I think we are drifting perilously close to exceptionalism in the debate about the Covid-19 vaccine for children and adolescents. The narrowed…
It’s been another drama-filled, and data-packed, hectic few weeks in the Covid vaccines landscape. But the visual theme of this roundup post is the gigantic global airlift that’s underway at last, and the relief and hope that comes with it.
There are the usual updates on the vaccines that have released efficacy results – and all the phase 3 trials that are underway, with over 460,000 participants so far. I’ve highlighted major community studies, too, the developments in combinations of vaccines, and trials in children and in pregnancy. And if after all that, you’d still like to read more, I wrote about why differences between vaccines matter for The Atlantic, and Julia Belluz asked me a bunch of tough questions about vaccines in Vox.
Because there’s so much to unpack in this post, major sections and vaccines have some summary points at the top, and there are links so you can navigate around. But first some explanations for heavily used terminology in this post.
Key terms used in this post:
- Vaccine efficacy is a rate of risk reduction in symptomatic Covid-19 unless otherwise specified. Vaccine efficacy of 80% or 90% means if a vaccinated person is exposed to the virus, their risk of getting the disease is lowered by that proportion, so it depends on how high their risk of being exposed, and that varies. It’s not an absolute drop in percentage points.
- When available, a range of statistical certainty for efficacy is shown, eg 92% (CI: 88-95). The distance between 88% and 95% in this example is small: it means there is a lot of certainty that 92% is about what we can expect. However, the wider that range is, the more uncertain we are.
- The rate of efficacy set for whether a Covid vaccine works well enough is 50% (with a CI starting at 30% at least).
- And I have a recent post explaining the terms used, and assessment processes, for adverse events and safety in these trials – including the difference between “severe” and “serious”.
- Community impact data
- Steps towards signs of immunity as a measure of vaccine efficacy
- Trials in children and in pregnancy
- Vaccine combinations
- The new landscape with 11 vaccines with phase 3 results
- Closer look at the 3 new vaccines
- What’s new for the other 8
- Vaccine price landscape and access to vaccine manufacture
- Overview of phase 3 trials and what’s new
- Other news
- Addendum: phase 3 trial recruitment status and studies
- Sources for study records and notes on using the collection
Community impact data
- Studies in Israel show the BNT-Pfizer vaccine can get as good results in vaccine rollouts as it did in the phase 3 trial, and it may be very effective at reducing infections as well as disease and severe outcomes.
- Some early community data from the UK suggests the Oxford-AstraZeneca vaccine, with second dose delayed, might increase in effectiveness over a month to 70% or more (as it did in exploratory trial analyses here and here).
- Some early community data from the UK showed vaccination of healthcare workers with BNT-Pfizer or Oxford-AstraZeneca vaccines reduced the risk of Covid-19 in unvaccinated members of their households.
- The first stage of a whole-of-town trial* of vaccination with Sinovac’s CoronaVac is complete in Brazil: close to all vaccine-eligible adults in the city have had their first injection. (*A stepped wedge trial.)
- Note: The prevalent strain in Israel and the UK was the B.1.1.7 (“UK”) variant of concern.
Now that the vaccines are being rolled out, there’s going to be a deluge of data – people often call it “real world data” (as though people in clinical trials are living in an alternate reality!). It’s going to be very “noisy”, when so much else is going on – there’ll be lockdowns and easing of restrictions, as well as changes in people’s behavior related to vaccination, pandemic fatigue, and new seasons.
On top of all that, differences in who gets vaccinated early and who doesn’t won’t be random, and may be related to the risk of getting Covid-19 or having a worse outcome if you do. Teasing out what you can attribute to vaccines in all that is hellish complicated: you need study designs that can reduce bias. Good randomized trials minimize it upfront, but other studies have to deal with biases that are deeply embedded. Natalie Dean has written an important op-ed about the importance of planning to ensure study data can be pooled to save us being hopelessly mired in confusing data. And WHO has just released guidance on the collection and use of vaccination data.
I’m going to concentrate on studies that have used a design that reduces the biases (such as matched controls), done in very broad groups of people or geographic regions. We’ve had results of 4 studies like that in the last few weeks – and an inspiring and important one is underway in Brazil, so I’ve included news on its progress, too. Lars Hemkens and Steve Goodman have pointed to 2 areas where vaccine rollout is being randomized within priority groups: Minnesota in the US, and Saarland in Germany.
Another important one to look forward to is a massive test-negative case control study for healthcare workers across the US by the CDC (protocol here). (The CDC has a list of their studies on vaccine effectiveness, all with protocols, here.) We can expect to see several test-negative case control studies, and you can read more about that type of study and how they can reduce biases in data here. These studies are based on test results where a community is using the same testing service.
Before we get to those 4 community studies, a quick look at 3 early reports using data linked across national healthcare systems (Israel, England, and Scotland), plus the first data I’ve seen from Brazil (for São Paulo).
Israel is being supplied with enough BNT-Pfizer vaccine to cover all vaccine-eligible residents quickly and study the results. As of writing, 47% of the population – over 4 million people – are fully vaccinated with that vaccine, with over 5 million having had 1 shot. The latest data comes from a press release: 2 weeks after the second dose, data linked across the healthcare system suggest 97% effectiveness in reducing the risk of all Covid-19 disease outcomes and 94% against symptomatic infection – but that cannot account for the impact of say, inequity in vaccine distribution.
In the first report from Public Health England, based on linking data across the health system there, was too soon to have much data on anything other than the BNT-Pfizer vaccine: and it’s mostly about a single dose of the vaccine in people over 80. After 28 days, vaccine effectiveness, they estimated, was 57% (CI: 48-63).
Public Health Scotland have a preprint (now on medRxiv) that’s the first study of risk of getting Covid-19 in the other people in the households of vaccinated people – a critical way to explore the risk of transmission. It was based on linking data across the health system, to see what happened in vaccinated National Health Service (NHS) workers’ households. In data up to March 3, there were 194,362 household members of 144,525 healthcare workers (just over half in direct patient care), vaccinated with either BNT-Pfizer or Oxford-AstraZeneca vaccine: about 25% of the vaccinated workers had a second dose – 20% remained unvaccinated.
Data adjusted for a range of factors found a relative risk reduction of 30% (CI: 22-37) 2 weeks after 1 dose – but as only some of the risk comes from the person they live with, they estimate the risk reduction from vaccination is more like 60%. And 2 weeks after the second dose, the reduction was 54% (CI: 30-70) – smaller numbers, so much more uncertainty here. (Not enough data on hospitalization to be certain, but that reduced, too.)
Over in São Paulo, it’s too early to be sure of effects – vaccination only started there at the beginning of February, with Sinovac’s CoronaVac. Brazil is struggling through their worst Covid-19 wave yet, being swamped by the P.1 variant (that emerged in that country), and any sign of hope is welcome.
It seems the number of deaths in people aged 90 and over, who were a priority group for vaccination, could already be dropping, instead of increasing along with the surge. The data come from local health authorities in São Paulo, reported by a newspaper. On the first day of vaccination in the city, around 10,000 of the city’s people aged 90+ were vaccinated – a third of people in that age group, and it’s estimated that over 95% have now had at least shot.
The effects of vaccination had barely had a chance to kick in for the February data, so it’s awfully early to give vaccination credit. But there had been 246 hospitalizations with Covid-19 for people in that age group in January: there were 104 in February. And there were 127 deaths in January, and 38 in February. Fingers tightly crossed!
- Israel – major matched control study
- Scotland – cohort study with propensity scoring
- England – test-negative case control study
- USA – propensity matched study
- Brazil – first community data and progress in a whole-of-town stepped wedge trial
Israel – major matched control study (BNT-Pfizer vaccine)
The Covid vaccination program began in Israel on December 19. This study of almost 1.2 million people includes people who were vaccinated up to February 1. It’s a bit under 600,000 people who were vaccinated with the BNT-Pfizer vaccine, matched on demographic (age, sex, sector/neighborhood) and clinical characteristics (influenza vaccine, pregnancy, chronic conditions that increase risk) with the same number of people who had not. They excluded some people who had uncharacteristically high exposure to the coronavirus – like healthcare workers on Covid wards and nursing home residents.
As more and more elderly people started to get vaccinated, it was difficult to find unvaccinated matches, so the group overall trends to the young side (median age was 45). So they were less likely to experience Covid-19’s worst outcomes.
Of all the infections diagnosed (10,561), only 57% of the people developed symptomatic disease, 369 people were hospitalized, 229 had severe Covid-19, and 41 people died. Efficacy from 7 days after the second dose, which was the time period in the large Pfizer trial, was:
- Infection: 92% (CI: 88-95);
- Symptomatic disease: 94% (CI: 87-98) (the trial’s primary efficacy outcome);
- Hospitalization: 87% (CI: 55-100) (high rate of uncertainty);
- Death: 92% (CI: 75-100).
The study didn’t have sequencing data for the viruses causing all the infections. But at the time this data was collected, about 80% of Covid-19 disease in Israel was caused by the B.1.1.7 (“UK”) variant of concern.
Scotland – cohort study with propensity scoring
Propensity matching involves analyzing a set of factors in people related to the risk of exposure. This study is a preprint, based on a database linking vaccination, primary (family) doctors, Covid testing, hospitalization, and mortality records for 5.4 million people in Scotland (almost everyone).
It’s hard to interpret these results, because of limitations in the preprint itself. For example, it doesn’t provide raw numbers you need to put it into perspective – like the number of people who got which vaccine (out of BNT-Pfizer and Oxford-AstraZeneca). However, they did report “total person years” that people were vaccinated – that’s a calculation of how long people had been exposed to the virus 28 days after that 1 shot. (People were getting only 1 dose of the vaccine during this study.)
They randomly chose a propensity-matched group of unvaccinated people, using age group, socioeconomic status, sex, the number of previous Covid tests, and clinical risk groups.
The preprint doesn’t report overall efficacy results – just at 6 time intervals, beginning 7 days after the vaccination. Efficacy against hospitalization ranged from 47% (CI: 39-53) in the second week, peaking at 84% (CI: 74 to 90) in week 5, and then dropping.
The authors break the data down by vaccine type. If you see people saying that the Oxford-AstraZeneca is over 90% effective, or that it’s more effective than the BNT-Pfizer vaccine, it’s probably because of this study. This is very encouraging data for that vaccine, there’s not enough data yet. For that peak week that gets cited, these are the results:
- BNT-Pfizer: 3,346 person years, 18 hospitalizations: efficacy of 85% (CI: 76-91);
- Oxford-AstraZeneca: 521 person years, 2 hospitalizations: efficacy of 94% (CI: 73-99).
England – test negative case control study
This preprint is another from Public Health England. It’s based on data in the Pillar 2 testing system of the National Health Service (NHS). That’s community-wide, but it doesn’t include testing within hospitals. Data for everyone aged 70 years or more (over 7.5 million people in England) were linked with the National Immunisation Register, hospital emergency admissions (not for planned procedures), and deaths.
The study compares the test results of the people in that age group who were vaccinated and unvaccinated – but only for people who had symptoms for up to 10 days before the test (as the PCR test is less accurate after that). Vaccination began in England in early December with the BNT-Pfizer vaccine, and early January with the Oxford-AstraZeneca vaccine. By December, the B.1.1.7 (“UK”) variant of concern was common. Initially, people got 2 doses of BNT-Pfizer, but by the time the second vaccine was introduced, everyone had a single shot. Data in this study were up to February 21. They included data on people’s age, gender, ethnicity, NHS region, a socioeconomic status indicator, and whether they lived in a care home.
There were more than 108,000 people who tested negative in this study, and over 44,000 positive. Vaccine efficacy against infection was:
- Aged 80+, BNT-Pfizer 28-34 days after at least one dose: 70% (CI: 59-78) (when it reached a plateau);
- Aged 80+, BNT-Pfizer from 14 days after 2 doses: 89% (CI: 85-93);
- Aged 70+, BNT-Pfizer 28-34 days after at least one dose: 61% (CI: 51-69) (when it reached a plateau);
- Aged 70+, Oxford-AstraZeneca 28-34 days after at least one dose: 60% (CI: 41-73), increasing to 73% (CI: 27-90) after day 35.
They concluded a single dose of either vaccine had about an 80% efficacy rate against hospitalization. There was only enough data on deaths for the BNT-Pfizer vaccine: efficacy was 85%.
USA – propensity matched study
This one is a preprint, studying data from the Mayo Clinic’s healthcare system in 4 states. People could have been vaccinated with either of the mRNA vaccines (BNT-Pfizer and Moderna). There were 31,069 people who had received at least 1 shot and had never had a SARS-CoV-2 test before. They were propensity matched on demographics (age, sex, race, ethnicity), location (zip code), and number of previous SARS-CoV-2 tests. (The people they were matched with came from just under 220,000 eligible people.)
Brazil – progress in a whole-of-town stepped wedge trial
Serrana is a town of over 45,000 people inland in the state of São Paulo. A major stepped wedge trial using Sinovac’s CoronaVac is underway there. (They’re called stepped wedge trials because of the shape of the graphs produced for these studies.) It’s called Project S, with the goal of vaccinating close to all the eligible adults in the town. Their original target had been around 30,000 people: 28,380 volunteered and 27,619 of them got their first vaccination, which is an impressive achievement.
The town is divided into quarters: each of them is a cluster that gets randomized as a whole. Everyone who’s enrolled gets vaccinated at school setups in that part of town over a couple of days. Each week, another town quarter is vaccinated. At the end, they’ll be looking for differences between these delayed groups – and will learn about what happens when a whole community has been vaccinated.
Steps towards signs of immunity as a measure of vaccine efficacy
- The FDA and EMA (Euro drug regulator) have issued guidance for modified Covid vaccines based on early phase trials safety and immunogenicity (signs of immunity).
- Statistical methods have been proposed for evaluating potential correlates of immunity in the large “Operation Warp Speed”-funded phase 3 trials.
It takes a large phase 3 trial, and the SARS-CoV-2 virus circulating quite widely for many months, to get an answer about the efficacy of a vaccine. Immunogenicity (signs of immune response), on the other hand, can be established much more quickly. These are signs that the immune system remembers the virus and can mount a defense against it if it enters the body, and you can measure for them in people’s blood.
—By the way, if you haven’t seen comedian Vick Krishna’s dramatization of how mRNA vaccines against SARS-CoV-2 get immune systems to defend against it, it’s a fabulous introduction to the first line of defense, antibodies.—
Both the FDA and EMA (Euro drug regulator) issued guidance in February that will allow for companies that have already been authorized to apply for authorization of vaccines modified to work on 1 or more variants of concern, based on showing immunogenicity is comparable to that achieved by the original vaccines in phase 3 trials. This means smaller, shorter, phase 1 trials – the same process used each year for new versions of flu vaccines.
The FDA’s guidance calls for immunogenicity studies in 2 groups of people – people who haven’t been vaccinated or been infected with SARS-CoV-2 before; and people who have been vaccinated before. And they need at least 7 days of adverse event data. Moderna has already registered and started a trial like this with their vaccine modified for the B.1.351 (“SA” variant). (Here’s the trial register entry for it.)
The EMA’s guidance is more detailed. It calls for the same groups of people, but has specific statistical requirements for the outcomes, for example.
The other big news came from the program formerly known as Operation Warp Speed (OWS). A preprint was posted on the statistical methods that will be used to determine correlates of immunity to Covid-19, using data from the big OWS-funded phase 3 trials. Part of the funding deal was collecting uniform data that will enable testing to see how strongly different measures correlate to protection shown in those trials. Those phase 3 trials that may have these results available for analysis soon: Moderna and J&J, and for 2 trials in the US that haven’t released any results yet – Oxford-AstraZeneca and Novavax.
Trials in children and pregnant women
- There are completed, ongoing, or planned trials in young people for 8 Covid vaccines, mostly in adolescents, but some in young children and infants. (Little data is public.)
- There are ongoing trials in pregnancy for 2 Covid vaccines.
Children and anyone who knew they were pregnant were generally excluded from trials for Covid vaccines, but trials have started to fill the major holes in knowledge this created. I’ve broken the trials down into age groups for children and young people, but the information available on them is patchy. There are trials that are completed, underway, or planned in 2021 of 8 vaccines so far in adolescents; of 7 in children aged 5 up to adolescence; and 5 in infants/small children. The only trial with publicly available results is still BNT-Pfizer’s for 16- and 17-year olds.
There are only trials I know of for pregnant women for 2 vaccines, and they follow. (Unless otherwise stated, the sources are records in my public Zotero collection tagged children and teenagers.)
- BNT-Pfizer: Some results already for ages 16 and 17 from their phase 3 trial; 3,000 between 12 and 17 recruited, but waiting on full results.
- Moderna: A phase 2/3 for 3,000 young people aged 12 to 17. It’s called TeenCove, and it has just reached fully recruited.
- Oxford-AstraZeneca: Phase 2 trial for ages 12 to 17 planned to start in March. This is the first half of a 300-child trial.
- Sputnik V: Trial announced for ages 14 to 18. No trial register entry found yet.
- Sinovac’s CoronaVac: Teenagers were included in a phase 1/2 trial for 552 children and adolescents. The results have not been made public.
- Sinopharm’s Beijing vaccine: Teenagers were included in a phase 1/2 trial (number unknown). Results are available, but have not been made public.
- CanSino: Teenagers were included in a (presumably phase 2) trial specifically for children and young people. It has been completed and the data are being reviewed by the NMPA (China’s drug regulator). (I haven’t found a registry record for this trial.)
- [Update March 18] Novavax: The EMA has approved a pediatric trial program, including teenagers. Not known when this will start.
Children 5 and over up to adolescence:
- BNT-Pfizer: A trial in 5 to 11 year-olds will be start in “the next couple of months”.
- Moderna: A phase 2/3 trial for 6,750 children includes this age group.
- Oxford-AstraZeneca: Phase 2 trial for ages 6 to 11 planned to start a few weeks after the trial for teenagers above. This is the second half of a 300-child trial.
- Sinovac’s CoronaVac: Children in this age group are included in the completed phase 1/2 trial for 552 children and adolescents for this vaccine.
- Sinopharm’s Beijing vaccine: Children in this age group are included in a phase 1/2 trial (number unknown). Results are available, but have not been made public.
- CanSino: Children from age 6 were included in a (presumably phase 2) trial specifically for children and young people. It has been completed and the data are being reviewed by the NMPA (China’s drug regulator). (I haven’t found a registry record for this trial.)
- [Update March 18] Novavax: The EMA has approved a pediatric trial program, including 6 to 12 year-olds. Not known when this will start.
- BNT-Pfizer: A trial in children under five planned for later in 2021, youngest age not specified.
- Moderna: A phase 2/3 trial for 6,750 children includes infants from 6 months.
- Sinovac’s CoronaVac: The completed phase 1/2 trial for 552 young people included children from the age of 3.
- Sinopharm’s Beijing vaccine: Children from the age of 3 were included in a phase 1/2 trial (number unknown). Results are available, but have not been made public.
- [Update March 18] Novavax: The EMA has approved a pediatric trial program, including infants from birth to age 6. Not known when this will start.
- BNT-Pfizer: A placebo-controlled phase 2/3 trial for 4,000 pregnant women in the US. (Women in the placebo group to be offered vaccine at the end of the trial.) Recruitment began in February.
- J&J: An open label phase 2 trial (no comparison group) on safety and signs of immunity, for 400 women in the US.
Some good news: Helen Branswell reports on a presentation at the CDC for about 30,000 pregnant women who have been vaccinated – “Reports of reactions are very similar to non-pregnant people”. And there’s a discussion about the data provided to drug regulators on this here.
Still, we have a familiar situation with drugs that are used in pregnant women: excluded from the trials, and having to make decisions based on less information than the rest of us – despite the fact that they can have higher-than-average risk when they have Covid-19.
- Sputnik V is a combination of 2 Covid vaccines (rather than 2 shots of the same vaccine), and has shown high efficacy in a phase 3 trial.
- There are now 3 other pairs of Covid vaccines being trialed in combination (and a 4th being discussed) – and 1 of those trials is also testing dosing intervals.
- A study in mice found a combination of 2 vaccines had higher efficacy than 2 shots of either alone.
It’s called heterologous prime-boost vaccination: it’s where instead of first (“prime”) and second (“boost”) injection of the same vaccine, they’re 2 different ones. The theory is that this could widen immune responses more than same-same vaccination.
For Covid-19, Sputnik V was the first to go down this route. Although both are the same type of vaccine – viral vector – the first injection is based on adenovirus 26 (Ad26 – the same vector used in J&J’s vaccine), and the second is based on adenovirus 5 (the same vector used in CanSino’s vaccine).
At the end of January, a preprint was posted of preclinical work, testing this theory in mice with the Oxford-AstraZeneca vaccine (based on a chimpanzee adenovirus) and the vaccine candidate from Imperial College London. It’s a self-amplifying RNA vaccine (saRNA) – which may be more potent than mRNA vaccines, but also more cost-effective to produce.
The Imperial College group aren’t associated with a drug company: they had public R&D funding, and aim to sidestep the drug industry, and the licensing fees and profits that go with it. And they also see a role as a potential boost for the Oxford-AstraZeneca vaccine. Hence the preclinical study.
They compared a single shot (for each); a combination of 1 shot of each; and the normal same-same regimen (2 shots for each). The highest immune response came from the combination, followed by the same-same for the Imperial College vaccine.
Here are all the clinical trials of combinations (other than the standard Sputnik vaccine trials), in chronological order of their registration or announcement:
- Oxford/AstraZeneca and Sputnik V’s Ad26: alternating shots, phase 1/2 trial for 100 people in Belarus and Russia;
- Oxford/AstraZeneca and Sputnik V’s Ad26: alternating shots, phase 1/2 trial for 100 people in Azerbaijan;
- Oxford/AstraZeneca and Sputnik V’s Ad26: alternating shots, phase 1/2 trial for 100 people (apparently somewhere near Azerbaijan, but not specified);
- The UK government announced it would be doing alternating dose trials for Oxford/AstraZeneca and BNT-Pfizer vaccines, testing them separated by 8 weeks and 12 weeks (8 arms in total). It’s due to start in April, and extra vaccines could be added if they are introduced in the UK. The trial is called Com-Cov, and you can find out more about it here, and the committee overseeing it here;
- Reported talks about a possible trial of a combination of Sputnik V and CanSino’s adenovirus 5 vaccine;
- A phase 1 trial was registered by the NIAID (the part of the NIH headed by Fauci), for a combination of a viral vector vaccine based on chimpanzee adenovirus and one saRNA vaccine.
The new landscape with 11 vaccines with phase 3 results
With a single exception, each vaccine has only been tested alone, and we don’t have a rigorous basis for comparing them. On the other hand, with 11 vaccines around the world with phase 3 results, it’s hard to keep track of them and keep them in perspective. I decided an oversimplified “sketch” of this landscape was more likely to help with that perspective, than mislead.
As more vaccines have joined this group, many of the differences have only grown: these trials have many fundamental differences. On the other hand, some caveats that apply to lining vaccines up against each other have reduced.
For example, now that we have some solid data from vaccine rollouts, for example, we know that the trial results can at least sometimes apply in other places and times, even despite variants. As we’ll see later, the BNT-Pfizer vaccine is achieving results as good as in the trial, or even better, in Israel, where a variant of concern dominated when it was introduced.
Some critical caveats now:
- The number of people in the trials, and the quality of those trials (and the amount of data available), all vary greatly. That means that there’s a great deal more certainty for some vaccines than others.
- Vaccine efficacy is a relative reduction in the size of risk of disease – not an absolute drop in percentage points of a risk that is 100%.
- The participants can be very different. For the vaccines which have much higher rates of adverse events in people under 55 than over, the age spread in trials could affect that considerably.
- Some of the vaccines have been tested against variants of concern that reduced their efficacy, while others have not.
- Some of the vaccines reach their peak efficacy sooner than others, and their efficacy rates are likely to improve when later results come in.
The data behind some of them is very preliminary – sometimes just a few data points in a press release. So vaccines will shift positions, sometimes even a lot: they’re like counters that could move around on a board.
The top left is where vaccines with high efficacy and low rates of adverse events would sit – and the bottom right is lower efficacy and higher adverse events. They all “work” though. The evidence I used to manually position the counters is in the table below. They were numbered in the order in which efficacy results for them were made public.
Update: The infographic was removed when the next monthly roundup was posted.
|>43k people (half on placebo)|
Reviewed & detailed reports public; protocol public
|Most common systemic adverse event: fatigue (56%)|
Most commonly severe: fatigue (4%)
|>30k people (half on placebo)|
Reviewed & detailed reports public; protocol public
|Most common systemic adverse event: fatigue (65%)|
Most commonly severe: fatigue (10%)
|3||Sputnik V (Gamaleya)||92%|
|>22k people (3:1 placebo)|
Reviewed & detailed report public; protocol not public
Evidence: strong (with reservations about methodology); adverse event data used from very small early phase trial, as adverse events not routinely solicited in a representative group in phase 3
|Most common systemic adverse event: feverishness/mild fever (95%)|
(delayed 2nd dose)
(Standard dose, February data, includes “UK”, “SA” strains)
|>17k people in grouped trials (half in control group, half on varied vaccine regimens), >32k in US/LatinAmerican trial (two in vaccine to each in placebo)|
Reviewed & detailed reports public; US/LatAm trial only press release; protocols public
Evidence: strong from US/LatinAmerican trial, though weak to moderate from group of trials with reservations about methodology; adverse event data from MHRA
|Most common systemic adverse event: fatigue (62%)|
Most commonly severe: malaise (4%)
|5||Sinopharm – Beijing||79%|
|Up to 30k people (half on placebo)|
Reviewed, negligible details public; protocol not public
Adverse event data from earlier phase trial
Evidence: potentially strong (too little known) (Other trials in progress)
|Most common systemic adverse event: fever (4%)|
|Brazil >12k people (half on placebo)|
Reviewed, basic details public; protocol public
Turkey >10k people (half on placebo)
Press announcement only; protocol not public
Evidence: moderate (further trials in progress)
|Most common systemic adverse event: fatigue (<2%)|
No severe event reached 1%.
(UK trial only, including “UK” strain)
96% (Original strain only)
|>14k people (half on placebo) (UK trial)|
Press release only; protocol public
Evidence: moderate; adverse event data only available for small early phase trial (large trial in progress)
Note: the results from a small phase 2b trial in SA showed it worked, but with much lower efficacy because of the “SA” strain (perhaps 49% or 60%). However the evidence was very weak.
|Most common systemic adverse event: fatigue (36%)|
Most commonly severe: fatigue (3%)
|8||J&J||66% at 28 days (Including “SA” strain)|
~70% after 56 days;
72% at 28 days USA
|>43k people (half on placebo)|
Reviewed, detailed report; protocol public
Evidence: strong (further large trial on 2 shots in progress)
|Most common systemic adverse event: fatigue (38%)|
Most commonly severe: fatigue (1%)
|9||CanSino||69% at 14 days|
65% at 28 days
|ca 40k people (half on placebo)|
Press release only; protocol not public
Adverse event data only available for small early phase trial
Evidence: potentially strong (too little known)
|Most common systemic adverse event: fatigue (34%)|
None severe reached 1%
|10||Sinopharm – Wuhan||73%|
2nd trial stopped for lack of efficacy
|Up to 30k people (half on placebo)|
Reviewed, negligible details public; protocol not public
2nd trial 6k people (half on placebo)
No data released
Adverse event data from earlier phase trial
Evidence: potentially strong (too little known)
|Most common systemic adverse event: fever (5%)|
|Under 26k people (half on placebo)|
Press release of interim results only; protocol not public
Adverse event data from earlier phase trial
Evidence: potentially strong (too little known)
|Most common systemic adverse event: fatigue (3%)|
Closer look at the 3 new vaccines
- Trial efficacy readout in a press release, reporting minimal data.
This is a single-dose vaccine, based on an adenovirus 5 viral vector, and can be kept in refrigeration (not freezing). A booster shot has been developed for at 6 months, but that wasn’t included in the trials.
In applying for authorization in China, the company released minimal data points from its phase 3 trial. It’s an international trial, with about 40,000 adult participants, and while no upper age limit specified in their trial registration, it may not have many older people in it. The press release announced the trade name for this vaccine is Convidecia. Vaccine efficacy against symptomatic disease was:
- At 14 days: 69% against symptomatic Covid-19 and 96% against severe disease;
- At 28 days: 65% against symptomatic Covid-19 and 90% against severe disease.
Numbers of events and confidence intervals for efficacy weren’t released, and there was no data on adverse events. In the phase 2 trial, systemic adverse reactions were common (the most common was fatigue, at 34%), but severe ones were not – and there were no serious adverse events. However, that was only in 129 people at the dose apparently used in the phase 3 trial.
A trial in children aged 6 to 18, presumably phase 2, has been completed and the data are being reviewed by the NMPA (China’s drug regulator). (I haven’t found a registry record for this trial.)
Sinopharm – Wuhan
- Trial efficacy readout in a press release, reporting minimal data from the UAE-led phase 3 trial in the Middle East.
- The vaccination arm for this vaccine in an ongoing phase 3 trial in Peru was suspended for inadequate efficacy.
This vaccine had seemed to fall by the wayside, but added first good news, then a dilemma in the last month. Sinopharm went to phase 3 trial, first in the UAE but expanding, with 2 inactivated vaccines: one from its Beijing Institute of Biological Products and another from its one in Wuhan. However, while the Beijing vaccine went into emergency use widely globally, we heard less about the Wuhan vaccine.
Then, on February 24, the Wuhan Institute issued a press release of efficacy results. Based on the 45,000-person trial in UAE and nearby countries – which included 15,000 for each vaccine, plus a placebo group – vaccine efficacy for the Wuhan vaccine was 72.5% (with no details on events or CI). According to the trial registry entry, this was symptomatic Covid-19 from 14 days after the second injection. The trial was limited to people up to the age of 60.
There was no mention of safety or adverse events. In the phase 2 trial (224 people), adverse reactions were all mild, with the highest rate for fever of 5%. A very low rate of adverse reactions (as expected for this type of vaccine). The vaccine was authorized by the NMPA (China’s drug regulator) on February 27.
On March 10, though, the University Peruana Cayetano Heredia running a trial for this and Sinopharm’s other vaccine (from Beijing) in Peru announced they were seeking to suspend the Wuhan arm of their phase 3 trial for lack of efficacy, and offer the participants the Beijing vaccine (which was showing efficacy in the trial). The researchers released no data – that’s still only known to the trial’s data monitoring board, as the study isn’t unblinded yet.
The trial in Peru was originally registered as a trial for 6,000 people, also aged up 60. However it expanded to 12,000 people (4,000 each for the 2 vaccines plus placebo group), and included people over 60. (The trial was recently at the center of a scandal called Vacunagate (“vaccinegate”), leading to the firing/resignation of the lead investigator and others – including 2 government ministers – because of providing vaccines to family, friends, and government members outside the trial and the national vaccination program.) The country’s Covid commission called for an international audit of the trial.
This poses a major dilemma for the countries that have authorized this vaccine – but does not affect the far more widely used Sinopharm vaccine, from Beijing. But the continuing lack of data for the Sinopharm vaccines underscores another serious problem: that many drug regulators are not empowered to release trial data without permission of the companies developing the vaccines.
Records in my collection for this vaccine here (check the notes field to see if a record includes the Wuhan vaccine, the Beijing one, or both). No studies on variants on the Wuhan vaccine.
- Interim trial efficacy readout in a press release, reporting minimal data.
Covaxin is the trade name for BBV152, an inactivated virus vaccine from Bharat Biotech in India. This vaccine includes an adjuvant (an ingredient that aims to increase the vaccine’s impact on the immune system.) They issued a press release on efficacy in their first of 3 analyses for this trial: this first interim analysis at 43 events (people with symptomatic Covid-19, from 14 days after the second injection); a second when there are 87 events; and the final when there are 130 events. (Their press release reports that they will release a preprint for both the second and final analyses.)
The trial includes 25,800 people aged between 18 and 98, of whom 2,433 are over the age of 60. That makes this population relatively young for a Covid vaccine trial – it’s under 10% aged over 60, compared to 42% over 55 in the BNT-Pfizer trial.
There were 7 events in the Covaxin group compared to 36 in the placebo group: a vaccine efficacy rate of 80.6%. They didn’t provide their calculation of the CI, or range of uncertainty, but it’s still quite wide, meaning it could theoretically end up a fair bit lower or higher (though still clearing the 50% efficacy hurdle).
There’s no detail on adverse events in the press release, although they say there are no serious safety concerns. In their phase 2 trial, there were no severe reactions, and no systemic adverse reaction had a rate of moderate level for more than 2% of participants. If the phase 3 trial is similar, this is a vaccine with minimal adverse reactions. (You can read about what this means in my explainer post on adverse events.)
This vaccine had already been rolled out in India in what was called “clinical trial mode” – requiring particular consent and data collection – but that restriction has now been lifted.
Records in my collection for this vaccine here. Includes 1 laboratory study on B.1.1.7 (“UK” variant of concern). There’s a report that there may also be a trial on the way in the Philippines, but I haven’t seen a trial register entry for it.
What’s new for the other 8
Janssen-Johnson & Johnson (J&J)
- Extensive data from ENSEMBLE, the largest and most international Covid vaccine trial so far, released in an FDA evaluation report.
- Data showed the “moderate to severe” primary outcome was almost identical to the “symptomatic Covid-19” outcome for other vaccines.
- The efficacy of this vaccine might increase for up to 2 months, but it’s too soon to be sure about whether it does.
- The vaccine enabled SA’s vaccination program to proceed almost as planned.
- Trial in pregnancy soon to launch, and the 2-dose international trial (ENSEMBLE 2) continues.
It was a big month for this vaccine! Part of the reason this vaccine’s trial results arrived later than those of other frontrunners was because of its design: it had set a higher bar for the number of events – symptomatic Covid-19 – needed to make a call on efficacy. As a result, when that call came, the trial had far more events than the trials for the BNT-Pfizer and Moderna vaccines put together: 582 for the primary efficacy analysis. (BNT-Pfizer had 170; Moderna, 196.)
This vaccine is a single shot, viral vector vaccine – based on adenovirus 26. Efficacy was specified at 2 points for this trial – called the ENSEMBLE trial: 14 days after the injection, and from 28 days onward. There is a second trial – ENSEMBLE 2 – which is studying having a second injection at 56 days (2 months). Early phase trials had pegged 56 days as about the time that efficacy would plateau. However, even with the extra time and events the ENSEMBLE trial had, only 55% of the trial’s participants had reached that time point. So the results remain quite short-term. Like the Novavax trial we’ll see shortly, results in the ENSEMBLE trial had international differences in efficacy. Here are the efficacy rates from 28 days after the injection (which corresponds roughly to the time at which efficacy was calculated in the BNT-Pfizer trial, 7 days after that vaccine’s second injection):
- Efficacy for its “moderate to severe” endpoint: 66.1% (CI: 55-75);
- Efficacy for all symptomatic Covid-19 (FDA harmonized): 66.7% (CI: 56-75);
- Efficacy for severe Covid-19: 85.4% (CI: 54-97);
- Efficacy for “moderate to severe”, USA: 72.0% (CI: 58-82);
- Efficacy for “moderate to severe”, SA: 64.0% (CI: 41-79) (where almost all Covid-19 was caused by the B.1.351 (“SA”) variant of concern);
- Efficacy for “moderate to severe”, Latin America: 61% (CI: 47-72).
After 28 days, no vaccinated person required hospitalization or intensive care for Covid-19 (versus 5 in the placebo group). No vaccinated person died, although 7 died in the placebo group, all in SA and all after 14 days (5 after 28 days).
Over weeks, efficacy of this vaccine was increasing, although the numbers aren’t yet large enough to be sure about how high efficacy will be for the full group when they are all past 56 days. It was around 70% at that point for the group who had reached that point – roughly 5-percentage points higher – and it might have increased somewhat after that. There was roughly the same increase in efficacy against severe disease.
The rate of adverse events solicited in the week after the injection was lower than for several other vaccines. The most common systemic adverse event was fatigue (38%), with the rate of severe fatigue only 1%. It’s the first Covid vaccine that provided very clear data on how long reactions last: it was about 2 days.
The rate of serious or life-threatening adverse events was similar in the vaccine and placebo groups. However, the FDA judge 3 serious events to be vaccine-related: an allergic reaction (but not as severe as anaphylaxis); pain from a possible injection injury; and a very serious general reaction that resolved in 4 days. There were 4 events for which they could not rule the vaccine out: a person with pericarditis (inflammation around the heart that can cause chest pain) that resolved; one with Gullain-Barré syndrome (a nerve disorder of the limbs), which is a known rare reaction to vaccine; and a person with a deep vein thrombosis (DVT) that was resolving.
The US government put its shoulder to the wheel to increase production of this vaccine – including a deal for Merck to help produce it, as well as a company in India (discussed in the increased access section below).
Records in my collection for this vaccine here. Includes one laboratory on the D614G variant (none on variants of concern), and clinical trial data on B.1.351 (“SA” variant of concern).
- Expanding existing trials to estimate effect on asymptomatic infection, and to study a booster (third injection) for people in their earlier trials.
- Ongoing and planned trials for children and in pregnancy.
- Developing a booster for the B.1.351 (“SA”) variant of concern.
- And community impact studies show that this vaccine can be as effective in general use as it was in its phase 3 trial – and highly effective at reducing asymptomatic infection as well (see community impact section).
This vaccine dominates the post-phase 3 impact studies discussed above. And current and planned trials for children and in pregnancy were discussed in another previous section. BNT-Pfizer have also added a new step to their trials: they’re going back and testing blood samples to assess gauge efficacy on asymptomatic infection (here and here). And they have expanded an early stage trial of their original set of vaccine candidates to look at safety and signs of immunity in people who are immunocompromised.
B.1.351 (“SA” variant) possibly crushed one vaccine (Oxford-AstraZeneca) and reduced the efficacy of the only other 2 vaccines that have faced it on scale (J&J and Novavax). One theory being considered by BNT-Pfizer is to see if a third shot of their vaccine could so strengthen immunity, that people would be protected against B.1.351 (and other variants). It’s an extension of their earlier trials, but the trial registry records haven’t been updated on these details. (This is being studied by Moderna too – see below.) They are also developing a booster for B.1.351, but a trial for that hasn’t been registered.
And how is Pfizer using the phenomenal power this vaccine has given them, and how are they decided which countries get how many doses? A fascinating in-depth story digs in.
This vaccine is listed by WHO and distributed in the COVAX scheme. Records in my collection for this vaccine here. Includes 18 laboratory studies on variants, including B.1.1.7 (“UK”), B.1.351 (“SA”), and P.1 (“Brazil”) variants of concern.
- An additional month’s worth of efficacy data from the trials of this vaccine, together with community use data from the UK, provide support for efficacy increasing to over 70% in time, when a second dose of this vaccine is delayed.
- In a small trial in SA, the vaccine did not provide protection against the B.1.351 (“SA”) variant of concern. (The trial was powered to detect vaccine efficacy against symptomatic disease, but not protection against severe disease, so that question remains open.)
- New data from the vaccine trials more than doubled the number of people over the age of 55 studied. Together with data from the UK on large-scale community use in elderly people, there is enough data to allay concerns about efficacy in older people. [Update March 23] Interim results of the US/Latin American trial confirm efficacy in older people.
- Drug regulators around Europe have suspended use of either an EU-wide batch of the vaccine, or all use of the vaccine in their countries, pending full investigation of apparent clusters of serious adverse events. Germany has concluded that there was a higher-than-expected rate of a serious and rare blood clotting condition, which may possibly be associated with the vaccine. [Update March 23] The EMA came to the same conclusion.
- Additional month’s worth of trial efficacy data
- South African trial and B.1.351 variant of concern
- Vaccine use in older people
- Investigation of serious adverse events in Europe
- Other information
Additional month’s worth of trial efficacy data
The original publication of efficacy results for this vaccine combined data on 11,636 people in 2 phase 3 trials (Brazil and UK) as of November 4. An update was published in February, reporting on data requested by drug regulators focused on results after a single dose. That’s because based on an unplanned situation in the original trial, a second dose early may have reduced the vaccine’s efficacy. And with vaccine scarce, a single shot each would spread supplies out further while waiting for vaccine supply to increase.
This new paper had data as of December 6. And because there were now enough events – people with symptomatic Covid-19 – in efficacy groups in another 2 trials (UK and SA), 4 trials contributed data to the new analysis, with 17,178 people.
For the group they could analyze who had not had their second shot by 90 days, efficacy 22 days after the first shot was 76% (CI: 59-86). For the group with 3 months or longer between doses, it was 81·3% (CI: 60-92) – that’s not enough to support waiting longer, but it suggests immunity didn’t seem to be lost in those 3 months.
There is a lot of uncertainty around those efficacy rates, and those trials were not designed to test this dosing interval concept. But those efficacy rates are considerably higher than vaccine efficacy after 2 standard doses in the original dataset (62%), or after 2 doses with less than 6 weeks in between in this later set – 55·1% (CI: 33-70).
Although it’s too early to be sure how high this vaccine’s efficacy rate is over time, along with early community data, it appears that effectiveness over a month after a single dose could be higher than 70%. There is now a trial by the UK government that’s exploring the impact of changing the dosing (see the section on vaccine combinations).
South African trial and B.1.351 variant of concern
A preprint was posted reporting results of the phase 2 trial of this vaccine in SA. These were the results that led SA to switch its vaccination program from the Oxford-AstraZeneca vaccine to the J&J vaccine (now in a journal). This was a trial in a young, predominantly Black African group. The B.1.351 (“SA”) variant of concern swept through this community in a few weeks.
This was a small trial – just over 2,000 people who were HIV-negative (plus a small group of people living with HIV). But it was powered to detect vaccine efficacy, and it failed to meet the trial’s pre-specified level of efficacy. The rate was 21.9% (CI: -50 to 60), because 93% of the people who developed Covid-19 were infected with the B.1.351 variant.
You can see how much that reduced the vaccine’s efficacy. The vaccine had been doing well before the variant arrived in November, although the numbers are very small: 75.4% efficacy (CI: 8.9 to 95.5). Whereas the efficacy against that variant specifically was only 10.4% (CI: -77 to 55). (You’ll see in the results for the Novavax and J&J vaccines that their efficacy also took a hit up against this variant, but it wasn’t this big, and they still provided protection.)
The researchers make the point that even though the vaccine did not protect people against mild to moderate disease, it doesn’t necessarily mean it can’t protect people from more severe outcomes. The variant only diminishes some aspects of the immune response the vaccine sets in motion, and a second line of defense might make a difference in how severely ill people become. They include lab data suggesting the virus mutation didn’t affect T-cells that way. However, the trial couldn’t test that hypothesis because no one in the placebo group got severe Covid-19 either.
Vaccine use in older people
Around the time of my last post, there were differences in opinion internationally about using this vaccine in older people. The original data for the vaccine included under 1,200 people over the age of 55. Not long before, we had seen data for another vaccine suggesting it had lower efficacy in older people (although it wasn’t certain). Given the uncertainty, several countries restricted use of this vaccine to those under 65 (or another age). Others didn’t, pointing to the data on signs of immunity in that group of people.
The updated December data discussed above more than doubled the data on this vaccine for older people, as they had been recruited later in the clinical trial program – there was now data on over 1,700 people over the age of 55. In addition, very high use in older people in the UK showed good early results (see the section on community data). In reviewing the growing data basis, several countries are revising their recommendations (eg Germany early this month).
Investigation of serious adverse events in Europe
As I’m writing this, we’re waiting to hear from the EMA (Euro drug regulator) about the results of their investigation into serious adverse events, with European countries widely suspending the use of the Oxford-AstraZeneca vaccine while waiting. Many are arguing there is no need to do anything differently while the investigation runs its course.
Let’s re-cap what’s known about what’s happening:
- March 7: Austrian authorities reported they were suspending use of a batch of the vaccine, because there had been 2 serious events needing investigation. Both were related to thromboses (blood clots): one person died, the other was recovering.
- March 10: The EMA reported that 2 other reports of thromboembolism had come in for that batch, as of March 9, and investigation was continuing. Reports related to blood clots, they said, were very rare for the vaccination program overall. The batch was 1 million doses that went to 17 EU countries, and 5 of them had suspended use of the batch at that point.
- March 11: Danish authorities reported use of the vaccine was on hold while a death there was being investigated. The MHRA (UK drug regulator) reported the rate of reported blood clotting problems was extremely rare in the UK’s data collection – and the number of countries in Europe suspending its use was then 8. (It doesn’t appear, though, that doses from this batch had been used in the UK.)
- March 12: A spokesperson for WHO was reported as saying there was no link between the vaccine and blood clots.
- March 13: Norwegian authorities reported they were investigating a death with similarities.
- March 14: AstraZeneca reported these problems were extremely rare in their data collection, and there was no quality problem with the batch.
- March 15: EMA reported they were still investigating and there would be a meeting on the 18th to consider results. Germany’s Paul Ehrlich Institute (PEI) reported “additional cases” that were a “striking accumulation” of very rare disorders, and suspended the vaccine.
- March 16: PEI reported 6 cases of rare clotting in the brain with low platelet levels, cerebral venous sinus thrombosis (CVST), and a similar 7th case, occurred in the 16 days after vaccination in people not at high risk of the condition (aged 20 to 50), with 3 of the people dying. In that age group, they calculated the expected rate would be 1 case (a statistically significant difference). That does not prove the vaccine caused these rare events, but it cannot be ruled out. The EMA’s investigation is continuing. PEI advises anyone feeling increasingly unwell in the days after an injection with this vaccine with a persistent severe headache or spots of blood on their skin seek medical attention.
Now, apparently all, or almost all, of the 17 countries that received doses from this batch have suspended either use of that specific batch, or the vaccine completely, while waiting for the results of the EMA’s investigation and conclusion.
It’s an extraordinarily difficult situation in a pandemic. Some have been pointing to the low number of reports and the large number of vaccinations beyond this vaccine batch, and saying it’s simply a matter of statistics: the number of blood clot reports isn’t higher than you’d expect in any group of people who hadn’t been vaccinated, so there’s nothing to worry about – and the risks of not vaccinating are higher. See, for example, David Spiegelhalter here, and Tom Chivers here. They did this before the regulators had reported on how many cases were coming in.
It was never that simple. Those of us on the outside still don’t know how many events are being investigated across Europe, and what type of clotting problems they are – nor even whether this might in the end be related to a specific batch. If CVST is vaccine-related, it is very rare. A statement from the International Society on Thrombosis and Haemostasis concluded, based on the available data before PEI’s release, that the risk of not vaccinating would be higher.
All the data still isn’t available, and the investigation is ongoing. I doubt this many expert committees and responsible agencies would be taking this step lightly. If they’re being over-cautious, they face backlash – and they would, too, if events later showed they hadn’t been cautious enough. There could be several outcomes here, for example, ongoing investigation, or a change to the product information and recommendations for the Oxford-AstraZeneca vaccine. Germany, too, is waiting for the EMA investigation for further decisions about the use of the vaccine. PEI says a decision will be made by the EMA at the European level, and then each country will make its own decision after that.
Communities facing a mounting Covid wave can’t afford a setback to vaccination and communities can’t afford to lose confidence that potential risks of vaccines are taken very seriously – even if they are rare, or turn out to be unrelated to vaccines at all. The costs of the first are immediate. The costs of the second might be paid down the line in vaccine hesitancy.
Now that we’re in this situation, we need them to do a thorough job of this investigation and share enough information so we can absorb it, and move on, better informed.
Update March 18: The EMA could neither rule there was a definitive link between this unusual syndrome, nor that there was not. Their expert committee recommended a warning be added to the product information leaflet. See the thread below, and the report by Gretchen Vogel and Kai Kupferschmidt in Science.
The first major, standardized, placebo-controlled trial of this vaccine is expected to release its efficacy results any day now. The trial includes more than 32,000 people in the US, Latin America, and perhaps in Europe, too. Here is a Twitter thread I wrote a few weeks ago on what I’ll be looking out for.
There was an interesting story on the background of the SA trials for this and the Novavax vaccine: they happened because Shabir Madhi, a professor at Witwatersrand University, lobbied developers to do it (and the Gates Foundation funded the trials).
This vaccine is listed by WHO and distributed in the COVAX scheme. Records in my collection for this vaccine here. Includes 3 laboratory studies on variants, including B.1.1.7 (“UK”) and B.1.351 (“SA”) variants of concern, as well as clinical trial data on both.
- Trial for booster targeting the B.1.351 (“SA”) variant of concern underway.
- Studying a booster (third injection) for people in their earlier trials.
- The first Covid vaccine to release a full clinical study report package to the public.
The most eye-popping news of the last month was the speed with which the Moderna and NIH teams got a modification that also targets the B.1.351 (“SA”) variant of concern up and running. News that this variant even existed only reached us all in December – but by late February, Moderna had sent a modified vaccine to the NIH, and a phase 1 trial for 210 people was registered in the first week of March: they could have results within 5 months.
Moderna has also adapted their early phase trials from last year to offer people a booster shot, as is BNT-Pfizer. In part, it’s to study if boosters are needed within, say, a year. In part it’s to see whether having another boost is enough to protect people from variants.
The Moderna trial also became the first to have its full clinical study report and associated materials, like the statistical analysis plan, publicly released (on the Health Canada website). And they published results of last year’s phase 2 trial, filling in the last major gap in their data.
Records in my collection for this vaccine here. Includes 7 laboratory studies on variants, including B.1.1.7 (“UK”), B.1.351 (“SA”), and P.1 (“Brazil”) variants of concern, and a clinical trial is underway of a modification for the vaccine for B.1.351.
This vaccine also in: trials in children and pregnancy.
Vaccine, vaccine, vaccine, va-cc-i-ine
I’m begging of you please don’t hesitate!Dolly Parton, encouraging Covid vaccination (Yes, she sang it!)
How it started… helping fund NIH-Moderna’s phase 1 trial.
How it’s going….
- Press release with detailed final trial efficacy readout for UK phase 3 trial and SA phase 2b trial – applying for authorization to multiple regulators.
- Their UK and US trials are going to continue as crossover trials – everyone gets 2 shots twice; those who get the vaccine first time round get placebo in the second round, and vice versa.
This vaccine is a protein subunit vaccine – a more traditional type that includes Hepatitis B vaccine. This vaccine includes an adjuvant (an ingredient that aims to increase the vaccine’s impact on the immune system.)
Novavax released their final efficacy results for their phase 3 trial in the UK and phase 2 trial in SA, solidifying the findings discussed in detail in my previous post. Here are the final numbers for the UK trial (over 15,000 people):
- Efficacy against symptomatic Covid-19 (a week after dose 2): 89.7% (CI 80-95) (10 vaccine vs 96 placebo);
- Efficacy against the original SARS-CoV-2: 96.4% (CI 74-99.5);
- Efficacy against B.1.1.7 (“UK”) variant of concern: 86.3% (CI 71-94);
- Severe disease: 0 in vaccinated group versus 5 in placebo (4 of which were B.1.1.7); and
- No hospitalizations or deaths in vaccine or placebo groups.
For the phase 2b trial in SA (for which there is now a preprint), out of the 4,300+ participants, many were previously infected with SARS-CoV-2, and so are not included in the primary efficacy analysis. That analyzed results for 2,665 people who were HIV-negative and 240 people who were living with HIV, where the “majority” (not specified) with Covid-19 were infected by the B.1.351 (“SA”) variant of concern:
- Efficacy 48.6% (CI: 28-63);
- Efficacy for people who were HIV-negative was 55.4% (CI: 36-69); and
- No hospitalizations or deaths in vaccine or placebo groups.
Rate of severe adverse events was “low”, they reported in their press release (but no data). If these results are confirmed in the 30,000-person US trial, this is one of the most efficacious Covid vaccines (and could have the lowest rate of adverse events of the group of higher efficacy vaccines). In the phase 2 trial for this vaccine, the most common systemic adverse event was fatigue (36%), and it was the most common severe event, too (3%).
Novavax said they’re applying for authorization in several countries based on these data (but don’t say which). (For comparison: the Oxford-AstraZeneca vaccine was authorized in UK/Europe and elsewhere on efficacy data for under 12,000 people.)
Other Covid vaccine developers with phase trials that have efficacy results have started letting people in their placebo (or other control) groups know their status, and offer them the vaccine. That is fair to the participants, but it does reduce how much can be learned about the vaccine from the trial.
Novavax has chosen an innovative path that allows their UK trial to continue – and the same is happening in their big US trial. Participants have been invited back to continue in a crossover trial. That means they won’t be told if they were in the placebo group or not, but everyone will get 2 shots again: for those in the placebo group, it will be the actual vaccine, and the vaccinated group will get placebo shots. With people vaccinated at such different time intervals, questions like how long vaccine effects last can be studied. (Here’s a New York Times background story on this topic, before Novavax announced they were moving to a crossover trial, and here’s a study looking at the pros and cons of this approach.)
Records in my collection for this vaccine here. Includes 2 laboratory studies on variants, including B.1.1.7 (“UK”), B.1.351 (“SA”), and P.1 (“Brazil”) variants of concern, and clinical trial data for B.1.1.7 and B.1.351.
- Publication of results of the large phase 3 trial in The Lancet.
- Phase 3 trial of Sputnik Light – a single shot – has started in Russia.
Last post I said I thought this vaccine would surprise a lot of people, but that we really needed to see more about the quality of the trial, given the methodological problems with the early phase trial. (I discussed that in this previous post.)
The phase 3 trial for Sputnik V has now been published in The Lancet. The protocol was still not released, and the publication is short on key details. One of the things reported about the protocol was that it originally didn’t specify the number of events the trial needed, which isn’t reassuring.
There were 16,501 randomized to vaccine and 5,476 to placebo (planned 3:1 randomization). At the time of this report, around 2,000 had not yet had the second injection, and safety data verification hadn’t been done on nearly a third of the vaccinated people. However, serious adverse events had been reviewed, and none were determined to be related to the vaccine.
There is a problem with the way adverse reactions were monitored, though. They relied on spontaneous reporting, not formally soliciting particular adverse events routinely for a representative group (see my explainer on this). It means that we can expect adverse reactions are likely to be underestimated. (They weren’t reported in this paper.)
The rate of adverse events in the extremely small early phase trial – only 20 people had both injections – was very high, in part because it was a relatively young group of participants. The most common systemic reaction was feverishness/mild fever, reported for 95% of people, with a rate of headache of 45%. There were no severe reactions, and the highest rate for a moderate grade systemic reaction was 10% for headache. If this were to pan through to general use, then the adverse events would be very common, but not as severe as for some other Covid vaccines.
The outcome data generally, including for ascertaining Covid-19 after 21 days, relied quite heavily on routine medical records in the electronic health record system in Moscow – I can’t comment on how reliable that is, but that’s another issue to look out for when EMA’s evaluation of this vaccine. (Their review started recently.)
The participants are at relatively low risk of severe Covid-19 outcomes (eg 99% white, 90% aged 18-60). These factors don’t necessarily affect vaccine efficacy, but they may – age didn’t seem to in this trial. Efficacy reported in this trial was very high: 91.6% (CI: 86-95) from the day of the second dose. Severe cases weren’t reported separately, but no one in the vaccinated group developed moderate or severe Covid-19. The rate of hospitalization wasn’t reported. Two people died of Covid-19 in the vaccine group, but that was so early, they must have already been infected when vaccinated. (No one in the placebo group died of Covid-19.)
I think we’re in the same situation with this vaccine as we are with several of them: regardless of how good the vaccine might be, there seem to be potentially critical weaknesses in the clinical trial program. Small trials in some other countries could be reporting results soon, though.
Difficulties in production have plagued this vaccine, especially for the second shot: the combination of that and the Russian government’s geopolitical goals (aka “vaccine diplomacy”) is sure to mean this is a vaccine that many countries will be able to produce locally.
And the phase 3 trial for Sputnik Light has started. It’s a single shot of the first of Sputnik V’s 2 vaccines – the one based on adenovirus 26.
Records in my collection for this vaccine here. Includes no studies on variants. (Gameleya reports it has done well in lab tests for B.1.1.7 (“UK”) and B.1.351 (“Brazil”) variants of concern, but that study hasn’t been released.)
Sinopharm – Beijing
- Some people in the UAE who had lower immune response to this vaccine are now being offered a booster (their third shot).
We are still waiting for the release of data on this vaccine – for background, see my last post. We still have only an overall vaccine efficacy rate of 79.3% from a press release, without details of the number of events (people with symptomatic Covid-19) or CI. In the extremely small early phase trial, the most common adverse event was fever (4%), with no moderate or severe reactions reported (for the 4μg dose used in phase 3 trial).
In the UAE, which led the 45,000-person phase 3 trial in the Middle East for this and the Wuhan vaccine, they have begun administering a second booster (so that’s a third injection) to some people identified as having low antibodies despite vaccination. The number of people is reportedly “minimal”, but no more detail has been provided – including how people who could benefit from a third shot are being identified. No data has been released on the effects of a second booster.
Records in my collection for this vaccine here (check the notes field to see which are the Beijing vaccine, the Wuhan one, or both). Includes 1 laboratory studies on the B.1.351 (“SA”) variant of concern.
This vaccine also in: trials in children and pregnancy.
- Trial efficacy readout for the Turkish trial for this vaccine – the second trial to report – at a press conference.
- There’s an informal report about longer dosing interval increasing efficacy of this vaccine, but this was a small unplanned analysis and it’s too soon to know whether it does.
In my previous post, we had heard from the researchers running the Brazilian trial for this vaccine, and Anvisa, Brazil’s drug regulator. They had found a 50.4% (CI: 35-62) efficacy rate in a trial of just over 12,000 healthcare workers, with a 78% efficacy rate against disease requiring medical care.
The researchers had suggested that the efficacy rate of 50% was due to having pursued even the most mild symptoms vigorously for testing, and the trial being exclusively in healthcare workers. The data haven’t been reported in detail yet, though. Adverse events were very low: the most common systemic reaction was fatigue (<4%), and the rate of any kind of severe reaction was <1%.
The researchers later reported that a group of people – under 1,400 – had a 3-week gap between doses instead of 2 weeks, and the efficacy rate for them was around 70%. The trial wasn’t designed to answer questions about dosing intervals, and 1,400 is a very small number. It was presumably this data that led to the national vaccine committee changing their recommendation for this vaccine in Colombia: 56 days between shots. However, the recommendation wasn’t accepted, and the interval there remains up to 28 days.
The suggestion that 50% might be artificially low for this vaccine got a boost this last month when researchers reported interim results for the phase trial in Turkey at a press conference. That trial included 10,200 people. The reported efficacy rate was 83.5%, from 14 days after the second injection, based on 41 events (symptomatic Covid-19) – 9 in the vaccine group and 32 in placebo. They expect much of the Covid-19 to have been the B.1.1.7 (“UK”) variant of concern, which has spread widely in Turkey. No vaccinated person was hospitalized for the disease, versus 6 people in the placebo group.
A small lab study – testing blood samples of only 8 people infected by the variant – found that CoronaVac might struggle to provide enough protection against the P.1 (“Brazil”) variant of concern. However, Reuters has been told that there are lab results coming for both CoronaVac and the Oxford-AstraZeneca vaccine with good results against the variant. (The first community data in Brazil are discussed above in the community impact section.)
There is a report that Sinovac will be running a trial in older people in the Philippines, but I haven’t seen a trial register record.
Records in my collection for this vaccine here. Includes 1 laboratory study on the P.1 (“Brazil”) variant of concern.
Vaccine price landscape and access to vaccine manufacture
- The issue of the price of vaccines after the pandemic drawing focus.
- Pressure for international waiver on intellectual property for vaccines during the pandemic may be achieving some positive results.
- Major expansion of vaccine production planned – an extra billion doses for the Indo-Pacific.
- China reported a massive increase in its production plans, and the African Union revealed the prices it’s paying for vaccines.
This is a critical issue for everyone – even those living in the few countries who will have all the vaccine doses they could want in the next couple of months. Once this emergency is over, the prices for at least some vaccines could go sky-high. There are at least 2 vaccines in development that are planning at least some royalty-free licensing after the pandemic: Imperial College (discussed in the combinations section above), and NDV HxP-S in Asia.
There was both a setback, and a possible early result, of the campaign to waive intellectual property rights for Covid-related medicines and products, including vaccines, so that generics could be produced locally (as was done for HIV medicines in 2001). Hopes had been high, with WHO supporting the proposal by South Africa and India at the World Trade Organization (WTO) – see the director general’s, Tedros Ghebreyesus, Guardian op-ed – if not now, he asks, then when? It’s not a short-term solution on vaccines specifically, though it could make a difference in the longer term, if the HIV experience is a guide.
However WTO again passed, with the move opposed by Europe, UK, and USA. MSF is campaigning the UK government to change its position. But the push may have been one of the factors behind a major US move to expand vaccine production for India, Asia, and the Pacific – along with concern about the extent of Chinese vaccine diplomacy.
The new plan was part of the announcement by the QUAD countries – Australia, India, Japan, and USA. (QUAD is shorthand for the Quadrilateral Security Dialog.) Their series of actions to increase the supply and distribution of Covid vaccines included US support for an Indian company (called Biological E) to produce a billion vaccine doses (including J&J’s vaccine) in the Indo-Pacific. And Australia is expanding its existing commitment to supplying vaccines for 9 Pacific Island countries and Timor-Leste (presumably Australian-produced Oxford-AstraZeneca vaccine).
There have been 2 other major developments on access and price since my last post. China announced its production targets, and they’re far higher than any we’ve heard before: 2 billion doses this year and 4 billion annually by the end of 2022 – and Sinovac is reportedly producing a million doses a day.
Secondly, we saw the prices the African Union paid for vaccines for the continent (shown per person vaccinated):
- $6 for Indian versions of Oxford-AstraZeneca (Covishield) and Novavax;
- $10 for J&J (with half the costs of vaccinating people);
- $13.50 for BNT-Pfizer; and
- $19.50 for Sputnik V.
Moderna was unaffordable ($32 to $37 per dose).
As per the last post, the cheapest so far still seem to be Covaxin (around $2 in India) and CanSino ($4 for a single dose).
Overview of phase 3 trials and what’s new
- There are now 23 vaccines in, or about to be in, phase 3 trials – including 3 additions since the last post.
- There are another 3 phase 3 trials coming over the horizon.
- Several options possible for evaluating vaccines as placebo controls become less viable.
The 3 additional vaccines in phase 3 trials underway since my last round-up are:
- GrAd-CoV-2, from ReiThera in Italy, is a viral vector vaccine (based on a gorilla adenovirus). The phase 3 trial is small – 10,300 people – and running in Italy.
- SOBERANA 1, also called Finlay-Fr-1, from the Finlay Institute in Cuba: it’s been added to the SOBERANA 2 phase 3 trial, aiming to recruiting 44,010 people in Cuba. Both of these are protein subunit vaccines, a more traditional vaccine type (like Novavax). The vaccine(s) will also be trialed by the Pasteur Institute in Iran, and doses have been sent there, but no details yet on the trial.
- Sputnik Light, which is the first of the 2 injections for Sputnik V, running as a stand-alone in a small – 6,000 people – trial in Russia. That’s a viral vector vaccine, based on adenovirus 26 (the same human adenovirus on which the J&J vaccine is based).
Vaccines coming into phase 3 from here on in face an additional challenge the front-runners didn’t face: whether they can run placebo-controlled trials in areas where vaccination is now an option. With many countries having very low vaccine access, it may still be an option. Depending on regulators’ requirements, the options could include:
- Non-inferiority trials: comparing to another vaccine that has been through phase 3 trials – showing that they are at least as good as the other vaccine;
- Smaller trials large enough for safety, and with immunogenicity data supplementing efficacy data (discussed above) – some vaccines are already in use in some countries based on small trials; or
- Human challenge trials: where people agree to be exposed to the virus thus testing efficacy quickly in a low number of people, while establishing safety in several thousand people presumably in a phase 2 trial (and immunogenicity in groups too high risk for human challenge trials).
Human challenge trials seem likely for at least the vaccine developed by Imperial College London: 90 people aged 18 to 30 have signed up for a human challenge trial, to be quarantined in a London hospital, to find out the minimum amount of virus needed to infect someone. (The Imperial College vaccine is the self-amplifying mRNA vaccine used in a preclinical comparison with the Oxford vaccine, discussed above.)
Several vaccines that already had phase 3 trials started or registered now have additional ones, so check out the updated table in the addendum below if you’re interested in any particular vaccine. There are also another 2 vaccines that are anticipating phase 3 trials, but reported clearly they are still in phase 2: Inovio (US) and AnGes (Japan) (appears to have fully recruited its phase 2 trial). And another vaccine may be soon to start a phase 3 trial: Arcturus, a US company working with a university in Singapore. Theirs is a low-dose, single shot, freeze-dried mRNA vaccine and they plan to run a 15,000-person trial in 3 as-yet-unvaccinated countries.
And in other news, CureVac, the developer of the second German mRNA Covid vaccine, is aiming to have a minimum number of events (symptomatic events) for each of multiple variants, and anticipates having results before mid-year.
- WHO has established a vaccine injury compensation scheme for low- and middle-income countries getting vaccines through COVAX. It’s a “no-fault” scheme – no need for courts – with the costs covered by a levy charged on all doses of vaccine.
- Johns Hopkins University has a vaccination tracker for the US and internationally, showing how many people are fully or partially vaccinated. That gets over the problem of other trackers counting first and second doses the same way (and accounting for how many people got vaccines that only require a single dose).
- France was, I think, the first country to recommend a single dose of vaccine for people who have previously been infected with SARS-CoV-2.
- First Health Canada, and then the EMA (Euro drug regulator), began releasing complete clinical study report and protocol packages for authorized vaccines – they have BNT-Pfizer and Moderna so far. At EMA, you have to request access. At Health Canada, they are fully open (BNT-Pfizer, Moderna). (I have added the Health Canada versions as a category to my Zotero collection.)
- The participant from the vaccinated group who was hospitalized after a serious adverse event in the Oxford-AstraZeneca vaccine trial in India and sought compensation, proceeded with a lawsuit. (Background discussed in a previous post.)
- A group of regulators is now in a collaboration on Covid-19 assessments with EMA (Euro drug regulator): Australia, Canada, Japan, Switzerland, and WHO.
- Researchers at Sweden’s Uppsala University are hoping to do a head-to-head, cluster trial of all authorized vaccines integrated into vaccine rollout in 4 regions of the country – starting this month if they get the green light from the national drug regulator. People could opt out, but if they didn’t, they’d be randomized to vaccines. More on that (in Swedish).
This will pass if we can think of others and help each other.Pelé, encouraging Covid vaccine
Addendum: The phase 3 trial tables
Phase 3 trials: recruitment progress
|Vaccine||Target or final size||Single or similar trials?||Reaching target?|
Johnson & Johnson
|73,783||2 large trials||Single-dose trial with 43,783 reported.
Second 2-dose trial advanced, perhaps nearing recruitment.
|40,500||Mostly single trial||Press release readout for results of single-dose trial with ca 40,000.|
|50,331||Mostly single trial||Trial with 46,331 aged 16 and over reported; extension to people aged 12 not yet reported. Trial for 4,000 pregnant women began in February.|
UK (Oxford Uni)
|54,690||3 very different large trials (plus some small)||2 major trials 10,000+ each (UK and Brazil) reported.
Major trial in US and other countries, registered for 30,000, recruited 32,459 as of late January (begun August 2020).
Small trial in India has final results, but not published.
|30,918||1 trial||Began in March.|
|39,020||1 large, 1 small||Large international trial began in early January in Peru.|
|3,000||1 trial||Apparently fully recruited.|
|10,300||1 trial||Phase 2/3 began February/March.|
|40,170||1 large, 3 small||
Trial of 30,420 reported. Trial of 3,000 adolescents reached full recruitment in March.
|45,000||2 trials||Trial of 15,000 in UK fully recruited. US/Mexico trial of 30,000 fully recruited. (Efficacy results also from 4,442 in a phase 2b trial in South Africa.)|
Finlay Institute Cuba
|44,010||1 trial||Began in March. Unknown number also soon in Iran.|
|Sputnik V, Sputnik Light (Gam-COVID-Vac)
|41,700||Mostly single trial. Small trial of Sputnik Light.||
Sputnik Light trial began in February.
|7,320||Single trial||Phase 2 of 2/3 trial, start date not known.|
Chinese Academy of Sciences
|29,000||Single trial||Started in November.|
|30,000||Single trial||Fully recruited.|
|Inactivated virus vaccines|
|2 BBIBP-CorV vaccines
|60,300+||2 large trials, several small|
|31,020+||2 large trials, several small, 1 unknown|
Bharat Biotech, Indian Medical Research Council
|29,500+||Mostly a single trial||Trial efficacy readout for 25,800 participants.|
Scientific Research Institute
|3,000||Single trial||Fully recruited, results expected in April.|
Chinese Academy of Sciences
|34,020||1 trial||Began in January.|
|Total participants||Over 690,000
|About 460,000 likely to be already recruited.|
The phase 3 trials, and the preclinical and clinical trial results reported for those vaccines
Johnson & Johnson
(Trial for 824 pregnant woman to start)
43,783 (single shot) (Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, USA) Results reported
30,000 (2 shots) (Belgium, Colombia, France, Germany, Philippines, South Africa, Spain, UK, USA)
(Plus unreported trial in children)
|Primate, non-primate (b2 only)||b1:
b1 & b2:
(Phase 2 for people with allergies underway: 3,400, includes Moderna)
4,000 (b2)* (USA)
UK (Oxford Uni)
560 (from the major phase 2/3 trial)
2,026 (from South Africa, HIV-negative)
300 (Phase 2 trial underway for ages 6 to 17)
|Primate, non-primate||247||n.a.||(Phase 2/3 trial)||
|Primate, non-primate||Unpublished (90)||n.a.||(Starting)||
(Phase 1 for variant modification underway: 210)
(Phase 2 for people with allergies underway: 3,400, includes BNT-Pfizer)
3,000 young people**
6,750 infants and children**
1,288 (Australia, USA)
4,387 (South Africa)
Small bridging trial planned in India
SOBERANA-2 (Finlay-Fr-2)/SOBERANA-1 (Finlay-Fr-1)
2: Unpublished (40)
1: 30 (Unpublished studies for 676 & 60)
2: Unpublished (910)
(Additional unknown number planned in Iran & possibly Mexico)
Sputnik V & Sputnik Light (Gam-COVID-Vac)
Sputnik Light: (Phase 1/2 trial underway: 110)
6,000 – Sputnik Light (Russia)
|Non-primate||Unpublished (60)||n.a.||n.a. (phase 2/3)||
(Unpublished, 50 aged 60+)
|Primate, non-primate||n.a.||Unpublished (1,048)||n.a.||
|BBIBP-CorV x 2 (1 Wuhan, 1 Beijing)
Primate, non-primate (Wuhan)
45,000 (both vaccines)
3,000 (Beijing only)
300 (Wuhan only)
? (both vaccines)
? (Beijing only)
|Primate, non-primate||239||Phase 1/2 trial for ages 3 to 17 underway||950||
13,060 (originally 9,000)
1,040 (non-inferiority study of vaccine lots)
Bharat Biotech/Indian Medical Research Council
28,500 (India) Efficacy readout in press release
1,000-2,000 (planned, Bangladesh)
Scientific Research Institute
Chinese Academy of Medical Sciences
|Unpublished||Unpublished: 200 (aged 18 to 59)||Unpublished: 471 (aged 60+)||742 (aged 18 to 59)||
34,020 (Brazil, Malaysia)
* 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 is my eighth monthly roundup post of the Covid vaccine race:
Disclosures: My interest in Covid-19 vaccine trials is as a person worried about the virus, as one of my sons is immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.
My thanks to Nancy Baxter for the suggestion of how to name the vaccines in the infographic, and to Jorge Gamboa, Meg (@childrenneedus_), Mitra Taj, and Hans Vasquez who alerted me to information about developments in Colombia and Peru. Thanks to KittyK for alerting me to an error I’d made in the name of the Moderna trial for teens (corrected soon after posting).
Update March 17: Added start of Medicago’s phase 3 trial.
Update March 18: Added EMA approval of Novavax pediatric trial plan. Added EMA conclusions on the serious adverse events in Europe, and the earlier statement by the Norwegian Medicines Agency.
Update March 22/23: Added brief notes on the press release of US/Latin American trial results for the Oxford-AstraZeneca vaccine; the conclusion of the EMA investigation; and the NIH statement of concern about the AstraZeneca press release. Deleted and updated on March 30, incorporating updated AstraZeneca trial press release, in both infographic and table.
The infographic scale was determined by 95% as the highest established efficacy rate with 50% as the minimum set by WHO and the US FDA, enabling a breakdown into equal-sized low-medium-high areas: data shown in table. The low-medium-high scale for rates of adverse events was set with the rate for the inactivated vaccines as lowest established rate, with the highest rate just above the highest for the most common systemic adverse event any of these vaccines at the other end (75%), after taking both the rate of the most commonly reported severe outcome and the age of the trial population into account. This was new, resulting in some calibration from the previous post.
Sources for study records
Source records are in my public Zotero collection of Covid-19 vaccines that have any published preclinical or clinical results (or preprints), or that are in phase 3 trial (more details below, including how to use it) for general populations. It also includes the matched control studies I am featuring. Please let me know if I’m missing any! On March 16, the collection included 432 entries:
- 116 vaccine groups with published or posted results;
- 21 trial protocols, for 9 vaccines (including 1 vaccine with additional protocol versions in a clinical study report package);
- 150 preclinical preprints/articles;
- 29 preclinical or serum studies of vaccines and new variants;
- 137 trial registry entries associated with these vaccines;*
- 47 clinical trial preprints*/articles/letters:
- 19 for phase 1 trials;
- 12 for phase 1/2 trials;
- 8 for phase 2 trials;
- 2 combined reports of phase 2 and 3 trials;
- 1 combined report of phase 1 to 3 trials;
- 3 phase 3 trials;
- 2 author replies to letters to the editor about their publications;
- 17 trial efficacy readouts for phase 3 (press releases), for 11 vaccines;
- 23 documents reporting on or reviewing phase 3 data at regulatory agencies, for 6 vaccines;
- 2 full clinical study report packages;
- 3 termination notices, for 4 vaccines (all but one of which have other records in this collection);
- 4 featured community impact studies, for 3 vaccines;
- Records for 5 vaccines tagged as trials including children/teenagers;
- Record for 1 vaccine tagged as adapted for variant;
- Record for 1 vaccine tagged as geographic.
* May not include all entries where a trial is registered in multiple registers, or a preprint is posted to multiple servers.
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. Preprints may also be uploaded to multiple preprint servers: rather than check if versions have differed, I keep the first preprint in the collection (sometimes over-written with updates in the same server).