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The Clinical Trial Results Stampede Begins: Covid-19 Vaccine Race, Month 7

We’re now into the seventh month since sequencing of the genome of SARS-Cov-2, the virus that causes Covid-19. This is the second of monthly roundup posts on the Covid-19 vaccine race.

This month, we’ve had a rush of important “first-in-human” trials results. But before we dig into them, let’s take a helicopter view of the state of the vaccine race now that a bunch are at the phase 3 trial stage. Those are the big trials you need to find out whether a vaccine protects people from getting infected and/or getting sick and severely ill. They’re essential to get marketing approval from agencies like the US Food and Drug Administration (FDA).

We can’t really compare the vaccines to each other yet. There is a lot of churn as they settle on issues like dose, and for some groups, settling on choices among multiple candidates. They are measuring outcomes in different ways, too. The numbers of people are still relatively small, and only some have results for people older than 55. On top of that, we know so little about Covid-19 and immunity to it, so we don’t have definite thresholds for biological indicators.

As if all that’s not bad enough, the compressed timelines mean a lot is being shoehorned into single trials. Some of the trials are expanding like concertinas every few weeks. I’ve seen one trial grow to 30 arms – so far. Interpretation is going to get awfully complex, even within many of these individual trials. (My explainer on the nightmares this kind of multiple testing causes here.)

Cartoon joke about a 46-armed vaccine trial

I took some fiendish delight in fiddling around with the meaningless image for the cartoon above – I clearly had a lot of pent-up feels about the pain of doing the real thing! But while the diagram is nonsense, the trial she’s describing isn’t exaggerated at all, as you’ll see below.

Phase 3 trials underway or on the starting blocks

There are 7 Covid-19 vaccines in 6 phase 3 trials that have already started, or will start in the next few weeks. Others are breathing down their necks, too. Just as it’s hard to compare them on all the grounds I’ve already discussed, it’s hard to compare them in terms of speed in the race, too. So much can change so quickly, when so many racers are so close together.

I’ve put them in the table below, noting what studies they have published/preprinted, and what’s known about phase 3 trials either underway, or likely to be in the next few weeks. I’ve listed the vaccines in alphabetical order by name, with the gene technology-based ones first, and the “old school” inactivated vaccines afterwards.

Keep in mind when you look at the sizes of studies, that some are studying a single dose, while others have multiple groups with different doses (and in one case, multiple vaccines). For phase 3 studies, how big they need to be depends on issues like, how likely are people to be exposed to infection – if the trial is in a community with little virus circulating, it needs to be larger or there won’t be enough “events” to measure. The size of the effect they expect is another issue like that – the more effective a vaccine is, the fewer participants it will take to reveal a difference with placebo.

Vaccine

Company
Country
PreclinicalPhase 1
results


People
Phase 1/2
results


People
Phase 2
results


People
Phase 3

People
Country
Ad5-nCoV
CanSino
China
Non-primate only108n.a.508(Reportedly
40,000 planned)
BNT162b1-b3
BioNTech/Pfizer
Germany
(“De”)
Unpublishedn.a.b1:

45
(USA)

b1:

60
(De)
n.a.b2:

30,000* (USA – coming: Argentina, Brazil, Germany)
ChAdOx1 nCov-19(Covishield)
AstraZeneca
UK (Oxford Uni)
Primate, non-primaten.a.1,077n.a.10,260**
(UK)

2,000
(Brazil)
mRNA-1273
Moderna
USA (NIH)
Primate, non-primate45n.a.Unpublished30,000
(USA)
Inactivated vaccines:
BBIBP-CorV x 2
Sinopharm
China
Primate, non-primaten.a.Unpublished
(1,120)
n.a.15,000 (UAE)
PicoVacc (CoronaVac)
Sinovac
China
Primate, non-primateUnpublished
(144)
n.a.Unpublished
(600)
8,870 (Brazil)
Vaccines with published or preprint results (and/or Phase 3 trial register entry)
* a combined phase 1/2/3 trial, with 2,000 phase 1/2
** a combined phase 2/3 trial
n.a. = not applicable (where only combined phase 1/2 trial so far reported)
Sources: tagged in my public Zotero collection

Ad5-nCoV (CanSino, China)

This team is one of the 3 I discussed last post. What’s new this month is the publication of their phase 2 interim results, in The Lancet. Their phase 3 trial wasn’t registered as of writing. Their spokesman had said they would be negotiating with various countries to run a 40,000-person phase 3 trial after the phase 2 results were public. Place is key: if there’s very little Covid-19 in circulation, then the trial won’t have enough events to show how the vaccine performed against placebo – events like people getting sick, or severely ill. The candidate countries they’re in discussion with? United Arab Emirates (UAE), Canada, Brazil, Indonesia, and Mexico.

Update:

How’s the vaccine itself shaping up? This one’s challenge is the “Ad5” part, short for Adenovirus 5. While people aren’t likely to be immune to the SARS-Cov-2 part of the vaccine, many people’s immune systems recognize the horse it’s riding in on – Adenovirus 5. Derek Lowe, a chemist in drug development, wrote that’s about 30% of people in the US, 50% in China, and 80% in China. People older than 55 also showed less strong immune responses.

The authors of the trial report wrote that a lower dose they studied appeared to be enough: presumably that’s what’s going to phase 3 trial. The vaccine produced both antibody and T-cell response. Only 1 person (1%) with the lower dosage reported severe levels of adverse effects. And it’s likely to be a single injection. That puts it towards the lower end of adverse effects for the Covid-19 vaccines so far – but it’s far too early to know how it will pan out. A single injection would have several advantages, including potentially for effectiveness outside trials, because of the possibility of drop-off for second injections.

This vaccine is the first to get authorized for use: it has one year’s authorization for use in military forces.

BNT162b2 (BioNTech/Pfizer, Germany)

This is the second of the ones I discussed last time. They had sent several vaccines into a phase 1/2 trial in the US, and released a preprint with interim results for the one called b1. That paper reported on antibodies. A single injection at the lowest dose had no adverse effects that were moderate or worse.

Their new preprint was from a phase 1/2 trial in Germany for b1, this time with interim data showing T-cell response. The preprint doesn’t report much on adverse events, although the authors suggest similarity to the US one. (Neither preprint has much data on this, though.)

Update: BNT/Pfizer announced on July 27 that they had the go-ahead from the FDA to start phase 3 for b2 – and they are hoping to be seeking emergency use authorization as soon as October. It will be 2 injections of a 30 microgram dose. The Phase 3 trial registry record also includes arms for people aged 65 to 85.

Although they are a German company, they chose their US phase 1/2 trial to scale up to phase 3. It’s running in many sites, including coronavirus hotspots. Along with groups broken down for age, the whole 1/2/3 trial adds up to 22 arms. Sites in Argentina, Brazil, and Germany are reportedly to be added.

The primary effectiveness outcome measure is disease (broken down into people who had signs of SARS-Cov-2 infection before vaccination and those who did not). Secondary measures include severe disease, and signs of having been infected.

This month, the US signed its biggest contract yet for purchasing doses of coronavirus vaccine by the end of this year with Pfizer: $1.95 billion.

ChAd5-Ox1 Cov-19 aka Covishield (Oxford University/AstraZeneca, UK/Sweden)

This is the third of the vaccines that were covered in the last post, too. At that point, they had no published results in humans. But I had questions about why paracetamol/acetaminophen arms got added to their trial registry reports soon after they started. That became clear when their interim results of their phase 1/2 trial were published. It has by far the largest number of participants we can see so far.

This vaccine, too, showed response for both antibodies and T-cells. But adverse effects rated moderate were very common for several, and some reported to be severe were common. It’s for the 2-injection regimen at the same dose which has gone into phase 3 trials. As I’ve said, it’s far too soon to be able to compare vaccines to each other – especially when some have released comparatively little data. That said, the decision to add groups with paracetamol could be a signal that tolerability is a particular issue to watch with this vaccine.

Last time, I wrote that this vaccine had a high “activist risk”, in part because it had no placebo group. Having another vaccine as a comparator, though, helps to put the adverse effects in perspective. Take headaches in people without routine acetaminophen for example. Here’s what that looked like in one example of an adverse effect where moderate rating was very common for the Covid-19 vaccine, but not for the comparator one:

VaccineNoneMildModerateSevere
Covid-19 (n = 487)32%34%28%6%
Meningococcal (n = 477)59%35%5%1%
Headaches for people without preventive paracetamol

This was the first non-Chinese vaccine known to start phase 3 trials. The dose is the same as for the results above: 100 micrograms. One is a phase 2/3 trial aiming for just over 10,000 participants in the UK, where there currently aren’t major outbreaks. That’s the trial with 30 arms, including different age groups. They’re almost all adults. Confusingly, there’s an entry in a different trial register that has some differences, including in number of participants. There, the number of children in the 5 to 12 year age group is listed as 60.

The other is a phase 3 trial for 2,000 healthcare worker participants in Brazil, which is currently a coronavirus hotspot. The control groups are meningococcal vaccines again. The primary effectiveness outcomes are illness, with severe illness and infection among the other measures.

Reportedly, phase 3 trials are also coming in the US and India soon, too, but it’s not clear how long that will take to set up. I couldn’t find a trial registration entry for either. BNT/Pfizer, NIH/Moderna, and the inactivated virus vaccines below appear to be further ahead on large trials in areas with outbreaks. Perhaps that’s why this group is the only one out of this set of vaccine developers that’s openly discussing possibly running a human challenge trial. These trials are controversial. They involve exposing a small number of people to the virus to get a quick answer on protection from the virus and illness and other information – but they’re too small to answer questions about adverse effects. I think that last feature means that the activist risk factor here would be through the roof.

Those reports of a deal for a trial in India say this vaccine is going to be called Covishield, at least there. I wonder how long it will be till I stop thinking of it as Chad?

By the way, the “Ch” is for chimpanzee, and the “Ad” for adenovirus – which means it’s not an adenovirus that humans get, unlike the CanSino vaccine discussed above.

mRNA-1273 (Moderna/NIH, USA)

This is the last of the vaccines discussed in my last post. Since then, the first of its interim results in humans have been published – a phase 1 trial, so it’s small. It doesn’t have non-vaccine comparisons. No phase 2 data yet. The phase 3 trial is large and simple: 30,000 people getting either a 2-injection regimen of the mid-range dose (100 micrograms) from the phase 1 trial, or a placebo (saline injection).

Again, the primary effectiveness outcome measure is Covid-19, with both severe illness and infection among the secondary outcomes. It’s for adults with no upper age limit, and it’s in 87 locations around the US, including coronavirus hotspots.

Back to the interim phase 1 results: the publication reported both antibody and T-cell responses. For the 15 people at the dose going forward in the phase 3 trial, all reported adverse effects, and for all but 3 people, they were enough to interfere with their activities – none were severe.

With no phase 2 data, and such a straightforward plan for the phase 3 trial, there’s not much else to say – other than that this vaccine, along with Chad – sorry, Covishield! – has the vaccine hype problem I discuss later.

BBIBP-CorV (Sinopharm/CNBG, China)

Now we’re into “old school” inactivated vaccines that are in phase 3 trials. Clinical trial data hasn’t been published here yet. I’ve seen BBIBP-CorV discussed as 1 or 2 vaccines, so I could be wrong here: I’m assuming it’s 2.

Sinopharm is state-run, with a corporate subsidiary, the China National Biotec Group (CNBG). BBIBP-CorV vaccine(s) has/have been through a phase 1/2 trial, with 1,120 people. CNBG posted some interim results on their website in June, which reports positive antibody responses, but no detail on adverse effects. It has reportedly been said that adverse effects will be lower than other vaccines – which would not be surprising for inactivated vaccine.

The phase 3 trial is underway in Abu Dhabi, United Arab Emirates (UAE). UAE was reporting about 500 people or so with new confirmed Covid-19 a day in June, according to Wikipedia. It’s a country of about 10 million people. So there’s some virus circulating.

If I’m understanding the trial registry entry properly, this will surely be the first phase 3 trial with interim results. The trial measures effectiveness in protecting against infection just 14 days after the 2-injection vaccination course is completed. It’s for 15,000 adults with no upper age limit, with 2 groups of 5,000 people for each vaccine and a 5,000-person placebo group. (It’s not specified what each of the 2 groups are, but it’s why I’m assuming there are 2 vaccines.)

China can reportedly produce 200 million or more doses of this vaccine a year, including using a new production facility that was scheduled for completion at the end of July. A production deal has also been reported between UAE/China and Indonesia.

PicoVacc aka CoronaVac (Sinovac, China)

Another inactivated vaccine, again with only preclinical results published. Again, the company’s website includes a statement on the first-in-human trial.

The phase 1 and phase 2 trials have a combined trial register entry, for 744 anticipated participants. The statement reports 743 participants aged 18 to 59 with 2 injections: over 90% of people showing “seroconversion” and “a good safety profile”.

The statement also said there will be a phase 2 trial with elderly adults, and then children and adolescents. There is a trial register entry for phase 2 in people 60 and over.

The phase 3 trial is underway in Brazil, recruiting 8,870 healthcare workers. There are 4 arms, for 2 injections in 2 age groups – 18 to 59 and 60 and over – with a placebo group each in the same age groups. The primary effectiveness outcome measure is Covid-19, first in 2 weeks after the full course of injections, then at 1 year. Severe disease and infection are among the secondary outcomes.

The dangers of vaccine hype

The phrase of the month was the classic “promising results”. My thoughts on that are here, but the cartoon below sums up what I think: promising results are the larval stage of disappointing ones. Not always, of course, but look at the history of something labeled “disappointing”, and you’ll generally find some version of “promising” preceded it.

Cartoon of promising results being the larval stage of disappointing results

In my Month 6 post, I talked about the high “activism risk” of downplaying vaccine adverse effects. This month, quite extreme downplaying exploded across mass and social media, triggered by uncritical acceptance of claims in press releases of journals, vaccine developers, and drug companies. The general message was that particular vaccines had only minor side effects. I unpacked that and discussed why I think that’s dangerous in an op-ed over at WIRED. There was good news, though: for all of the vaccines that have published human data now, none had serious adverse events at the doses known to be going on to phase 3 trials.

For me, vaccine hype is a matter of principle and ethics. Many people seem to believe, and quite strongly, though, that what I wrote is harmful. In the op-ed, I didn’t get into the research about why I believe what I do about downplaying adverse effects.

The op-ed will be used as ammunition against vaccines, for sure: anything that discusses adverse effects head-on will be. I believe though, that harm comes from myth-making about trivial adverse effects, not its corrective. Without any discussion at all, the myth-making becomes a coverup, and perfect fodder for sowing doubt about trustworthiness of people who advocate for vaccines.

At the very latest, you can’t hide levels of adverse effects that are higher than people expect once a vaccine is rolled out. You don’t need to be an epidemiologist to see it if the rate is very high: it’s happening all around you. If there’s a potent scare campaign, uptake of a vaccine can plunge dramatically, as it did with HPV vaccines in several countries. (I talk about this in one of my – many! – posts about HPV vaccine battles.)

Trust is critical, and it’s complicated. With vaccines, trust “is not constant over time and space, [it] can be reinforced or disrupted at any given moment, and may take a long time to rebuild” (Ozawa 2016). “Overstating vaccine safety” is one of the major communications strategies identified as unhelpful for health professionals who want to maintain patients’ trust (Leask 2012). The authors of a systematic review concluded that the implications of retaining people’s trust in reliability of information-givers is critical across the board:

If trust is lost in the vaccine-related players, then trust is more likely to be placed in other influencers, who may be indifferent to vaccination or may actively oppose it.

Heidi Larson & colleagues (2018)

It’s going to be an awfully tough and daunting tightrope to walk for Covid-19. There are some standards that can help here, but not enough. There are rules for pharmaceutical companies in the USA and Europe about communicating adverse effect information in product leaflets that include a helpful objective standard I try to adhere to:

  • FDA: Common effects are “e.g., all adverse reactions occurring at a rate of 10 percent or greater in the treatment group and at a rate at least twice the placebo rate”.
  • European Medicines Agency (EMA): An adverse effect is “very common” if 1 in 10 or more (10%); “common” if 1 in 100 or more (1%) and less than 10%; “uncommon” if 1 in 1,000 or more and less than 1%; “rare” if 1 in 10,000 or more and less than 1 in 1,100; and “very rare” if less than 1 in 10,000 people.

It’s critical that the community can develop realistic expectations of these vaccines. At the moment, it’s looking as though the first vaccines at least might not be as highly effective as we want them to be – and likely less so for the people most vulnerable to this awful disease. Many won’t be able to have the vaccine at all, and so will have no choice but to rely on everyone else to get us to community immunity. What might that mean?

Authors of recent simulation experiments concluded if there were 100% uptake, a Covid-19 vaccine would only need to be 60% effective to “extinguish an ongoing epidemic”. If the virus was roaring around, but only 75% of people got vaccinated, the vaccine would need to be 80% effective. The standards being set by FDA and others is an acceptance of effectiveness as low as 50% – and that could be for effectiveness against getting seriously ill from Covid-19, not necessarily for not getting infected and transmitting it to people who aren’t vaccinated.

It seems more likely than not that we will get vaccines. But we could still be on a knife’s edge. We need to start getting prepared for what could be a very heavy lift to achieve community immunity globally. We can’t afford to torch our trustworthiness.

In other recent news…

  • CONCTVACT was announced: it’s an Africa CDC Consortium for Covid-19 Vaccine Clinical Trials, launched by the African Union Commission. The aim is to negotiate more than 10 late-stage trials on the continent & secure access to the vaccines too. It will have an independent review board.
  • Of the 5 pharmaceutical companies at a hearing with US lawmakers on July 21, only 2 spokespeople undertook to set a price for Covid-19 vaccine without profit during the pandemic: AstraZeneca and Johnson & Johnson. The 3 that didn’t were from Merck, Moderna, and Pfizer.
  • CureVac: the German company signed a big deal with pharma giant GSK. for its mRNA vaccine.
  • Sinopharm reportedly tested its vaccine on company executives in February – before authorities had issued approval for a first-in-human trial.
  • NIH-Moderna: more revelations about Moderna executives’ stock selling – and reports of delays caused by disagreements between the NIH and Moderna about the phase 3 trial protocol. Moderna is in patent disputes about the vaccine’s RNA technology, too, which is sure to get fierce and expensive.

There has also been a spate of vaccines entering first-in-human trials, either phase 1 or phase 1/2. At some point, I’ll get back to helping make sure that the Wikipedia page is up-to-date on them: if you can pitch in, please do! But in this monthly roundup, I’ll keep concentrating on trials with published results, and news on phase 3 trials.

Want to sign up for a clinical trial for Covid-19 vaccine?

The US has a sign-up platform – currently only for people in the US, but they say it will expand internationally: it’s called the COVID-19 Prevention Network.

In the UK, you can sign up to be available for approved coronavirus vaccine studies at the COVID-19 Vaccine Research Registry.

If there isn’t a system like that for you locally, try googling for a vaccine trial in your country: big trials will often have their own website that comes up high in a search. Another option is to search a local clinical trial registry (Wikipedia has a list) or this international one. Search for SARS-Cov-2 and vaccine. If there are any listed as recruiting or not yet recruiting in your area, there could be contact details.

If I’m missing a sign-up service, please let me know via Twitter or in the comments below. (I moderate all comments, so if it’s just a message and you don’t want the comment published, just let me know.)

Finally, a definite sign I’m becoming optimistic there really will be Covid-19 vaccines! I’ve started joking about what their proper names are going to be:

~~~~

Cartoon of facing off coronavirus

All the monthly Covid vaccine race posts

First-in-Human Covid-19 Trials and Tales of Phase 1 Clinical Trials Past

All previous Covid-19 posts

I’m deeply grateful to Zhiwei Xu (and Jenny Doust who connected us) who bailed me out when I hit a wall at one stage looking for the trial register entry for Sinopharm’s phase 3 trial.

Update on 28 July: BNT/Pfizer announced their phase 3 trial would be for b2. The first version of this post drew from the trial register record for the trial, which listed 3 candidates at the time of writing.

Update on 29 July: NIH/Moderna published a further article on preclinical research for mRNA-1273, in primates. Table updated.

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.)

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 July 23, it included:

  • 19 vaccine groups with published or posted results;
  • 18 with preclinical reports;
  • 2 vaccines with phase 1 trial reports;
  • 3 with phase 1/2 reports;
  • 1 phase 2 report;
  • 21 trial registry entries associated with these vaccines (some with multiple, some with none).
Discussion
    1. It is – the vaccines are in alphabetical order by name, in both the green table and the text that follows, so keep scrolling and you’ll see it.

  1. Dear Hilda

    I am a general internist working in Argentina
    Me and some of my colleagues from Argentina think that a position paper about covid-19 immunogenicity as surrogate for vaccine efficacy and approval may be relevant at this time, because we are skeptical that “significant” infection reduction may be achieved until the end of the year in ongoing trials

    Are you working in any similar project? what do you think about it?

    any other relevant info to share? any other ideas?

    Many thanks for your valuable time
    Kind regards

    1. Not working on it, and I believe that would be running a large risk of getting it wrong, as well as facing public acceptance issues. I’m not counting out preliminary data showing effectiveness sooner than the end of the year.

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