I think we are drifting perilously close to exceptionalism in the debate about the Covid-19 vaccine for children and adolescents. The narrowed…
The second year since the genome sequencing of the new coronavirus has begun. And it’s off to a drama-packed start. Major outbreaks in several countries were breeding grounds for mutant strains that are crushing their communities and spreading across the globe. There’s been fierce debates about efficacy of some vaccines – and there are lots of confusing claims and data.
There are about 400,000 people in phase 3 trials for Covid vaccines now, with just as many still needed for the trials that are already underway – and still more to come. Communities in many parts of the world are pulling out all the stops to get vaccinated, but access to vaccine is extremely limited, with inequitable distribution between and within countries. Results for 3 new vaccines that work have radically changed the landscape and that’s wonderful news, but one major manufacturer had a setback, and another pulled out of Covid vaccine development. That’s a lot to unpack! You can navigate around the post with these links:
- Vaccine efficacy and new variants
- The new landscape with 8 vaccines
- Closer look at the 3 new vaccines
- What’s new for the other 5
- Vaccine price landscape
- Overview of phase 3 trials and what’s new
- Other news
- Addendum: phase 3 trial recruitment status & studies
Vaccine efficacy against new variants: the first clinical evidence
New variants of SARS-CoV-2 can be better at dodging our immune systems, so some are spreading more easily and taking over. That was dangerous, but at first the news emerging about lab tests on vaccines’ ability to neutralize variants was pretty good. The 2 mRNA vaccines (here and here), and then one of the inactivated vaccines (India’s Covaxin) seemed to more or less clear the new hurdles.
Some developers announced they were working on adaptations to the new variants, so booster shots would be ready for extra protection to target specific strains if needed. The US FDA is going to provide guidance on immunogenicity trials needed for these adapted vaccines – they’re talking about trials for around 400 people at the moment. And a part of the US “Operation Warp Speed” program involves standardized testing in the big trials they support to establish immunogenicity correlates, or stand-ins, for estimating impact on immunity. (Protocol for that study here.)
The stakes around this shifted, though, when Novavax posted some early results from its trials in the UK and South Africa (SA). Along with the exciting news that their vaccine’s efficacy could be as high as that of the 2 mRNA vaccines for the original strain of the virus, there was the first human data to show what happens when a powerful vaccine goes toe to toe with variants that could be able to escape detection by our immune system more often. And then more arrived with the J&J trial.
- Including the “UK” variant drops the efficacy in the Novavax UK trial somewhat – by about 5 percentage points. In a phase 2b trial, in South Africa, the “SA” variant lowered efficacy considerably more (although that trial is too small to be sure by how much). The J&J vaccine trial had a substantial group of participants from SA, 95% of whom were infected with the new variant: overall efficacy was considerably lower there, too.
- Having been infected with the original strain may not be enough to protect people from getting re-infected. In a webinar, one of the investigators presented data showing that the rate of Covid-19 in people who had signs of past infection before the Novavax vaccine trial was the same as for people who had never been infected. That was true in the trial for Tozinameran (BNT/Pfizer vaccine), too. Might new variants make this more likely, though?
The most important message is a reassuring one: those 2 vaccines still work, even in areas with the variants causing the greatest concern – at the moment, those are B.1.351 (the “SA” variant) and P.1 (the “Brazil” variant). B.1.17 (the “UK” variant) is less worrying, though still potentially taking a bite out of vaccine efficacy. (The CDC has a guide to the various names people are calling the variants, and when and where they were first identified.) No detail data has been released yet for tests on the vaccines I haven’t mentioned so far.
Bottom line? Suppressing outbreaks is critical to stop mutations spreading and more of them developing. And expect variant-specific boosters and multivalent vaccines to improve protection in the near future. (A multivalent or polyvalent vaccine protects against more than one strain – bivalent for 2, for example, and quadrivalent for 4.)
And then there were 8 … and a complicated new Covid vaccine landscape
Let’s start with an overview of the current landscape of vaccines with at least some efficacy results public:
- There are 2 mRNA vaccines – Tozinameran (the generic name for the BNT/Pfizer vaccine, brand name Comirnaty) and the Moderna vaccine. (I compared them in detail in my last roundup post.)
- There is 1 protein subunit vaccine, a more traditional type of vaccine – from Novavax*, with data on the “UK” and “SA” strains.
- There are 3 vaccines based on adenovirus vectors – not quite as new as mRNA vaccines, but still a recent type of vaccine. They are the Oxford/AstraZeneca vaccine (called Covishield when produced in India), Sputnik V, and the single shot from J&J*. J&J has data on the “SA” strain.
- There are now 2 inactivated vaccines with at least some phase 3 results released – a vaccine type with a long tradition. They are Sinovac’s CoronaVac* and Sinopharm’s Beijing vaccine.
Those marked * are the 3 vaccines with first details of phase 3 trial released this month.
The vaccines all have different pros and cons built in. For example, the current form of both mRNA vaccines have refrigeration requirements that make them more difficult to distribute and use than the others, especially Tozinameran. (Powdered versions to mix with liquid for injections on the spot might come, but not quickly.)
Only 5 vaccines are likely to have at least a billion doses produced this year: Oxford/AstraZeneca, Novavax, Tozinameran, J&J, and Moderna. For perspective: the global population is 7.8 billion, including 2.2 billion children, and almost all the vaccines need 2 doses.
The trials were all different in fundamental ways, such as:
- How they defined the events (Covid-19 illness) that were the primary efficacy outcomes.
- The number of people in the trials, and the quality of those trials (and the amount of data available), all vary greatly.
- Only the 2 mRNA vaccine trials, Novavax and J&J included a substantial number of people over the age of 55 – which is critical, as they’re more at risk of severe Covid-19 and older immune systems don’t necessarily respond as well to vaccines either.
- The proportion of people at high risk of Covid-19 because of race or risk factors like occupation and obesity vary a lot, too.
- The phase 3 trials from earlier in the pandemic were testing the vaccine against the original strain, not the new variants.
If comparing the vaccines’ efficacy simplistically isn’t already fraught, then doing it in a graphic is even more perilous. I nevertheless decided an oversimplified “sketch” of this landscape was still more likely to help with perspective, than mislead. So, with all those caveats in mind, I went ahead and made a manual infographic.
Update: The infographic was removed, shortly before the next monthly roundup was posted.
Except for the mRNA vaccines (numbers 1 & 2), the data behind them is very preliminary. The other 5 could shift, perhaps even a lot: they’re like counters that could move around on the 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, at least in the short-term – and immunity could even increase over the first month or two, as well. 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.
|>43k people (half on placebo)|
Reviewed & detailed reports public; protocol public
|>30k people (half on placebo)|
Reviewed & detailed reports public; protocol public
|3||Sputnik V (Gamaleya)||92%|
|>22k people (a third on placebo)|
Reviewed, very little detail public; protocol not public
Evidence: statistically strong (open questions about methodology); adverse event data used from small early phase trial, as adverse events not routinely solicited in the trial
(standard dose, February data)
|>11k people (half on placebo, half on varied vaccine regimens)|
Reviewed & detailed reports public; protocol public
Evidence: weak, from group of trials (but a strong trial in progress); adverse event data from MHRA
|5||Sinopharm – Beijing||79%|
|Up to 30k people (half on placebo)|
Reviewed, negligible details public – not clear if 79% is overall efficacy or a subgroup; protocol not public
Evidence: potentially strong (too little known)
|>12k people (half on placebo)|
Reviewed, basic details public; protocol public
Evidence: weak to moderate (further trials in progress)
|7||Novavax||89% (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.
|8||J&J||66% (including “SA” strain)|
72% in the US
|>43k people (half on placebo)|
Press release only; protocol public
Evidence: strong (further large trial on 2 shots in progress)
A closer look at the 3 new vaccines
Novavax – another high efficacy result
This is an interim readout for 2 trials: a phase 3 trial of more than 15,000 people in the UK, and a phase 2b trial of over 4,400 people in SA that had efficacy endpoints. (The protocols for both were released previously.) The readout was reported in a press release, with additional data released in a slide presentations (reported here by Kai Kupferschmidt and here by Meg Tirrell).
The Novavax vaccine is the first protein subunit vaccine for Covid-19, which is a common type of vaccine (like the hepatitis B vaccine). It uses a specific part of the virus to generate an immune response (which is not enough of the virus to cause the disease), plus an adjuvant (an ingredient to boost the immune system response). It’s 2 injections, 3 weeks apart, and the vaccine is stable in normal refrigeration. The vaccine uses a nanoparticle – which means it only needs a very small amount of the protein subunit in each dose – helping it be one of the 5 vaccines that could have at least a billion doses produced in 2021. There might be more than 2 billion doses because of major production planned in India, which puts it near the top.
It’s the only vaccine with results showing how it fares against both the “UK” and the “SA” strains of the virus – and they are working on formulations targeted at them both now as well. Those strains depressed the efficacy of the vaccine, but it still offered protection against both.
People over the age of 65 made up 27% of the phase 3 trial in the UK (around 4,000), up to age 84. Racial diversity wasn’t reported. (For perspective, in the Oxford vaccine trial, around 5% of participants were Asian, and 92% were white.) The proportion of people at risk of severe Covid-19 hasn’t been reported yet either.
The efficacy results are for the first 14,049 people. There were 62 events (symptomatic Covid-19), with 6 in the vaccine group and 56 in the placebo group: an efficacy rate of 89.3% (CI: 75-95). That puts it in the top cluster with the mRNA vaccines and Sputnik V at this point.
Over half of the people sick with Covid-19 had the new “UK” variant (variant: 32, original strain: 24, unknown: 6). Efficacy against the non-“UK”-strain(s) was 96% vs 86% against the “UK” strain – based on 4 vs 2 events in the vaccine group, which is too small a number to be sure about the size of the effect (the range of uncertainty wasn’t reported). However, it’s clear that it protects against the strain, but with reduced efficacy.
There were no safety concerns reported. The results from their small phase 1 trial (131 people getting differing doses or placebo) suggest adverse events could be lower or similar to the other high efficacy Covid vaccines.
What about SA? It worked, but there is too much uncertainty to be confident about the rate of efficacy. The efficacy rate was for the first 2,684 people. It was 49%, but the range of uncertainty was very wide, as you’d expect from such a small group (6-73%).
They’ve checked the strains for most of the people with Covid-19 in that trial, and 93% of them were infected by the new variant. Efficacy was higher in the people who were HIV negative – 60% (20-80%). That doesn’t mean, though, that the efficacy is very low in people who are HIV+: there were only 148 people who were HIV+ in this early dataset, so we can’t place too much weight on it. (There will be 245 people in this group in the final results.)
As with all the vaccine results so far – except J&J’s – there weren’t enough people with severe Covid-19 to give a solid estimate of efficacy here (there was only 1 person with severe Covid-19, and they were in the placebo group). Typically, though, when a vaccine is preventing symptomatic disease, it also lessens the severity, but we still need more data to be certain with each vaccine.
There is also a trial planned for 30,000 people in the US and Mexico: they reported 16,000 are recruited for that trial. The protocol for that trial shows they will need 144 events for an answer – and they allow for an interim result at 72 events (and another at 108). It’s estimated they could have the final data and enough of the 2-month safety data required for an FDA application by the end of March or early April.
However, there is already more, and higher quality, data for this vaccine than there is for the Oxford/AstraZeneca vaccine, with a similarly wide range of uncertainty for the phase 3 trial: that was considered enough for emergency use authorization in several parts of the world. When the final results are in for the UK trial (which should be soon), it’s likely several countries will consider authorizing it. Update February 1: An application for authorization in Canada has already been submitted.
Records in my collection for this vaccine here.
CoronaVac – the inactivated vaccine from Sinovac (China)
This is the first inactivated virus vaccine – a traditional form of vaccine – with enough basic results publicly available. There’s still no full release of results for any of its trials yet. But there is basic data available now for the Brazilian trial in around 12,123 healthcare workers (with 595 aged 60+), from the authorization reports by Anvisa (Brazil’s drug regulator), and a press conference including that trial’s investigators. (The protocol for the trial had been published in October.)
In this trial, the investigators put in a lot of effort into trying to capture even very mild Covid-19 illnesses. The trial participants were healthcare workers with patient contact, and presumably particularly likely to be vigilant about signs of disease and get tested. The investigators argue that the inclusion of very mild Covid-19 makes their efficacy results difficult to compare to other vaccines. The overall efficacy for 9,223 participants was 50.4% (CI 35–62%) (calculated by hazard ratio, which takes into account the time since vaccination). No one in the vaccinated group had severe Covid-19 or required hospitalization for the illness.
The investigators broke that down like this:
|Number of events|
|Number of events|
|Moderate to severe Covid-19|
(needing medical care)
It will be hard to know if a particularly high rate of mild illness was detected in this trial, although that picture might become clearer as more results for this and other trials are published. For now, we know the vaccine is over the minimum WHO and FDA threshold for efficacy, and protection against serious Covid-19 illness is high. But the range of uncertainty is quite large.
There was only a 2-week gap between injections in this trial, so the picture of efficacy is sooner than usual in these trials. In an interview, they said there was a small group of people with a 3-week gap, and efficacy for them was around 70%. But that was less than 1,400 people, and it wasn’t planned, so this is very uncertain. It’s a reminder, though, that efficacy estimates for this vaccine could be quite different in the future.
What isn’t uncertain is the very low rate of adverse events and ease of administration, which is what you would expect from an inactivated vaccine. Almost all adverse events were around the injection site (local) – pain, redness, and so on. The rate of systemic (non-local) adverse events in the first 7 days was less than 3%, with a rate for moderate adverse events of only 1%, and less than that for severe. With no serious adverse events related to the vaccine either, this is an easy-to-tolerate vaccine.
Another reminder that efficacy rates could change a lot for this vaccine came from very early results from a trial in Turkey in healthcare workers that will eventually be around 13,000 (much the same planned size as the Brazilian trial), and from a small trial in Indonesia (1,600).
In Turkey, they were reporting on results for the first 1,322 people, with 3 people with Covid-19 in the vaccinated group, and 26 in placebo: that’s 91% efficacy (CI: 71–97%). But there had been earlier reports that 40 events were needed for an analysis – and 2 of the 3 events were described as asymptomatic, which doesn’t meet the definition for an event in the trial’s registry record.
For the Indonesian trial, an efficacy rate of 65% was reported when emergency use authorization was issued, based on 25 Covid-19 illnesses in the trial, with no serious adverse events associated with the vaccine. (No further data, though.) A BPOM (national drug regulator) spokesperson also reported that the vaccine had been formally certified Halal.
This is the first Covid vaccine to be rolled out on in scale in Brazil.
Records in my collection for this vaccine here.
J&J single shot – and the most international trial yet
This is another trial readout. And this time, we didn’t get critical data like confidence intervals (the range of uncertainty). Apparently, that was on FDA advice – which would be a most unhelpful intervention! At least, given this is final data – a whopping 468 events with the 2-month minimum safety follow-up – a full FDA data release should only be a few weeks away.
This vaccine is a viral vector vaccine. That means another harmless virus is modified, then used to carry instructions that activate the immune system to mount a defence to the SARS-Cov-2 virus. That’s the same vaccine type as the Oxford/AstraZeneca vaccine, but based on a different virus – adenovirus 26 – which is also the basis of the first shot of the 2 in Sputnik V’s course. J&J are the manufacturers of the only viral vector vaccine that has ever been approved by the EMA (Europe’s drug regulator) – an ebola vaccine – so it’s coming from a base that’s been successful before.
- Efficacy for severe Covid-19 was 85% across all the regions (Latin America, South Africa, and USA) at 28 days – with 0 vaccinated people getting severe Covid-19 after day 49;
- There were 0 deaths from Covid-19 among the vaccinated group, but 5 in the placebo group. (Between the other 2 big Covid vaccine trials – for the mRNA vaccines – there was a single Covid death, in Moderna’s placebo group.)
Severe Covid-19 was a secondary endpoint, so there could be more uncertainty around this result than the primary endpoints, which were illness at days 14 and 28.
From 28 days after the injection, the vaccine had 66% efficacy against moderate to severe Covid-19 – and protection started to build from day 14. This was a primary endpoint, and there are so many events, that should be a very reliable result. Efficacy was 72% in the US, 66% in Latin America, and 57% in SA (where 95% of people were infected with the “SA” variant). Although we don’t know how much certainty there is around those differences, the variants seem to have depressed the vaccine’s efficacy – but it still offers some protection against illness not severe enough for the person to need hospitalization, and, critically, high protection against severe illness.
The trial included over 14,600 people older than 60 (34%), and 41% of participants are at risk of severe Covid-19. The population was diverse: 59% are White, 45% are Hispanic/Latinx, 19% are Black/African American, 9% are indigenous American, and 3% are Asian. Protection was said to be similar across age and race groups.
It’s always risky comparing results from very different trials. It’s even tougher here, where the endpoint seems so different to the other trials – “moderate to severe” disease, instead of “symptomatic Covid-19”. We have examples now to show efficacy reducing as you go down the seriousness of infections scale, from severe, to any symptomatic illness, to asymptomatic infection. So how does this relate to the other efficacy results we’ve seen?
According to the trial’s protocol, the definition of “moderate to severe” is so broad, it’s clear the overlap with the other trials’ primary outcome must be substantial. On this point, Eric Topol tweeted after speaking with J&J, “there are no substantive differences”. That seems plausible. The lines are very blurry here. (The Novavax UK trial reported a mild/medium/severe breakdown, and removing the mild events barely changes efficacy. However, mild events made a big difference in the CoronaVac trial – albeit, argue the investigators, with considerable effort to find even very mild illness.)
We’ll get a clearer perspective when we see the full J&J data: for example, secondary endpoints in this trial include all symptomatic Covid-19, and asymptomatic SARS-CoV-2 infection by day 29. Asymptomatic infection will be determined by blood tests for all participants, as well as anyone who tested positive without getting sick (eg a test from contact tracing).
The readout didn’t say much about safety and adverse events. There were no safety concerns reported, serious adverse events were actually less common in the vaccine group, and there was no anaphylaxis (allergic reaction). The only adverse event they reported on was fever: 0.2% had severe fevers, and 9% had any level of fever. That, along with their early phase results and a single injection, suggests that adverse events aren’t as high as some other Covid vaccines.
There’s another large trial underway – for 30,000 people – getting 2 doses, 2 months apart, called ENSEMBLE-2. That one only began in mid-November, so results from that aren’t likely for another month or more. This isn’t a slam dunk – there’s a question about whether people might develop immunity to the viral vector as well as Covid-19. (Indeed, some people could have immunity even before getting the vaccine, so that will be a focus of attention, too.) With people already exploring using different vaccines for the first (“prime”) and second (“booster”) shots, there could be more consideration down that road for this vaccine, as well.
The J&J vaccine can be kept in normal refrigeration for at least 3 months, and they have committed to providing it at an affordable price and non-profit for emergency use during the pandemic. It’s the vaccine with the biggest current planned provision to South Africa (30 million doses over the year), and there are plans to manufacture it in SA for export as well (with option for further SA purchase).
Update February 1: An application for authorization in Canada has already been submitted.
Records in my collection for this vaccine here.
Developments on results for the other 5
Oxford/AstraZeneca: ongoing efficacy debates
Debates and confusion about this one were intense last week, with Germany’s national vaccine committee recommending it be used only for adults under the age of 65. There was a blaze of claims and counter-claims when someone in the know leaked this to German media, including a claim that the vaccine had an efficacy rate of less than 10% in people 65 and over. (Copy of the whole document, in German, online here.)
It turned out to be true that it was less than 10%. But here’s the thing: Oxford’s trials for their vaccine just didn’t include enough people over the age of 55 to give any reasonable estimate of efficacy. Between the trials’ sizes, varied dosing issues, and more, even the efficacy estimate for people up to the age of 55 is quite imprecise – see how wide the range in the table above is compared to others. The strongest results have a range with a difference of 10% between them – the uncertainty around the Oxford/AstraZeneca estimate is more than twice as wide as that. After 65, though, the numbers are just too small to mean anything.
Let’s walk through what this looks like, and how a few extra people sick with Covid-19 can change things, when the uncertainty is large.
Take the Moderna vaccine, which had over 7,000 people 65 and older. In their interim analysis, there were 0 events in the vaccine group, and 15 in the placebo group. So their first take was that efficacy for older people was just as high. By the final analysis, though, there were 4 events in the vaccine group, and only an extra 14 in the placebo group: efficacy was now getting close to 10 percentage points lower than overall efficacy – 86% (CI: 61–96%). Check that range of uncertainty – it’s very wide, even in a group that size. It could fluctuate quite a lot as events accrue in this trial. But crucially, because the likely range for that fluctuation is over 60%, we can be confident it works – we just don’t know how well.
For the data in the Oxford/AstraZeneca vaccine trials released data so far, there were only 1,169 people aged 65+ in them. Because most of those were recruited later on, only around half were included in the efficacy data being analyzed so far. In the calculation from Germany, because 341 of them had the vaccine and 319 placebo, with 1 person getting sick in each group, the range of uncertainty about the 6% efficacy is -1405 to 94% – far too uncertain to be meaningful.
Drug regulators from several countries, and now the European Union as well (EMA) approved it for all adults. We’re seeing different decisions for older people for some other vaccines, too. China’s not using their vaccines on people from 60 until more trial data is available, and the same in Indonesia. And when Anmat, Argentina’s drug regulator, first authorized Sputnik V, it was only for people up to 60 – more on that below. Update: Italy’s expert committee recommending authorization of the Oxford/AstraZeneca vaccine for use in adults up to age 55, followed by Belgium. Update: Austria announced it was also restricting use in people 65 and over, followed by France, Poland, and Sweden. Update: Spain followed (65 and over), then Norway. Swissmedic, Switzerland’s drug regulator, is not authorizing it based on the UK and Brazil data: they announced they are waiting to see results from the US trial.
Where to from here for the Oxford/AstraZeneca vaccine? There are several major data developments to watch out for in the next few weeks:
- The big US trial should release some results in the next few weeks;
- Some data from their small phase 1/2 trial in South Africa may be coming soon, with a first clue about any impact of the new variant;
- Release of the full assessment report from EMA (Euro drug regulator).
Up to now, we’ve only seen results from 2 small trials that didn’t have standardized doses and dosing regimens (among other problems). The results of their small trial in India haven’t been released. The US trial is the first adequately powered, standardized, double-blind, and placebo-controlled trial for this vaccine. It won’t answer questions about the current dosing interval hypothesis – the injections are planned to be 4 weeks apart – but it will give us the first reliable estimate of the vaccine’s efficacy. And there will be the first sizable result for older people: the trial’s protocol indicates at least 25% will be recruited among people 65 or older.
They need 75 events for an interim results, 150 for final from this trial. Their FDA application is expected in early March, but that requires at least 2 months’ worth of safety data for a substantial number of people: interim results could be available weeks sooner.
Watch out, too, for news about possible combinations with other vaccines. Phase 1/2 trials for a shot of AstraZeneca and a shot of the adenovirus 26 Sputnik V vaccine are starting soon. And a preprint of a preclinical study on a 2-shot combination with the Imperial College’s sRNA vaccine was posted this week: they found the highest immune response came from a shot of each, followed by the response for 2 shots of the Imperial College vaccine.
Records in my collection for this vaccine here.
Update February 3: A preprint with an additional month’s worth of data was released. This moves this vaccine closer to the efficacy reported for J&J’s, but with wider confidence intervals: no data reported on variants. I think we are in much the same place we were before on this vaccine. (My Twitter thread here.)
Sputnik V has taken some serious steps forward
I keep seeing Novavax described as “the” surprise success this week. But I think Sputnik V could end up surprising many of us, too. From a shaky start with mega-politicization and hype, and scientifically weak early phase studies, the vaccine concept – a 2-dose course, but with different vaccines – and the Sputnik vaccines, have come a long way. (Sputnik V is developed by Gamaleya in Russia.)
When the Oxford vaccine hit efficacy issues, the Sputnik team suggested teaming up for an Oxford/Sputnik crossover – one shot of Oxford’s, one shot of Sputnik’s adenovirus 26 vaccine – and small early phase trials for that are planned to start soon in Azerbijan and Ukraine.
Further credibility came with the news that there had been talks with Germany, and Germany was willing to produce it if it was authorized by the EMA. Recently, that went a step further: Germany has offered technical support for its application to EMA. According to the vaccine’s Twitter account this week, there is a rolling submission to EMA and they could supply vaccine to Europe after the main part of Russia’s vaccination campaign is complete in the next few months.
The adoption of the vaccine in Argentina has also contributed to putting the vaccine on the map. Anmat, the country’s regulator, originally authorized it only for people up the age of 60 because of lack of data. Recently, they lifted that age restriction, and in doing so, revealed the extent of data for Sputnik V (although not the studies themselves). There was data for nearly 20,000 people in the phase 3 trial who received both injections, with no serious adverse events judged to be vaccine-related. And high efficacy was reported for 2,144 people aged 60+: 92% (CI 67–98%) – still a small number, but it fills a critical blank for this vaccine.
There are still open questions though, including about the quality of the science in the trial, given the earlier issues. This is also one of the 2 vaccines that includes a vaccine based on adenovirus 5: the possible impact of pre-existing immunity to that virus will get a lot of focus. (CanSino’s is the other vaccine based on this adenovirus.)
And then there’s Sputnik Light: using the first adenovirus 26 injection as a single shot, and dropping the adenovirus 5 shot altogether. This step seems to have been at least partly driven by manufacturing problems with the adenovirus 5 vaccine. They started a phase 1/2 trial for it with 110 people (and no control group, or group of people getting Sputnik V). No data has been released from that, but they announced on the back of the J&J news that they would be launching Sputnik Light in February.
Records in my collection for this vaccine here.
Update February 3: The phase 3 trial for Sputnik V has now been published. Disappointingly, the protocol was still not released, and the publication is short on key details. The participants are at relatively low risk of severe Covid-19 outcomes (eg 99% white, 90% aged 18-60). Methodological problems include the way adverse events were monitored – relying on spontaneous reporting, not formally soliciting particular adverse events routinely. The data, including for ascertaining Covid-19 after 21 days, relies quite heavily on routine medical records in the electronic health record system in Moscow – I can’t comment on how reliable that is. (See my Twitter thread on this publication.)
Sinopharm’s Beijing vaccine: still mostly waiting for data
Early in December, the UAE announced the vaccine efficacy rate for this vaccine was 86% against Covid-19, but that wasn’t defined – and there is no publicly available protocol for this trial, as far as I know. The announcement also reported no one who was vaccinated got moderately or severely ill with Covid-19. This UAE-led trial is the biggest one for Sinopharm’s 2 vaccines, and it only includes adults up to 60 years of age.
Since then, Sinopharm has reported the efficacy rate for the Beijing vaccine is 79% – lower, because they centrally define Covid-19 differently. (There is also a smaller trial in Peru.) Still no data, though. (I’ve seen an unconfirmed report that the UAE tested all the participants in that country every 2 weeks.)
Sinopharm also recently announced that they encountered no safety problems in their study of children aged 3 to 17, but again, didn’t release any data. I assume that was from this phase 2 trial in children and people aged 60 and over, which was mentioned in their early phase publication in The Lancet. If so, it’s probably a few dozen children and teenagers.
Records in my collection for this vaccine here. (Check the notes field to see which one is Sinopharm’s Beijing vaccine, and which is Wuhan vaccine.)
The 2 mRNA vaccines
- The trial for Tozinameran (BNT/Pfizer vaccine) had continued enrolling teenagers from the age of 12. They reached their target, at just over 3,000 participants aged between 12 to 17. The Moderna trial for 3,000 young people is having trouble recruiting, though: it took a month to enrol 800.
- The EMA (Euro drug regulator) released the most comprehensive analysis yet of Moderna’s vaccine. They had concerns about manufacturing issues in the US, and authorized only production in Europe. And they reported that an unspecified but important number of possible events (Covid-19 illnesses) hadn’t been adjudicated (assessed) and so weren’t included. They weren’t concerned it added substantial bias, but they do believe efficacy estimates could be a bit different when the final results come in. One of those people, though, had severe Covid-19, so be wary of sources saying Moderna is 100% effective against severe disease. (The NEJM article doesn’t mention that person, but I had included this in my comparison of the 2 vaccines last roundup because the FDA pointed it out.)
- The partnership between BNT and Fosun in China for distribution and ultimately manufacture of Tozinameran took a step forward, with vaccine authorization in Hong Kong.
- The CDC reported that in over 4 million injections of Moderna’s vaccine, anaphylactic (allergic) reactions were rare – 2.5 per million – and most weren’t serious. For the first 1.9 million injections of Tozinameran, it was rare, too – 11.1 per million. (That’s why people need to stay a while after being vaccinated, so it can be treated.)
- Reassurance from a WHO expert group after concern was sparked by a statement from the Norwegian medicines agency: deaths in the elderly in Europe did not increase after vaccination. An EMA expert group has also reviewed that and safety data generally in Europe: they also concluded there was no cause for concern, and will report once a month. Neither of these groups published data.
- And the first study (a preprint) from Israel of Tozinameran in wide use. It’s a retrospective cohort study of linked database records of the members of a large state-mandated health insurer, Maccabi Healthcare Services, who were vaccinated in a month: 503,875 aged 16 up. That month, Covid-19 was spreading rapidly throughout Israel, despite a lockdown. They compared the rate of diagnosed Covid-19 (with or without symptoms) in the first 12 days after the first injection with the rate from 13 to 24 days (which is before the second injection): it was 0.57% in the first 12 days, and 0.27% afterwards, with a reduction kicking in at 18 days. The weighted-average daily incidence of diagnoses was 51% lower in that second period (after a single dose).
Another roiling landscape: vaccine prices
I need to be blunt: the world is on the brink of a catastrophic moral failure – and the price of this failure will be paid with lives and livelihoods in the world’s poorest countries… [I]t’s also self-defeating.Tedros Adhanom Ghebreyesus, WHO Director-General, January 18
Rich countries’ capacity to enter into huge contracts, sometimes at premium prices, and what Ghebreyesus called their “me-first approach” has some of them laying tabs on more of the world’s planned vaccine production than they need for their population. Fully supplying COVAX first would have ensured that 20% of the globe, including healthcare workers and other priority groups, would have been vaccinated first. That said, though, COVAX needs vaccines to have the WHO tick to go, and that’s only been issued for Tozinameran so far. (Sinopharm and Sinovac are being assessed now, and with EMA approval for the Oxford/AstraZeneca vaccine, that may get the tick soon, too.) Meanwhile, rich countries are not only hogging the world’s limited supply of vaccines, some of them are fighting over it.
One of the reasons for the spread of some vaccines to lower income countries is “vaccine diplomacy”. For example, China has been offering countries loans to enable access to their vaccines (including reportedly $1 billion to Latin America and the Caribbean).
Vaccine affordability is fundamental to access. Claims about it are now a PR exercise, too. It’s hard, though, to establish what’s actually happening, since deals vary internationally, and generally aren’t made public. What follows uses prices for the EU leaked in December, unless another source is linked. The EU prices, however, are reportedly lower than elsewhere, and may be part of why they have a lower supply than the UK and USA. The 4 cheapest to vaccinate a person so far (US dollars):
- Covaxin, inactivated vaccine from Bharat in India: around $2 in India. (Potentially large supply.)
- CanSino’s adenovirus-based vaccine, single dose, up to $4. (Likely small supply.)
- Oxford/AstraZeneca (and partners), from less than $5 in Europe, to claims it’s over $10 in South Africa, and Brazil. (More on that below.) (One of the largest supplies.)
- J&J, single dose, less than $9. (One of the largest supplies.)
The most expensive vaccine so far appears to be Moderna’s at over $30 per person, with Sinovac’s CoronaVac reportedly close to that in Asia as well. Update: Tozinameran (BNT/Pfizer) is close behind, while Sputnik V is in the middle of the range – around $20 per person.
For the Oxford/AstraZeneca vaccine, a cap of $6 per person for lower and middle income countries and no profits during the pandemic was long reported. J&J has also committed to non-profit vaccine during the emergency use phase of the pandemic.
AstraZeneca’s chief denies that there is a large variation in prices, and has re-affirmed that no profit is being made. However, one of the major producers of the vaccine, the Serum Institute of India, is encompassed in his comments. And its chief has indicated that there would be a profit margin for the vaccine. AstraZeneca have spoken of the non-profit guarantee as for low- to middle-income countries, and SA is in that classification (OECD). However, it’s possible, for example, that the costs had been under-estimated early on, and with differing yields and manufacturing problems, costs are varying. But if there’s no profit involved, then I find it hard to understand why they don’t make this information public and end the speculation and distress this is causing.
Meanwhile, there’s also controversy with Pfizer over pricing. In the US, it’s because of delivering a reduced number of vials now that people are commonly (but not always) able to extract a sixth dose out each vial. Sweden is reportedly withholding payment over being charged for 6 doses per vial.
Accessibility also comes down to costs and feasibility of distributing and administering vaccines. Critical, too, will be manufacturers’ licensing production to as many manufacturers as can manage it – a realistic option outside Europe and America mostly for the traditional types of vaccines (and viral vector vaccines, perhaps to a more limited extent). Blocking patents during the pandemic is being advocated by India and South Africa (and it’s part of MSF’s access campaign, too). (A Biden executive order reportedly allows for violation of patents in the US during the pandemic emergency.)
Overview of all phase 3 trials
There are now 20 vaccines in, or about to be in, phase 3 trials, including these 4 since my last round-up:
- QazCovid-in, an inactivated vaccine from Kazakhstan, started a phase 3 trial locally for 3,000 people – it’s not clear if they plan to do a bigger trial;
- SOBERANA-2 (soberana = Spanish for “sovereign”), from Cuba’s Finlay Institute of Vaccines, is the first Latin-American vaccine to get to this stage. It’s a protein unit (conjugate) vaccine, so it’s another traditional type. Trial planned for 15,000 people in Havana (which doesn’t have a major outbreak), and 50,000 in Iran (which does). Production is planned in both countries. Cuba plans to produce 100 million doses in 2021 – their population is 11 million;
- UB-612, a peptide-based vaccine that’s hoped to prevent infection as well as disease by COVAXX, registered a small phase 2/3 trial for Asia, Latin America, and the US (7,320 people). It’s planned to be produced in India for UNICEF and low-income countries; and
- ZyCoV-D, a 3-shot DNA vaccine from Zydus Cadila in India, started a trial in India, for 28,216 people from age 12, with endpoints starting at 70 days (the third shot is at 56 days).
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). There was also a mention of a phase 3 trial for Grad-CoV2 (from ReiThera in Italy), but I haven’t been able to confirm any study past phase 1.
Other major developments for vaccines that have phase 3 trials:
- The Serum Institute of India, the giant vaccine manufacturer which will be producing a large proportion of Novavax vaccine, currently plans to run the bridging trial it needs for Indian regulators in February.
- Curevac, the German company producing another mRNA vaccine, partnered with Bayer for commercial production, and say they’ll be too late for the US market. (The US is likely to have vaccine for the whole population soon.)
- There’s a report that the CanSino viral vector vaccine will be a single shot. Update: And their interim results will reportedly be released in early February.
- The phase 2/3 trial for Medicago’s vaccine expanded to the US (as well as Canada).
- Seriously deficient informed consent practices and handling of adverse events monitoring were alleged for Bharat’s Covaxin trial in India.
- The WHO’s SOLIDARITY trial for vaccines, with a shared protocol and placebo group for multiple vaccines, has been delayed again – but could be up and running in the next month or so. At least 2 vaccines are being planned for, though we don’t know yet which ones, and it will be running in at least the Philippines and Colombia, for people aged 18 to 59.
And in other news…
- Sanofi and GSK had a setback in a phase 1 trial – a lack of immune response in older people – that sent them back to do further development on their vaccine.
- Much more welcome news from Sanofi followed: they are re-tooling in Frankfurt to help Pfizer get more Tozinameran out. It will take a few months to get rolling, but it will speed up production of 125 million doses this European summer. Also joining the effort for this vaccine: Novartis and Merck.
- Merck has spare capacity because the 2 vaccines they supported were shelved, including one that was being developed by France’s Pasteur Institute.
- Update 1: Clover announced it was discontinuing its vaccine with a GSK adjuvant, just as the 34,000-person phase 2/3 trial had been planned to start in the Philippines. They will go ahead with the one with a Dynavax adjuvant which they had also been testing – by mid-year. Update 2: The next day, Invima (Colombian drug regulator) announced it had approved a phase 2/3 trial for Clover’s vaccine there – and it will be 34,000 altogether, including Australia (presumably phase 2 again) and Belgium.
The first batch of vaccine that will be supplied by the WHO under the COVAX banner is Tozinameran (BNT/Pfizer) – although it’s only 40 million doses. They were provided to COVAX at cost by Pfizer. Update: PAHO (Pan-American branch of WHO) announced that WHO approval for the Oxford/AstraZeneca vaccine is imminent, and notifications for distributions from mid-February have gone out to countries in the Americas. For the Tozinameran, countries could apply: 72 did, but only 18 were successful.
Others being evaluated which, if successful, could be approved in March at the earliest, are Oxford/AstraZeneca’s vaccine, Sinopharm’s Beijing vaccine, Sinovac’s CoronaVac, and the Moderna vaccine. (WHO pre-qualification is a requirement for distribution: background on WHO emergency listing and Covid-19 vaccines.)
Addendum: The phase 3 tables
Phase 3 trials: recruitment progress
|Vaccine||Target or final size||Single or similar trials?||Reaching target?|
Johnson & Johnson
|75,000||2 large trials||1 with 45,000 fully recruited.
The other should be far advanced, perhaps weeks away from full.
|40,500||Mostly single trial||Major trial reportedly close to fully recruited, but not clear.|
|46,331||Single trial||Fully recruited (including over 3,000 young people, 12-17).|
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 30,000, recruited 32,459 as of late January.
Small trial in India fully recruited.
Small trial in Chile ended early when the vaccine was approved locally.
|30,000||1 trial||Just begun.|
|39,020||1 large, 1 small||Just begun (early January in Peru, with trial approved then in Mexico as well).|
|3,000||1 trial||Possibly fully recruited (per ambiguous status on trials register).|
|33,420||1 large, 1 small||Trial of 30,420 fully recruited. Trial of 3,000 young people less than a third recruited in January.|
|45,000||2 trials||Trial of 15,000 in UK fully recruited. US/Mexico trial past halfway. (Efficacy results also from 4,442 in a phase 2b trial in South Africa.)|
Finlay Institute Cuba
|65,000||1 trial||Start date unknown.|
|Sputnik V (Gam-COVID-Vac)
|35,700||Mostly single trial||Trial in Russia stopped recruiting at 31,000. Small trial in UAE half-recruited in December.|
|7,320||Single trial||Phase 2 of 2/3 trial, start date not known.|
Chinese Academy of Sciences
|29,000||Single trial||Months to go.|
|30,000||Single trial||Start date not known.|
|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 for 25,800 participants in India fully recruited.|
Scientific Research Institute
|3,000||Single trial||Fully recruited.|
Chinese Academy of Sciences
|34,020||1 trial||Just begun.|
|Total participants||Over 725,000
|About 400,000 likely to be already recruited.|
The phase 3 trials, and the preclinical and clinical trial results reported for those vaccines
Johnson & Johnson
45,000 (single shot) (Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, USA) Some results reported
30,000 (2 shots) (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
Small bridging trial planned in India
|Unpublished||Unpublished (40)||n.a.||Unpublished (910)||
Sputnik V (Gam-COVID-Vac)
|Non-primate||Unpublished (60)||n.a.||n.a. (phase 2/3)||
7,320 (phase 2/3)
|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)
Bharat Biotech/Indian Medical Research Council
1,000-2,000 (planned, Bangladesh)
Scientific Research Institute
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 is my seventh monthly roundup 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.
Background notes: 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.
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 vaccine with the highest rate at the other end: qualitative judgment, based on the data sources shown in table.
My thanks to Kurti Blahowetz, who helped me out with translating the Russian clinical trial register record for EpiVac Corona.
Correction soon after posting: Table of efficacy data originally included the trial size for Novavax (>15k) instead of the number in the efficacy analysis (>14k).
Updates February 1: Clover vaccine version with GSK adjuvant discontinued, PAHO announcement of COVAX deliveries and WHO Oxford/AstraZeneca approval, CanSino interim results coming, Italy authorizing Oxford/AstraZeneca only for 18-55, authorization applications to Canada for Novavax and J&J vaccines. And a correction, thanks to Fernanda on Twitter: the original mentioned the “Brazil” strain in connection with the J&J trial, but their readout only specified the “SA” strain. (Thanks, Fernanda!)
Update February 2: Clover vaccine trial back on, now in Australia, Belgium, Colombia.
Updates February 3: Added details of new data release for Oxford/AstraZeneca and Sputnik V vaccines, amended infographic to move it from EMA-reported efficacy (60%). Added European countries authorizing with age restrictions for Oxford/AstraZeneca. Added Tozinameran and Sputnik V to the prices section.
Update February 5: Spain and Norway restrictions, and Switzerland’s “nein” for Oxford/AstraZeneca added.
Sources for study records
Records are 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 January 31, the collection included 328 entries:
- 99 vaccine groups with published or posted results;
- 18 trial protocols, for 8 vaccines;
- 137 preclinical preprints/articles (including laboratory testing of new variants);
- 113 trial registry entries associated with these vaccines;*
- 36 clinical trial preprints*/articles/letters:
- 16 for phase 1 trials;
- 10 for phase 1/2 trials;
- 5 for phase 2 trials;
- 1 combined report of phase 2 and 3 trials;
- 2 phase 3 trial;
- 2 author replies to letters to the editor about their publications;
- 10 trial efficacy readouts for phase 3 (press releases), for 6 vaccines;
- 12 documents reporting on or reviewing phase 3 data at regulatory agencies, for 4 vaccines;
- 2 termination notices, for 3 vaccines (none of which have other records in this collection).
* 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.
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.