AstraZeneca announced in a press release on Monday that its COVID-19 vaccine showed positive results in an interim analysis of clinical trial data.
The announcement marks the third vaccine to show strong efficacy in late-stage trials against the pandemic coronavirus, SARS-CoV-2. Though AstraZeneca’s vaccine efficacy numbers are not as impressively high as those for the vaccines before it—mRNA vaccines from Pfizer/BioNTech and Moderna—AstraZeneca’s does offer some advantages over those vaccines.
In all, the news adds to ballooning optimism that effective vaccines could bring an end to the global crisis in the coming year.
The vaccine and its data
AstraZeneca partnered with researchers at the University of Oxford to develop the viral vector-based vaccine called AZD1222 (also called ChAdOx1 nCoV-19). The vaccine involves having genetic material coding for the notorious SARS-CoV-2 spike protein carried into the body by a relatively benign virus. In this case, the virus is a weakened type of adenovirus—a pathogen that can cause common colds and other mild infections in humans and some animals. The adenovirus used is one that mainly infects chimpanzees. When the adenovirus package delivers the code for the SARS-CoV-2 spike protein, the immune system can then train itself to recognize and destroy anything with the same spike protein—and that would be all SARS-CoV-2 viral particles, which are studded with spike proteins.
The AZD1222 results announced today come from a pooled analysis of clinical trials conducted in the United Kingdom and Brazil, involving over 23,000 participants. AstraZeneca’s independent monitoring board found AZD1222 was on average about 70-percent effective at preventing COVID-19, the disease caused by SARS-CoV-2. The interim analysis was triggered when 131 cases showed up in participants across the trials, who were given either two doses of AZD1222 or a comparator vaccine, the meningococcal vaccine MenACWY. The efficacy rate is calculated based on how those 131 cases split into the MenACWY group versus the AZD1222 group.
But the results were a little more complicated than that simple split. Participants who received AZD1222 got one of two dosing regimens, so the results were split further. In one regimen, participants were given a half-dose of AZD1222 followed by a booster shot with a full dose. In the trials, 2,741 participants got this regimen, and it appeared about 90-percent effective at preventing COVID-19.
In the other regimen, participants receiving AZD1222 got two full doses of the vaccine. In other words, they got the same high dosage level in their first shot as in their booster shot. In the trials, 8,895 participants got this regimen, and it appeared about 62-percent effective at preventing COVID-19.
The pooled efficacy data yields the average efficacy at around 70 percent. This is impressive, given a goal of around 50 percent. However, it’s not quite as high as the stunning mRNA vaccine efficacy results reported in previous weeks. Those included 95 percent efficacy for Pfizer/BioNTech’s vaccine and 94.5 percent efficacy for Moderna’s.
AstraZeneca’s better result with the regimen starting with a half dose has already led to head scratching among experts. Most importantly, it’s unclear if the 90-percent efficacy result will hold up as AstraZeneca collects more data and conducts further analyses. We don’t yet know how the 131 cases split in the subgroup analyses. That final efficacy number is very likely to change as more data is collected. But, if that finding does hold up, some experts have already begun speculating as to why.
Several think it may be down to the adenovirus packaging. Though the vaccine is aimed at spurring immune responses against the SARS-CoV-2 spike protein carried by the adenovirus, some immune responses will inevitably attack the adenovirus itself. If the two-dose regimen starts out high, it may tip the immunity scales toward a stronger anti-adenovirus response rather than an anti-spike response when the booster shot is delivered. This is speculative, though, and understanding what’s actually happening will require far more data.
On a positive note, needing less vaccine in the first dose—if that really does end up being the case—means more people can be vaccinated with the same amount of vaccine manufacturing capacity.
And on yet another positive—though very preliminary—note, the Oxford researchers reported that AZD1222 appeared to reduce asymptomatic infections with SARS-CoV-2. The primary analysis looked at symptomatic cases of COVID-19, but some participants in the trial were regularly screened for asymptomatic infection. This finding is particularly eyebrow-raising since the mRNA vaccine trials exclusively looked at only symptomatic COVID-19 cases. However, the finding is extremely preliminary as the researchers did not present any data on it.
As with the mRNA vaccines, AstraZeneca said no serious adverse events related to the vaccine “have been confirmed.” In earlier trial results, mild side effects from AZD1222 were common, including pain, feeling feverish, chills, muscle ache, headache, and malaise. Some participants were preemptively given paracetamol (acetaminophen/Tylenol) to lessen these effects.
If you’ll recall, AstraZeneca paused its trials at least twice, once in July and another in September, for standard safety reviews. Trials paused in July when a UK participant showed neurological symptoms and was later diagnosed with multiple sclerosis. In September, another participant developed symptoms in line with transverse myelitis—a condition involving inflammation of the spinal cord that can, in rare instances, be linked to vaccination. Both cases were eventually dubbed unrelated to the vaccine itself and the trials resumed.
Otherwise, no hospitalizations or severe cases of COVID-19 were reported in the study.
A significant advantage to AstraZeneca’s adenovirus vaccine is that it is relatively easy to scale up production and doesn’t require specialized storage conditions. Adenovirus vectors are more established in the vaccine arena, compared with mRNA-based vaccines, which are brand-new. Manufacturing capacity to produce vast quantities of adenovirus already exists.
AstraZeneca noted in its press release that it is “making rapid progress in manufacturing with a capacity of up to 3 billion doses of the vaccine in 2021 on a rolling basis, pending regulatory approval. The vaccine can be stored, transported and handled at normal refrigerated conditions (2-8 degrees Celsius/36-46 degrees Fahrenheit) for at least six months and administered within existing healthcare settings.”
The mRNA vaccines require cooler storage conditions. Most notably, Pfizer and BioNTech’s vaccine requires storage at a troublesome -70°C. In a recent press release, Pfizer emphasized that the companies “developed specially designed, temperature-controlled thermal shippers utilizing dry ice to maintain temperature conditions of -70°C ± 10°C. They can be used as temporary storage units for 15 days by refilling with dry ice.” The vaccine can further be stored at normal refrigerated 2-8°C conditions for five days.
Pfizer and BioNTech are aiming to have up to 50 million vaccine doses in 2020 globally and up to 1.3 billion doses by the end of 2021.
Moderna announced in a recent press release that its vaccine remains stable for six months at -20° C (-4°F), up to 30 days at normal refrigerator temperature (2-8 degrees C or 36-46 degrees F), and up to 12 hours at room temperature. Moderna currently plans to have about 20 million doses of mRNA-1273 ready to ship in the US in 2020 and produce an additional 500 million to 1 billion doses globally in 2021.
All three vaccines are now headed to regulators worldwide for authorization. Pfizer submitted its request for an Emergency Use Authorization from the US Food and Drug Administration on Friday.
All three vaccines have yet to have their full datasets published, so much uncertainty remains about the data and analyses. The efficacy numbers will likely change as trials continue, safety monitoring grows longer, and peer reviewers look over the analyses. Rare side effects are also more likely to pop up as time goes on.
While preliminary studies on the vaccines suggested they all prompt a variety of immune responses in participants, how long any protection from any of these vaccines may last is completely unknown. It’s still unclear what levels of immune responses equate to full protection from an infection or severe disease. And in a one-year-old pandemic with a completely new-to-us pathogen, it’s impossible to say with certainty how long those protective immune responses will stay protective.
Last, there’s so far no data on how well the vaccines protect against asymptomatic infections. Preventing disease—and in particular, life-threatening disease—is the top priority in these trials. However, preventing asymptomatic or mild infections will be key to putting an end to SARS-CoV-2 transmission overall.