After a year of setbacks, AZD1222 has been associated with 100% prevention of severe COVID-19 in US trial participants. Could emergency authorization come soon?
March 23, 3:30 PM Update: An independent panel of experts tasked with overseeing AstraZeneca's COVID-19 vaccine trials wrote in a letter to the pharmaceutical company that it had deliberately misled the public on the overall phase 3 US trial efficacy of AZD1222.
According to the panel, the vaccine's efficacy, based on their review of available data, is closer to 69-74%, versus the 79% reported by AstraZeneca in a press release Monday morning.
The independent panel accused AstraZeneca of using clinical trial data “most favorable for the study as opposed to the most recent and most complete.”
“Decisions like this are what erode public trust in the scientific process,” the board wrote.
From Monday: AstraZeneca has reported interim efficacy and safety data for its COVID-19 vaccine AZD1222, showing 79% efficacy in the prevention of symptomatic disease, and 100% efficacy in preventing severe disease versus placebo.
As the company considers prepares a US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) application, discussion around the two-dose adenovirus-based candidate co-developed by University of Oxford investigators has turned optimistic—after a year of early and robust development becoming offset by global research and distribution setbacks.
Previously called the ChAdOx1 nCoV-19 vaccine, the candidate is a recombinant adenovirus vector genetically modified to code for the SARS-CoV-2 spike protein. As an Oxford investigator explained at the time of phase 1 research last summer, AZD12222 was designed to induce both antibody and T cell response.
“We hope this means the immune system will remember the virus, so that our vaccine will protect people for an extended period,” the investigator stated.
AstraZeneca received more than $1 billion in financial support from the US Biomedical Advanced Research and Development Authority (BARDA) in May 2020, in an agreement to produce at least 400 million doses of the vaccine and initiate the 30,000-plus participant, phase 3 trial assessing the product versus placebo.
The US-based, double-blind phase 3 trial (D8110C00001) involves 32,449 participants aged 18 years or older randomized 2:1 to either two-dose AZD1222 or placebo.
Participants recruited across 88 trial centers were either deemed healthy or with medically stable chronic diseases at baseline, and were at increased risk of SARS-CoV-2 virus exposure. The 2 intramuscular doses of 5 x 1010 AZD1222 viral particles were administered 4 weeks apart.
That said, AstraZeneca acknowledged previous trial data showing an extended interval between doses—up to 12 weeks—has demonstrated greater efficacy and strong immunogenicity data. Such considered strategies going forward could also result in a greater count of persons receiving their first dose during vaccine rollout.
The trial population was comprised of approximately 79% white/Caucasian patients, 8% black/African American, 4% Native American, 4% Asian, and 22% participants reporting Hispanic ethnicity.
Representative of heightened severe COVID-19 risk, the trial included 20% participants being 65 years and older, and about 60% having severely associated comorbidities including diabetes, severe obesity, or cardiac disease.
In the interim findings reported Monday morning, based on 141 symptomatic cases of COVID-19 in the participant population, investigators observed a 79% efficacy in symptomatic COVID-19 prevention, and 100% efficacy in severe disease and hospitalization prevention in vaccinated participants.
Among participants ≥65 years old, vaccine efficacy was 80% overall.
In a review of outcomes from the independent data safety monitoring board (DSMB), no safety concerns associated with AZD1222 were reported—as well as in a specific review of thrombotic events, and more specifically, cerebral venous sinus thrombosis (CVST). No CVST events were observed in the trial population. The vaccine was generally well-tolerated by participants.
In a statement accompanying the announced preliminary findings, co-principal investigator Ann Falsey, MD, professor of Medicine at the University of Rochester School of Medicine called the interim outcomes a reconfirmation of AZD1222’s benefit across all adult populations. Nonetheless, she expressed excitement for the first report of similar efficacy among participants ≥65 years old.
“This analysis validates the AstraZeneca COVID-19 vaccine as a much-needed additional vaccination option, offering confidence that adults of all ages can benefit from protection against the virus,” Falsey said.
Previously among the very first COVID-19 vaccine candidates to report promising immunogenicity and to receive federal and global support for research and development, AZD1222 has experienced a more arduous pathway toward possible EUA acceptance than past vaccines.
In September 2020, its US phase 3 trial was paused for 7 weeks to observe a pair of non-fatal, hospitalizing neurological adverse events in placebo participants.
In February 2021, South Africa health authorities announced their intention to withhold available doses of the vaccine from its frontline caregivers after research indicated AZD1222 was associated with approximately 20% efficacy in preventing COVID-19 in patients from the region, which was experiencing greater transmission of the B.1351 variant.
And earlier this month, Denmark, Norway and Iceland suspended use of the product after reports of severe blood clots among vaccinated persons.
That said, independent reviews have cleared the vaccine of causal association to neurological or thrombotic events, and it has since been authorized in more than 70 countries.
With the FDA awaiting phase 3 results to accompany an EUA application—set back 7 weeks by the independent review last fall—the US has had a stockpile of millions of prepared AZD1222 doses for weeks now.
AstraZeneca has expressed intention to submit their phase 3 findings for peer-reviewed medical journal publication, as well as in accompaniment of its EUA application.
If its application is accepted, the company will have AZD1222’s known benefit-risk profile be discussed in a public forum hosted by the FDA’s Vaccines and Related Biologic Products Advisory Committee (VRBPAC) prior to a formal decision.
That said, The New York Times reported Monday that the vaccine is unlikely to become available for distribution before May, when federal officials have predicted the 3 previously authorized COVID-19 vaccine developers will be producing enough product to fulfill President Joseph Biden’s pledge of a dose available for every US adult.
With the emergence of more transmissible SARS-CoV-2 variants worldwide, and discussion on the likelihood of endemic COVID-19 status, however, another beneficial vaccine which can be distributed and stored in normal refrigeration for up to 6 months may come to benefit the US population at some point.
“These results add to the growing body of evidence that shows this vaccine is well tolerated and highly effective against all severities of COVID-19 and across all age groups,” Mene Pangalos, Executive Vice President, of BioPharmaceuticals R&D, said in a statement.” We are confident this vaccine can play an important role in protecting millions of people worldwide against this lethal virus.”