AstraZeneca Phase 3 Interim Report
Overview
On Monday, November 23rd, AstraZeneca and University of Oxford released interim data from their Phase 3 clinical trial of ADZ1222, their COVID-19 vaccine. The Phase 3 trial included two dosing regimens where one showed results of 90% efficacy and the second regimen showed 62%. Combined, the entire Phase 3 trial shows an average of 70% efficacy. These results join the race to end the COVID-19 pandemic alongside Pfizer and Moderna. This article will offer background into AZD1222 and the Interim Report, bring insight into the vaccine’s distribution timeline and the outcomes of the results, and identify any unanswered questions.
Background
The AZD1222 (ChAdOx1 nCoV-19) vaccine from AstraZeneca (AZ) is a non-replicating viral vector vaccine. Essentially, the company uses a weakened common cold virus as a carrier of genetic information of SARS-CoV-2. This mechanism utilizes the virus’s capability of inserting its own genetic code into the infected individual while only risking the illness of the common cold rather than potentially harmful symptoms of COVID-19. From there, human cells can recognize foreign DNA in order to initiate and promote an immune response.
AZ ran a trial on a single dose of AZD1222 on rhesus macaques (primates). Protection against lower respiratory tract infections was observed. Following this pre-human trial, AstraZeneca ran a single-blind, randomized Phase 1/2 trial from April to May where participants either received AZD1222 or MenACWY, a meningococcal vaccine, which acted as a control. The company concluded that the single dose of AZD1222 was safe and tolerated despite increased systemic and local reactions compared to the control, MenACWY. Participants who received AZD1222 reported higher instances of fatigue and headaches that were categorized as only mild or moderate side effects. Overall, neutralizing antibodies were observed after a single-dose and, in fact, increased after a second-dose booster was administered.
In August of 2020, AZ & the University of Oxford entered into the Phase 3 of testing, the largest round of testing completed by the company so far. The trial spans multiple sites in the US and the UK. However, only a week after testing began, the trial was stalled due to an unknown severe adverse reaction occurring in the United Kingdom. It was later released that a female participant developed transverse myelitis, an inflammation syndrome in the spinal cord. After a week of review, AZ resumed the trial with permission from a Medical Regulatory institution.
Interim Report for Phase 3
Unlike Pfizer and Moderna, AztraZeneca (AZ) and University of Oxford ran two dosing regimens during their Phase 3 clinical trial. The first dosing regimen included a half dose of AZD1222 followed by a full dose at least a month apart. The second regimen is two full doses at least a month apart. In the interim report, the first regimen has 90% efficacy while the second has 62%, with an average efficacy of 70%. This analysis was conducted by an independent Data Safety Monitoring Board.
Alongside the data results, AZ and Oxford met primary endpoints required to present submissions for Emergency Use Listing from the World Health Organization (WHO). If granted, AZD1222 can be placed on an accelerated pathway to produce and make available to low-income countries. AZ expects to produce up to 3 billion doses of the vaccine by the end of 2021.
Alongside these results, AstraZeneca and Oxford indicates that as the study continues and new data points accrue, the vaccine efficacy may change. As already mentioned in the Pfizer Report, the flu vaccine is found to only have 40% to 60% efficacy depending on the demographic. With even major changes in the study, the efficacy of AZD1222 could very easily match or rest above the flu vaccine’s efficacy. Furthermore, DSMB had no current concerns for severe adverse reactions, but expects AstraZeneca and Oxford to continue to collect this information as the study progresses.
Tentative Timelines
AZD1222 is not available to the public, but the vaccine trail has met endpoints to create a submission for Emergency Use with the WHO. It’s expected for AZ and Oxford to make this submission within the next few weeks and for the WHO to follow up. With only a month left in the year 2020, it’s not very likely for the vaccine to be mass distributed to the public, only to healthcare professionals.
Other pharmaceutical companies are planning to make submissions for Emergency Use through the FDA, rather than the WHO. With the United State’s plan to leave the WHO, it’s unknown whether a second approval needs to occur in order for the US public to gain access to AZD1222.
For vaccine distribution, there seems to be no public program provided by the WHO. However, under medical practice, it seems that healthcare professionals and vulnerable populations will be the first to receive the vaccine. As AZD1222 moves beyond approval and toward mass production, more information will be released.
Positive Outcomes
First, this is the third vaccine to reach sufficient Phase 3 data to submit Emergency Use. A variety of vaccines can allow health officials to supply particular persons and areas with vaccines that are best suited based on health and resources. Moreover, this allows a larger number of doses to be made throughout 2021, shortening the length of the COVID-19 pandemic.
Second, AstraZeneca is the first vaccine to reach this stage that only requires refrigeration, compared to Pfizer and Moderna which require freezing temperatures or below. This allows AZ to distribute AZD1222 to areas that don’t have deep freezers, which reaches a larger portion of the global population. This is crucial to stopping COVID-19 around the world.
Lastly, AZ did not have any patients who received AZD1222 become hospitalized or have severe COVID-19 symptoms. Although anecdotal, this shows the potential for the vaccine to play a role in reducing the severity of COVID-19 symptoms. If correlation, potentially causation, is proven, AZD1222 will be an essential vaccine for individuals at high risk for severe COVID-19.
Challenges
Similarly to Pfizer and Moderna, there’s a question as to how these vaccines will be distributed. There is currently no plan presented by President Trump, nor President-elect Biden. However, a CDC panel did release that the first demographic to receive the vaccine will be healthcare workers, which is a very common practice. Following that, it will most likely be distributed to elderly patients in nursing homes.
Furthermore, all three vaccines require 2 doses. This means that production numbers are cut in half for the complete dosage of an individual. Alongside that, it’s expected of individuals to return within 28 days in order to receive the second dose. This brings up the question as to how people will be monitored and notified through this process.
Unanswered Questions
Although these results reveal more about the COVID-19 pandemic, there are still questions left unanswered.
First, AZ won’t know how long immunity will last for their vaccine until a couple years after mass distribution. There might be some information on lasting immunity that comes from volunteers in earlier stages of the clinical trials. AZ will be waiting with Pfizer and Moderna for this information.
Second, there’s no clear understanding on whether AZD1222 can help prevent the spread of SARS-CoV-2 when the person is experiencing minimal to no symptoms. In other words, does the vaccine also function as a transmission blocker?
Third, who will get the vaccine first? When it comes to vaccine distribution, health professionals and vulnerable populations typically receive the vaccine first. That will most likely be the case in the COVID-19 pandemic, but as doses are being produced, it is unknown the demand for the COVID-19 and who will be first in line.
Lastly, the specific efficacies in certain demographics are unknown. The interim report did not include information as to the ages of the volunteers who had COVID-19, bringing into question a skewed efficacy that doesn’t fit for the elderly demographic.