Candidate: AZD1222 (formerly ChAdOx1 nCoV-19)

Category: VAX

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.

Status: AstraZeneca confirmed October 23 that the FDA had authorized a re-start of the up-to-30,000-patient Phase III trial of AZD1222 (NCT04516746) 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. “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.

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.

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.

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: 200 Candidates and Counting

To navigate through the >200 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:

● ANTIVIRAL
● VAX
● ANTIBODY
● RNA

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