If someone told you in March, when the World Health Organization finally called the Covid-19 outbreak a pandemic, that we’d have three strong coronavirus vaccine candidates by mid-November, you might have called that person delusional.

Yet with Monday’s news from AstraZeneca and University of Oxford that early results from their phase 3 trial demonstrate their vaccine’s effectiveness, that’s exactly the scenario we’re in.

In a press release, the pharmaceutical giant and its Oxford co-developers reported interim findings from two groups in their ongoing trials — one in the UK and one in Brazil. The trials used different approaches to inoculating the people who participated, and found two levels of efficacy, which they averaged to 70 percent. The researchers also found no severe cases or hospitalizations in the study participants who got the vaccine.

In the UK trial group AztraZeneca reported on, the vaccine — known as AZD1222 — was given as a half dose, followed by a full dose around one month later, resulting in 90 percent efficacy. In the Brazil group, study participants were given two full doses at least one month apart, and the efficacy was 62 percent.

The researchers aren’t sure why there was this striking gap in vaccine performance — and in a press conference, said that the half dose may better prime the immune system to respond to the second full vaccine. But while the company framed the reason for the half dose was “serendipity” — in reality, the trial participants were given a smaller dose in error. And while it appears the accidental dosing regimen may have outperformed two full doses, independent researchers wondered about whether it was administered to enough people to know for sure. (More on that in a moment.)

Either way, 50 percent efficacy is the floor set by the US Food and Drug Administration and the European Medicines Agency (the FDA equivalent in Europe) for approval. The AstraZeneca-Oxford research team will “immediately” submit their findings to regulatory agencies around the world, seeking early approval.

While the efficacy outcome falls short of the 95 percent preliminary result recently reported by both Moderna and Pfizer/BioNTech, the results, if real, could be promising. At around $3 to $4 per dose, the AstraZeneca-Oxford shot is the cheapest of the three current options and should be easier to distribute globally (since it can be stored in regular refrigerators). That’s why lower-income countries around the world have been pre-purchasing access.

But, as with all the new coronavirus vaccine candidates, there are some big caveats to consider. And since the results came via press release and lacked detailed data, they raise questions we don’t yet have answers to. Here’s the rundown.

The Oxford-AstraZeneca vaccine could be a game changer for low- and middle-income countries

Among the Covid-19 vaccines furthest along in development, the AstraZeneca-Oxford candidate is among the most likely to be affordable to low- and middle-income countries. And considering much of the world’s population currently lives in low- and middle-income settings, it’s the jab that — with a 90 percent efficacy result — could make a big dent in the pandemic worldwide.

It also uses a novel approach to inoculation, one that’s different from Pfizer-BioNTech and Moderna — and from conventional vaccines.

Vaccine makers have typically used the virus itself or a fragment of the virus, often in a weakened or inactivated form, to inoculate recipients. But this new generation of vaccines uses genetic instructions for making parts of the SARS-CoV-2 virus that causes Covid-19. All three candidates — Pfizer, Moderna, and AstraZeneca-Oxford — deliver the instructions for making the SARS-CoV-2 spike protein, or the part of the virus that lets it enter human cells. And it’s these instructions, which human cells then use to manufacture parts of the virus, that are injected into vaccine recipients, essentially coaching the immune system to fight off the invader should it arrive.

The Moderna and Pfizer-BioNTech vaccines both use mRNA as their platform for delivering the genetic instructions. AstraZeneca-Oxford’s uses DNA instead, and the DNA is delivered to cells with the help of another virus known as an adenovirus. (Other Covid-19 vaccine developers, like CanSino Biologics and Johnson & Johnson, are also using adenovirus vectors.)

AstraZeneca, unlike Moderna and Pfizer/BioNTech, has promised to sell its shot at cost — around $3 to $4 — and not to profit from the vaccine while the pandemic is ongoing (though public money has gone into funding its research effort). According to the FT, that price is “a fraction” of the expense of the other vaccine candidates, which are expected to cost between $15 and $25 per dose.

Also unlike the two other leading vaccine candidates, it doesn’t require extremely cold temperatures for storage. That’s the distribution hurdle Moderna and Pfizer-BioNTech are working to overcome.

Moderna’s vaccine requires long-term storage at minus 20 degrees Celsius (minus 4 degrees Fahrenheit) and is stable for 30 days at refrigerator temperatures between 2 and 8 degrees Celsius (36 to 46 degrees Fahrenheit). Meanwhile, the Pfizer-BioNTech vaccine demands ultra-cold temperatures of minus 70 degrees Celsius (minus 94 degrees Fahrenheit) or lower, with about five days of shelf life at refrigerator temperatures. The AstraZeneca-Oxford vaccine can be stored in a normal refrigerator for at least six months.

So these are the reasons why the AstraZeneca-Oxford vaccine has become a leading contender lower-income countries are relying on to end their epidemics. For now, the shot “accounts for more than 40% of the supplies” going to low- and middle-income countries, according to Bloomberg. AstraZeneca said the company has the capacity to supply 3 billion doses of the vaccine in 2021.

“[T]he vaccine’s simple supply chain and our no-profit pledge and commitment to broad, equitable and timely access means it will be affordable and globally available supplying hundreds of millions of doses on approval,” said Pascal Soriot, CEO of AstraZeneca, in a statement.

The US is also poised to benefit. In May, the Biomedical Advanced Research and Development Authority (BARDA) under the Department of Health and Human Services pledged up to $1.2 billion to back the AstraZeneca-Oxford vaccine, aiming to secure 300 million doses for Americans.

Of course, if the shot only has around 70 percent efficacy, officials will have to grapple with how and where it’s used at all. “If it’s 70%, then we’ve got a dilemma,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told Stat. “Because what are you going to do with the 70% when you’ve got two [vaccines] that are 95%? Who are you going to give a vaccine like that to?”

The caveats

That’s not the only caveat to consider. The AstraZeneca-Oxford results so far came via press release, and gloss over nuances we’d need to understand to know how the vaccine works in people. AstraZeneca-Oxford also released fewer details about their research than the other two companies, and reported their results in a way that made drawing comparisons among the three candidates difficult. Let’s go over what we know.

  • Before clinical trials begin, research groups are supposed to publicly share a plan — called a protocol — for how they’ll run the studies and analyze and share the results, and they’re supposed to stick to it. That helps ensure experimenters don’t move the goalposts to come to more favorable conclusions.

But AztraZeneca and Oxford have only shared two of the protocols for their phase 3 studies after the trials began. We have the protocol for their US phase 3 study, and as writer and meta-scientist Hilda Bastian points out in Wired, a UK protocol published in a Lancet study appendix, also shared after the trial started.

“The appendix doesn’t say when this became the plan. We don’t even know if the Oxford-AstraZeneca team followed it,” Bastian writes. Again, in the press release, AstraZeneca also only disclosed data for subgroups in two of the trials, not the four specified in the UK protocol, she told Vox. “We do know [what’s in the protocol] is not what they reported.” “Transparency can increase confidence in the trials and are essential for establishing the quality of the science. [Six companies or research groups] have released protocols for their phase 3 studies — why not Oxford?” asked Peter Doshi, who has been a prominent critic of Covid-19 vaccine trials.

  • The press release doesn’t report details of what side effects the study participants experienced. The company only reported there were no serious safety events confirmed to date, and that the vaccine “was well tolerated across both dosing regimens.” We do know that the UK trial for AZD1222 was paused in July and again in September after two volunteers reported neurological problems. Investigations later found no link between the vaccine and these symptoms, and regulators allowed the trial to resume in October.
  • While we know the number of participants included in each in the UK and Brazil trials (2,741 in the UK versus 8,895 in Brazil), we don’t know how many got the vaccine (versus a placebo or meningococcal vaccine), which raised a statistical question about how many people were infected with the virus in the UK group that saw 90 percent efficacy. Some statisticians have suggested the number may be very small — and potentially unreliable:
  • The press releases also lack details about the demographics of people participating in the trials. AstraZeneca said its trial participants come from “diverse racial and geographic groups who are healthy or have stable underlying medical conditions,” but without knowing the exact numbers, it’s hard to gauge how well they reflected the groups most at risk of severe disease (including older adults and people of color).
  • The trials also didn’t use a simple placebo to measure efficacy. In the UK arm of the trial, volunteers were randomly assigned to receive the AZD1222 vaccine or the meningococcal vaccine. In the Brazil arm, the comparison group was given the meningococcal for the first dose and a saline placebo for the second dose.
  • Another factor to consider: AstraZeneca-Oxford measured their results in a different way from their two major competitors. The Moderna and Pfizer/BioNTech trials only captured Covid-19 infections in their trial pool that advanced far enough to produce symptoms, while the AstraZeneca trials conducted weekly swab tests among their participants, allowing them to detect much less severe cases — including potential asymptomatic infections — among their volunteers. These differences make it trickier to draw apples-to-apples comparisons of the efficacy of the different vaccines.

Together, these factors highlight that there’s still a lot to learn about the new vaccines, even as they’re all set to roll out imminently. The Moderna, Pfizer-BioNTech, and Oxford-AstraZeneca teams have all vowed to publish their trial results in peer-reviewed journals. But distribution on a limited emergency use basis may begin as soon as next month, pending approval from regulators.

For now, it’s worth pausing over how remarkable it is that there are several SARS-CoV-2 vaccine candidates that have reported high levels of efficacy, featuring technologies that have never been deployed at a large scale in humans before.

If the AstraZeneca-Oxford, Moderna, and Pfizer-BioNTech groups pass regulators, the coronavirus vaccines may be the beginning of an entirely new approach to inoculating people against disease.

Clarification, December 4: An earlier version of this story stated that AstraZeneca/Oxford only shared the protocol for their US study. While that was the only phase 3 protocol registered on their clinical trials database, the researchers also shared the protocol for the UK trial in an appendix in a journal article.

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