Candidate: COVID-19 Vaccine AstraZeneca (marketed in some countries as Vaxzevria or Covishield; formerly AZD1222 and ChadOx1 nCoV-19)
Type: Vaccine based on an adenovirus vaccine vector and the COVID-19 spike protein. After vaccination, the surface spike protein of the coronavirus is produced, which primes the immune system to attack the coronavirus if it later infects the body.
2022 Status: AZ Mulls Scrapping Plans for U.S. Approval—Sir Menelas (Mene) Pangalos, PhD FRSB FMedSci, AstraZeneca Executive Vice-President, BioPharmaceuticals R&D, told the Financial Times on March 17 that AstraZeneca was considering not submitting its COVID-19 Vaccine to the FDA for authorization and/or approval, if the company deemed that the regulatory review would take too long: “We don’t need to push it in places we are not needed or wanted,” Pangalos was quoted as saying by the FT.
In any case, he added, the company would continue talks with the FDA.
2021 Status: Researchers Identify “Potential Mechanism” Triggering Rare Blood Clots—Researchers from Cardiff University in the U.K., Arizona State University, and AstraZeneca published a study December 1 in Science Advances identifying a molecular “potential mechanism” in the viral vector of the vaccine that they reported may have led to blood clots in rare instances of vaccine recipients.
In very rare cases, the scientists suggested, the viral vector may have entered the bloodstream and bound to platelet factor 4 (PF4), where the immune system then viewed the complex as foreign. The researchers reported that the misplaced immunity could result in the release of antibodies against PF4, which bind to and activate platelets, causing them to cluster together and triggering blood clots in a very small number of people after the vaccine is administered.
UK MHRA Cites Side Effect—The U.K.’s Medicines and Healthcare products Regulatory Agency stated October 21 on its website that nerve disorder Guillain-Barré syndrome (GBS) “has been reported very rarely following vaccination” with the AstraZeneca COVID-19 vaccine (Vaxzevria), a week after the European Medicines Agency added GBS as a possible side-effect last month.
“Healthcare professionals should be alert of GBS signs and symptoms to ensure correct diagnosis, in order to initiate adequate supportive care and treatment, and to rule out other causes,” MHRA stated.
Similar Safety Profile to Pfizer/BioNTech Vaccine—AstraZeneca’s COVID-19 vaccine (Vaxzevria in Europe) showed a similar safety profile to Pfizer/BioNTech’s BNT162b2, with standardised incidence ratios (SIRs) for venous thromboembolism (VTE) of 1.29 and 0.90 after first- and second-dose BNT162b2, and 1.15 after first-dose of AstraZeneca’s vaccine, compared with 8.04 in participants diagnosed with COVID-19. SIRs for thrombocytopenia were 1.35 and 1.19 after first- and second-dose BNT162b2, 1.03 after first-dose AstraZeneca vaccine, and 3.52 in COVID-19-diagnosed participants. Arterial thromboembolism (ATE) rates were similar to expected rates for BNT162b2 and ChAdOx1, as were rates of thrombocytopenia syndrome (TTS) for BNT162b2, while fewer than five such events were seen for the AstraZeneca vaccine.
Effective vs. Delta Variant—AstraZeneca on June 15 trumpeted data from Public Health England (PHE) showing that COVID-19 Vaccine AstraZeneca offered high levels of protection against the Delta variant of SARS-CoV-2 (B.1.617.2, identified in India). In a preprint posted on PHE’s website, researchers reported that two doses of COVID-19 Vaccine AstraZeneca were 92% effective against hospitalization due to the Delta variant and showed no deaths among those vaccinated. The vaccine also showed a high level of effectiveness against the Alpha variant (B.1.1.7; identified in Kent, U.K.) with an 86% reduction of hospitalizations and no deaths reported. The analysis included 14,019 cases of the Delta variant—of which 122 were patients who were hospitalized in England between April 12 and June 4.
CEO Soriot Defends Vaccine—In an interview with the Financial Times published May 21, AstraZeneca CEO Pascal Soriot defended his company’s vaccine and its development despite setbacks such as manufacturing snafus that have cut the number of doses distributed below what it committed to the European Union: “You can look at the glass half empty: we’ve delivered less than we expected to deliver in Europe. You can look at the glass half full: we’ve delivered more than 400 million doses [worldwide] and we’ve saved tens of thousands of lives.”
Soriot acknowledged that the U.K. government had been guaranteed priority in numbers of doses as part of the agreement it struck with University of Oxford in return for investing in the vaccine, before AstraZeneca agreed to partner with the university to manufacture and distribute the jab.
Soriot also dismissed critics of the company’s vaccine rollout as “armchair generals” whose criticisms were “traumatic.”
JAPAN APPROVES VACCINE—Japan’s Minister of Health, Labour and Welfare Norihisa Tamura gave final approval May 21 to two COVID-19 vaccines, those of AstraZeneca and Moderna. Japan has ordered 120 million doses of the two-dose AstraZeneca vaccine, but will not immediately distribute them pending a decision on whether to place age restrictions on the jab due to reported cases of rare blood clots elsewhere in the world. Japan plans to finish inoculating its 36 million citizens ages 65 and older by the end of July.
Oxford Biomedica Sees Double—AstraZeneca has committed to an increase in the number of batches required from Oxford Biomedica in the second half of 2021, Oxford Biomedica said May 18. As a result, it has raised revenue guidance for expected cumulative revenues from AstraZeneca by the end the year from in excess of £50 million (about $71 million) to more than £100 million ($141 million)—and thus expects significant growth in Group Operating EBITDA in 2021.
German Officials Agree to Expand Vaccine Availability—Federal and state officials in Germany on May 6 agreed to expand availability of AstraZeneca’s COVID-19 vaccine by lowering the minimum eligible age for vaccination from 60 to 18. The German officials also agreed to reduce the minimum waiting time between doses of the two-dose vaccine from 12 weeks to 4 weeks. The changes require approval by Germany’s parliament.
$275M in Q1 SALES—AstraZeneca said April 30 that its COVID-19 vaccine generated $275 million in first quarter 2021 sales, in its Q1 earnings report. Sales in Europe were $224 million, “emerging markets” sales were $43 million, and $8 million in “established rest of the world (RoW).” AstraZeneca defines “emerging markets” to include China and much of the Asia-Pacific region outside Japan, Russia, Brazil, the rest of Latin America, the Middle East and Africa. Established RoW includes Canada, Japan, and Australia.
In a separate study posted April 30 in a preprint, the ISARIC4C (Coronavirus Clinical Characterisation Consortium), a UK-wide consortium of doctors and scientists, found that the vast majority of post-vaccination cases of COVID-19 and deaths from the virus occurred in frail elderly patients following vaccination with a first dose of either the AstraZeneca or Pfizer/BioNTech vaccines: 526 cases including 113 deaths from 3,598 patients vaccinated out of 52,280 hospitalized COVID-19 patients studied. The study has been submitted to the U.K. government’s Scientific Advisory Group for Emergencies (SAGE) panel.
AstraZeneca may need until mid-May to complete its application for emergency use authorization (EUA) for its COVID-19 vaccine, reflecting the company’s struggle to furnish the agency with necessary data, The Wall Street Journal reported, citing unnamed sources. An especially time-consuming task, they said, has been compiling efficacy, virus-transmission and safety statistics from almost four months of vaccinations in the U.K.
AstraZeneca is progressing in its preparation of the FDA submission, a spokeswoman told the WSJ, but would not disclose a timeframe for when it will submit its EUA application to the FDA.
The U.S. said it will distribute 60 million doses of COVID-19 Vaccine AstraZeneca to other countries as they become available. Ten million of the doses could be released “in the coming weeks” subject to FDA clearance, and the other 50 million in May and June, White House Press Secretary Jen Psaki told reporters during a briefing.
She said supplies of other emergency-authorized vaccines were sufficient to meet demand, while AstraZeneca vaccine doses have been stockpiled by the government in the absence of an EUA authorizing their use.
LABELS TO CITE “RARE” BLOOD CLOT RISK—The European Medicines Agency (EMA) and the U.K. Medicines and Healthcare products Regulatory Agency both requested updates to the prescribing labels of COVID-19 Vaccine AstraZeneca, known in the EU as Vaxzevria, that include blood clots as an extremely rare potential side effect, following separate reviews.
“AstraZeneca has been actively collaborating with the regulators to implement these changes to the product information and is already working to understand the individual cases, epidemiology and possible mechanisms that could explain these extremely rare events,” the company stated.
The EMA received reports of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis as of April 4. An EMA safety committee reviewed in depth 62 cases of CVST and 24 cases of splanchnic vein thrombosis reported in the EU drug safety database (EudraVigilance) as of March 22, 18 of which were fatal.
The MHRA said it reviewed 79 cases (51 women, 28 men) of blood clots in the U.K. as of March 31—44 of the 79 cases were of CVST with thrombocytopenia; the other 35 were of thrombosis in other major veins with thrombocytopenia. The 79 cases resulted in 19 deaths (13 women, six men)—14 from CVST with thrombocytopenia; five from thrombosis with thrombocytopenia. Of the deaths, 11 were of people under age 50, of whom three were under 30.
Separately, the World Health Organization (WHO) concluded that a causal relationship between the vaccine and blood clots is considered “plausible” but not confirmed, adding that further studies were needed. A WHO statement did not quantify the number of blood clot cases, except to say they were “very rare with low numbers” among 200 million vaccine recipients worldwide.
Pediatric Trial Pause—The University of Oxford said April 6 that a clinical trial in the U.K. assessing AstraZeneca’s COVID-19 vaccine in children had been paused to allow the country’s Medicines and Healthcare products Regulatory Agency (MHRA) to study a possible link between the vaccine and blood clots in adults. The MHRA has identified 30 cases of rare blood clot events out of 18.1 million doses of the vaccine administered up to and including March 24. Seven deaths have resulted from those 30 cases.
“Whilst there are no safety concerns in the paediatric clinical trial, we await additional information from the MHRA on its review of rare cases of thrombosis/thrombocytopaenia that have been reported in adults, before giving any further vaccinations in the trial,” the university said in a statement.
The European Medicines Agency (EMA) and World Health Organization (WHO) are conducting their own investigations on the vaccine-blood clot link, and were set to report results later in April.
The trial pause came the same day that Marco Cavaleri, chair of the EMA’s vaccine evaulation team, told Italian news outlet Il Messagero: “It is clear that there is an association (of the brain blood clots) with the vaccine. However, we still do not know what causes this reaction.” AstraZeneca declined comment on Cavaleri’s reported remarks when contacted by Reuters.
The European Medicines Agency (EMA) said March 26 that its Committee for Medicinal Products for Human Use (CHMP) recommended approval of a fourth site for the production of active substance for COVID-19 Vaccine AstraZeneca, a Halix facility in Leiden, the Netherlands.
Positive U.S. Trial Results–AstraZeneca on March 22 released positive safety and efficacy results from a large Phase III study in the U.S., Chile, and Peru for its COVID-19 vaccine—and specifically, no increased risk of blood clots along the lines of the 30 reported in Europe earlier this month. The pharma giant released results from the Phase III D8110C00001 trial (NCT04516746), showing the vaccine to be 79% effective at preventing symptomatic COVID-19 and 100% effective at preventing severe disease or hospitalization in the whole cohort. It was also 80% effective at preventing symptomatic disease in over 65s who made up 20% of the participants.
Ireland Suspends Dosing—Ireland on March 14 suspended dosing of COVID-19 Vaccine AstraZeneca following a new safety alert from the Norwegian Medicines Agency disclosing four new reports of serious, rare thromboembolic (clotting) events, including some complicated by thrombocytopenia (low platelet count) in adults under 65 years of age after vaccination. To date, no reports of similar events have been received by Ireland’s Health Products Regulatory Authority (HPRA). As of March 14, more than 117,000 doses of COVID-19 Vaccine AstraZeneca® have been administered.
The suspension of dosing had been recommended by Ireland’s National Immunisation Advisory Committee (NIAC). Ireland joins Norway, Iceland, and Denmark in suspending dosing. Italy and Rumania paused dosing from a specific batch, while Thailand and the Democratc Republic of the Congo have delayed the start of planned vaccinations with the AstraZeneca vaccine.
AstraZeneca has stated that it knew of 15 reports of deep-vein thrombosis and 22 of pulmonary embolism among those who had received the vaccine across the European Union and Britain as of March 8: “This is much lower than would be expected to occur naturally in a general population of this size and is similar across other licensed Covid vaccines.” The company also said its safety data of more than 10 million records shows no evidence of an increased risk of pulmonary embolism or deep vein thrombosis.
U.S. EUA Filing Near–AstraZeneca is preparing to file for U.S. emergency use authorization (EUA) for its COVID-19 vaccine later this month or early April, Reuters reported March 12, citing unnamed “sources with knowledge of the ongoing clinical trial.” The company has accumulated data on at least 150 cases of COVID-19, two of those sources are saidf to have told the news organization. “We expect data from our U.S. Phase III trial to be available soon, in the coming weeks, and we plan to file for emergency use authorization shortly thereafter,” an AstraZeneca spokeswoman said.
Additional European Shortfall—AstraZeneca confirmed in a March 12 statement that it will only be able to deliver 30 million doses of its COVID-19 vaccine, less than the 40 million dose commitment it made in February, and far short of its initial 90 million dose promise for the first quarter.
“Half of the EU’s supply in the second quarter, and 10 [million] doses in the first quarter were due to be sourced from the company’s international supply chain. Unfortunately, export restrictions will reduce deliveries in the first quarter, and are likely to affect deliveries in the second quarter,” AstraZeneca acknowledged. “Despite the challenges, it aims to deliver 100 [million] doses in the first half of 2021.”
Authorized in Canada—Health Canada on February 26 authorized COVID-19 Vaccine AstraZeneca and a version manufactured by Verity Pharmaceuticals and the Serum Institute of India (SII), which the agency deemed as comparable to the AstraZeneca vaccine. Both are the third and fourth vaccines authorized for prevention of COVID-19, and the first viral vector-based COVID-19 vaccines authorized in Canada. The vaccines are indicated for use in people over 18 years of age.
Later that day, Anita Anand, Minister of Public Services and Procurement, said that in addition to 20 million doses already secured through an earlier agreement with AstraZeneca, Canada had secured 2 million doses of the Verity/SII vaccine. The first 500,000 doses will be delivered to Canada in coming weeks, while the remaining 1.5 million doses will arrive by mid-May, Anand said
AstraZeneca issued a statement February 24 insisting it will be able to meet its target of delivering 180 million doses of its vaccine to the European Union in the second quarter: “Approximately half of the expected volume is due to come from the EU supply chain, while the remainder would come from its international supply network.” The statement came in response to a Reuters report attributed to an unnamed European official that stated the company would only be able to deliver about 40 million doses in Q2.
AstraZeneca and the European Union are in weekly meetings designed to increase the number of doses of COVID-19 Vaccine AstraZeneca in the EU beyond the 40 million committed for the first quarter, Reuters reported February 15, citing two ounnamed “senior EU officials.” According to the report, the additional doses for the EU could come from manufacturers outside Europe, such as the Serum Institute of India.
The EU and AstraZenca initially agreed to 80 million doses, before the company cut its commitment to 31 million, citing production problems, then added 9 million more doses following criticism.
AstraZeneca said February 10 that it and IDT Biologika were exploring options to accelerate output of finished COVID-19 Vaccine AstraZeneca in the second quarter, in order to help support Europe’s immediate vaccination needs during the pandemic. The first AstraZeneca vaccines began shipping on February 5 as part of the initial 17 million doses due to be delivered over the next weeks, with more planned in March, the company said.
AstraZeneca and IDT Biologika said they will make a joint investment to build large additional drug substance capacity for the future, with the intent of strengthening Europe’s vaccine manufacturing capability with. Details of the agreement are to be finalised. Both companies plan to invest in capacity expansion at IDT Biologika’s production site in Dessau, Germany to build up to five 2,000-liter bioreactors capable of making tens of millions of doses per month of the vaccine. The new facilities are expected to be operational by the end of 2022, AstraZeneca added.
South Africa on February 8 halted the rollout of COVID-19 Vaccine AstraZeneca after a study involving some 2,000 participants concluded that the vaccine offered “minimal protection” against mild and moderate forms of the virus. The nation had received 1 million doses of vaccine, and was preparing to start vaccinating people. South Africa Health Minister Zweli Mkhize said his government would instead offer two other COVID-19 vaccines, Johnson & Johnson’s Janssen COVID-19 Vaccine Candidate, and Pfizer/BioNTech’s BNT162b2.
Data from four clinical trials posted February 3 by researchers from the University of Oxford, AstraZeneca, and partners showed a single dose of COVID-19 Vaccine AstraZeneca to be 76% effective from 22 to 90 days following vaccination, while a two-dose regimen proved more effective the longer the interval between doses. The vaccine also showed potential for reducing transmission of the virus.
According to the data—posted in Preprints with The Lancet and under review for formal publication in The Lancet—the vaccine’s two-dose efficacy rose from 54.9% when doses were spaced less than six weeks apart, to 82.4% when the interval between doses was 12 or more weeks.
That finding is supported by additional immunogenicity data that showed binding antibody responses in volunteers ages 18-55 years that were more than two-fold higher after an interval of 12 or more weeks, compared with an interval of less than 6 weeks. For those volunteers, the geometric mean titer ratio (GMR) was 2.19, with GMR ranging from 2.12 to 2.26.
European Commission President Ursula von der Leyen announced via Twitter January 31 that AstraZeneca will deliver 9 million additional doses in the first quarter, raising its commitment to 40 million doses, will start deliveries a week earlier than planned, and will expand its manufacturing in Europe. The company appeared to be responding to EU criticism over earlier plans to reduce production 60% from its initial commitment of 80 million doses. Citing unspecified production problems, an EU official told Reuters.
Conditional Approval from European Commission—AstraZeneca’s “COVID-19 Vaccine AstraZeneca” (formerly AZD1222 in Europe) on January 29 was granted a conditional marketing authorization (CMA) in the European Union for active immunization to prevent COVID-19 caused by SARS-CoV-2, in individuals 18 years of age and older. The European Commission granted the CMA following a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), which cited positive data from a rolling review of trial data from a primary analysis of the Phase III program.
“Today’s approval underscores the value of AstraZeneca’s COVID-19 vaccine, which is not only effective and well tolerated, but also easy to administer and, importantly, protects fully against severe disease and hospitalizations,” AstraZeneca CEO Pascal Soriot stated. “Easy to administer” is an apparent allusion to the vaccine’s allowing for storage and shipping at -20º C, a conventional freezer temperature.
AstraZeneca on January 25 denied reports in two German news outlets, Handelsblatt and Bild, alleging that AZD1222 had an efficacy rate in adults aged 65 and older of only 8%: “Reports that the AstraZeneca/Oxford vaccine efficacy is as low as 8 per cent in adults over 65 years are completely incorrect,” the company said in a statement.
Three days earlier on January 22, AstraZeneca warned in a statement that supplies of AZD1222 for Europe will be “lower than originally anticipated” due to “reduced yields at a manufacturing site within our European supply chain.” The company did not elaborate.
Brazil’s health regulatory agency Anvisa on January 17 authorized emergency use of AZD1222 as well as Sinovac’s CoronaVac as vaccines to protect against COVID-19.
AZD1222 on January 1 became the first COVID-19 vaccine to win emergency authorization in India, Information and Broadcasting Minister Prakash Javadekar told reporters the following day, adding that at least three more vaccines were under review for similar authorization. In India, AZD1222 is produced by the Serum Institute of India and marketed under the name COVISHIELD. India aims to vaccinate 300 million people—22% of its population of 1.35 billion people—in the first six to eight months of 2021.
2020 Status—Authorized for Emergency Use in the U.K., December 30, 2020—The UK Medicines and Healthcare products Regulatory Agency (MHRA) on December 30 authorized emergency use of AZD1222, indicated for active immunization of individuals 18 years or older. The authorization recommends two doses administered with an interval of between four and 12 weeks. This regimen was shown in clinical trials to be safe and effective at preventing symptomatic COVID-19, with no severe cases and no hospitalisations more than 14 days after the second dose.
AstraZeneca said it is working with Public Health England and National Health Service (NHS) England to support deployment and rollout of the vaccine, in line with the MHRA and the UK’s Joint Committee on Vaccination and Immunisation’s dosing recommendation. The company added that it aims to supply “millions” of doses in the first quarter of 2021, as part of an agreement with the government to supply up to 100 million doses in total.
Health Canada responded to the U.K. emergency authorization with a statement saying that it was expediting the review of AZD1222 and other COVID-19 vaccines through rolling submissions, in which data is reviewed as it becomes available from the sponsor. “There is still information and data to be provided by AstraZeneca for review,” Health Canada stated, adding that it “cannot provide a definite timeline for the completion of the review at this time.”
Noel Wathion, Deputy Executive Director of the European Medicines Agency (EMA), told the Belgian newspaper Het Nieuwsblad on December 29 that his agency would most likely not be able to approve AZD1222 in January: “They have not even filed an application with us yet, not even enough to warrant a conditional marketing licence,” Wathion said, adding: “We need additional data about the quality of the vaccine. And after that, the company has to formally apply.”
The comments came after an unnamed AstraZeneca spokesperson told Reuters on December 22 that the vaccine should prevent against the COVID-19 variant that has infected patients in the U.K. and some other nations: “AZD1222 contains the genetic material of the SARS-CoV-2 virus spike protein, and the changes to the genetic code seen in this new viral strain do not appear to change the structure of the spike protein.”
Researchers from the University of Oxford, AstraZeneca, and clinical partners on December 8 published an interim analysis in The Lancet confirming data released by the company two weeks ago from four ongoing clinical trials—two in the U.K., one each in Brazil and South Africa. Overall, AZD1222 showed vaccine efficacy of 70.4% after two doses and protection of 64.1% after at least one standard dose.
One dosing regimen in 2,741 participants (1,367 given the vaccine, 1,374 given meningococcal group A, C, W, and Y conjugate vaccine [MenACWY]) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart. A second dosing regimen in 4,440 of 8,895 participants showed 62.1% efficacy when given as two full doses at least one month apart.
Significantly, the median interval between doses for the SD/SD group in the COV002 trial (U.K.) was 69 days, while most participants in the COV003 trial (Brazil) (2493 of 4088) received a second dose within a median 36 days of the first. AZD1222 “is efficacious and could contribute to control of the disease in this pandemic,” the researchers concluded.
U.K. Health Secretary Matt Hancock on November 27 requested that the the U.K. Medicines and Healthcare products Regulatory Agency authorize a temporary supply should data prove strong enough—whether or not it has been authorized by the European Medicines Agency, a post-Brexit stipulation set to expire at the end of 2020. By accelerating approval of the vaccine, the MHRA hopes to begin its distribution in December 2020. The U.K. has purchased 100 million doses, and has projected that 4 million would be available by the end of 2020.
Also on November 27, Thailand signed a $200 million agreement to procure 26 million doses of AZD1222, to be delivered in mid-2021. The doses are expected to protect 13 million people in Thailand’s population of about 69 million.
The Disease Control Department of Thailand’s Ministry of Health agreed to purchase AZD1222 for 3.67 billion baht ($121 million), while the country’s National Vaccine Institute signed a non-refundable advance market commitment contract worth 2.38 billion baht ($79 million) with AstraZeneca to reserve the supply of the vaccine candidate.
First Phase III results announced November 23 – AstraZeneca announced preliminary positive Phase III results on November 23 based on two trials comprising 11,363 participants that resulted in an average efficacy of 70%. One dosing regimen in 2,741 participants showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart. A second dosing regimen in 8,895 participants showed 62% efficacy when given as two full doses at least one month apart.
Participants in the U.K. were to have received two full doses. But after researchers accidentally gave the first dose at half strength—due to an error related to the manufacturing of the doses, the company said in a statement—the researchers proceeded with the second full-dose booster shot as planned. “The reason we had the half dose is serendipity,” Mene Pangalos, PhD, AstraZeneca’s Executive Vice-President, BioPharmaceuticals R&D, told Reuters. “Yes, it was a mistake.”
On November 24, Moncef Slaoui, MD, chief adviser for Operation Warp Speed, the U.S. initiative to accelerate development of COVID-19 vaccines and drugs, told reporters on a conference call that participants who received the half-strength initial dose had been 55 years old or younger—raising questions about the efficacy reported for participants randomized to the initial half dose.
The following day, Pangalos told The New York Times that AstraZeneca is planning a global trial to compare the two dosing regimens, and defended the decision to announce results for the half-dose: “The reality is, it could end up being quite a useful mistake. It wasn’t putting anyone in danger. It was a dosing error. Everyone was moving very fast. We corrected the mistake and continued on with the study, with no changes to the study, and agreed with the regulator to include those patients in the analysis of the study as well.”
AstraZeneca and the University of Oxford will only be able to deliver 4 million doses by the end of 2020 out of 100 million doses ordered by the U.K. government, missing an earlier goal of delivering 30 million doses of AZD1222 to the U.K. by the end of September 2020, Kate Bingham, Chair of the government’s Vaccine Taskforce, told the House of Commons Health and Social Care Committee. She said the 30 million doses should be available to the U.K.’s most vulnerable people in need of vaccination by the start of summer 2021.
“The projections that were made in good faith at the time were assuming that absolutely everything would work and there would be no hiccups at all,” said Bingham, who is also Managing Partner, SV Health Managers.
She also defended herself against criticism from some U.K. officials for presenting information marked “official sensitive” at “Inside the Race to Develop a COVID-19 Vaccine,” a webinar presented to venture capitalists October 21 by Falk Marques Group.
The U.S. Army on October 28 awarded a firm-fixed-price contract of more than $286.9 million with AstraZeneca (W15QKN-21-C-0003) covering 200 million doses of AZD1222, to be produced at company sites in West Chester Township, OH, and Albuquerque, NM. The contract will be funded through “other procurement,” Army funds the service branch uses to finance the procurement, production, and modernization of equipment not otherwise provided for, under a fiscal year 2021 budget when that spending plan is finalized.
On October 26, AstraZeneca could not confirm a report in The Sun that London hospitals have been told to get ready to receive the first batches of AZD1222 as early as next week—including a “major London hospital trust” that was told to put other clinical trials on hold so it could get ready to vaccinate health workers.
AstraZeneca confirmed October 23 that the FDA had authorized a re-start of the Phase III trial that the company paused globally in September, sparked by a “potentially unexplained illness” involving a participant from the U.K. The resumption was first reported by The Wall Street Journal, which identified the ill patient as a woman. “The FDA reviewed all safety data from trials globally and concluded it was safe to resume the trial,” AstraZeneca stated.
The FDA’s action followed the resumption of the trial in the U.K., Japan, South Africa—and Brazil, where the health agency Anvisa two days earlier reported the death of a patient who volunteered to take the vaccine. The patient—a Brazilian national but otherwise unidentified—is believed to have been in the control group given a meningitis shot and not among patients dosed with AZD1222, after an unnamed source told Reuters that the Brazilian portion of the trial would have been suspended had the death been linked to the vaccine. The Federal University of Sao Paulo said an independent review committee had also recommended the trial continue.
“The restart of clinical trials across the world is great news as it allows us to continue our efforts to develop this vaccine to help defeat this terrible pandemic,” AstraZeneca CEO Pascal Soriot said.
On October 22, researchers at Bristol Universty posted a preprint on ResearchSquare validating that AZD1222 accurately follows the genetic instructions programmed into it by the University of Oxford scientists who developed the vaccine. The researchers used direct RNA sequencing to analyze transcript expression from the vaccine genome in human MRC5 and A549 cell lines that are non-permissive for vector replication alongside the replication permissive cell line, HEK293. Investigators also studied the proteome and phosphoproteome of A549 and MRC5 cells infected with the vaccine candidate.
The European Medicines Agency (EMA) was expected to begin an accelerated “rolling review” of AZD1222, Bloomberg News reported September 30, based on an unnamed source. Such reviews, used in emergency circumstances, allow regulators to continuously assess trial data for “highly promising” drugs or vaccines, with the aim of helping their developers pursue EMA recommendations and European Commission approvals as quickly as possible.
AstraZeneca said September 25 it agreed to supply the government of Canada up to 20 million doses of AZD1222 in 2021, should clinical trials prove to be successful. The price was not disclosed.
U.S. Secretary of Health and Human Services Alex Azar II told CNBC on Setpember 23 that the trial remained on hold in the U.S. pending “answers to important questions” over the vaccine’s safety for patients being sought by the FDA. Azar spoke nearly two weeks after the trial resumed in the U.K. AstraZeneca said it resumed the U.K. portion of the trial after receiving confirmation from the country’s Medicines Health Regulatory Authority (MHRA) that it was safe to do so.
“As part of the ongoing randomised, controlled global trials of the Oxford coronavirus vaccine, our standard review process was triggered and we voluntarily paused vaccination to allow review of safety data by an independent committee,” AstraZeneca stated in pausing the trial on September 8. “This is a routine action which has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring we maintain the integrity of the trials.”
“We are committed to the safety of our participants and the highest standards of conduct in our trials,” AstraZeneca added.
AstraZeneca has not disclosed the nature of the adverse reaction. The New York Times reported that the patient developed transverse myelitis, citing an unnamed source—while STAT later reported AstraZeneca CEO Pascal Soriot told investors on a private conference call organized by J.P. Morgan that the patient had neurological symptoms consistent with the disorder.
However, NIH director Francis S. Collins, MD, PhD, seemed to give credence to the Times’ report when he told a Senate committee on September 9 that the reason for the trial pause was a “spinal cord problem.”
Also that day, AstraZeneca CEO Pascal Soriot told investors in a private conference call that development of AZD1222 remained on track and that the vaccine could still be ready by the end of 2020 or early 2021, as long as the trial’s independent data and safety monitoring board resumes the trial. UK health secretary Matt Hancock said on the national radio news/talk station LBC that AZD1222 vaccine would “most likely” be available in the first few months of 2021.
“We have got 30 million doses already contracted with AstraZeneca. In fact they are starting to manufacture those doses already, ahead of approval, so that should approval come through – and it’s still not certain but it is looking up – should that approval come through, then we are ready to roll out,” Hancock said. “The best-case scenario is that it happens this year. I think more likely in the early part of next year – in the first few months of next year is the most likely.”
The pause was the second for the trial, AstraZeneca stated: “There was a brief trial pause in July while a safety review took place after one volunteer was confirmed to have an undiagnosed case of multiple sclerosis, which the independent panel concluded was unrelated to the vaccine.”
Soriot was one of nine CEOs of leading developers of vaccine candidates against COVID-19 who on September 8 signed a statement that pledged “a united commitment to uphold the integrity of the scientific process” by pursuing approvals or emergency use authorizations (EUAs) only for vaccines that pass muster in Phase III trials by proving safety and effectiveness.
On September 7, Australia’s federal government has reached agreement with Melbourne-based CSL to manufacture a total 84.8 million doses of AZD1222 and V451, a vaccine developed by CSL with the University of Queensland, for supply and distribution within the country. Should both vaccines succeed in clinical trials, Australia has agreed to purchase 51 million doses of V451 and approximately 30 million doses of AZD1222 for a combined A$1.7 billion ($1.2 billion), based on a two-dose per person regime for both vaccines.
CSL said it will use the funding in part to establish at-risk components required to produce commercial-scale manufacture of a recombinant vector-based COVID-19 vaccine, including the acquisition of specialized equipment, recruitment, training and redeployment of personnel and retooling and reconfiguration of existing manufacturing facilities to current GMP standards.
CSL is expected to deliver 3.8 million “early access” doses of AZD1222, almost entirely manufactured in Melbourne, in January and February 2021.
“Australia needs some hope,” Morrison said. “There are no guarantees that these vaccines will prove successful, however the agreement puts Australia at the top of the queue, if our medical experts give the vaccines the green light.”
AstraZeneca has selected Albany Molecular Research, Inc. (AMRI) to provide sterile fill/finish of AZD1222 through 2021 at AMRI’s drug product manufacturing facility in Albuquerque, NM, under a supply agreement announced September 3 by AMRI. The value of the agreement was not disclosed.
AstraZeneca will use the Albuquerque facility’s cGMP manufacturing capacity to potentially produce millions of doses of AZD1222 annually, AMRI said, adding: “Both organizations are committed to delivering on unprecedented manufacturing timelines.”
AstraZeneca on September 1 said it launched a 30,000-patient Phase III trial in the U.S. of AZD1222, a study that will account for most of the 50,000 participants on which the company intends to assess the vaccine. The Phase III D8110C00001 trial (NCT04516746) is intended to evaluate the safety, efficacy, and immunogenicity of AZD1222 (formerly ChadOx1 nCoV-19) for the prevention of COVID-19.
Participants will be randomized to receive two doses of either AZD1222 or a saline control, four weeks apart, with twice as many participants receiving the potential vaccine than the saline control. Local and systemic reactions and immune responses will be assessed in 3,000 of the participants, AstraZeneca added.
Also on September 1, AstraZeneca agreed to pay Oxford Biomedica a £15 million ($20.1 million) upfront capacity reservation fee under an 18-month supply agreement announced by Oxford Biomedica, part of a three-year Master Supply and Development Agreement with AstraZeneca for large-scale commercial manufacture of AZD1222.
The capacity will be reserved in up to three manufacturing suites in Oxford Biomedica’s new 7,800 m2 (83,959 square foot) Oxbox commercial manufacturing center in Oxford, U.K., for an initial 18 month period. The new GMP facility is suitable for manufacturing viral vectored vaccines and gene therapy vectors up to 1,000 litre scale.
Of the three Oxbox suites, two will become operational in the next two months—significantly earlier than originally planned—as a result of Oxford Biomedica’s partnership established in June with the UK’s Vaccine Manufacturing Innovation Centre (VMIC), a not-for-profit organization established to provide the UK’s first strategic vaccine development and advanced manufacturing capability.
Oxford Biomedica said it expects to receive more than £35 million ($46.8 million) in additional revenue plus materials costs for the manufacture of multiple large-scale batches of AZD1222 through the end of 2021. The companies can extend the supply period for AZD1222 by an additional 18 months into 2022 and 2023 by mutual agreement. Oxford Biomedica and AstraZeneca have expanded upon a supply agreement inked in May which related exclusively to manufacture of AZD1222 at 200L scale and associated process development.
AstraZeneca on August 31 declared its “commitment to the highest safety standards and to broad and equitable access” worldwide for AZD1222. To that end, the company said it was implementing a clinical development program set to enroll a diverse population of more than 50,000 volunteers—including 30,000 in the U.S., Latin America, Asia, Europe, Russia, and Africa. AstraZeneca also articulated a pair of core values it said will govern its development of AZD1222: “Follow the science” and “put patients first.”
AstraZeneca received regulatory approval to conduct part of its Phase III trial of AZD1222 in Russia, the country’s clinical trials registry disclosed August 21. The trial will include 150 participants and be conducted at four medical facilities in St. Petersburg and Moscow, Reuters reported. In July, AstraZeneca confirmed it would manufacture an undetermined number of doses of AZD1222 in Russia through R-Pharm, which agreed in return to export the vaccine within the nine-country Commonwealth of Independent States.
AstraZeneca said August 14 that it concluded an agreement with the European Commission (EC) to supply up to 400 million doses of AZD1222. The EC said the agreement gives all European Union (EU) member states the option to access the vaccine in an equitable manner at no profit during the pandemic. EU member states may also redirect doses to other European countries.
The accord expands AstraZeneca’s agreement inked in July with the Inclusive Vaccines Alliance (IVA), formed by Italy as well as France, Germany, and the Netherlands to secure COVID-19 vaccine doses as quickly as possible. AstraZeneca agreed at the time to supply the IVA with up to 400 million doses of AZD1222 at no profit, starting by the end of 2020.
As of August 14, AstraZeneca said it had developed a global supply capacity “towards” three billion doses of AZD1222 through supply announcements with Russia, South Korea, Japan, China, Latin America, and Brazil. The company added that it “continues to engage with governments, multilateral organisations and partners around the world to ensure broad and equitable access to the vaccine” upon successful clinical trials.
AZD1222 is under study in late-stage Phase II/III trials ongoing in the UK and Brazil, a Phase I/II trial in South Africa, and trials planned in the U.S., Japan, and Russia. Results from the late-stage trials are anticipated later this year.
On August 13, Mexican President Andrés Manuel López Obrador announced an agreement by AstraZeneca, University of Oxford, and the Carlos Slim Foundation agreeing to produce AZD1222 in Mexico and Argentina. The agreement calls for production of an initial 150 million doses across Latin America—except for Brazil, which is covered by a separate agreement—with the first doses set to be delivered in the first half of 2021.
AstraZeneca will eventually make at least 400 million for distribution throughout the region, Sylvia Varela, head of AstraZeneca Mexico, told reporters at the announcement, held at Mexico’s National Palace in Mexico City.
Argentina’s President Alberto Fernández disclosed the agreement a day earlier. Argentina will product the vaccine’s active ingredient, while Mexico will pack, fill, and finish the vaccine.
Fernández said the vaccine will cost $3 to $4 in Argentina—while in Mexico, López Obrador said, the vaccine will be universal and free.
On August 7, Japan’s government reached agreement with AstraZeneca to receive 120 million doses of AZD1222, health minister Katsunobu Kato said. The vaccine will be available next year, with the first 30 million doses set to reach patients by March.
Researchers from AstraZeneca, the University of Oxford, and partners on July 20 published positive preliminary data from the Phase I/II COV001 trial (NCT04324606) showing AZD1222 to have an acceptable safety profile, and favorable immunogenicity against the virus. Among the 543 participants randomized to AZD1222, a single dose resulted in a four-fold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants at Day 28 after injection, the researchers reported. In all participants, a T-cell response was induced, peaking by day 14, and maintained two months after injection.
Spike-specific T-cell responses among AZD1222 participants peaked on day 14, while anti-spike immunoglobulin G (IgG) responses rose by day 28 and were boosted following a second dose, the researchers reported. Neutralizing antibody responses against SARS-CoV-2 were detected in 32 of 35 participants after a single dose when measured via microneutralisation assay (MNA80) and in all 35 participants when measured via the 50% plaque reduction neutralization assay (PRNT50). After a booster dose, all participants had neutralizing activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg virus neutralization [VN] on day 56). Neutralizing antibody responses correlated strongly with antibody levels measured by ELISA
“The preliminary results of this first-in-human clinical trial supported clinical development progression into ongoing phase 2 and 3 trials,” the researchers concluded in their study, published in The Lancet.
The single-blinded, randomized, multi-center study is designed to determine the efficacy, safety, and immunogenicity of AZD1222 in 1,077 healthy adult volunteers aged 18–55 years across five trial centers in southern England. The trial compared a single dose of AZD1222 against the meningococcal conjugate vaccine MenACWY as a control. Ten participants also received two doses of AZD1222 one month apart. The trial, a collaboration between the Group and the Jenner Institute, started in March and began recruiting patients on April 23, after U.K. Health Secretary Matt Hancock pledged £20 million in government funding to support development of the vaccine.
A week earlier, IQVIA said it will partner with AstraZeneca to accelerate development of AZD1222 by speeding up U.S. clinical studies designed to demonstrate its efficacy–including an “expansive” trial that is expected to begin enrolling participants “this summer.” The partnership will use IQVIA’s Virtual Trial solutions including Study Hub, which can facilitate either all-virtual or hybrid in-person and virtual studies.
IQVIA said the partnership was part of Operation Warp Speed, through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.
World Health Organization (WHO) Chief Scientist Soumya Swaminathan, MD, MBBS, told reporters June 26 she considered AZD1222 “probably the leading candidate” among COVID-19 vaccine candidates in development worldwide. WHO counts more than 200 such candidates worldwide, of which 15 are in clinical trials.
AstraZeneca will receive fast-track access to sterile vaccine drug product manufacturing capacity for clinical trial supply of AZD1222 from Symbiosis Pharmaceutical Services, through a supply agreement of undisclosed value announced by Symbiosis on June 22. The agreement with Symbiosis, based in Stirling, Scotland, U.K., is the 10th supply-and-manufacturing deal signed by AstraZeneca for AZD1222.
Sarah Gilbert, PhD, professor of vaccinology at Oxford University, a leader of the effort to develop AZD1222, told the U.K. House of Commons Science and Technology Committee on June 23 that researchers were “very interested in looking at delivery of the vaccine to the respiratory tract, either intranasal delivery or aerosol delivery. In addition to Gilbert, Oxford’s team is led by Professors Andrew Pollard, MBBS, PhD; Teresa Lambe, PhD; Sandy Douglas, DPhil; and Adrian Hill, DPhil. The team started work designing a vaccine in January.
Gilbert was among scientists at Oxford and The Pirbright Institute who published a preprint study in bioRxiv on June 20 reporting that 42 days following the start of dosing, T cell responses were higher in one mouse strain—and especially so in pigs—that received a second “boost” dose of AZD1222 28 days after the initial “prime” dose, compared to receiving only a prime dose. “Further clinical studies are needed to assess immunogenicity after prime-boost vaccination and the impact on clinical efficacy and durability of the immune response,” the researchers cautioned.
Hill, the director of Oxford’s Jenner Institute, told a webinar of the Spanish Society of Rheumatology that the “best scenario” for AZD1222 reaching the market would be in October—one month later than projected June 16 by Cobra Biologics when it said it signed a supply agreement with AstraZeneca to provide GMP manufacture of AZD1222 Oxford-led consortium to rapidly develop, scale-up and produce the vaccine.
Joining Cobra and University of Oxford’s Jenner Institute are cGMP contract manufacturing organizations ADVENT and Halix, Pall Life Sciences, University of Oxford Clinical Biomanufacturing Facility, and the Vaccines Manufacturing and Innovation Centre. Cobra said earlier this year it was planning to facilitate efficient production of a GMP working cell bank, then 200L GMP viral vaccine. Consortium partners said they expected to develop and manufacture the vaccine candidate in multiple batches, to support a 1 million dose scale batch size as soon as the summer.
A day earlier, AstraZeneca further boosted its manufacturing capacity by agreeing to use Catalent’ manufacturing facility in Anagni, Italy, to increase its vial filling and packaging capacity, and prepare for large-scale commercial supply of AZD1222. The value of the agreement, announced June 15, was not disclosed. AstraZeneca also agreed to use the molecule-to-market contract development and manufacturing (CDMO) services of Emergent BioSciences, through a collaboration disclosed June 11 and valued at $87 million.
Earlier in June, AstraZeneca said it had come to terms with partners to produce up to 2 billion doses of AZD1222 per year, double the 1 billion dose goal it articulated a month earlier. The pharma and SII (formerly the Serum Institute of India) agreed to produce 1 billion of the doses for low- and middle-income countries, starting with 400 million doses by year’s end. AstraZeneca will also receive a combined $750 million toward manufacturing and distributing 300 million doses by year’s end from two groups: $383 million from CEPI, the Coalition for Epidemic Preparedness, and $367 million from GAVI, The Vaccine Alliance.
The New York Times reported June 3 that AstraZeneca, the University of Oxford, and partners were among developers of five COVID-19 vaccines identified by President Donald Trump’s administration as most likely to produce a vaccine for the virus, citing unnamed “government officials.” According to the report, the five will receive additional government funding, assistance with clinical trials, and financial and logistical support for manufacturing. A formal announcement is expected in coming weeks.
In May, AstraZeneca said it received $1.2 billion from the Biomedical Advanced Research and Development Authority (BARDA) toward development, production, and delivery of AZD1222. The development and production work to be funded by BARDA will begin this fall, AstraZeneca said. It will include a Phase III trial designed to recruit 30,000 participants, as week as another trial to evaluate the vaccine in children. The trial is set to start in June and run to the end of August, AstraZeneca CEO Pascal Soriot told Bloomberg News.
On the production end, AstraZeneca has concluded its first manufacturing agreements to produce at least 400 million doses of the vaccine, as well as gain total manufacturing capacity for 1 billion doses so far.
AstraZeneca agreed to furnish BARDA with 300 million doses, the U.S. Department of Health and Human Services (HHS) said—four days after the U.K. government secured the other 100 million doses by agreeing to pay AstraZeneca £65.5 million ($80 million).
AstraZeneca said the U.K. will receive the first 30 million doses of AZD1222 in September. The U.S. set to receive the vaccine in October, according to HHS’ announcement.
AstraZeneca said April 30 it will oversee global development, manufacturing, and distribution of the COVID-19 vaccine candidate created by researchers at University of Oxford, and now under study in a human clinical trial. AstraZeneca, the University, and its spinout company Vaccitech—which has joint rights to the platform technology behind the vaccine candidate—said they will start work immediately while hammering out final terms of their collaboration agreement. The partnership is designed to enable rapid production and distribution of the vaccine should it prove effective in clinical studies.
AstraZeneca, the University, and its spinout company Vaccitech—which has joint rights to the platform technology behind the vaccine candidate—said they will start work immediately while hammering out final terms of their collaboration agreement. The partnership is designed to enable rapid production and distribution of the vaccine should it prove effective in clinical studies.
The Jenner Institute and MilliporeSigma said April 14 they had begun preparations for the large-scale production of the former ChAdOx1 nCoV-19, building on a partnership to develop more robust and scalable vaccine manufacturing processes launched in April 2018. Joining the partners April 15 was HALIX, which will apply its viral vector bioprocessing expertise to support the manufacture of Oxford vaccine clinical trial material by transferring an industrial scale drug substance process to its new GMP facilities with capacity up to 1,000 L SUB scale, from a Pall facility in the U.K.
On March 23, Oxford Prof. Sarah Gilbert was awarded £2.2 million ($2.7 million) by the U.K. government toward the research, one of six COVID-19 research projects to receive a combined £20 million ($24.5 million).
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: