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What do we know so far about AstraZeneca's vaccine?

This article was published on
March 23, 2021

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March 28, 2021: The United States has not granted AstraZeneca an emergency use authorization for its vaccine, as its clinical trials in the country were not completed until the second half of March 2021. Additionally, the National Institute for Allergy and Infectious Diseases released a statement noting its concern that AstraZeneca's trial information was outdated and may have provided "an incomplete view of the efficacy data."  

AstraZeneca responded by stating its interim results were based on an early analysis with its data but noted that the interim findings were consistent with its later, fuller primary analysis. While the company originally said its vaccine efficacy rate was 79% for preventing symptomatic COVID-19 and 100% efficacy at preventing severe disease and hospitalization, AstraZeneca later lowered the first percentage to note its vaccine efficacy was 76% at preventing symptomatic cases of COVID-19.

March 14, 2021: Several nations have paused their use of the AstraZeneca COVID-19 vaccine due to recent reports linked to blood clotting, bleeding under the skin, and other related issues. There is no definitive link between the vaccine and these health conditions but the World Health Organization, many national health agencies, and AstraZeneca are investigating. Currently the AstraZeneca vaccine has received emergency use authorization in over 70 countries and an Emergency Use Listing granted by the World Health Organization which accelerates the pathway to access in up to 142 countries through the COVAX Facility.

Recently, leaders from France and Germany questioned the effectiveness of the AstraZeneca vaccine in people over 65 because of a perceived lack of data within this group. However, the World Health Organization has recommended the vaccine for adults 65 years and older and are "very confident" the vaccine will be effective and safe in this group based on the data. During early stages of clinical trials, the vaccine generated a immune system response in older groups similar to that in younger people so there is little evidence suggesting a lack of effectiveness in older populations.

AstraZeneca worked in partnership with the University of Oxford to create their vaccine for COVID-19. This vaccine has been approved for emergency use authorization in dozens of countries around the world and uses a formula called a 'viral vector' where a weakened common cold virus (adenovirus) is used to deliver instructions to the body for how to fight COVID-19.

AstraZeneca worked in partnership with the University of Oxford to create their vaccine for COVID-19. This vaccine has been approved for emergency use authorization in dozens of countries around the world and uses a formula called a 'viral vector' where a weakened common cold virus (adenovirus) is used to deliver instructions to the body for how to fight COVID-19.

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What our experts say

The University of Oxford vaccine is an adenovirus vaccine currently being used under an emergency use authorization in over 70 countries as of March 16, 2021. Here's a breakdown of everything you need to know so far about this vaccine's development.

Collaborators: AstraZeneca is collaborating with the University of Oxford and its spin-out company, Vaccitech, on vaccine development and testing for ChAdOx1/AZD1222.

The National Institute of Allergy and Infectious Diseases (NIAID) (which is part of the National Institutes of Health) and the Biomedical Advanced Research and Development Authority (BARDA) (part of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response) are providing funding support for the Phase 3 trial.

Latest information on how well the vaccine works: On November 23, 2020, with primary efficacy analysis data from its phase three trial in the United Kingdom and Brazil, AstraZeneca's experimental COVID-19 vaccine was reported to have 70.4% efficacy (it reduced the risk of symptomatic COVID-19 by 70.4%).

The study recorded 131 infections among 23,000 total trial participants, but the company did not say how many received the vaccine and how many received the placebo. Surprisingly, data from 8,895 trial participants who were given two full doses of the vaccine at least one month apart showed it had a 62% efficacy rate, while 8,895 participants who received a half dose followed by a full dose of the vaccine at least one month later demonstrated roughly 90% efficacy.

There has been one COVID-19-related death in the study, which occurred in the placebo group. No hospitalizations or severe cases of COVID-19 occurred in vaccinated participants.

Approvals: On December 30, 2020, the United Kingdom's Medicine and Healthcare Products Regulatory Agency granted an emergency authorization for AstraZeneca's COVID-19 vaccine for adults 18 years of age and older. The authorization recommends two doses between 4 and 12 weeks of time. Otherwise, this vaccine is not yet approved for public use by any regulatory agency.

Distribution timeline: The company has not submitted its Phase 3 trial data to any national drug regulatory agencies and has not yet pursued a United States Food and Drug Administration (U.S. FDA) Emergency Use Authorization (EUA) or an application for Conditional Marketing Authorization (CMA) with the European Medicines Agency (EMA). However, the company expects it will have 200 million doses ready by the end of 2020 and can produce 100 million to 200 million doses per month once production is ramped up in 2021. AstraZeneca also said it was planning to distribute the vaccine in late 2020 and will likely be able to make up to three billion doses next year.

Distribution plan: As of December 1, 2020, AstraZeneca promised to supply 300 million vaccines to low and middle income countries on a not-for-profit basis through a vaccine partnership called COVAX. The COVAX partnership is made of up individual organizations including GAVI, the vaccine alliance; the World Health Organization; and the Coalition for Epidemic Preparedness Innovations (CEPI) in order to obtain equitable distribution to 92 developing countries. Additionally, AstraZeneca says it plans to produce up to 3 billion doses of the vaccine in 2021 on a rolling basis. The company has not submitted its Phase 3 trial data to any national drug regulatory agencies and has not yet pursued a United States Food and Drug Administration (U.S. FDA) Emergency Use Authorization (EUA) or an application for Conditional Marketing Authorization (CMA) with the European Medicines Agency (EMA). The U.S.-based portion of the trial is being supported by Operation Warp Speed.

How the vaccine is being studied: Vaccines are tested and studied in multiple phases (phased testing) to determine if they are safe and work to prevent illness. Before a vaccine is tested on humans, in the preclinical phase it is tested on laboratory cells or animals. Once it is approved for human research, there are three phases that take place before the vaccine can be considered for approval for public use. During the first stage (Phase I), the new vaccine is provided to small groups of people—the first time the vaccine is tested in humans. The second stage (Phase II) involves testing the vaccine on people who have similar characteristics (such as age and physical health) to the target population, or the group for which the vaccine is intended. The goal of this stage is to identify the most effective dosages and schedule for Phase III trials. The final stage (Phase III) provides the vaccine to thousands of people from the target population to see how safe and effective it is. Once the vaccine has undergone Phase 3 testing, the manufacturer can apply for a license from regulatory authorities (like the FDA in the US) to make the vaccine available for public use. Once approved, the drugmaker will work with national governments and international health organizations to monitor vaccine recipients for potential side effects from the vaccine that were not seen in clinical trials (this is called surveillance). This phase also helps researchers understand how well a vaccine works over a longer time frame and how safe it is for the population.

Type of vaccine: This vaccine was developed using an adenovirus—a weakened, harmless virus that usually causes the common cold in chimpanzees—as a way to transport the vaccine's ingredients into the human body. This type of vaccine is called a "vector vaccine," because the adenovirus serves as the vector (or vehicle) for getting the drug into human cells. The adenovirus can stimulate a response from a person's immune system when their body detects it in cells. When the vaccine is injected, it penetrates into the body and gives a blueprint (DNA) for how to defend itself against COVID-19. In this case, that means the cells start to produce club-shaped spike proteins found in coronaviruses, including COVID-19. These three-dimensional spike proteins are so similar to a normal COVID-19 infection that it causes inflammation and the creation of antibodies and T cells. Then when a vaccinated person is eventually exposed to COVID-19, their body would attack the virus because it already recognizes how to respond to those spike proteins, and can fight against them to prevent infection. Essentially, the vaccine helps train human bodies to detect and eliminate a real COVID-19 infection through showing it mock spike proteins, before COVID-19 can cause any severe symptoms or a severe infection.

Vaccine ingredients: The active ingredient of this vaccine, as mentioned above, is made from a modified adenovirus which causes the common cold in chimpanzees. This virus has been modified so that it cannot cause an infection. The vaccine is used to deliver the genetic code for the coronavirus spike protein which will allow the body to fight the virus if it comes into contact with it later. In addition, the vaccine contains inactive ingredients such as histidine -- an amino acid that helps stabilize the vaccine, polysorbate 80, an emulsifier -- which prevents any glass it's being stored in from absorbing it -- and a very small amount of alcohol, which helps to keep the vaccine from degrading over time. The vaccine also contains very small traces of magnesium chloride hexahydrate and disodium edetate (EDTA), which are types of salts that help keep the vaccine stable. Finally, the vaccine also contains sodium chloride (regular table salt) that also helps keep the vaccine solution stable at a certain pH. All vaccine ingredients are present in very small amounts and there is no evidence that they can cause harm in these amounts. This vaccine does not contain any human or animal products, or any allergens such as lactose, latex, milk, gluten, egg, peanuts, or maize (corn).

Dosage: AstraZeneca is currently planning a global trial to compare two dosing regimens of half and full dosages for trial participants, though only full dosage trials were originally planned. Original plans for an initial injection followed by a secondary injection at least one month later are still in place. Early trial phases used dosages of 5 × 1010 viral particles in their vaccine injections. Later stage trials used ~2.5 x1 010 viral particles in half doses or ~5 x 1010 viral particles in full doses. AstraZeneca has yet to determine how many trial participants will be involved but said the number will be in the thousands. On December 30, 2020, the United Kingdom's Medicine and The United Kingdom's authorization of the vaccine recommends two doses between 4 and 12 weeks of time.

Vaccine storage conditions: Storage requirements are important to consider for new vaccines. In order for vaccines to be safe and effective, they must be held at the correct temperature during distribution and storage in health centers, pharmacies, and clinics. Maintaining the correct storage temperature can be difficult, especially if the vaccine's temperature requirement is very cold. The AstraZeneca vaccine can be stored and transported and handled at normal refrigerated conditions. This temperature range is between 2-8 degrees Celsius/ 36-46 degrees Fahrenheit and can remain effective for at least six months at that temperature.

Preclinical testing: Early doses of the vaccine were shown to be effective in protecting rhesus macaques from pneumonia caused by COVID-19, according to U.S. National Institutes of Health and University of Oxford collaborators. The six animals who were vaccinated 28 days before being infected with COVID-19 were compared to three other animals that did not receive the vaccine. The six vaccinated animals had no signs of no signs of the virus replicating in their lungs, much lower levels of respiratory illnesses and no lung damage in comparison to the unvaccinated animals .The vaccine was then permitted to advance to clinical trials in humans.

Phase 1/2 trial: Beginning April 23 through May 21, 2020, 1077 participants were enrolled in AstraZeneca's early trials and received either the vaccine or the MenACWY vaccine (as part of the control group to whom vaccinated participants are compared ). Healthy adults aged 18-55 years old with no lab-confirmed history of COVID-19 infection or symptoms were enrolled in the trial. Ten of these adults openly received a vaccine booster (second) injection 28 days after the first injection was given. By day 14, T-cell responses were at their highest and anti-spike IgG responses rose by day 28. Neturalizing antibodies were detected in 32 of 35 (91%) of patients after a single dosage of vaccine and in all participants who received a booster dosage. Side effects were more present in the vaccinated group but many were improved with paracetamol including pain, feeling feverish, chills, muscle ache, headache, and malaise. About 60% of the 1000 trial participants experienced side effects. There were no serious adverse events related to ChAdOx1 nCoV-19.

Phase 2/3 trial: The earliest data we have from Phase 2 and 3 trials are single-blinded, multi-centre, randomised, controlled trials is from the UK and Brazil. Participants are selected for participation and randomly assigned to either receive the experimental vaccine or an injection of MenACWY or saline. These trial phases involve 23,000 trial participants aged 18 and over from diverse racial and geographic groups who are healthy or have stable underlying medical conditions. For the 2,741 trial participants who received a have dose of the vaccine followed by a full dose at least one month apart, vaccine efficacy was reported to be 90%. In the 8,895 trial participants who received two full doses at least one months apart, vaccine efficacy was was reported to be 62%. The combined efficacy from both of these dosing regimens in 11,636 people was reported to be 70%. No hospitalizations or severe cases of the disease were reported in participants receiving the vaccine, but no published studies have been released about potential side effects. After an alleged serious adverse reaction in one Phase 3 trial participant, AstraZeneca voluntarily halted its clinical trials temporarily to investigate. The participant is expected to make a full recovery and most trials have resumed. Current trials are also underway US, Japan, Russia, South Africa, Kenya and Latin America with planned trials in other European and Asian countries. In total, the company expects to enroll up to 60,000 participants globally.

Reported side effects and safety concerns: Completed Phase 3 study results have yet to be published, but some early trial data showed that 60% of trial participants reported side effects from the injections. These symptoms included pain, feeling feverish, chills, muscle ache, headache, and malaise and many were treated with paracetamol. Injection-site pain and tenderness were the most common local adverse reactions within48 hours of the injection and a significant number of side effect symptoms were reported in each age group over 

Impact on different populations: Older adults (56 years and older) were reported to have a strong immune response to the injections.

Other relevant notes: N/A

Context and background

As the race for new COVID-19 vaccines continues, several candidates have recently made headlines with their positive reporting. However, the collaboration between the University of Oxford and AstraZeneca was forced to pause for several weeks during September of 2020 when a United Kingdom volunteer who had received the vaccine reportedly experienced spinal cord inflammation. This was allegedly similar to another neurological event that had happened previously in a vaccinated volunteer. However, these events were determined to be unrelated to the vaccine, so most study sites restarted their trial. The trial in the United States continued with a longer pause, but no definite reason was given for this delay. United States trial sites resumed their studies in late October of 2020.

AstraZeneca has already reached agreements with several nations to deliver over to 2 billion doses of its vaccine if it is approved. It has already begun manufacturing the vaccine in large quantities so it can be rapidly deployed if regulatory agencies confirm that it is effective.

On December 30, 2020, the United Kingdom became the first country to grant emergency authorization for the vaccine to its citizens 18 years of age and older.

Resources

  1. ChAdOx1 nCoV-19 vaccine for SARS-CoV-2 (Lancet)
  2. Oxford's ChAdOx1 nCoV-19 clinical trials (Oxford)
  3. COVID-19 Oxford Vaccine Trial (Oxford)
  4. Covid: 6,000 UK volunteers to be injected with vaccine in phase 3 trial (Guardian)
  5. Two Companies Restart Virus Trials in U.S. After Safety Pauses (NYT)
  6. Coronavirus Vaccine Tracker (NYT)
  7. Pfizer and AstraZeneca slide as Moderna's rival COVID-19 vaccine shows strong efficacy (MI)
  8. Nobody has looked at AstraZeneca vaccine data yet - UK health official (Reuters)
  9. AstraZeneca says COVID-19 vaccine could arrive in January of next year (CBS)
  10. About the Oxford COVID-19 vaccine (Oxford)
  11. Oxford Covid vaccine works in all ages, trials suggest (The Guardian)
  12. AstraZeneca Covid-19 vaccine is 70% effective on average, early data show (STAT)
  13. Why Oxford’s positive COVID vaccine results are puzzling scientists (Nature)
  14. AstraZeneca’s Coronavirus Vaccine, Easy and Cheap to Produce, Appears Effective (NYT)
  15. Experts have questions about AstraZeneca's vaccine data (CNN)
  16. What We Know About AstraZeneca’s Head-Scratching Vaccine Results (NYT)
  17. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19 (AstraZeneca)
  18. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial (Lancet)
  19. AstraZeneca COVID-19 vaccine trial Brazil volunteer dies, trial to continue (Reuters)
  20. After Admitting Mistake, AstraZeneca Faces Difficult Questions About Its Vaccine (NYT)
  21. Investigational ChAdOx1 nCoV-19 vaccine protects monkeys against COVID-19 pneumonia (U.S. NIH)
  22. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques (bioRxiv)
  23. The Science is There: Key Considerations for Stabilizing Viral Vector-Based Covid-19 Vaccines (Journal of Pharmaceutical Science)
  24. AUSTRALIAN PRODUCT INFORMATION: COVID-19 Vaccine AstraZeneca (Australian Public Assessment Report for prescription medicines)
  25. COVID-19 vaccines (Vaccine Knowledge Project)
  26. (ChAdOx1-S) solution for injection
  27. AstraZeneca Covid-19 vaccine study put on hold due to suspected adverse reaction in participant in the U.K. (STAT)
  28. AstraZeneca’s COVID-19 vaccine authorised for emergency supply in the UK (AZ)
  29. Update on the safety of COVID-19 Vaccine AstraZeneca (AZ)
  30. Netherlands halts use of AstraZeneca COVID-19 vaccine (Reuters)
  31. Why did a German newspaper insist the Oxford AstraZeneca vaccine was inefficacious for older people—without evidence? (BMJ)
  32. WHO panel recommends AstraZeneca vaccine for adults 65 and older (ABC News)
  33. Covid-19: Fact-checking Macron's over-65s claim about the Oxford-AstraZeneca vaccine (BBC)
  34. NIAID Statement on AstraZeneca Vaccine (United States National Institutes of Health)
  35. Update following statement by NIAID on AZD1222 US Phase III trial data (AstraZeneca)
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  37. AZD1222 US Phase III primary analysis confirms safety and efficacy (AstraZeneca)

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