawabi, addressed the committee making the decision (September 14).
  • Indonesia: Authorization for use of Sinopharm’s vaccines, Sinovac’s CoronaVac, and CanSino’s vaccine, is currently planned for November – presumably pending assessment of trial data.

The plans for use of CoronaVac this year in Brazil and Turkey also imply emergency use authorization or approval is expected there.

China was the first country to begin emergency Covid-19 vaccine use, and it’s also the one using the vaccines on the largest scale. By late September, it was reported that 350,000 people had received Sinopharm vaccines, tens of thousands the Sinovac one, and the extent of military use of CanSino’s one hasn’t been reported. A pilot scheme in one province for rolling out vaccines through the usual CDC vaccination system has started.

Officially, there have been no serious adverse events, but no formal report of adequate surveillance has been published. At a press conference in Brazil, it was reported that 50,027 Sinovac employees had been vaccinated, with a 5.3% rate of non-severe adverse events, and a 0.03% rate of severe events – but that’s all I’ve been able to find. Now that we’ve heard about results from Brazil, along with the phase 2 trial, unless they mean a 5.3% rate of moderate adverse events, that would be implausibly low.

Russia was up next, but their Industry Minister said the goals that had been announced weren’t feasible – they have been having trouble scaling up production of stable vaccine.

I haven’t seen a report of how many people have been vaccinated in the UAE, but it’s the only place I’ve seen a report for what you sign up for when you get vaccinated in the program – and it’s clearly going to be an important supplementary source of safety data:

Meanwhile, emergency use authorization of Covid-19 vaccines became a political football in the US election, leading to a majority of Americans being concerned about anything other than full FDA approval. Now, Helen Branswell reports, “there are serious signs” that the FDA “is getting cold feet”, too. They may be considering the more limited route of an expanded access program – that’s the way convalescent plasma was made available, for example. The reason? Concern about the impact on ongoing clinical trials of issuing authorizations.

Apparently, the concern has been heightened by BNT/Pfizer’s plans to unblind their trial and offer vaccination to the people in the placebo group if the vaccine is effective. And then, Branswell reports, there’s the concern that people would pull out of trials anyway and go and get vaccinated under emergency use.

I’m not convinced about that last concern. When I wrote a post here back in 2015 about the problems of trials being stopped early, I dug into this. I found 2 studies where the people in trials were told of the results and asked if they wanted to continue: in one (breast cancer), few pulled out, and in the other (HIV), only 26% did. It’s shocking, isn’t it?, that we consult trial participants so rarely about these decisions, that we don’t have a strong evidence base to guide us on these issues.

First trials in children underway

Cartoon about including children in clinical trials

Safety is a key issue here. Children can react more strongly to vaccines, and while they can get sick from Covid-19, the risk of the disease is very low for them. So the benefit-harm balance could tip very differently than for adults. The American Academy of Pediatrics called on the US government to ensure that children and pregnant women are included in the vaccine trials, so that informed decisions about safety can be made. The recommendation wasn’t acted on for the NIH/Moderna trial. But others have moved forward.

In September, the BNT/Pfizer phase 3 trial expanded to include 16- and 17-year olds. A few days later, Sinovac registered an early stage randomized trial (phase 1/2) for CoronaVac in China, for 552 children aged 3 to 17 years.

In mid-October, Pfizer announced that they now had FDA approval to drop the age for participation in their phase 3 trial to 12 years.

In late October, the leader of the Brazilian phase 3 trial for Sinovac’s CoronaVac announced children and pregnant women (as well as people over 60) would be studied too. That hasn’t been registered yet, and presumably isn’t yet underway.

The Oxford/AstraZeneca phase 2/3 trial in the UK registered a group for some younger people, but that hasn’t been acted on.

The first vaccine trial in children may have happened well before this, though. A first-in-human trial (phase 1) was registered in China reporting that it began in February, including babies from 6 months. I was shocked at the time. That far in the front line was too much for me. I haven’t seen any further information on that vaccine or that trial, though, so it’s not possible to know if any babies or children were vaccinated.

The 2 trial pauses for safety review lifted

Both the Oxford/AstraZeneca and Janssen/Johnson & Johnson (J&J) phase 3 trials have just got the FDA’s green light to resume. Let’s start with the one that was paused quite recently: J&J, on October 11. It’s not clear from the company’s statement if the serious adverse event occurred in a person in the vaccination arm of the trial. However, it was determined it was unrelated to the injection.

Matthew Herper summarized, with Helen Branswell, the first reports of what’s known. Anonymous sources reported it was a stroke in a young man.

The Oxford/AstraZeneca trials were first put on hold back on September 6. (I detailed the timeline in my last monthly post.) While its trials in other countries resumed, the US one didn’t restart till the same time as J&J’s did: Late October. It was the second time the trial was paused for safety review, and it’s still not clear what happened. So there’ll be a lot of eyes on the informed consent form for the re-started US trial.

In late October, too, the death of a participant in the Oxford/AstraZeneca trial in healthcare workers in Brazil was reported. The trial wasn’t paused, so although little has been said publicly about it, it must have been a person in the placebo group. Unconfirmed reports are that it was a 28-year-old doctor who tragically died of Covid-19. Which would make it the opposite of a safety concern about the vaccine: It’s a reminder of why the vaccine trials are so important.

Overview of phase 3 trials

For the vaccines at the front of this race, it’s a waiting game now – if the virus is circulating, it takes time till enough people get sick to show a difference. You can increase the chances an answer will come more quickly, though, by increasing the size of the trial. And that’s what several of these trials have done. For example, BNT/Pfizer and NIH/Moderna phase 3 trials began on the same day, both aiming for 30,000 or thereabouts. They both got to 30,000, but NIH/Moderna are stopping there. BNT/Pfizer upped their goal to around 44,000 (and expanded the eligible groups, too).

Since the last post, the J&J trial started, and 2 vaccines were added to this list of phase 3 trials either underway, or definitely about to be: Novavax (USA) and Covaxin (India).

A spate of protocols for phase 3 trials were released. With a single exception (the CoronaVac trial in Brazil), it was the US trials that are going through the FDA’s processes and public release of data requirements:

There has been a lot of discussion of the different approaches to interim analyses in 3 of these that were published first (J&J’s and CoronaVac’s arrived later). See for example a post by statistician Stephen Senn. But there are other differences between the trials that will have important impacts. For example, their different approaches will mean the age mix will be different – and it highlights how much isn’t standardized between the trials (such as the all-important age groups).

This month I’ve added a new table, charting how close the phase 3 trials are to recruiting all their planned participants. Across the last few months, the trials have mostly enlarged their target sizes, and the front runners have shuffled a bit. Oxford/AstraZeneca and CanSino kept losing ground month over month, and BNT/Pfizer joined Sinopharm, Sinovac, and NIH/Moderna out in front, with J&J coming up quickly behind them – likely overtaking Oxford/AstraZeneca and CanSino, too.

What phase 3 trials might be next to join the group? Eyes peeled for a big US trial for the Novavax vaccine – and for one for a DNA vaccine from AnGes in Japan.

Phase 3 trials: recruitment progress

VaccineTarget sizeSingle or similar trials?Reaching target? (October 28)
Ad26.COV2-S
Johnson & Johnson
USA
60,000Single trialMonths away
Ad5-nCoV
CanSino
China
40,500Mostly single trialMajor trial reportedly fully recruited (or close)
BNT162b2
BioNTech/Pfizer
Germany
43,998Single trialLess than a week away: 96% recruited
ChAdOx1 nCov-19/AZD1222
AstraZeneca
UK (Oxford Uni)
54,1903 very different large trials (plus some small)Largest trial months away: 1 in 10,000 healthcare workers, months way (70% recruited after 4 months); 1 unknown. Small ones, unknown.
mRNA-1273
Moderna
USA (NIH)
30,000Single trialFully recruited
NVX-CoV2373
Novavax
USA
45,0002 trials (1 not yet underway)Months away (5,500 out of 15,000 recruited in 1)
Sputnik V (Gam-COVID-Vac)
Russia
43,600Mostly single trialTrial of 40,000 possibly months away (over 30% recruited)
Inactivated virus vaccines
2 BBIBP-CorV vaccines
Sinopharm
China
60,300+2 large trials, several smallTrial with 45,000 close (close to 90% recruited)
Others: months away
CoronaVac
Sinovac
China
27,980+2 large trials, 2 smallTrial with 13,060 healthcare workers close (over 90% recruited)
1 small trial fully recruited
Others: months away
Covaxin
Bharat Biotech, Indian Medical Research Council
India
28,500Single trial (not yet underway)Months away
Total participantsOver 430,000
planned
Over 150,000 likely to be already recruited
(Further details on trials in next table.)

Behind all these numbers are a lot of amazing stories. There’s a terrific story by Bojan Pancevskii and Jared S. Hopkins about BNT (BioNtech), the founders of that small company, and how they teamed up with Pfizer on their vaccine and vaulted into the first group of vaccines to approach the finishing line. And I gathered a bunch of fascinating women scientists here:

This next table breaks down where the phase 3 trials are, and what earlier stage results they have preprinted or published. The most striking thing about this to me is that we still have not seen phase 2 outcomes for the NIH/Moderna vaccine.

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. 60,000
(Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, 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) n.a. b1:

 

45
(USA)

b1:

60
(Germany)

b1 & b2:

195
(USA – incl 45 above)

n.a.

43,998 (b2)
(Argentina, Brazil, South Africa, Turkey, USA – cleared to start in Germany)

ChAdOx1 nCov-19/AZD1222
AstraZeneca
UK (Oxford Uni)
Primate, non-primate n.a. 1,077 n.a.

54,190:

12,390**
(UK)

 

30,000
(USA)

10,000
(Brazil)

1,700
(India)

100***
(Russia)

mRNA-1273
Moderna/NIH
USA
Primate, non-primate 85 n.a. Unpublished (600) 30,000
(USA)
NVX-CoV2373
Novavax
USA
Primate, non-primate n.a. 83 n.a.

45,000:

15,000
(UK)

30,000
(planned Mexico, USA)

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

Unpublished n.a. 76 n.a.

43,600+

40,000
(Russia)

100
(Belarus)

2,000
(Venezuela)

?
(UAE)

1,500** (India)

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 Unpublished
(144)
n.a. 600

27,980+:

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

 

13,300
(Turkey)

1,620
(Indonesia)


(Philippines)

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)

 

Clinical trial results since the last round-up

Janssen/J&J – Phase 1/2a trial

A preprint was posted reporting partial data for a phase 1/2a trial randomizing people to vaccine or placebo. Half were aged 18 to 65, and half were over 65 (up to 88). They had groups in each age group for high and low doses, and 1 or 2 injections. A single injection has gone into phase 3.

They didn’t unblind the data, as the participants are continuing in the trial – some having 2 injections still haven’t had their second injection. So we don’t know how many of the people had a higher dose than has gone into phase 3.

They reported on adverse events data for 796 people after the first injection (both doses) were midway along the spectrum for Covid-19 vaccines – common in the younger group, and less common in older people. There were 2 serious adverse events: 1 was vaccine-related fever (and the person was hospitalized because Covid-19 was feared); and the other was not deemed vaccine-related (hypotension). For the younger group, the rate of mild to moderate fever was 14% and severe fever 5%; for the older group, the rate for mild to moderate was 4% (no severe fevers).

 

NIH/Moderna’s mRNA-1273 – Phase 1 in people over 55

Still no phase 2 results for this vaccine, but they published encouraging results of a second phase 1 trial of their mRNA vaccine – this time 2 different doses, in people over 55, split in 2 groups (56 to 70, and over 70). Altogether, 40 people were in this trial: half in each age group, and half again between the 2 doses (10 people in each group).

This was very small, again. We have still seen very little data in humans for this vaccine. The signals for an immune reaction in both the age groups were at a level similar to that of the younger people in the other phase 1 trial.

As with the first trial, adverse events were at the higher end of the spectrum for Covid-19 vaccines. There were no serious adverse events, though. At the dose that’s gone to phase 3 trial, 70% had systemic reactions, including 1 out of the 20 people experiencing a severe adverse event (fatigue). There was another severe adverse event (hypoglycemia), but it was judged to be related to fasting and exercise, not the vaccine.

 

Sinopharm’s BBIBP-CorV (Beijing) – Phase 1/2

The results of the phase 1/2 trial of this inactivated vaccine was published in The Lancet, including 640 participants. Of those, 192 people in 2 age groups were randomized in phase 1 to various doses. There were no severe or serious adverse events. In phase 2, 448 people were randomized to 2 doses in different regimes. There were no serious adverse events, and 1 severe one (fever). All up, 23% of 336 injected with any dose of the vaccine experienced an adverse event. Fever was the single most common adverse event, ranging from 1 to 4% from group to group. So as with other inactivated vaccines, this one is at the low end of the spectrum for adverse events.

 

 

 

~~~~

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

 

Update [October 26]: Information about likely CoronaVac availability in Turkey added.

Update [October 28]: Added Novavax protocol. Updated Novavax and BNT/Pfizer vaccines in tables, status of Sinovac’s planned trial in the Philippines. Removed duplicate mention of Morocco.

Update [October 29]: Added reported detail about CanSino trial recruitment and locations to tables, corrected error in total CanSino participants.

Update [November 23]: Corrected calculation error in the table of recruitment progress. (Previously 60% instead of 70% for recruited in the Brazilian trial for the Oxford/AstraZeneca vaccine.)

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.

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 preclinical or clinical trial results either as publications or preprints, and associated trial registry entries. They are tagged with names and type of record (e.g. Phase 1). Please let me know if I’m missing any! On October 25, the collection included 150 entries:

  • 59 vaccine groups with published or posted results;
  • 69 preclinical reports;
  • 4 phase 1 trial reports;
  • 9 phase 1/2 reports;
  • 2 phase 2 reports;
  • 5 protocols for phase 3 trials;
  • 1 author reply to letter;
  • 60 trial registry entries associated with these vaccines.*

Discussion
  1. Hi, I have a question not so much about this, but about confidence intervals in general: if you have an effect size of 2.00 (95% CI: 1.33, 3.3), but the effect size is equally likely to fall anywhere in that 1.33 to 3.3 range, why have the initial estimate at all? What does that tell us in addition to knowing the range?

    1. The main thing is that the effect size was precisely that in the particular study: it’s not an estimate in the sense of an approximation. You need to know what happened in that study – including for when you want to compare or combine that study’s results with the results of other studies. (The effect size isn’t equally likely to fall anywhere along the range – and it can also fall outside that range.) Hope that helps.

  2. Hello–May I add another point to your list of issues with respect to the Oxford/AstraZeneca trial results (November news release)? With their efficacy numbers for their 2 subgroups and for the combined group, and their total number of Covid cases, one can derive their numbers of cases.

    The initial 1/2 dose group had 3 Covid cases in the vaccinated cohort, and 31 cases in the placebo cohort. For the initial full dose group, there are 27 Covid cases for the vaccinated cohort, and 70 cases for the placebo cohort.

    One can use Poisson statistics to compare their results, based on these numbers. For the 1/2 dose group, the efficacy is 0.90 +/- 0.08. For the full dose group, the efficacy is 0.61 +/- 0.10.
    And the difference between the efficacies for the 2 groups is 0.29 +/- 0.13, just over 2 standard deviations.

    So, statistically these 2 groups may indeed have different efficacies, but we would really need to wait for more cases. And, these statistical differences would only be valid if the data were not massaged.

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