The pausing of Astrazeneca’s phase III trial of its Covid-19 vaccine candidate is a timely reminder of why these projects should not be rushed to market. Few details are available on the nature of the adverse event seen in the study of AZD1222, but the news puts safety squarely back in focus after recent talk of emergency approvals based on preliminary data.
It is hard to say yet whether the hold will have a knock-on effect on other Covid-19 vaccine developers. But Johnson & Johnson and Cansino – which, like Astra, are using an adenoviral vector in their vaccines – face a particularly nervous wait.
More questions than answers
Right now, all that is known is that the US phase III trial of AZD1222 has been put on hold after an unnamed adverse event was seen in a trial participant in the UK – possibly in a phase II/III study – as reported by Stat.
Later, the New York Times reported that the event might have been transverse myelitis, an inflammation of the spinal cord that can be triggered by viral infections.
Astrazeneca would not confirm whether transverse myelitis had been seen, saying only that its standard review process had been triggered and that it had “voluntarily paused vaccination to allow review of safety data by an independent committee”.
The company described this as “a routine action”. Astra’s shares on the London Stock Exchange fell as much as 2%, but had largely recovered by the end of the day.
There are still many unanswered questions, the most urgent being: was the event transverse myelitis and, if so, was it related to AZD1222?
This is not the first time a study of AZD1222 has been put on hold: another trial was paused in July after a participant developed transverse myelitis, according to a volunteer information sheet. This was later deemed to be unrelated to the vaccine, although two similar events would raise alarm bells, should this come to pass.
Even if the event turns out to be something less serious than transverse myelitis, or even if it is unrelated to the vaccine, Astra could still be facing a delay of weeks or months while it combs through its safety database, Leerink analysts estimated.
If the worst is confirmed, it might be time for J&J and Cansino to start worrying. AZD1222 uses a chimp adenoviral vector that expresses the coronavirus spike protein, while J&J and China’s Cansino use human adenoviruses to deliver the spike protein.
Currently, no marketed vaccines employ chimp adenoviral vectors, although J&J recently got EU approval for an Ebola vaccine that uses adenovirus 26, the same vector as in its Covid vaccine candidate. Another Ebola vaccine, Merck & Co’s Ervebo, which uses a different viral vector, vesicular stomatitis virus, is approved in the US.
The hold at least has little read-through to developers of the other advanced Covid-19 vaccines candidates, Biontech/Pfizer and Moderna, as their projects both use a different approach, mRNA.
However, mRNA is also an unproven technology, and the news only underscores the need to be cautious about projects that have been tested in relatively few people so far.
The same is true for those developing more conventional recombinant protein-based vaccines, such as Novavax and Sanofi/Glaxosmithkline. The former has said it plans to start a UK phase III trial in the third quarter, while a project from the latter two groups is set to go into pivotal development in December.
However, all the Covid-19 vaccine developers could see their sales affected by vaccine hesitance in the general population if and when a product gets to market.
There were already concerns that rushing vaccine development could make people wary about getting a coronavirus shot, and help fan anti-vaccine sentiment. A safety scare would only add to this, even if nothing worrying is found, and might make volunteers more afraid to enrol.
The latter issue should not trouble Biontech/Pfizer and Moderna, which have recruited their phase III studies at impressive speed and have now almost reached their targets. Perhaps the biggest surprise is that, with so many patients receiving novel vaccines, there had been no big safety scares before this one.
|Covid-19 vaccines in phase III trials|
|Project||Company||Description||Phase III trial ID||Recruitment|
|BNT162b2||Biontech/Pfizer||mRNA vaccine||NCT04368728||25,189 of 30,000 target*|
|mRNA-1273||Moderna/NIAID||mRNA vaccine||NCT04470427||21,411 of 30,000 target**|
|AZD1222||Astrazeneca/ Uni of Oxford||Chimp adenovirus vaccine||NCT04516746 (US phIII) NCT04400838 (UK phII/III)||17,000 patients enrolled so far in UK, Brazil, South Africa|
|Ad26.COV2-S||Johnson & Johnson||Adenovirus type 26 vaccine||NCT04505722||Starting in Sept, 60,000 target|
|Ad5-nCoV||Cansino Biologics||Adenovirus type 5 vaccine||NCT04526990 (Pakistan)||Not yet recruiting, 40,000 target|
|CoronaVac||Sinovac||Inactivated virus vaccine||NCT04456595 (Brazil) & NCT04508075 (Indonesia)||Unknown, 8,800 & 1,600 target|
|*As of Sept 7, 2020. **As of Sept 4, 2020.
Source: EvaluatePharma, clinicaltrials.gov
This story has been corrected to include details of J&J's Ebola vaccine.