As results for the big phase 3 trials for the BNT-Pfizer and Moderna were looming, a debate ramped up: when would the…
We’re into the 12th month since sequencing of the genome of SARS-Cov-2, the virus that causes Covid-19. And we have 2 Covid vaccines across the line of convincing phase 3 trial results released, plus emergency use authorization or approval. How far are we now, and why did some sprint ahead while others fell behind? Let’s start with what we know from the handful of vaccines with at least some data released.
Main takeaways about Covid vaccines so far
- There are important, often major, differences in the characteristics and effects of the vaccines.
- 2 vaccines have been convincingly shown to have high efficacy against getting sick with Covid-19 – BNT/Pfizer’s and NIH/Moderna’s.
- There is a material difference in the rate of adverse events reported between those 2 vaccines:
- Most people had adverse events after the BNT/Pfizer vaccine, but they were generally not severe;
- NIH/Moderna adverse events were more frequent and severe – severe adverse events were common.
- There are too many question marks around the trials of another 2 vaccines to be confident about results – Oxford/AstraZeneca’s and Sputnik V.
- 2 inactivated virus vaccines from China are reported to have good efficacy and very low adverse events, but the data to substantiate that isn’t public. Other types of vaccines anticipated to also have lower rates of adverse events don’t have phase 3 results yet either, but could be public in the next few weeks.
- We don’t know to what extent being vaccinated with any of these vaccines reduces the risk of a person spreading Covid-19 if they don’t know they’re infected – but the vast majority of virus transmission is from people with symptoms.
- We don’t know much about the effects of these vaccines in young children, for people on immunosuppressant medication (including steroids and cancer medications), and in pregnancy and breastfeeding. (A trial of Moderna’s vaccine in people with cancer is being discussed.) We don’t know how long immunity will last.
For people worried about changes in the virus and if this could reduce vaccine efficacy, there would have to be major changes for vaccines to misfire, although vaccines could be adapted to circulating strains in future. (More on that moving target in this Twitter thread.)
Before we dig into details about what we know from results released in the last few weeks for 4 vaccines, let’s put this in context.
3 things needed to get to the finishing line early
The higher the efficacy of the vaccine, the quicker a trial could get you to convincing results. Consider the famous 1954 field trial for the Salk polio vaccine. It was huge, but the result came from just 143 children who got paralytic polio (the “events”). Because the vaccine could prevent most disease, that was enough to be certain. If a difference is small, however, you need more events to be confident you’re seeing a genuine difference.
But if you have a trial placed in the middle of an event storm – here, that event is symptomatic Covid-19 – and vaccine efficacy is high, then the chances of being able to show quickly that the vaccine makes a difference rises dramatically, because people in the control group will quickly get sick more often.
So to be in the front of the pack across the finishing line for a Covid vaccine you needed all 3 of these:
- vaccine with high enough efficacy and safety;
- a tour-de-force phase 3 trial; and
- major Covid outbreaks where a trial was running.
BioNTech(BNT)/Pfizer and NIH/Moderna had all 3 – although NIH/Moderna was completely reliant on outbreaks in the US, and BNT/Pfizer didn’t have all their trial eggs in that one basket.
Back in June/July, the BNT/Pfizer vaccine wasn’t being discussed as a frontrunner in the media. I wrote then, though, that it was one to watch closely. That was mostly because they were investing so carefully in the early development and trials – they tested 4 candidates, in 4 doses (10 μg, 20 μg, 30 μg, and 100 μg), in different age groups before settling on the 30 μg of one to go forward because it achieved high immune response with fewer adverse events.
On top of that, BNT were working with Pfizer, whose head of vaccine development ensures they are a vaccine clinical trial juggernaut – and that meant they could not only catch up to those who had gone into phase 3 earlier, like the Oxford group, but they could overtake them. Moderna had the NIH’s tremendous clinical trial capacity in their corner. Both groups chose the same strategy. They set up large clinical trials – 30,000 each initially – each spread across more than 100 sites, to increase the chances that enough participants would be in the coronavirus’ path.
There was a tour-de-force phase trial in the United Arab Emirates (UAE) for the 2 Sinopharm inactivated vaccines, too – but they lacked number 3: UAE didn’t have roaring outbreaks in the trial’s early months. That was great for the UAE, but it meant there was no quick result from the trial.
Contrast this with the first non-Chinese vaccine to start a phase 3 trial: the Oxford vaccine. They started a phase 3 trial in the UK, for only 10,000 people across only 19 sites. When the first Covid-19 wave receded in the UK, they had neither the number 2 nor the number 3 requirement. By the time they started a 30,000-person trial in the US, they were more than a month behind BNT/Pfizer and NIH/Moderna.
The 2 vaccines that made it to the finishing line in under a year
Tozinameran – the BNT/Pfizer vaccine: the data
The BNT/Pfizer vaccine was the first to release phase 3 results demonstrating vaccine efficacy – and it’s the first to get its generic drug name (INN) from the WHO: it’s called Tozinameran. We probably won’t know its trade name, though, till next year.
Results released this month, from 43,651 participants randomized in their phase 2/3 trial, with 172 events for the primary vaccine efficacy analysis (FDA data submission):
- FDA review of the data, including re-analysis (53 pages);
- Pfizer/BNT data briefing submitted to the FDA (92 pages);
- a publication in the New England Journal of Medicine.
The Moderna vaccine: the data
Results released this month, from 30,418 participants randomized in their phase 3 trial, with 196 events for the primary vaccine efficacy analysis:
- FDA review of the data, including re-analysis (54 pages);
- Moderna data briefing submitted to the FDA (84 pages, with 7-page addendum).
Comparing Tozinameran & Moderna’s vaccine
First off, a very big caveat. Comparing data directly from 2 very different trials is problematic: when you see differences, they could be related to differences in the trials, not differences in the vaccines. Keeping that in mind, let’s start with some characteristics of the 2 vaccines:
|30 μg||100 μg|
|0.3 ml||0.5 ml|
3 weeks apart
4 weeks apart
The vaccines are different, but the volume in each Tozinameran injection is smaller, and has a lower “dose” of its vaccine in it than the one Moderna uses. The placebo content was the same, but the volume in those injections was larger in the Moderna trial, too.
The primary efficacy analysis for both vaccine trials was based on symptomatic Covid-19 a week after the second dose, in people who did not have evidence of previous infection at the start of the trial.
The Tozinameran trial expanded to people aged 12 to <18, but the number below 16 was very small – they’re still recruiting young people. The Moderna trial was only for adults – they’re running a separate trial for teenagers.
For the total group, these 2 vaccines had the same, very high, efficacy:
- Tozinameran: 95.0% (95% CI 90.3, 97.6)
- Moderna vax: 94.1% (95% CI 89.3, 96.8)
(Statistics note: 95% CI’s in parentheses indicate the range of uncertainty around the result. For the Tozinameran trial, it’s a credible interval – they undertook Bayesian statistical analyses – and for the Moderna vax it’s a confidence interval.)
Both vaccines also showed high efficacy across age groups, although efficacy dropped off a little more for older people with the Moderna vax. However, the range of uncertainty is greater for this minority group in the trials, and so expect these rates to fluctuate as more data comes in down the line:
- Tozinameran, for people aged 65 to 74: 92.9% (95% CI 53.2, 99.8) – it would be higher if they included people 75 and older in this calculation (none got Covid-19 in the vaccine group, but 5 in the placebo group did).
- Moderna vax, for people 65 and over: 86.4% (95% CI 61.4, 95.5).
What about severe Covid-19? The 2 vaccines are similar here, too, but again, the numbers are too small for a definitive answer:
- Tozinameran: 1 person who had the vaccine was classified as having severe Covid-19, versus 3 in the placebo group. The person in the vaccine group was classified as severe because their oxygen saturation level measured low at their illness visit, but they never needed medical care.
- Moderna vax: 1 person over 65 with additional risk factors for severe Covid from the vaccine group was hospitalized for severe Covid-19, versus 15 with severe Covid in the placebo group.
What about asymptomatic Covid-19? Neither trial has an answer on that. However, the Moderna addendum had some preliminary data from swabs they took before each dose: 14 people tested positive without ever developing symptoms in the vaccine group between injections, versus 38 in the placebo group. Small numbers, and these people hadn’t yet got the full benefit of vaccination, but it suggests the vaccine could have reduced asymptomatic infection.
Adverse events: tolerability and safety
There’s a continuum here: mild (grade 1), moderate (grade 2), severe (grade 3). (Grade 4 reaches are life-threatening conditions or needing hospitalization.) And there’s another category, serious adverse events (SAEs). Events that might sound “minor”, can become life-threatening or trigger long-term illness if they go up to the top end of the severity scale. But the lines between these categories can be blurry.
Because the Moderna vaccine had a stronger “dose”, there was always a question: would that translate into a more adverse reaction? It seems it does. But the adverse reactions aren’t so high they’re a deal-breaker for this vaccine, especially when the pay-off is such a high level of protection. And neither vaccine caused the FDA concern about safety. As you would expect in very large trials, particularly with thousands of elderly people, there were some deaths, but none that were judged vaccine-related.
The rate of SAEs was low (<0.5%) and similar in the vaccine and placebo groups. The FDA considered 2 SAEs were likely to be vaccine-related: a shoulder injury related either to the way the injection was administered or the vaccine itself, and 1 lymphadenopathy (swollen lymph nodes in the vaccinated arm is a known potential vaccine reaction). Pfizer/BNT also regarded a person with no previous cardiac problems who had ventricular arrythmia (abnormal heartbeats) possibly related too, but the FDA did not. Pfizer/BNT reports another in the journal publication: right leg paresthesia (tingling and prickling).
The FDA drew attention to other issues. The first was 4 people reporting Bell’s Palsy in the vaccine group – that’s not a higher rate than could occur ordinarily in a group that size, as it’s not a rare condition. (It causes temporary muscle weakness in the face.)
They also drew attention to the higher number of people with non-serious lymphadenopathy: 64 in the vaccine group versus 6 in the placebo group.
Again, the rate of SAEs was low, and similar in vaccine and placebo groups (1%). The FDA considered 3 SAEs were likely to be vaccine-related: 1 person with intractable nausea/vomiting, and facial swelling in 2 people who had had cosmetic dermal fillers.
In this trial, people were asked about lymphadenopathy, which can generally mean you get more reports of it, because people look out for it. It was common: 21% of younger people and 12% for the 65+ group. (It was 6-8% in the placebo group.) The FDA also considered that Bell’s Palsy in 1 participant might have been vaccine-related.
There were few pregnancies in either trial, with no adverse outcomes known in the vaccine groups. In addition, the Moderna group had results from an animal study that had reassuring results about the impact on pregnancy and fetal development.
Adverse reactions in the days after vaccination
According to the FDA report, the percentage of people who had 1 or more severe or worse systemic adverse event with the Moderna vaccine was 17% (4% in the placebo group). (Systemic events are those that aren’t specifically injection-related.) But it doesn’t provide the same calculation in the report for the Tozinameran trial, and the data in the Pfizer/BNT briefing doesn’t correspond either. I think the best way to get a handle on this is looking at the most common severe events, although total adverse events were also more frequently reported for the Moderna vaccine.
The breakdowns get complicated, because they’re reported in 2 age groups – and the age cut-offs are different between the 2 vaccines. The younger group had more adverse reactions than the older group for each. Overall, though, these trials aren’t dramatically different by age. The median age in the Tozinameran group was 51; it was 53 for the Moderna vaccine. So to get a simpler picture, I added them up manually, using the reactions after the second injection, because the second injection had higher adverse events for both vaccines. NB: Please rely on the source data, though, not my non-quality-controlled calculations.
For this data, we’re in a different situation to the rest. Generally, the Tozinameran results have less uncertainty around them, because it’s a bigger trial. But for the detailed reaction data, the opposite is the case. The Tozinameran results for their detailed 7-day data is for a subset: about 4,100 people, whereas the Moderna data is for the whole group. On the other hand, the Moderna group only reports totals and more severe outcomes, not a breakdown of mild and moderate events.
Below are severe injection pain, plus the most common severe systemic adverse events (grade 3 and 4). Because some of these adverse events can be severe in daily life, I’ve included placebo rates as well – it’s not all a reaction to the vaccine. (I don’t know if the difference in the volume of placebo injected in these 2 trials could make a difference.)
- Severe injection pain:
- Tozinameran, 1% (placebo rate was 0)
- Moderna vax, 4% (placebo <0.5%)
- Severe fatigue:
- Tozinameran, 4% (placebo <0.5%)
- Moderna vax, 10% (placebo 1%)
- Severe headache:
- Tozinameran, 2% (placebo 1%)
- Moderna vax, 5% (placebo 1%)
- Severe myalgia (sore or weak muscles):
- Tozinameran, 2% (placebo <0.5%)
- Moderna vax, 9% (placebo <0.5%)
Could the higher rate of severe adverse events be an artifact of differences in measurement and reporting between the trials? That could account for some difference. However, a shift towards greater severity is plausible given the difference in dose strength. We don’t know if the same difference will be evident between mild and moderate adverse reactions.
Reports of adverse events in the vaccine rollout
One of the big challenges we will all face now is how to keep concerns about adverse events in proportion with a constant stream of reports coming at us from all directions. I think this helps: it’s the European Medicines Agency (EMA – Europe’s FDA equivalent) convention for describing medicine adverse events:
- very common: 1 or more in 10 people;
- common: 1 or more in 100 people (but less than 1 in 10);
- uncommon: 1 or more in 1,000 people (but less than 1 in 100);
- rare: 1 or more in 10,000 people (but less than 1 in 1,000); and
- very rare: less than 1 in 10,000 people.
Right off the bat, we started hearing reports every time someone had a severe allergic reaction to Tozinameran. That can feel alarming. But at the time I was finishing this post, over 400,000 people had had their first injection. So even when there are multiple incidents, they could still be very rare. In a few weeks, people will be getting their second injections, and it could be a real challenge to maintain a sense of proportion. While we wait for the authorities to investigate and report, keeping the scale of vaccination in mind will be critical.
The 2 vaccines with phase 3 results and question marks
The Oxford/AstraZeneca vaccine
I’ve been discussing my concerns about the non-US trials for this vaccine for months, coming to a head here at WIRED after its press release for a pooled analysis of the UK and Brazilian trials. When the Oxford group published that analysis on December 8, some questions were resolved, but the reasons for my concern deepened.
A few things were clarified by the publication: firstly, the conflicting reports about the 2 neurological serious adverse events (SAEs) in the UK were settled. They were both transverse myelitis (inflammation around the spinal cord), 1 judged likely to be unrelated to the vaccine, and the other possibly related. Secondly, the reasons for the imprecise dosing were clarified: there were manufacturing issues and inconsistent potency from manufacturer to manufacturer, and batch to batch – and that wasn’t only related to the group that got the low-dose-first-then-standard course.
We could see results for the 2 phase 3 trials in the pooled analysis. The UK trial standing alone would not meet the threshold for efficacy set by the WHO and the FDA, and the Brazilian trial could at best be described as squeaking it in. (The requirement is for a lower bound of the confidence interval – a measure of the range of uncertainty about the effect – to be above 30%: for the Brazilian trial it was 30.7%.)
There was even less standardization in the trials than it had appeared. Because of a combination, apparently, of originally intending this to be a single dose vaccine, plus supply problems, the interval between first and second doses varied enormously, and was mostly considerably more than 4 weeks apart. In the UK trial, for example, for the low-dose-first group, 53% of people had their second injection more than 12 weeks after the first – less than 1% got it within 8 weeks. Whereas in the Brazilian trial, 61% got their second injection within 6 weeks (from about 5 weeks to about 8 weeks).
Out of all this, there are a few main reasons why I think we need to wait for the US trial to come to any conclusion about this vaccine. That trial could confirm what the December analysis showed, or it could swing the balance in either direction:
- The people in the UK and Brazilian trials didn’t include enough older people – only 718 people of the people who had the vaccine were aged 56 or older (and only 224 of those were aged 70 or over). (For context: there were 8,396 aged over 55 in the BNT/Pfizer trial’s results at the FDA, including 860 people aged 75 or more.)
- Dosing wasn’t standardized across or within the UK and Brazilian trials: manufacturing inconsistencies in batches meant that the difference in dose could be higher within the standard category than between it and the “half dose” – there was less difference between the highest possible “half dose” and the lowest possible “standard dose”.
- The trials in the UK and Brazil used meningococcal vaccine for 1 or both injections for people in the control group (one of the control doses in the Brazilian trial was a placebo). Although it’s unlikely that the meningococcal vaccine was protective against Covid-19, that can’t be ruled out either – there’s a (non-randomized) trial to see if it does underway in Cuba.
- Between the phase 3 trials for this vaccine, in the UK, Brazil, and India, there were 3 neurological serious adverse events (SAEs) in the Covid vaccine groups, in around 23,000 people. The US trial has apparently not been stopped for an SAE again, with around 23,000 people recruited so far: if that means there were no further neurological SAEs, that would greatly improve the safety profile for the vaccine.
- No data was published about mild, moderate, and severe adverse reactions.
As I’m writing this blog post, the MHRA (UK drug regulator) had not made its decision about whether or not there would be an emergency use authorization for this vaccine. The UK’s priorities for vaccination are the oldest people in the UK (along with healthcare, social, and longterm care workers). The elderly are at greater risk of the disease because of ageing immune systems, but this can make them less responsive to vaccines, too.
With the current estimate of 62% efficacy for standard dosing in people up to the age of 55, it may not have adequate efficacy in the old and there’s little safety data for them. This is a terrible decision for the MHRA to have to make in a raging pandemic. No wonder their answer hasn’t come quickly.
A new trial of the low-dose-first/standard-dose-second combination has been publicly discussed, but hasn’t been confirmed. The US trial is going ahead as is: 2 standard doses, with results expected in February, from an apparently reduced goal of 30,000 adult participants because the outbreak in the US means they are accruing people sick with Covid-19 so quickly. (It had been planned for 40,000 adults.)
Gam-COVID-Vac – the Sputnik V vaccine
Still no full results here, but they issued a press release when they reached the events they needed to call it: 91.4% vaccine efficacy, based on 78 events. Gam-COVID-Vac is based on adenovirus vectors. Although it’s counted as “a vaccine”, there are actually 2 vaccines, each based on a different adenovirus, and each person gets 1 shot of each.
Why do I think there are question marks here? For several reasons. The small phase 1/2 trials they reported had serious flaws, as well as being tiny – only 38 people had Gam-COVID-Vac, so the track record isn’t reassuring. (I discussed that in my month 9 roundup.) For example, there were comparison groups, but they weren’t randomized, and they ended up with some groups with only young men.
The protocol for the trial hasn’t been made public, and each of their 3 interim readouts have raised questions, too. In the recent one, they still provide no information on outcomes by age group, and no data on safety – just some essentially content-free statements, like, “no unexpected adverse events”, and “some of those vaccinated had short-term minor adverse events” (then listing pain from the injection and some “flu-like” symptoms). I don’t think we can come to any conclusions about this vaccine till we see more.
Another critical race to watch: getting WHO pre-qualification
The WHO has a process for “pre-qualifying” vaccines. This is key. Once a vaccine is on this list, UN agencies can procure it – and being on the list is a requirement for distribution through the international COVAX scheme, that aims to ensure 20% of people in every country get vaccinated. Every country in the world doesn’t have its own drug regulatory agency, and the WHO list can be essential for them, too.
The WHO pre-qualification process involves assessing data, but also auditing manufacturing and more. And there is provision for emergency listing, too. Their page on Covid-19 vaccines is here. AstraZeneca appears to be the first they’re assessing, presumably because it both applied, and is on the COVAX list.
Overview of all phase 3 trials
As well as the 4 already discussed, there are another 12 vaccines in phase 3 trial – including 5 candidates which got to the starting gate since the last round-up post:
- CoVLP (Medicago – Canada) – a nicotine plant-based, virus-like particle (VLP) vaccine, with a GSK adjuvant;
- CVnCoV (CureVac – Germany) – an mRNA vaccine;
- EpiVacCorona (FBRI/VECTOR – Russia) – a peptide-based vaccine;
- SCB-2019 (Clover – China) – a protein subunit vaccine; and
- an unnamed inactivated vaccine from the Chinese Academy of Medical Sciences.
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 currently 2 in that category: Inovio (US company) and AnGes (Japanese).
However, I’ve added EpiVacCorona to the table, despite it not being clear that a large-scale trial is underway, because it’s already in use. This is from the FRBRI, or VECTOR, in Russia. It’s a peptide-based vaccine, and is the second Russian vaccine to gain emergency use authorization there.
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.
Other major developments for vaccines with phase 3 trials in the last month:
- Johnson & Johnson reduced the size of its 60,000-person international trial for its single shot vaccine because so many participants were getting Covid-19 – and finally recruited 45,000 (data expected late January);
- AstraZeneca reduced the size of its 40,000-person US trial for the Oxford vaccine to 30,000 for the same reason (data expected by early February);
- Moderna registered a trial for 3,000 young people (aged 12 to 17) – not yet recruiting;
- Pfizer continued enrolling young people in its trial – over 1,400 recruited by mid-December;
- The trial in Peru for Sinovac’s inactivated vaccine, CoronaVac, was suspended to investigate a serious adverse event, and then resumed. That vaccine reportedly has good results from a trial in Brazil, but the results aren’t public yet. A spokesperson for the Butantan Institute, where the trial was run, has said they will be applying for full approval, not just emergency use authorization, this month.
- The UAE recently issued an emergency use authorization for 1 of the Sinopharm inactivated vaccines (the Beijing one), saying it had 86% efficacy, but those results haven’t been released yet.
- Prices the EU is paying per vaccine were leaked – here’s my Twitter thread on this. The cheapest: Oxford/AstraZeneca, with J&J second (because it’s a single dose). All others were considerably more expensive – the most expensive: Moderna. Mileage will vary in other parts of the world.
Which could be the next vaccines to report their first phase 3 results? The most likely in December and January are the Chinese inactivated vaccines, J&J’s adenovirus-based single injection, and the Novavax protein subunit vaccine, with the US trial for the Oxford/AstraZeneca vaccine close behind.
Phase 3 trials: recruitment progress
|Vaccine||Target or final size||Single or similar trials?||Reaching target? (November 30)|
Johnson & Johnson
|75,000||2 large trials||1 with 45,000 fully recruited.|
The other is months away.
|40,500||Mostly single trial||Major trial reportedly close to fully recruited, but not clear.|
|44,863||Single trial||Fully recruited, but continuing to recruit teenagers.|
|ChAdOx1 nCov-19/AZD1222 |
UK (Oxford Uni)
|54,790||3 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, registered for 40,000; reportedly full recruitment for 30,000 adults expected in January (additional 10,000 younger people to be recruited).
Small trial in India fully recruited.
Other small ones, unknown.
|30,612||1 trial||Just begun.|
|39,020||1 large, 1 small||Just begun.|
|3,150||1 trial||Reportedly 1,400 people recruited.|
|33,000||1 large, 1 small||Trial of 30,000 fully recruited. Trial of 3,000 young people just begun.|
|45,000||2 trials (1 not yet underway)||Trial of 15,000 in UK fully recruited.|
|34,000||1 trial||Not yet recruiting.|
|Sputnik V (Gam-COVID-Vac)|
|44,700||Mostly single trial||Trial of 40,000 more than half recruited.|
Chinese Academy of Sciences
|29,000||Single trial||Just begun.|
|Inactivated virus vaccines|
|2 BBIBP-CorV vaccines|
|60,300+||2 large trials, several small||Trial with 45,000 fully recruited. Trial with 12,000 fully recruited in Peru.|
Others: months away.
|29,980||2 large trials, 2 small||Trial with 13,060 healthcare workers in Brazil fully recruited.|
Trial for 13,000 in Turkey close to fully recruited.
1 small trial fully recruited.
Bharat Biotech, Indian Medical Research Council
Chinese Academy of Sciences
|34,020||1 trial||Just begun.|
|Total participants||Over 620,000|
|Over 280,000 likely to be already recruited.|
The phase 3 trials, and the preclinical and clinical trial results reported for those vaccines
Johnson & Johnson
|Primate, non-primate||n.a.||1,045 (partial report)||n.a.||
45,000 (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)
|Primate, non-primate (b2 only)||b1:
b1 & b2:
UK (Oxford Uni)
|Primate, non-primate||n.a.||1,077||560 (from the phase 2/3 trial)||
|Non-primate||247||n.a.||(Phase 2/3 trial)||
|Primate, non-primate||85||n.a.||Unpublished (600)||
3,000 young people
|Primate, non-primate||151||n.a.||(Phase 2/3 trial)||
Sputnik V (Gam-COVID-Vac)
|Unpublished||Unpublished (2 of 50 each)||n.a.||Unpublished (900)||
|BBIBP-CorV x 2 (1 Wuhan, 1 Beijing)
45,000 (both vaccines)
3,000 (Beijing only)
300 (Wuhan only)
? (both vaccines)
? (Beijing only)
13,060 (originally 9,000)
(Awaiting local approval)
Bharat Biotech/Indian Medical Research Council
Chinese Academy of Medical Sciences
29,040 (Brazil, Malaysia)
Vaccines with published or preprint results (and/or Phase 3 trial register entry)
* a combined phase 1/2/3 trial
** 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)
The first vaccine crashed (that we know of) – and a major setback for another candidate
Mostly, we won’t know when a vaccine is abandoned by its developers, unless it’s a very prominent one. We’ll only get a sense of the casualties on the field down the line, when someone starts scraping through the records and asking, “Whatever happened to….?”
But a high-profile vaccine came to a very public end this last month. It was an Australian one, developed at the University of Queensland – and it was 1 of the 10 CEPI-supported vaccines being fast-tracked internationally. It crashed to the ground just before it was due to go into a phase 2 trial. It turns out a fragment of the HIV virus had been used to develop it. People generated some temporary antibodies that HIV tests mistook for signs of actual HIV infection. (More on this in this month’s previous post.)
Another high-profile vaccine hit a major setback. It’s being developed by 2 major drug companies, Sanofi and GSK. They’re going back to the drawing board on the vaccine formula, because the version they took into phase 1/2 clinical trial didn’t work well enough in older people. If all goes well, the next version could clear clinical testing by the end of 2021.
This is my sixth monthly roundup of the Covid vaccine race:
My latest Covid vaccine piece at WIRED: tips for reading about Covid vaccine results
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.
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.
Update December 20: The original version had missed including CureVac’s trial (not yet recruiting) in the tables. Thanks to Ioana A. Cristea, who pointed out my error on Twitter.
Update December 22: Status for CureVac changed to “just begun” (originally not recruiting, based on trial register entry). Thanks to Mike Dee on Twitter. Small phase 3 trial newly registered for CureVac, added. Corrected a sentence that conflated grade 4 and SAEs 0 – thanks to gmt999 on Twitter.
Update December 23: Recruitment status for Covaxin updated.
Update December 26: CoronaVac trial in Turkey corrected to 13,000 participants (was 13,300).
Update January 26: J&J trial in green table corrected to 45,000 from the original 40,000.
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 December 20, the collection included 255 entries:
- 77 vaccine groups with published or posted results;
- 16 trial protocols, for 8 vaccines;
- 96 preclinical preprints/articles;
- 99 trial registry entries associated with these vaccines;*
- 30 clinical trial preprints/articles/letters:
- 13 for phase 1 trials;
- 9 for phase 1/2 trials;
- 4 for phase 2 trials;
- 1 combined report of phase 2 and 3 trials;
- 1 phase 3 trial;
- 2 author replies to letters to the editor about their publications;
- 8 trial efficacy readouts for phase 3 (press releases), for 4 vaccines;
- 5 documents reporting on or reviewing phase 3 data at regulatory agencies, for 2 vaccines;
- 1 vaccine termination notice.
* 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.