Phase 3 Clinical Trial of Investigational Vaccine for COVID-19 Begins

Multi-Site Trial to Test Candidate Developed by Moderna and NIH

July 27, 2020

People 18 years of age and older who are interested in participating in this trial can visit https://www.coronaviruspreventionnetwork.org/ or ClinicalTrials.gov and search identifier NCT04470427 for details. Please do not contact the NIAID media phone number or email to enroll in this trial.  

A Phase 3 clinical trial designed to evaluate if an investigational vaccine can prevent symptomatic coronavirus disease 2019 (COVID-19) in adults has begun. The vaccine, known as mRNA-1273, was co-developed by the Cambridge, Massachusetts-based biotechnology company Moderna, Inc., and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The trial, which will be conducted at U.S. clinical research sites, is expected to enroll approximately 30,000 adult volunteers who do not have COVID-19.

“Although face coverings, physical distancing and proper isolation and quarantine of infected individuals and contacts can help us mitigate SARS-CoV-2 spread, we urgently need a safe and effective preventive vaccine to ultimately control this pandemic,” said NIAID Director Anthony S. Fauci, M.D. “Results from early-stage clinical testing indicate the investigational mRNA-1273 vaccine is safe and immunogenic, supporting the initiation of a Phase 3 clinical trial. This scientifically rigorous, randomized, placebo-controlled trial is designed to determine if the vaccine can prevent COVID-19 and for how long such protection may last.”

Moderna is leading the trial as the regulatory sponsor and is providing the investigational vaccine for the trial. The Biomedical Advanced Research and Development Authority (BARDA), of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response and NIAID are providing funding support for the trial. The vaccine efficacy trial is the first to be implemented under 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. 

“Having a safe and effective vaccine distributed by the end of 2020 is a stretch goal, but it’s the right goal for the American people,” said NIH Director Francis S. Collins, M.D., Ph.D. “The launch of this Phase 3 trial in record time while maintaining the most stringent safety measures demonstrates American ingenuity at its best and what can be done when stakeholders come together with unassailable objectivity toward a common goal.”

The NIH Coronavirus Prevention Network (CoVPN) will participate in conducting the trial. The network brings together expertise from existing NIAID-supported clinical research networks. The mRNA-1273 vaccine candidate will be tested at approximately 89 clinical research sites in the United States, 24 of which are part of the CoVPN. Investigators will use public health data and incidence trajectory modeling to identify sustained high-incidence areas and emerging hot zones, so sites near these locations can be prioritized for enrollment.

“Thanks to President Trump’s leadership and the hard work of American scientists, the investigational vaccine developed by NIH and Moderna has reached this Phase 3 trial at record pace,” said HHS Secretary Alex Azar. “Operation Warp Speed is supporting a portfolio of vaccines like the NIH/Moderna candidate so that, if the results of clinical trials meet FDA’s gold standard, these products can reach Americans without a day’s delay.”

NIAID scientists developed the stabilized SARS-CoV-2 spike immunogen (S-2P). SARS-CoV-2 is the virus that causes COVID-19; the spike protein on its surface facilitates entry into a cell. Moderna’s mRNA-1273 uses the mRNA (messenger RNA) delivery platform to encode for an S-2P immunogen. The investigational vaccine directs the body’s cells to express the spike protein to elicit a broad immune response. A Phase 1 clinical trial found the candidate vaccine to be safe, generally well-tolerated and able to induce antibodies with high levels of virus-neutralizing activity. Moderna initiated Phase 2 testing of the vaccine in May 2020.  

Hana M. El Sahly, M.D., principal investigator of the NIAID-funded Infectious Diseases Clinical Research Consortium site at Baylor College of Medicine in Houston; Lindsey R. Baden, M.D., principal investigator of the NIAID-funded Harvard HIV Vaccine Clinical Trials Unit at Brigham and Women’s Hospital in Boston; and Brandon Essink, M.D., principal investigator and medical director of Meridian Clinical Research, will serve as co-principal investigators for the Phase 3 trial of mRNA-1273.

As part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership, NIH and other HHS agencies and government partners, in collaboration with representatives from academia, philanthropic organizations, and numerous biopharmaceutical companies, advised on the trial protocol design and endpoints to ensure a harmonized approach across multiple vaccine efficacy trials.

The trial is designed to evaluate the safety of mRNA-1273 and to determine if the vaccine can prevent symptomatic COVID-19 after two doses. As secondary goals, the trial also aims to study whether the vaccine can prevent severe COVID-19 or laboratory-confirmed SARS-CoV-2 infection with or without disease symptoms. The trial also seeks to answer if the vaccine can prevent death caused by COVID-19 and whether just one dose can prevent symptomatic COVID-19, among other objectives. 

Trial volunteers will receive two intramuscular injections approximately 28 days apart. Participants will be randomly assigned 1:1 to receive either two 100 microgram (mcg) injections of mRNA-1273 or two shots of a saline placebo. The trial is blinded, so the investigators and the participants will not know who is assigned to which group.

Volunteers must provide informed consent to participate in the trial. They will be asked to provide a nasopharyngeal swab and a blood sample at an initial screening visit and additional blood samples at specified time points after each vaccination and over the two years following the second vaccination. Scientists will examine blood samples in the laboratory to detect and quantify immune responses to SARS-CoV-2. 

Investigators will closely monitor participant safety. They will call participants after each vaccination to discuss any symptoms and will provide participants with a diary to record symptoms and a thermometer for temperature readings. 

If a participant is suspected to have COVID-19, the participant will be asked to provide a nasal swab for testing within 72 hours. If the test is positive for SARS-CoV-2 infection, the participant will be followed closely and referred for medical care if symptoms worsen. Participants will be asked to provide a daily assessment of symptoms through resolution and have saliva sampled periodically, so investigators can test for SARS-CoV-2 infection.

Study investigators will regularly review trial safety data. An independent data and safety monitoring board (DSMB) will review blinded and unblinded data—including safety data and cases of COVID-19 in both groups—at scheduled data review meetings.

Adults who are interested in joining this study can visit Coronaviruspreventionnetwork.org or visit ClinicalTrials.gov and search identifier NCT04470427 to find a study center to volunteer. ClinicalTrials.gov includes a complete listing of study locations.
 

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Questions & Answers

Phase 3 Clinical Trial of Investigational Vaccine for COVID-19 mRNA-1273

Please visit ClinicalTrials.gov and search identifier NCT04470427 to see all study locations.

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.

People 18 years of age and older are eligible to participate in the trial. Randomization will be stratified based on age: those who are 18 to 65 years and those who are 65 years and older. Of those ages 18 to 65 years, randomization will be stratified by health status: people with certain pre-existing health issues such as chronic lung disease, cardiac diseases, obesity, diabetes, and liver cancer and people who do not have any of these health issues. People over the age of 65 and people of any age with certain health issues are at higher risk for complications of COVID-19. Randomization is stratified based on these criteria to ensure one group does not have a significantly younger or healthier population compared to the other. 

People under the age of 18 years, people with a known history of COVID-19, people who are pregnant or breastfeeding, people who are ill or have a fever three days before or at screening or vaccination visits, people who have a compromised immune system, and people who have had a significant adverse reaction to vaccination in the past (such as a severe allergic reaction) will be ineligible to participate in the trial at this time. 

The NIAID-funded COVID-19 Prevention Network (CoVPN) is working with stakeholders to implement a community engagement plan 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. Community engagement is an umbrella term that 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 influencers, 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.

Unlike guinea pigs, people can say yes or no about joining 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 are reminded that they may leave a study at any time without losing any of their rights or benefits. The COVID-19 Prevention Network (CoVPN) makes every effort to ensure people understand the study fully before they decide whether or not to join. The Phase 3 trial of mRNA-1273 follows U.S. federal regulations on research, as well as international ethical standards and any country-specific requirements for the countries where the research is conducted.

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.

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; 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 would prevent disease or decrease its severity in at least 50% of people who are vaccinated (50% vaccine efficacy). The Phase 3 clinical trial of the mRNA-1273 vaccine candidate is designed to detect a target vaccine efficacy of 60%.  

Investigators anticipate that the trial will take approximately three months to enroll 30,000 volunteers. However, since the trial is testing a two-shot regimen with about one month in between shots, some participants may not receive their second shot until the end of November 2020. It is difficult to predict exactly how long it will take to generate enough data to determine the efficacy of the vaccine candidate since this is dependent on the actual incidence, distribution and control of SARS-CoV-2.

Symptomatic COVID-19 is defined as having SARS-CoV-2 infection and either two systemic symptoms (such as fever, chills, headache, or sore throat) or at least one respiratory symptom (cough, shortness of breath, or pneumonia).

Severe COVID-19 is defined as having SARS-CoV-2 infection and one of the following:

  • Clinical signs of severe systemic illness, or
  • Requirement for high-flow oxygen, non-invasive or mechanical ventilation, or ECMO, or
  • Significant acute renal, hepatic or neurologic dysfunction or 
  • Admission to an intensive care unit or death

Participants will not receive a second shot should they become infected in between vaccinations. For participants in whom COVID-19 is suspected, vaccination will be held until test results are available.

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.

Data on side effects and immune responses at various vaccine dosages from the Phase 1 and 2 clinical trials were used to select the dose for the Phase 3 study. The 100 microgram (mcg) dose is generally well-tolerated and shows levels of neutralizing activity at or above convalescent sera.

The Food and Drug Administration reviewed the trial protocol and notified Moderna 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). All U.S. sites in this trial use a single IRB (Advarra). The purpose of an IRB is to ensure the rights and welfare of human research participants.

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 terminate the study at any time if deemed necessary for safety. The DSMB for this trial is a multi-disciplinary team developed in consultation with the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership.

NIAID and Moderna co-developed and tested the vaccine, which combines Moderna’s proprietary mRNA delivery platform with the stabilized spike protein from SARS-CoV-2. Accordingly, the vaccine includes components for which several organizations, including the US Government and Moderna, either have or are seeking patent protection. The vaccine product is Moderna’s, and Moderna—like any entity seeking to manufacture and sell a vaccine or pharmaceutical product—is solely responsible for securing regulatory approval for its product. 

NIAID is seeking patent protection for the stabilized spike protein technology to preserve the US Government’s rights in this invention and to provide incentive for commercial partners to invest the capital and resources needed to advance their development, commercialization, and public use as vaccines. NIAID has adopted a non-exclusive licensing approach for these rights in order to allow multiple vaccine developers to utilize these immunogens in their proprietary vaccine platforms. NIH model license agreements are available at: https://www.ott.nih.gov/resources#MLA.