August 31, 2020
People 18 years of age and older who are interested in participating in this trial can visit coronaviruspreventionnetwork.org or ClinicalTrials.gov and search identifier NCT04516746 for details. Please do not contact the NIAID media phone number or email to enroll in this trial.
A multi-site, Phase 3 clinical trial evaluating an investigational COVID-19 vaccine known as AZD1222 has begun. The trial will enroll approximately 30,000 adult volunteers at 80 sites in the United States to evaluate if the candidate vaccine can prevent symptomatic coronavirus disease 2019 (COVID-19). The United Kingdom-based global biopharmaceutical company AstraZeneca is leading the trial as regulatory sponsor. The National Institute of Allergy and Infectious Diseases (NIAID), 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 trial.
“Safe and effective vaccines will be essential to meet the global need for widespread protection against COVID-19,” said NIAID Director Anthony S. Fauci, M.D. “Positive results from preclinical research led by NIH scientists supported the rapid development of this vaccine candidate, which has also showed promise in early-stage clinical trials.”
The Phase 3 trial is being implemented as part of Operation Warp Speed, a multi-agency collaboration led by HHS that aims to accelerate the development, manufacturing and distribution of medical countermeasures for COVID-19. The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership also guided the development of the trial protocol to ensure a coordinated approach across multiple vaccine efficacy trials. NIH experts have emphasized the importance of a harmonized process to generate data for multiple investigational vaccines in parallel to assess the relative effectiveness of each.
“NIH is committed to supporting several Phase 3 vaccine trials to increase the odds that one or more will be effective in preventing COVID-19 and put us on the road to recovery from this devastating pandemic,” said NIH Director Francis S. Collins, M.D., Ph.D. “We also know that preventing this disease could require multiple vaccines and we’re investing in those that we believe have the greatest potential for success.”
Oxford University’s Jenner Institute and Oxford Vaccine Group developed AZD1222. The candidate vaccine was licensed to AstraZeneca for further development. The vaccine uses a non-replicating chimpanzee adenovirus to deliver a SARS-CoV-2 spike protein to induce an immune response. SARS-CoV-2 is the virus that causes COVID-19.
Scientists at NIAID’s Rocky Mountain Laboratories (RML), based in Hamilton, Montana, conducted a preclinical study of AZD1222. Their findings—recently published in Nature—indicate the candidate vaccine rapidly induced immune responses against SARS-CoV-2 in mice and rhesus macaques. A single dose of the vaccine protected six rhesus macaques from pneumonia caused by the virus. Based on the RML data, a Phase 1 trial of the candidate vaccine began on April 23 in healthy volunteers in the U.K. Investigators recently reported promising results in The Lancet. Currently, the vaccine candidate is being evaluated in Phase 2/3 trials in the U.K. and Brazil and in a Phase 1/2 trial in South Africa.
The NIAID COVID-19 Prevention Network (CoVPN) will participate in the Phase 3 clinical trial of AZD1222 in the U.S. The CoVPN is composed of existing NIAID-supported clinical research networks with infectious disease expertise and is designed for efficient and thorough evaluation of vaccine candidates and monoclonal antibodies for the prevention of COVID-19.
Ann R. Falsey, M.D., professor of medicine, University of Rochester School of Medicine in New York, and Magdalena E. Sobieszczyk, M.D., associate professor of medicine at Columbia University Medical Center in New York, will serve as coordinating investigators for the trial.
Volunteers 18 years and older are eligible and must provide informed consent to participate in the trial. Participants will be randomly assigned to the investigational vaccine group or the placebo group, and neither the investigators nor the participants will know who is assigned to which group. After an initial screening, participants will receive two injections of either the investigational vaccine or a saline placebo approximately four weeks apart. One person will receive a placebo injection for every two people who receive AZD1222, which will result in approximately 20,000 people receiving the investigational vaccine and 10,000 people receiving a placebo.
The trial primarily is designed to determine if AZD1222 can prevent symptomatic COVID-19 after two doses. The trial also will evaluate if the vaccine candidate can prevent SARS-CoV-2 infection regardless of symptoms and if it can prevent severe COVID-19. It also will assess if the experimental vaccine can reduce the incidence of emergency department visits due to COVID-19.
Participants will be closely monitored, particularly after injections, for safety and reactogenicity, which refers to symptoms—usually mild and self-limiting—that can occur after vaccination. Investigators will evaluate participants after each vaccination and will ask participants to record any symptoms after returning home as well. An independent Data and Safety Monitoring Board (DSMB) will provide oversight to ensure the safe and ethical conduct of the study.
Participants will be followed for two years after their second vaccination. They will be asked to provide blood and nasopharyngeal samples at their initial visit and will be asked to provide blood samples periodically for the duration of the trial. Scientists will examine the blood samples in the laboratory to measure and characterize immune responses. The severity of the disease observed will be measured and used to assess the activity of the investigational vaccine.
Participants suspected to have COVID-19 will be asked to undergo a nasal and nasopharyngeal swab for testing. Participants who test positive for SARS-CoV-2 infection will be followed closely and referred for medical care if symptoms worsen.
NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.
About the COVID-19 Prevention Network: The COVID-19 Prevention Network (CoVPN) was formed by the National Institute of Allergy and Infectious Diseases (NIAID) at the U.S. National Institutes of Health to respond to the global pandemic. Through the CoVPN, NIAID is leveraging the infectious disease expertise of its existing research networks and global partners to address the pressing need for vaccines and antibodies against SARS-CoV-2. CoVPN will work to develop and conduct studies to ensure rapid and thorough evaluation of vaccines and antibodies for the prevention of COVID-19. The CoVPN is headquartered at the Fred Hutchinson Cancer Research Center. For more information about the CoVPN, visit: coronaviruspreventionnetwork.org.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
About HHS, ASPR, and BARDA: HHS works to enhance and protect the health and well-being of all Americans, providing for effective health and human services and fostering advances in medicine, public health, and social services. The mission of ASPR is to save lives and protect Americans from 21st century health security threats. Within ASPR, BARDA invests in the innovation, advanced research and development, acquisition, and manufacturing of medical countermeasures – vaccines, drugs, therapeutics, diagnostic tools, and non-pharmaceutical products needed to combat health security threats. To date, BARDA-supported products have achieved 55 FDA approvals, licensures or clearances. To learn more about federal support for the nationwide COVID-19 response, visit www.coronavirus.gov.
Phase 3 Clinical Testing in the U.S. of AstraZeneca COVID-19 Vaccine Candidate Begins
Please visit ClinicalTrials.gov and search identifier NCT04516746 to see all study locations. Thirty-one trial sites are part of the NIH-funded CoVPN, 46 sites are BARDA-funded, and 3 sites are supported by the U.S. Department of Defense.
A working group led by experts from NIAID, CoVPN and the Department of Defense is using county-level COVID-19 public health data with incidence trajectory modeling, and information about essential facilities, to identify high-incidence areas and emerging hot zones so that sites near these locations are prioritized for enrollment.
Healthy adults 18 years and older are eligible to participate in the trial. Randomization will be stratified based on age: those who are 18 to 64 years and those who are 65 years and older, with at least 25% of participants to be enrolled in the older age category. People with medically stable chronic diseases are also eligible to participate in the trial, including people with HIV who are on antiretroviral therapy. People with certain health conditions, current SARS-CoV-2 infection or a history of laboratory-confirmed SARS-CoV-2 infection cannot participate in the trial; however, people who were unknowingly infected with SARS-CoV-2 previously—confirmed through blood tests done as part of the trial—may participate. Women who are pregnant or breastfeeding may not participate in the trial.
The NIAID-funded COVID-19 Prevention Network (CoVPN) is working with stakeholders to reach priority populations, including Native Americans, Black Americans (including African Americans), the Latinx community, people who are at higher risk of exposure to SARS-CoV-2 infection due to occupation, people with pre-existing health conditions, people living in assisted living facilities and communities experiencing health disparities. This community engagement effort encompasses community education, recruitment and retention. The CoVPN engagement team aims to build and maintain relationships with experts working with these groups and with community leaders, such as faith-based leaders, grass roots organizations and trade unions. They are holding listening sessions and virtual town halls to build trust in these populations. The CoVPN engagement team also is convening expert panels of scientists who are from and have experience working with priority populations to discuss the trial protocol and generate reports on significance, impact and ethics for specific priority populations.
People can say yes or no when invited to join a study. All study volunteers must go through a process called informed consent that ensures they understand potential risks and benefits of being in a study. They also may leave a study at any time. The COVID-19 Prevention Network (CoVPN) makes every effort to ensure that people understand the study fully before they decide whether or not to join. The Phase 3 trial of AZD1222 follows U.S. federal regulations on research, as well as international ethical standards.
The “Operation Warp Speed” program aims to accelerate the typical vaccine development process by initiating large-scale manufacturing alongside highly coordinated clinical research to ensure timely scale up once safe and effective candidates are identified. The program will not cut corners on vaccine safety or trial integrity.
The DSMB is an independent advisory group with expertise in ethics, statistics, vaccine development, patient care and clinical trials that advise a group composed of the study sponsor, NIAID and BARDA. The DSMB reviews interim and final data on safety and efficacy and makes recommendations to the sponsor regarding whether a protocol should be amended, or the study should proceed based on its review. The DSMB can recommend the study be terminated at any time if deemed necessary. All Phase 3 clinical trials of candidate vaccines for COVID-19 supported by Operation Warp Speed are overseen by a common DSMB developed in consultation with the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership.
The trial protocol and related materials also have been reviewed by the U.S. Food and Drug Administration and an Institutional Review Board (IRB). The purpose of an IRB is to ensure the rights and welfare of human research participants.
Trial statisticians estimate that 30,000 people will be needed for a high probability of detecting a statistically significant percent reduction in disease incidence in the vaccinated group compared to the unvaccinated placebo group. The target of 30,000 is calculated based on the estimated risk of symptomatic COVID-19 to trial participants; however, the final study size will depend on the actual proportion of people who develop COVID-19.
The U.S. Food and Drug Administration has published guidance for industry for the development and licensure of vaccines to prevent COVID-19. The document notes that FDA would expect that a COVID-19 vaccine candidate would prevent disease or decrease the severity of disease in at least 50% of people who are vaccinated (50% vaccine efficacy). The success criterion for the Phase 3 clinical trial of AZD1222 is statistically significant vaccine efficacy of at least 50%.
Symptomatic COVID-19 is defined as having SARS-CoV-2 infection and at least one respiratory symptom (pneumonia, shortness of breath or low oxygen requiring supplemental oxygen) or at least two of the following symptoms:
- New or worsening cough
- Muscle pain
- Vomiting and/or diarrhea
- Loss of smell and/or loss of taste
Severe or critical symptomatic COVID-19 is defined as having SARS-CoV-2 infection and any of the following:
- Clinical signs of severe systemic illness
- Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation, known as ECMO)
- Evidence of shock
- Significant acute renal, hepatic or neurologic dysfunction or
- Admission to an intensive care unit or death
Yes. The enzyme-linked immunosorbent assay (ELISA) can detect antibodies against a SARS-CoV-2 protein that is not present in the vaccine. Thus, the test will be able to differentiate between vaccine-induced immunity and natural infection.