NIH- and BARDA-Funded Trial Will Enroll Up to 30,000 Volunteers
December 28, 2020
People 18 years of age and older who are interested in participating in this trial can visit coronaviruspreventionnetwork.org, ClinicalTrials.gov and search identifier NCT04611802, or Novavax.com/PREVENT-19 for details. Please do not contact the NIAID media phone number or email to enroll in this trial.
The Phase 3 trial of another investigational coronavirus disease 2019 (COVID-19) vaccine has begun enrolling adult volunteers. The randomized, placebo-controlled trial will enroll approximately 30,000 people at approximately 115 sites in the United States and Mexico. It will evaluate the safety and efficacy of NVX-CoV2373, a vaccine candidate developed by Novavax, Inc., of Gaithersburg, Maryland. Novavax is leading the trial as the regulatory sponsor. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, are funding the trial.
“Addressing the unprecedented health crisis of COVID-19 has required extraordinary efforts on the part of government, academia, industry and the community,” said NIAID Director Anthony S. Fauci, M.D. “The launch of this study—the fifth investigational COVID-19 vaccine candidate to be tested in a Phase 3 trial in the United States—demonstrates our resolve to end the pandemic through development of multiple safe and effective vaccines.”
The trial is being conducted in collaboration with Operation Warp Speed (OWS), a multi-agency collaboration overseen by HHS and the Department of Defense that aims to accelerate development, manufacture and distribution of medical countermeasures for COVID-19. Some of the U.S. trial sites participating are part of the NIAID-supported COVID-19 Prevention Network (CoVPN). The CoVPN includes existing NIAID-supported clinical research networks with infectious disease expertise and was designed for rapid and thorough evaluation of vaccine candidates and monoclonal antibodies for preventing COVID-19.
Volunteers will be asked to give informed consent prior to their participation in the trial. They will be grouped into two cohorts: individuals 18 through 64 years old and those aged 65 and older, with a goal of enrolling at least 25% of all volunteers who are 65 years old or older. Trial organizers also are emphasizing recruitment of people who are at higher risk of severe COVID-19 disease, including those who are Black (including African Americans), Native American, or of Latino or Hispanic ethnicity, and people who have underlying health conditions such as obesity, chronic kidney disease or diabetes.
“We’ve come this far, this fast, but we need to get to the finish line,” said NIH Director Francis S. Collins, M.D., Ph.D. “That will require multiple vaccines using different approaches to ensure everyone is protected safely and effectively from this deadly disease.”
After providing a baseline nasopharyngeal and blood sample, participants will be assigned at random to receive an intramuscular injection of either the investigational vaccine or a saline placebo. Randomization will be in a 2:1 ratio with two volunteers receiving the investigational vaccine for each one who receives placebo. Because the trial is blinded, neither investigators nor participants will know who is receiving the candidate vaccine. A second injection will be administered 21 days after the first.
Participants will be followed closely for potential vaccine side effects and will be asked to provide blood samples at specified time points after each injection and during the following two years. Scientists will analyze the blood samples to detect and quantify immune responses to SARS-CoV-2, the virus that causes COVID-19. Of note, specialized assays will be used to distinguish between immunity as a result of natural infection and vaccine-induced immunity. The trial’s primary endpoint is to determine whether NVX-CoV2373 can prevent symptomatic COVID-19 disease seven or more days after the second injection relative to placebo.
Novavax’s investigational vaccine, NVX-CoV2373, is made from a stabilized form of the coronavirus spike protein using the company’s recombinant protein nanoparticle technology. The purified protein antigens in the vaccine cannot replicate and cannot cause COVID-19. The vaccine also contains a proprietary adjuvant, MatrixM™. Adjuvants are additives that enhance desired immune system responses to vaccine. NVX-CoV2373 is administered in liquid form and can be stored, handled and distributed at above-freezing temperatures (35° to 46°F.) A single vaccine dose contains 5 micrograms (mcg) of protein and 50 mcg of adjuvant.
In animal tests, NVX-CoV2373 vaccination produced antibodies that blocked the coronavirus spike protein from binding to the cell surface receptors targeted by the virus, preventing viral infection. In results of a Phase 1 clinical trial published in the New England Journal of Medicine, NVX-CoV2373 was generally well-tolerated and elicited higher levels of antibodies than those seen in blood samples drawn from people who had recovered from clinically significant COVID-19. NVX-CoV2373 also is being evaluated in a Phase 2b trial in South Africa, now fully enrolled with 4,422 volunteers, and data from a Phase 1/2 continuation trial in the United States and Australia is expected as early as first quarter 2021. Novavax also recently completed enrollment of more than 15,000 volunteers in a Phase 3 trial of the candidate vaccine in the United Kingdom, which is also testing two injections of 5 mcg of protein and 50 mcg of Matrix-M adjuvant administered 21 days apart.
An independent Data and Safety Monitoring Board (DSMB) will provide oversight to ensure the safe and ethical conduct of the study. All Phase 3 clinical trials of candidate vaccines supported through OWS are overseen by a common DSMB developed in consultation with the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative.
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 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.
About Operation Warp Speed: OWS is a partnership among components of the Department of Health and Human Services and the Department of Defense, engaging with private firms and other federal agencies, and coordinating among existing HHS-wide efforts to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics.
About the National Institute of Allergy and Infectious Diseases: 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 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.
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Phase 3 Clinical Trial of Novavax Investigational COVID-19 Vaccine
Novavax, Inc., of Gaithersburg, Maryland is the regulatory sponsor. The regulatory sponsor is in charge of the trial and manages the trial data.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, are funding the trial as part of Operation Warp Speed.
The trial is enrolling volunteers at approximately 115 clinical research sites in the United States and Mexico. Please visit clinicaltrials.gov and search identifier NCT04611802 to see study locations.
Trial statisticians estimate that 30,000 people will be needed for there to be a high probability of detecting a statistically significant percent reduction in disease incidence in the vaccinated group compared to the unvaccinated placebo group. 30,000 is calculated based on the estimated risk of symptomatic COVID-19 to trial participants.
People 18 years of age and older who are considered at risk of exposure to and infection with SARS CoV-2 are eligible to participate in this trial. Randomization is stratified by age group (18 to 64 years and ≥ 65 years).
People with certain chronic conditions and well-controlled HIV are eligible to enroll. Please visit clinicaltrials.gov and search identifier NCT04611802 for more information
It is common practice to first evaluate the safety and efficacy of an investigational vaccine in adult volunteers before evaluating in children and pregnant women. As recommended by the Food and Drug Administration, preclinical assessments of potential developmental and reproductive toxicity to anticipate any safety concerns should be completed before beginning clinical evaluation in these populations. Then, safety and immunogenicity studies are conducted and the immune responses in those studies would be compared to the immune responses from efficacy studies (known as “immunobridging”).
Long-standing systemic health and social inequities have put many people from racial and ethnic minority groups at increased risk of getting sick and dying from COVID-19. Race and ethnicity are risk markers for other underlying conditions that impact health—including socioeconomic status, access to health care, and increased exposure to the virus due to occupation (e.g., frontline, essential, and critical infrastructure workers). According to the CDC, people who are Black and African American, Hispanic or Latino, American Indian or Alaska Native and Asian are more likely to die from COVID-19 or be hospitalized for infection than people who are white. It is important that U.S. clinical trials enroll volunteer populations that at least reflects the diversity of the U.S. population, or ideally—reflect the population of those at increased risk of COVID-19.
Novavax and the NIAID-funded COVID-19 Prevention Network (CoVPN) are working with stakeholders to reach priority populations, including Native Americans, Black Americans (including African Americans), the Hispanic and Latino communities, 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.
The NIH Community Engagement Alliance (CEAL) Against COVID-19 Disparities is conducting outreach and seeking input from communities to raise awareness about COVID-19 and to address misinformation and mistrust about the pandemic and efforts to combat it. CEAL also is working to ensure that COVID-19 prevention and treatment clinical trials include racially and ethnically diverse communities most affected by the pandemic.
The trial is designed to follow participants and collect safety and immunogenicity data for about two years. However, a trial can be temporarily paused or stopped due to strong evidence of efficacy, safety issues or futility. However, even if an efficacy “stopping point” is reached, the trial will continue to follow participants to gather additional safety data. Exactly how long it will take to generate enough data to determine the safety and efficacy of the vaccine candidate depends on the actual incidence of COVID-19 among study volunteers. The trial is event-driven, meaning that statisticians have estimated that 141 cases of COVID-19 among trial participants must be observed for a high probability of detecting a percent reduction in disease incidence in the vaccinated group compared to the placebo group that is not due to chance. The primary analysis of data occurs once this threshold of cases has been observed.
NVX CoV2373 is a protein subunit vaccine that contains a stabilized form of the SARS-CoV-2 spike protein using the company’s recombinant protein nanoparticle technology. Other COVID-19 vaccines under development are nucleic acid vaccines that deliver instructions for cells to make the protein, whereas protein subunit vaccines deliver the protein directly.
People can say yes or no when invited to join a study of a COVID-19 vaccine candidate. 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. Study sites make every effort to ensure that people understand the study fully before they decide whether to join. As part of the trial, medical staff regularly and closely monitor volunteers.
The trial adheres to U.S. federal regulations on research, as well as international ethical standards. The Food and Drug Administration reviewed the trial protocol and notified Novavax that they determined it is safe to proceed with this trial. The trial protocol and related materials have also been approved by an Institutional Review Board (IRB). The purpose of an IRB is to ensure the rights and welfare of human research participants. The trial also is overseen by a Data and Safety Monitoring Board (DSMB). The DSMB is an independent advisory group that reports to the study sponsor. The DSMB reviews data on safety and efficacy and writes 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 sponsor pause or terminate the study at any time if deemed necessary for safety. The DSMB for this trial is a multi-disciplinary team formed by NIAID that is also overseeing additional Phase 3 COVID-19 vaccine trials supported by Operation Warp Speed.
It is important to continue to conduct rigorous trials of multiple types of COVID-19 vaccines to ensure we have an array of options. One-size-fits-all preventions do not always provide the best fit for everyone. COVID-19 vaccines initially available to certain priority populations are being authorized by the Food and Drug Administration under a mechanism known as Emergency Use Authorization (EUA). The issuance of an EUA is different than an FDA approval (licensure) of a vaccine. A vaccine available under emergency use authorization is still considered investigational. A placebo-controlled trial remains appropriate until a COVID-19 vaccine is approved for use and widely available in the U.S. At that point, a head-to-head clinical trial design comparing the investigational vaccine to the licensed vaccine would be appropriate.
Two-thirds of volunteers in the Phase 3 trial of NVX CoV2373 will receive the investigational vaccine. Should the vaccine show efficacy after interim or final analyses, placebo recipients will be offered the investigational vaccine.