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Covid-19 Vaccine Race, Month 6: First Emergency Use & Phase 3 Trials

We’re now into the sixth month since the genome of the new coronavirus was sequenced. Twelve to 18 months is the soonest a vaccine could be available: we’ve been hearing that since late February. So where are we now?

Hurtling along at breakneck speed, basically. Whether you find that exciting and/or frightening, either way, this one is a nail-biter. It’s a race of hares versus tortoises, where even tortoises are quick on their feet. But then, so is the disease we’re really racing against. More than half a million deaths had been already been attributed to Covid-19 in June, with thousands more being reported every day.

This is the first of monthly roundup posts about the Covid-19 vaccine race. Some background first about clinical trials: phase 1 and 2 trials are the first progressively larger safety and efficacy hurdles; in phase 3 come the large-scale randomized trials that tackle whether the vaccines work well enough, and safely enough, to get market approval. (More in my post on first-in-human trials for vaccines.) Usually, market approval from a regulatory agency like the US FDA is needed to use a vaccine in the community. But those agencies can also authorize emergency use of a drug – as the FDA did for Covid-19 use of the ill-fated hydroxychloroquine – and they could do it for a vaccine.

These are some of the main questions I’m keeping in mind as I try to keep perspective on any specific vaccine:

  • What’s the track record of the type of vaccine? For many of these vaccines, if the Covid-19 one makes it through to market approval, it will be the first of its type ever to get that far.
  • What’s the track record of the developers/manufacturers?
  • Are the trials looking good enough, and will the phase 3 trials be run in places with active outbreaks?
  • Do the phase 3 trials aim to prevent infection – which will be needed for community immunity – or only disease? And do they work well for older people?
  • Are the pre-clinical and clinical trial results transparent, and what’s the quality of the data?
  • What are the production and distribution implications of the vaccine?
  • How accessible is the vaccine going to be, to whom, and how quickly?
  • What’s the “activism” risk factor for this vaccine? That’s not a technical term: it’s my shorthand for thinking about how easy will it be for people to sow seeds of doubt about this vaccine, over and above it being fast-tracked?

That’s a lot of questions! There are so many hurdles for a vaccine to clamber over, it’s no wonder that few make it.

What are the big recent developments and published research? Let’s start with the last question in my list, to explain it, and a big move in June on that front. Campaigning against these vaccines is likely to be intense. The first ones will be the riskiest here, in part because of likely corner-cutting, and partly by definition: it’s easier to go faster with vaccines based on novel genetic engineering methods. That’s one of their attractions in the vaccine field. But they are so novel, they are facing the “first ever” hurdle.

To be super-simplistic: “old school” vaccines use the pathogen – the bacterium or virus that causes a disease – in some form to spur our immune systems to develop immunity to it, hopefully without making us sick. The new methods use a part of the pathogen’s genetic material to give our cells instructions on how to fight the real thing. For SARS-Cov-2, the virus that causes Covid-19, that’s typically using the protein spikes on the outside of the virus.

Cartoon dreaming of coronavirus spikes

This month, the European Commission removed a regulatory hurdle to those more novel types of Covid-19 vaccine: they announced temporary relaxation “from certain provisions of the GMO legislation to speed up clinical trials of COVID-19 vaccines and medicines containing genetically modified organisms”.  That’s great news for earlier access to any good vaccine based on genetic engineering. Activism risk factor? Very, very high! Fasten all seatbelts, and knuckle down on learning more about vaccines and genetics than you may ever have wanted to, because this is almost certainly going to be an all hands on deck situation. (I think the infographic/table at the end of this article is a useful overview of the types.)

Note: Some of what follows will be out-of-date – you can see my previous and subsequent Covid-19 vaccine posts here.

The vaccine with the first emergency use authorization (in China) & most published results up to phase 1

On Monday, June 29, the company developing a vaccine called Ad5-nCoV, CanSino, announced it had been authorized for use in the military by the country’s Central Military Commission.

This vaccine is the one with the most results published. On 18 June, Shipo Wu and colleagues posted a preprint of preclinical results. That same week, the Lancet published Feng-Cai Zhu & co’s paper on a phase 1 trial with 108 participants. That is still the only journal publication of phase 1 trial results I can find for a Covid-19 vaccine (although there is a preprint for one more discussed below). A CanSino spokesperson has said peer-reviewed phase 2 results are on the way from a journal in the next few days, with a 40,000 participant phase 3 trial to start soon. That trial hasn’t been registered yet, though, so nothing to assess yet.

The CanSino company was named for Canada/China, because the 4 vaccine executives who started it in 2009 studied in Canada before working internationally and returning to China. A phase 1/2 trial of Ad5-nCov has also been registered for Canada, where CanSino is collaborating with the National Research Council. CanSino’s goal is a vaccine to be available globally. The company had an ebola vaccine approved for emergency use in 2017.

Ad5-nCov uses the SARS-Cov-2 spike protein, carried by a form of adenovirus, Ad5. That’s called a viral vector, and Ad5 has been used before for other vaccines and it’s non-replicating: that means this part of the vaccine has a long track record. The problem with it is that many people are immune to Ad5, which will reduce its effectiveness. The company spokesperson said 60-70% effective would be worthwhile for an early vaccine. (Presumably, people would get a booster of something more effective down the line if/when that became an option.)

From what’s available so far, Derek Lowe concluded that there aren’t serious adverse events in the short-term, and there is “a real immune response to the Spike protein, but with headwinds from Ad5 antibodies”.

The people in the phase 1 trial were aged between 18 and 60, and there were 3 doses (low, medium, high). They were in Wuhan, which was under lockdown, and they all stayed at a hotel for 2 weeks. From 2% to 17% of people (depending on dose) reportedly had adverse events severe enough to interfere with their usual activities (mostly fever, but there were also fatigue, headaches, and muscle pain). They chose both low and medium doses to go ahead to phase 2.

The trial measured T-cell response to SARS-Cov-2, not just antibodies, and there will be follow-up to 6 months after vaccination. At least half of the people getting low and medium doses had at least the minimum antibody response they were measuring: over 90% had a T-cell response.

I think this seems to be a well-conducted and well-reported trial. It was registered at ClinicalTrials.gov and the first people got a dose on 16 March – the same day as the NIH/Moderna vaccine trial which we outside China credited with being first at the time. They were going neck-and-neck with the Oxford vaccine for being the first into phase 3 trial – they will apparently be looking at partner bids after the publication of the phase 2 trial results.

The Oxford vaccine: first trial to go international & first phase 3 trial

This is the most aggressively promoted vaccine, with the most inflated claims. What do we actually know about it? They posted a preprint in May about some preclinical tests in monkeys. That was received with doubt that the results are as positive for safety or efficacy as the developers claim. (The developers and the technology they use don’t have a track record of success.)

This vaccine, called ChAdOx1 nCov-19 seems to me to be at particularly high risk on the activism front. For example, they are the only vaccine among the frontrunners that doesn’t have an inactive placebo comparison group. It’s being compared to another vaccine, presumably to increase the effectiveness of blinding because you would get some adverse effects of vaccination. Not having an inactive placebo arm, though, is a frequent discrediting tactic for trials of vaccines.

In addition, soon after their phase 1/2 trial got started in April, they quietly added extra comparison groups to their trial registry entry: that involved people getting paracetamol (“Tylenol”) every 6 hours for 24 hours after the injection. That’s been dropped for the European phase 2/3 trial with 10,260 participants that they have registered, but the lack of openness about what happened will be a vulnerability if it’s never explained (and maybe even if it is). However, they are now running a phase 3 trial in Brazil, and it has the added paracetamol.

One of the ways this group is moving so fast is compressing and overlapping the clinical trial phases. So they got combined phase 1/2 trials underway before their preclinical test results were in, and have set up a phase 2/3 trial before the phase 1/2 results are in. The phase 2/3 trial only has disease outcomes as primary outcomes – being infected is a just an exploratory outcome. So it’s possible, if this vaccine gets through, that we won’t know if it can break the viral transmission chain. (That trial is also registered in Europe.)

It’s the first vaccine, as far as I can tell, to have begun a trial in a second country, including its phase 3 trial. The group announced at the end of June that the first of another 5,000 people in that phase 3 trial in Brazil had been injected – 55 is the oldest age people will be eligible for that trial. They had just previously announced people were being injected in South Africa. That is another phase 1/2 trial, aiming to randomize 2,000 people.

A BioNTech/Pfizer vaccine from Germany: First published phase 1/2 data for an mRNA vaccine

This one doesn’t get as much publicity, but I think this group is really one to watch closely. Unlike others, they didn’t put all their chips on a single possibility right out the gate: BioNTech sent several candidates into their first-in-human trial. On July 1, Mark Mulligan & co posted a preprint of results for BNT162b1.

These are the first first-in-human results for an mRNA vaccine – that uses modified RNA targeting that virus spike. There are no licensed vaccines like this. These are also the first results available for a compressed phase 1/2 trial. The trial registry entry for this trial reports it was for 200 people in Germany, in all the arms.

For BNT162b1, there were 12 participants randomized to each of 3 dosing regimes, and there were 9 in a placebo group. The vaccine stimulated an immune response with apparently higher levels than seen in the blood of people who have recovered from Covid-19. (More discussion on this at Derek Lowe’s blog at Science.)

Mild and moderate reactions were common, but for 1 person in the high dose group, pain was severe. There were no Grade 4 reactions (life-threatening or disabling). Flu-like symptoms were common, with severe fatigue and chills for some people. The data reported are for the first 2 weeks.

BioNTech has also been running a much bigger phase 1/2 trial for all 4 of the candidates in Germany and the US: 7,600 participants planned according to the trial registry entry.

No trial register entry yet for phase 3 here. Pfizer’s press release says they will pick a lead candidate from the 4 to go into a phase 2b/3 global trial with 30,000 people, possibly starting by the end of July if they get the green light from regulatory agencies. They also say they expect journal publication of the results in the preprint soon.

The NIH/Moderna vaccine: a US public/private partnership with little public data

This is the vaccine that got all the publicity in the English-speaking media for being the very first vaccine injected into people (including in my blog post). It’s another mRNA vaccine, so again, none like it has made it through to market. The company the NIH is partnering with is a young one that hasn’t got a vaccine all the way through before.

The NIH involvement gives this vaccine candidate a giant boost, of course. But it’s had the least data transparency of any of the frontrunners, and that’s disturbing. The lack of transparency alone gives this one a high “activism” risk factor rating, especially because it’s coupled with 2 high-profile pieces of suspicion fodder.

One is a graphic media account of an adverse reaction to a particularly high dose (not the dose that will go forward). The other is the first scandal: after reporting outcomes of just the first 8 people in a trial with 155 participants in a media release, causing a stock market surge, executives dumped $30 million of their stock. That press release was more than 6 weeks ago: and still, no data for that trial has been posted or published. (Trial register entry.)

However, on June 11, Kizzmekia Corbett and colleagues posted a preprint of some of this vaccine’s preclinical research. And the preprint doesn’t adhere to the NIH’s principles and guidelines for reporting preclinical research – for example, they don’t report on how they determined animal sample size. Jeez. When even the NIH doesn’t adhere to its own standards, for one of its highest profile projects, that’s really depressing.

Here’s hoping the vaccine is better than the process. It’s called mRNA-1273. The preclinical research they report on is only in mice (not primates, as with others).

The NIH and individual scientists are keeping some intellectual property right and patents in this vaccine, raising some interesting questions about where this is all headed if this vaccine gets approved.

Other vaccines with posted or published results

  • April 19: Qiang Gao & co, preprint. Preclinical research, primate and non-primate. PicoVacc is an inactivated virus vaccine. (China.)
  • April 25: Paul McKay & co, preprint. Preclinical research, non-primate. LNP-nCoVsaRNA is an mRNA vaccine. (UK.)
  • May 15: Di Yin & co, preprint. Preclinical research, non-primate. ShaCoVacc is an mRNA vaccine. (China.)
  • May 20: Trevor Smith & co, published in Nature Communications. Preclinical research, non-primate. INO-4800 is a DNA vaccine. (UK.)
  • May 20: Jingyou Yu & co, published in Science. Preclinical research, primate. Ad26.COV2-S is a non-replicating viral vector vaccine. (USA.)
  • May 28: Jesse Erasmus & co, preprint. Preclinical research, primates. LION/repRNA-CoV2S is an repRNA virus. (USA.)
  • June 11: Hui Wang & co, published in Cell. Preclinical research, primates and non-primate. This one has data and code published. BBIBP-CorV is an inactivated virus vaccine. (China.)
  • June 19: Yfat Yahalom-Ronen & co, preprint. Preclinical research, non-primate. A recombinant VSV viral vector vaccine. (Israel.)
  • June 23: Xiaoxiao Qi & co, published in Chemical Communications. Preclinical research, primate. (China.)
  • June 30: Jing-Hui Tian & co, preprint. Preclinical research, primates and non-primate. NVX-CoV2373 is a subunit vaccine. (USA.)
  • June 30: Andreas Herrmann & co, preprint. Preclinical research, non-primate. T-VIVA-19 is a recombinant fusion protein vaccine. (USA.)

Please let me know if I’m missing any! I have created a public Zotero collection of all the vaccines with preclinical or clinical trial results, and associated trial registry entries. On July 3 2020, it included 15 vaccines, 14 preclinical reports, 1 phase 1 trial report, and 1 phase 1/2 trial report. (There were 12 clinical trial register entries associated with these.)

Update July 18:

Probably doesn’t need to be said, at this point, but no one has so far published or posted about vaccine candidates that bombed.

And FDA guidance…

Finally, hot off the press, the FDA released its guidance on the development and licensing of Covid-19 vaccines. Primary outcome measures for phase 3 trials can be infection or disease. If infection isn’t a primary outcome for the trial, “it should be evaluated as a secondary or exploratory endpoint”. They also recommend powering trials for severe Covid-19, or at least include it as a secondary endpoint. If it becomes impossible to run these trials, human challenge trials “may be considered”.

And as Alec Gaffney points out, the FDA’s document might presage a more harmonized global approach to allowing vaccine use – which would be great, if the vaccines are good enough.

~~~~

Cartoon of facing off coronavirus

My other monthly Covid-19 Vaccine Race roundup posts

Note on updates: embedded tweets had been included as updates, but these were removed when my next “Vaccine Race” post was done on July 25.

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.)

Discussion
  1. Nicely written, thank you. As a layman and business owner who like many, many others may have to shut out doors for good, even with our $3000 SBA loan /s; and, with your knowledge of the process and emergency use authorizations, what’s your best guess for the {Oxford} vaccine release date – widely released? October perhaps? We can’t last through November. Might as well throw the keys in the door now if its going to be late November or December 2020 before the FDA decides they have pored over the data enough. If a vaccine is tested on > 10,000 people, what’s the chance something could go wrong enough to cause further delay? Social distancing in the US should not curtain the release due to people being overly anxious.

    1. I don’t know. A lot can go wrong in moving too fast: the first big trials will likely be in people selected to be less likely to have adverse effects, for example; there can be manufacturing disasters of various kinds (see my first vaccines post).

  2. Its welcomed information that the mainstream media fails to report. I think we all want these vaccines to work out perfectly and the trials to go smoothly so we can get them out to the general public ASAP. However, like with anything rushed there is always the presumption that corners were cut in order to speed things along. The general public must be convinced that the vaccines are a better choice then simply getting COVID 19 and developing the anti bodies. We already have people who don’t believe in being vaccinated for diseases that were once thought removed from being a threat. Now they are returning because some believe the vaccines are worse. We don’t want unrealistic expectations to destroy confidence in vaccines. We have already seen the public question experts who seem to flip flop of things like mask, transmission threat and treatments. If people start questioning the experts then we have a problem with the public accepting these vaccines. I am a type 2 diabetic and my wife is in heart failure. Neither of us want to get COVID 19 but we also do not want to experience serious side effects from a vaccine either. These companies need to avoid shortcuts and do the proper testing and trials to make sure the population can accept them. Otherwise they won’t be very effective if nobody feels safe with them.

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