As part of the U.S. government’s response to the COVID-19 pandemic, NIAID is conducting and supporting clinical research to prevent, treat, and better understand the respiratory illness. These efforts are made possible by the generous contributions of clinical research volunteers and are complemented by additional clinical research studies across the globe. They include clinical trials evaluating therapeutics and vaccine candidates against SARS-CoV-2, the novel coronavirus that causes COVID-19, as well as studies of people who have recovered from infection.

Organizational and Funding Approaches

Operation Warp Speed

Operation Warp Speed (OWS) is a partnership led by the U.S. Department of Health and Human Services (HHS) to invest in and coordinate the development, manufacturing, and distribution of COVID-19 diagnostics, therapeutics, and vaccines.

Notably, OWS will manufacture promising candidate vaccines at an industrial scale concurrent to the efficacy and safety Phase 3 trials.  Once safe and effective candidates are identified, OWS will be prepared to quickly implement a distribution plan.

NIAID is engaging established clinical trial networks to support OWS.

Accelerating COVID Therapeutic Interventions and Vaccines

On April 17, 2020, NIH announced the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership to develop a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines.

Coordinated by the Foundation for the National Institutes of Health (FNIH), ACTIV brings together NIH and other HHS organizations, including the Biomedical Advanced Research and Development Authority (BARDA), Centers for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA); other government agencies including the Department of Defense (DOD) and Department of Veterans Affairs (VA); the European Medicines Agency (EMA); and representatives from academia, philanthropic organizations, and numerous biopharmaceutical companies.

Leveraging HIV/AIDS Clinical Trial Networks

NIAID has established the COVID-19 Prevention Network (CoVPN) by merging four existing NIAID-funded clinical trials networks:

• HIV Vaccine Trials Network (HVTN), based in Seattle, WA
• HIV Prevention Trials Network (HPTN), based in Durham, NC
• Infectious Diseases Clinical Research Consortium (IDCRC), based in Atlanta, GA
• AIDS Clinical Trials Group, based in Los Angeles, CA

While continuing to perform clinical trials for vaccines and preventions for HIV and other infectious diseases, the network will use already existing structures and processes in their new COVID-19 roles. For example, the network has an established, extensive community engagement framework to reach out to potential research volunteers and explain the specific details involved in participating in a vaccine or monoclonal antibody clinical study.

CoVPN is a functional unit of OWS. The network will use a harmonized vaccine protocol developed by the ACTIV public-private partnership. This will enable analyses of correlates of protection across multiple vaccine trials. The network is expected to operate more than 100 clinical trial sites across the United States and internationally.

News Release: NIH Launches Clinical Trials Network To Test COVID-19 Vaccines and Other Prevention Tools – July 8, 2020

Vaccine Clinical Trials

NIAID is funding clinical trials ensuring the safety and efficacy of two vaccine candidates. Trials are being implemented as part of the multi-agency Operation Warp Speed. The public-private partnership, Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) also guides the development of the trial protocols to ensure a coordinated approach across multiple vaccine efficacy trials.

Clinical Trials of mRNA-1273

Based on promising results from early-stage clinical testing, the mRNA-1273 vaccine moved to Phase 3 clinical testing in late July, 2020. 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.

The trial, which is being conducted at U.S. clinical research sites, is expected to enroll approximately 30,000 adult volunteers who do not have COVID-19. The NIAID COVID-19 Prevention Network (CoVPN) will participate in conducting the trial. 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.

More information about the Phase 1 trial and Phase 3 trial can be found on ClinicalTrials.gov.

News Releases:

• NIH-Moderna Investigational COVID-19 Vaccine Shows Promise in Mouse Studies – August 5, 2020
• Experimental COVID-19 Vaccine Protects Upper and Lower Airways in Nonhuman Primates – July 28, 2020
• Phase 3 Clinical Trial of Investigational Vaccine for COVID-19 Begins – July 27, 2020
• Experimental COVID-19 Vaccine Safe, Generates Immune Response – July 14, 2020

Clinical Trials of AZD1222

Scientists at NIAID’s Rocky Mountain Laboratories (RML), based in Hamilton, Montana, conducted a preclinical study of AZD1222. Their findings—published in Nature —indicate that 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, 2020 in healthy volunteers in the United Kingdom. Investigators reported promising results in The Lancet. Currently, the vaccine candidate is being evaluated in Phase 2/3 trials in the United Kingdom and Brazil and in a Phase 1/2 trial in South Africa.

In early September 2020, a Phase 3 clinical trial evaluating AZD1222 began primarily 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.

The Phase 3 trial will enroll approximately 30,000 adult volunteers at 80 sites in the United States through the CoVPN.

The United Kingdom-based global biopharmaceutical company AstraZeneca is leading the trial as regulatory sponsor. NIAID and the Biomedical Advanced Research and Development Authority (BARDA), part of the HHS Office of the Assistant Secretary for Preparedness and Response, are providing funding support for the trial.

News Release:

• Phase 3 Clinical Testing in the U.S. of AstraZeneca COVID-19 Vaccine Candidate Begins – August 31, 2020
• Investigational ChAdOx1 nCoV-19 Vaccine Protects Monkeys Against COVID-19 Pneumonia – May 15, 2020

Prevention Clinical Trials

Monoclonal Antibodies To Prevent COVID-19 Infection

Two trials being conducted through CoVPN will test monoclonal antibodies for their ability to prevent COVID-19 in uninfected adults who are at high risk of acquiring SARS-CoV-2 due to living or working with infected individuals. One trial will test REGN-COV-2, a monoclonal combination supplied by Regeneron Pharmaceuticals, and a second trial will test a monoclonal antibody (LY-CoV555) made by Eli Lilly and Company.

More information about the trial using REGN-COV-2 and about the Lilly monoclonal trial are available at clinicaltrials.gov.

News Release: Clinical Trials of Monoclonal Antibodies To Prevent COVID-19 Now Enrolling – August 10, 2020

Treatment Clinical Trials

Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) Trial

The ITAC trial began on October 8, 2020 to test the safety, tolerability and efficacy of a treatment regimen consisting of the antiviral remdesivir plus a highly concentrated solution of antibodies that neutralize SARS-CoV-2, the virus that causes COVID-19. The study is taking place in hospitalized adults with COVID-19 in the United States, Mexico and 16 other countries on five continents. The antibody solution being tested in the trial is anti-coronavirus hyperimmune intravenous immunoglobulin, or hIVIG. The ITAC investigators hypothesize that giving people anti-coronavirus hIVIG at the onset of COVID-19 symptoms, before the body makes a protective immune response on its own, could augment the natural antibody response to SARS-CoV-2, thereby reducing the risk of more serious illness and death.

More information about the ITAC trial is available at ClinicalTrials.gov.

News Release: NIH Clinical Trial Testing Hyperimmune Intravenous Immunoglobulin Plus Remdesivir to Treat COVID-19 Begins

Accelerating COVID Therapeutic Interventions and Vaccines-2 (ACTIV-2)

This Phase 2 clinical trial, known as ACTIV-2, will evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the disease.

The trial, led by the NIAID-funded AIDS Clinical Trials Group (ACTG), is working to identify potential patient volunteers around the world currently infected with SARS-CoV-2 who have mild to moderate disease not requiring hospitalization. Volunteers will be invited to take an experimental therapy or a placebo as part of a rigorously designed randomized clinical trial. The trial also may investigate other experimental therapeutics later under the same trial protocol.

More information about ACTIV-2 can be found at ClinicalTrials.gov.

News Release: NIH Clinical Trial To Test Antibodies and Other Experimental Therapeutics for Mild and Moderate COVID-19 – August 4, 2020

Accelerating COVID Therapeutic Interventions and Vaccines-3 (ACTIV-3)

This Phase 3 randomized, controlled trial, known as ACTIV-3, uses an adaptive two-stage Phase 3 protocol design. The ACTIV-3 trial can be modified to test additional experimental therapeutics and flexibly allow novel therapeutics to enter at either Phase 1 or Phase 2. In addition, if a treatment appears to be safe and effective in the initial stage after review by an independent data and safety monitoring board (DSMB), the investigational therapeutic proceeds to Phase 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped.

The ACTIV-3 study will begin by studying the investigational monoclonal antibody LY-CoV555, which was identified in a blood sample from a recovered COVID-19 patient. The LY-CoV555 antibody was discovered by AbCellera Biologics (Vancouver, British Columbia) in collaboration with NIAID’s Vaccine Research Center. Subsequently, it was developed and manufactured by Lilly Research Laboratories, Eli Lilly and Company (Indianapolis, Indiana), in partnership with AbCellera. The investigational product also is being tested in another ongoing NIAID study, ACTIV-2, which is studying its safety and efficacy in people with mild to moderate symptoms of COVID-19 who have not been hospitalized. Safety data and other findings will be shared across the ACTIV-2 and ACTIV-3 studies through the DSMB.

More information about ACTIV-3 can be found at ClinicalTrials.gov.

News Release: NIH Launches Clinical Trial to Test Antibody Treatment in Hospitalized COVID-19 Patients - August 4, 2020

The Adaptive COVID-19 Treatment Trial (ACTT)

A randomized, controlled clinical trial to evaluate the safety and efficacy of the investigational antiviral drug remdesivir in adults hospitalized with COVID-19 began in February 2020 at sites throughout the United States and around the world and closed to enrollment on April 19, 2020, with 1,063 participants. The trial, known as ACTT, compared daily investigational treatment of remdesivir delivered intravenously to a placebo control. Remdesivir is an investigational broad-spectrum antiviral treatment developed by Gilead Sciences, Inc. Initial results from the study show that remdesivir accelerates recovery from COVID-19.

The next iteration of ACTT (ACTT-2) began on May 8, 2020, and is evaluating the safety and efficacy of a treatment regimen of remdesivir plus the anti-inflammatory drug baricitinib, which is approved in the United States and other countries as a treatment for rheumatoid arthritis. Taken orally, the drug inhibits cytokine signaling in the body that plays a role in causing inflammatory responses. Participants in this trial are receiving remdesivir or remdesivir with baricitinib.

The third iteration of ACTT (ACTT-3) began on August 5, 2020, and is evaluating the safety and efficacy of a treatment regimen consisting of remdesivir plus the immunomodulator interferon beta-1a. Trial participants are receiving either remdesivir or remdesivir plus subcutaneous interferon beta-1a. Subcutaneous interferon beta-1a is approved in the United States and more than 90 other countries for the treatment of multiple sclerosis and is marketed under the brand name Rebif. Interferon beta-1a has the same amino acid sequence as a naturally occurring protein called interferon beta, which is part of a class of proteins called type 1 interferons. Infected cells normally produce type 1 interferons to help the immune system fight pathogens, especially viruses.

More information about ACTT, ACTT-2 and ACTT-3 can be found at ClinicalTrials.gov.

News Releases:

• Statement—Fourth Iteration of COVID-19 Treatment Trial Underway– November 25, 2020
• NIH Clinical Trial Testing Remdesivir Plus Interferon Beta-1a for COVID-19 Treatment Begins – August, 05, 2020
• Peer-Reviewed Data Shows Remdesivir for COVID-19 Improves Time to Recovery – May  22, 2020
• NIH Clinical Trial Testing Antiviral Remdesivir Plus Anti-Inflammatory Drug Baricitinib for COVID-19 Begins - May 08, 2020

Evaluating the Efficacy of Hydroxychloroquine and Azithromycin To Prevent Hospitalization or Death in Persons With COVID-19

This Phase 2b trial aimed to determine whether a short course of hydroxychloroquine and azithromycin could safely and effectively prevent disease progression among adults with mild to moderate COVID-19.

Although recent research suggests that hydroxychloroquine may not be an effective treatment for patients hospitalized with COVID-19, the question of whether it offers benefit when given early in the course of the disease remains unanswered. The NIAID study, conducted by the AIDS Clinical Trials Group (ACTG), sought to fill this knowledge gap by testing it in a randomized, placebo-controlled trial—considered the gold standard for determining whether an intervention can benefit patients.

The study, conducted at sites across the United States, planned to rapidly enroll approximately 2,000 adults who had laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19, and were experiencing symptoms consistent with COVID-19. Participants were randomly assigned to receive either hydroxychloroquine and azithromycin or matching placebo pills to take at home for seven days. However, since its launch in May, the study had enrolled only 20 participants, despite efforts by the study sites to enhance recruitment, raising concerns that it would not be feasible to continue the trial to full enrollment.

On June 15, 2020, the FDA revoked an Emergency Use Authorization that had allowed hydroxychloroquine and the related drug chloroquine to be prescribed to hospitalized adolescents and adults with COVID-19. This revocation does not apply to clinical trials and is specific to hospitalized individuals rather than outpatients. However, the decision could have further dampened enthusiasm for enrollment in studies evaluating these drugs.

Based on these considerations and in close consultation with the study team, NIAID determined that it was highly unlikely that the trial would be able to enroll to completion and meet its intended objectives. The independent data and safety monitoring board (DSMB) concurred with this assessment and agreed it would be best to close the trial.

More information about A5395 can be found at ClinicalTrials.gov.

News Releases:

• NIH Clinical Trial Evaluating Hydroxychloroquine and Azithromycin for COVID-19 Closes Early – June 20, 2020
• NIH Begins Clinical Trial of Hydroxychloroquine and Azithromycin To Treat COVID-19 – May 14, 2020

Immune Response Clinical Trials

Characterizing Immune Responses in People With a History of Coronavirus Infection

An NIAID-supported study called HVTN 405/HPTN 1901 will describe immune responses to SARS-CoV-2 among people with a history of recovering from infection with the virus. This study also aims to develop antibody assays that can be reliably used in clinical research to detect immune responses to natural SARS-CoV-2 infection and distinguish them from responses to experimental vaccines and monoclonal antibodies against the virus. Information gathered in HVTN 405/HPTN 1901 will aid development of safe and effective vaccine and antibody interventions to prevent COVID-19.

More information can be found on the HVTN website.

COVID-19-Recovered Specimen Collection Research Study

Additional clinical research is underway to better understand the immune system’s response to SARS-CoV-2 in order to inform the development of medical countermeasures against COVID-19. In one such study, the NIAID Vaccine Research Center in Bethesda, Maryland, is collecting blood samples from adults 18 years of age or older who are fully recovered from confirmed COVID-19 infection.

More information on COVID-19 Recovered Specimen Collection Research Study can be found on ClinicalTrials.gov.

Study To Examine Immune Responses in People Hospitalized With COVID-19

An NIAID-supported study being conducted at 10 research sites across the United States will track the immune responses of people hospitalized with COVID-19. Investigators in NIAID's Human Immunology Project Consortium, in collaboration with researchers in the Asthma and Allergic Diseases Clinical Research Consortium, aim to determine how certain immunological measures correspond to, or may even predict, the clinical severity of COVID-19. Data collected in the Immunophenotyping Assessment in a COVID-19 Cohort, or IMPACC, study will help inform recommendations for COVID-19 care and, hopefully, identify new targets and optimal timing for experimental treatments.

More information on the Study To Examine Immune Responses in People Hospitalized With COVID-19 can be found on ClinicalTrials.gov.

Immune Response to COVID-19

Researchers in the Division of Intramural Research at NIAID are spearheading a large, international collaboration to unveil the innate and adaptive immune responses during acute COVID-19 infection and convalescence. This coalition of researchers will work with each other as well as with hospitals willing to share specimens and data to maximize the impact of patient samples. The overall goal is to identify immunological and virological correlates and predictors of clinical outcomes.

See more information on Immune Response to COVID-19.

Epidemiological Studies

Study To Quantify Undetected Cases of Coronavirus Infection

A study at the NIH Clinical Center in Bethesda, Maryland, aims to determine how many adults in the United States without a confirmed history of infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), have antibodies to the virus. The presence of antibodies in the blood indicates a prior infection. In this “serosurvey,” researchers will collect and analyze blood samples from as many as 10,000 volunteers to provide critical data for epidemiological models. The results will help illuminate the extent to which the novel coronavirus has spread undetected in the United States and provide insights into which communities and populations are most affected.

More information on the Study To Quantify Undetected Cases of Coronavirus Infection can be found on ClinicalTrials.gov.

Study To Determine Incidence of Novel Coronavirus Infection in U.S. Children

An NIAID-supported study is underway to help determine the rate of novel coronavirus infection in children and their family members in the United States. The study, called Human Epidemiology and Response to SARS-CoV-2 (HEROS), also will help determine what percentage of children infected with SARS-CoV-2, the virus that causes COVID-19, develop symptoms of the disease. In addition, the HEROS study will examine whether rates of SARS-CoV-2 infection differ between children who have asthma or other allergic conditions and children who do not.

Participants are being recruited for HEROS from families who are already participating in one of 13 ongoing, NIH-funded pediatric research studies. Families cannot volunteer for this study on their own.

Natural History Studies

The response team at the Integrated Research Facility in Frederick, Maryland, is actively engaged in the design of and support for multiple clinical studies. In partnership with PREVAIL in Liberia and PALM in the Democratic Republic of the Congo, the team is developing and implementing natural history studies to examine and analyze the progression to severe COVID-19 disease in these populations. These studies will also provide insight into the spread of disease in this region and aid the ability of partners in the region to respond to this pandemic. The team is also supporting the ACT international trial with preparation of critical laboratory reagents.