Emory University in Atlanta will begin enrolling healthy adult volunteers ages 18 to 55 years in a Phase 1 clinical trial of an investigational vaccine designed to prevent coronavirus disease 2019 (COVID-19).
Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit:NIAID
The trial, supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, began last week at Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. KPWHRI and Emory are part of NIAID’s Infectious Diseases Clinical Research Consortium.
The trial aims to enroll a total of 45 participants across the two sites. NIAID scientists and clinicians have been closely monitoring the outbreak of COVID-19 in Washington and throughout the United States. They decided to expand the trial to another geographic area to ensure efficient enrollment.
Evan Anderson, M.D., associate professor of pediatrics and medicine, and Nadine Rouphael, M.D., associate professor of medicine, will lead the study at Emory. Participants will receive two shots of the experimental vaccine approximately one month apart and will be followed for approximately one year. The vaccine, called mRNA-1273, was developed by scientists at NIAID’s Vaccine Research Center and the biotechnology company Moderna, Inc. The Coalition for Epidemic Preparedness Innovations (CEPI) supported the manufacturing of the vaccine candidate for the Phase 1 clinical trial.
An independent monitoring board has recommends the early termination of Ebola Therapeutics Trial in DRC Because of Favorable Results with Two of Four Candidates.
The
Pamoja Tulinde Maisha (PALM [together save lives]) study is a randomized,
controlled trial of four investigational agents (ZMapp, remdesivir, mAb114 and
REGN-EB3) for the treatment of patients with Ebola virus disease.
The
study began on November 20, 2018 in the Democratic Republic of the Congo (DRC)
as part of the emergency response to an ongoing Ebola outbreak in the North
Kivu and Ituri Provinces.
The
trial which enrolled 681 patients toward an enrollment total of 725 started in
August 9, 2019. Patients were enrolled at four Ebola Treatment Centers (ETCs)
in Beni, Katwa, Butembo and Mangina and the trial was overseen by staff from
the Institut National de Recherche Biomédicale (INRB); the DRC Ministry of
Health; and three medical humanitarian organizations: the Alliance for
International Medical Action (ALIMA), the International Medical Corps (IMC),
and Médecins Sans Frontières (MSF).
The trial is monitored by an independent Data and Safety Monitoring Board (DSMB) that meets periodically to review interim safety and efficacy data and to make recommendations to the study team and the sponsors.
As a result of their August 9, 2019 review, the DSMB recommended that the study be stopped and that all future patients be randomized to receive either REGN-EB3 or mAb114 in what is being considered an extension phase of the study.
This recommendation was based on the fact that an early stopping criterion in the protocol had been met by one of the products, REGN-EB3. The preliminary results in 499 study participants indicated that those individuals receiving REGN-EB3 or mAb114 had a greater chance of survival compared to those participants in the other two arms.
The
principal investigators of the study, its statistician and its co-sponsors
accepted this recommendation, and the ETC staff at the sites were promptly
informed. In addition to limiting future patient randomizations to REGN-EB3 and
mAb114, patients who were randomized to ZMapp or remdesivir in the last 10 days
now have the option, at the discretion of their treating physician, to receive
either REGN-EB3 or mAb114.
According to the US National Institute of Allergy and Infectious Diseases (NIAID), while the final analysis of the data can occur only after all the data are generated and collected (likely late September/early October 2019), the DSMB and the study leadership felt the preliminary analysis of the existing data was compelling enough to recommend and implement these changes in the trial immediately.
NIAD
states the complete results will be submitted for publication in the
peer-reviewed medical literature as soon as possible.
The
study is co-sponsored and funded by the INRB and the National Institute of
Allergy and Infectious Diseases (NIAID) of the U.S. National Institutes of
Health; carried out by an international research consortium coordinated by the
World Health Organization (WHO); and supported by four pharmaceutical companies
(MappBio, Gilead, Regeneron, and Ridgeback Biotherapeutics).
Antiretroviral therapy (ART) is usually very effective at suppressing HIV in the body, allowing a person’s immune system to recover by preventing the virus from destroying CD4+ T cells(link is external).
Colorized scanning electron micrograph of a T lymphocyte.NIAID
Scientists have now identified a rare, paradoxical response to ART known as extreme immune decline, or EXID. Five individuals evaluated at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, experienced a significant decline in CD4+ T cell levels despite suppression of HIV below detectable levels for more than three years, according to a report published online today in JCI Insight.
The research team was led by Irini Sereti, M.D., chief of the HIV Pathogenesis Section in NIAID’s Laboratory of Immunoregulation, and Andrea Lisco, M.D., Ph.D.
The NIAID researchers found that the immune systems of people with EXID fared even worse than those of another subset of individuals defined as immunological-non-responders, or INRs, who respond inadequately to ART. INR participants consistently taking ART for four years had CD4+ T cell counts that increased on average by 193 cells per microliter (µL) of blood. Participants who responded normally to ART increased their CD4+ T cell count by more than twice that amount. In contrast, the five participants with EXID experienced an average decline of 157 CD4+ T cells/µL while consistently maintaining viral suppression on ART.
According to the NIAID team, there seems to be no single cause of EXID among the five individuals studied. Their analyses revealed that genes influencing immune cell activity and autoimmunity—the immune system attacking a body’s own healthy tissue—may play a role. Specifically, two of the individuals with EXID produced antibodies that attacked their own T cells, while two others had overactive cellular immune responses that lead to increased inflammation. All five participants with EXID had HIV strains other than clade B HIV (the most common strain circulating in North America and Europe), indicating that certain combinations of an individual’s genes and the HIV strain may be associated with EXID. While EXID is likely an extremely rare response to ART, the researchers indicate that studying this phenomenon may further illuminate CD4+ T cell reconstitution and inflammation in HIV disease and suggest possible treatment strategies for INRs and individuals with EXID.
NIH-Supported Analysis Identified Elevated Mortality in Large Latin American Cohort
Dr. Samuel Pierre examines a patient at the GHESKIO clinic in Port-au-Prince, Haiti. Credit: NIAID
Among people with HIV in Latin America, those diagnosed with tuberculosis (TB) at an initial clinic visit were about twice as likely to die within 10 years as people not initially diagnosed with TB, according to findings from a large observational study. This increased risk persisted despite the availability of TB treatment and mirrored patterns seen previously in HIV-negative populations, according to research supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Investigators from the NIAID-supported Caribbean, Central and South America Network for HIV Epidemiology (CCASAnet) presented the findings today at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.
People with HIV are at greater risk of TB disease than HIV-negative people without HIV due to HIV-related immune system damage as well as geographical and behavioral risk factors shared by both diseases. In 2017, the World Health Organization estimates there were 920,000 new TB cases among individuals with HIV globally, and approximately 300,000 people with HIV died from TB. Due to this large burden of HIV and TB co-infection, NIAID supports research to improve TB prevention, diagnosis, and treatment in the context of HIV infection.
“Tuberculosis remains the leading cause of death for people with HIV globally,” said NIAID Director Anthony S. Fauci, M.D. “This new analysis shows how devastating TB can be for people with HIV and underscores the need to do more to prevent and treat this co-infection.”
Investigators analyzed the clinical records of 15,999 people with HIV who received care in CCASAnet clinics in Brazil, Chile, Haiti, Honduras, Mexico and Peru. Each participant remained in care for at least 9 months after their first clinic visit; they had not received antiretroviral drugs to treat HIV infection before arriving at the clinic.
Researchers found that 1,051 individuals—nearly 7 percent—were diagnosed with TB during their first visit and were prescribed anti-TB and HIV medications. After 5 years of observation, approximately 10 percent of patients with TB had died, compared with fewer than 6 percent of those without TB at their initial visit. This pattern continued: after 10 years of observation, more than 19 percent of the group initially diagnosed with TB had died, compared with 10.5 percent of the group without an initial TB diagnosis. Investigators measured 5- and 10-year survival rates beginning at 9 months after each patient’s initial clinic visit, at which time most people recover from TB with standard treatment.
“In recent years, the research community has observed that tuberculosis—even when treated and cured—is associated with an increase in an HIV-negative person’s long-term risk of mortality,” said Serena P. Koenig, M.D., M.P.H., assistant professor at Harvard Medical School and a lead study investigator. “Now we know this is also true for people living with HIV, but many questions remain as to why that is and how to lower that risk.”
In addition to an initial TB diagnosis, lower CD4 T-cell counts, older age and lower education levels also were associated with an increased risk of death in the 10-year follow-up period. The analysis did not take cause of death or personal health history—including previously cured TB infections—into account. Researchers also did not confirm how many individuals who received TB and HIV treatment continued treatment as directed, achieved HIV suppression to an undetectable viral load, cured their TB or experienced additional TB infections after successfully clearing TB disease identified at their initial clinic visit. The severity of TB infection was also not included in the analysis.
“Many factors may play a role in this increased risk of death among people with HIV,” said Catherine C. McGowan, M.D., associate professor at the Vanderbilt University Medical Center and co-principal investigator of the CCASAnet network. “Our study has revealed an important pattern in clinical outcomes, but further research is needed to improve our understanding of the relationship between HIV and tuberculosis coinfection and to guide evidence-based treatment recommendations for this significant population.”
Reference: Morality after presumed TB treatment completion in persons with HIV in Latin America. S Koenig et al. Conference on Retroviruses and Opportunistic Infections, Seattle. March 6, 2019.
Bone marrow transplantation can be a life-saving procedure, but also a grueling one. Once a compatible donor is found, a recipient must undergo nonspecific radiation or chemotherapy to destroy their own bone marrow, which may leave them weak and vulnerable to infection.
Immune cells, like this T lymphocyte, are generated by stem cells in the bone marrow. Stem cell transplantation can be curative when immune cells are faulty because of inherited mutations, or because of acquired diseases like cancer.
Credit: NIAID
Bone marrow recipients usually also require lifelong treatment with immunosuppressive agents that help them tolerate the donation but may increase their risk of infection and cancer.
In a new paper(link is external) published February 6 in Nature Communications, researchers from NIAID and Harvard University describe a way to better prepare a recipient to tolerate bone marrow donation, using an antibody-drug conjugate that combines a cell-targeting antibody with a cell toxin, which the antibody carries as cargo. Using this approach, they were able to selectively kill bone marrow stem cells in mice, making the mice much more likely to tolerate donor stem cells in bone marrow and to accept skin grafts, without complications or the need for long-term immunosuppression.
The technique uses a combination of a monoclonal antibody and a cell toxin to kill off the recipient’s original stem cells. The monoclonal antibody binds to a protein, CD117, which is common on the outside of the recipient’s blood-producing stem cells. This allows the drugs to selectively kill the stem cells while leaving most other cells unharmed, clearing the way for the donor stem cells to take hold after the transplant.
In a separate paper(link is external) also published in the same issue of Nature Communications, the Harvard team used NIAID funding to test the same antibody-drug combination on mice whose immune system proteins were very similar to those of donor mice. In the recipient mice, one dose of the antibody-drug combination removed over 99 percent of bone marrow stem cells, allowing new donor cells to easily take hold without serious complications. The recipient immune systems were later shown to function well when challenged with fungal spores and viruses.
In their collaborative study, NIAID and Harvard researchers took this idea a step further by testing the antibody-drug combination on mice whose immune system proteins were very different from those of the donor mice, a situation that can make rejection symptoms more likely. Fourteen out of fifteen mice that received bone marrow transplants using the antibody-drug combination remained healthy for almost two years—nearly the entire normal lifespan of a mouse. Most of the mice that were given the antibody-drug combination treatments before receiving skin grafts also did well. In mice receiving no treatments, the skin grafts were rapidly rejected.
Although the antibody-drug combination technique has not yet been tested in humans, these early results are remarkable, the researchers say, and the technique merits further investigation. Content last reviewed on February 26, 2019
A new commentary from National Institutes of Health scientists asserts that engaging men in HIV prevention and care is essential to the goal of ending the HIV pandemic.
Navy Petty Officer 1st Class Oliver Arceo draws blood from a sailor for routine HIV testing.U.S. Navy photo by Petty Officer 1st Class Marie Montez
The article by Adeola Adeyeye, M.D., M.P.A., and David Burns, M.D., M.P.H., of the National Institute of Allergy and Infectious Diseases (NIAID) and Michael Stirratt, Ph.D., of the National Institute of Mental Health (NIMH) also discusses potential solutions.
Scientific research has proven that people with HIV who take antiretroviral therapy (ART) as prescribed and achieve and maintain an undetectable level of virus in the blood have effectively no risk of transmitting the virus to their HIV-uninfected sexual partners.
Other research has shown that when HIV-uninfected people consistently take a single daily oral tablet of the antiretroviral drugs emtricitabine/tenofovir disoproxil fumarate, their risk of acquiring HIV infection is reduced by as much as 95 percent. The challenge is implementing these approaches, known as treatment as prevention and pre-exposure prophylaxis (PrEP), and other forms of HIV prevention in a timely manner among everyone who needs them.
The authors point out that in sub-Saharan Africa, men are less likely than women to know their HIV status, engage in HIV care in a timely manner, stay in care and maintain an undetectable level of virus in the blood. The authors also note that in the United States, disparities by age, race and ethnicity persist in the use of ART among men who have sex with men.
New strategies to engage men in HIV prevention and treatment must address three critical issues, the authors write. These are the lack of “touch points” where men naturally interact with the health care system; gender norms and prevailing constructs of masculinity, which typically subordinate health care to other concerns; and HIV stigma and discrimination.
The authors describe innovative approaches being explored to overcome these challenges, including establishing HIV testing and care in workplaces and sports programs, ART home delivery, HIV self-testing, and the MenStar Coalition(link is external) created by the President’s Emergency Plan for AIDS Relief (PEPFAR), Unitaid, the Elton John AIDS Foundation and others to expand HIV diagnosis and treatment for men.
Also, NIAID and NIMH are co-sponsoring two research Funding Opportunity Announcements designed to support development and testing of strategies to increase the engagement of men in HIV prevention and care domestically and globally.
An international research team has begun patient enrollment in a clinical trial testing multiple investigational Ebola therapies in the Democratic Republic of the Congo (DRC).
The randomized, controlled trial is enrolling patients of any age with confirmed Ebola virus disease (EVD) at a treatment unit in the city of Beni operated by ALIMA(link is external) (The Alliance for International Medical Action), a medical humanitarian organization.
Colorized scanning electron micrograph of Ebola virus particles (green) both budding and attached to the surface of infected VERO E6 cells (blue). Image captured and color-enhanced at the NIAID Integrated Research Facility in Fort Detrick, Maryland.NIAID/NIH
The trial, which will expand to additional DRC districts, is organized through an international research consortium coordinated by the World Health Organization (WHO). It is led and funded by the National Institute for Biomedical Research (INRB)(link is external), part of the DRC Ministry of Health(link is external), and the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, and also involves several additional international partners.
“Combatting Ebola requires a comprehensive response that draws on the strengths of all areas of public health. Biomedical research can lead to critical new tools, such as potentially life-saving therapies,” said NIAID Director Anthony S. Fauci., M.D. “Through scientifically and ethically sound clinical trials, we hope to efficiently and definitively establish the safety and efficacy of these investigational Ebola treatments, offering new ways to save lives.”
On Aug. 1, 2018, the DRC Ministry of Health declared the country’s 10th outbreak of EVD. As of Nov. 25, 2018, 240 deaths out of 419 confirmed and probable cases of EVD have been reported in the northeastern provinces of North Kivu and Ituri. Under the leadership of the DRC Ministry of Health, the WHO has coordinated the outbreak response with several international partners. NIAID, along with the U.S. Centers for Disease Control and Prevention, the U.S. Agency for International Development (USAID), and other U.S. government partners, have provided guidance and support to the multi-sectoral outbreak response.
“We urgently need a safe and effective treatment for this deadly disease,” said DRC Minister of Health Oly Ilunga Kalenga, M.D., Ph.D. “As we face a 10th outbreak of Ebola, we hope this clinical trial will give us more information about how best to treat patients.”
The trial aims to compare mortality among patients who receive one of three investigational Ebola drugs with a control group of patients who receive the investigational monoclonal antibody cocktail treatment ZMapp, developed by Mapp Biopharmaceutical, Inc. The therapies being tested include: mAb114, a single monoclonal antibody developed by NIAID, with early support from the INRB; and remdesivir (also known as GS-5734), an antiviral drug developed by Gilead Sciences, Inc. The trial has been approved to begin enrolling patients in these three groups, and plans are underway to amend the trial to include REGN-EB3 (also known as REGN3470-3471-3479), a monoclonal antibody cocktail developed by Regeneron Pharmaceuticals, Inc.
The participating Ebola treatment units will continue to provide all participants with supportive care for EVD. Ebola care includes supportive oral and/or intravenous fluids, electrolyte replacement, maintaining oxygen status and blood pressure, and pain management.
The investigational treatments have varying levels of data to support their use from testing in the laboratory, animals, and humans. However, none has been approved for treating EVD. ZMapp is the only investigational treatment previously tested in a randomized, controlled efficacy trial. Results from that study, conducted in the U.S. and West Africa during the 2014 to 2016 outbreak, suggested that ZMapp appeared to be beneficial, but as the outbreak waned, the trial ultimately could not enroll enough participants to definitively establish the drug’s efficacy.
“A randomized, controlled clinical trial is necessary to obtain reliable data about the safety and efficacy of investigational Ebola treatments,” said H. Clifford Lane, M.D., director of NIAID’s Division of Clinical Research. “It is possible to conduct rigorous clinical research in an outbreak setting, and we anticipate this trial will provide useful data.”
Professor Jean-Jacques Muyembe-Tamfum, M.D., Ph.D., director-general of the INRB, and Richard T. Davey, Jr., M.D., deputy director of NIAID’s Division of Clinical Research, are co-principal investigators for the study.
Trial participants will be randomly assigned to receive one of the investigational treatments by intravenous infusion. Site clinicians will monitor patients’ symptoms and take blood samples for laboratory tests. Patients will remain in the Ebola treatment unit until they fully recover from the disease. They will be asked to return to the clinic approximately two months after receiving treatment for a check-up and to provide additional blood samples for laboratory tests.
Plans are underway to expand the trial beyond the ALIMA site in Beni to additional Ebola treatment units operated by medical humanitarian organizations, including International Medical Corps. The trial also may be adapted to continue across more than one outbreak and in several countries. The number of participants enrolled in the trial ultimately will depend on the evolution of Ebola outbreaks. The study is designed to enroll 112 patients per arm, potentially over multiple outbreaks.
“This clinical trial marks a significant and important step forward for the DRC and our international partners,” said Dr. Muyembe. “We are eager to learn more about each of these investigational treatments as we continue to work tirelessly to identify new cases, trace contacts and control the spread of disease.”
An independent data and safety monitoring board will regularly review the study data.
Specimen-news.com 