SARS-CoV-2 is the virus that causes COVID-19. MK-4482, delivered orally, is now in human clinical trials. Remdesivir, an antiviral drug already approved by the U.S. Food and Drug Administration for use against COVID-19, must be provided intravenously, making its use primarily limited to clinical settings.
In their study, published in the journal Nature Communications, the scientists found MK-4482 treatment effective when provided up to 12 hours before or 12 hours after infecting the hamsters with SARS-CoV-2. These data suggest that MK-4482 treatment potentially could mitigate high-risk exposures to SARS-CoV-2, and might be used to treat established SARS-CoV-2 infection alone or possibly in combination with other agents.
The same research group, located at Rocky Mountain Laboratories, part of NIH’s National Institute of Allergy and Infectious Diseases in Hamilton, Montana, developed the hamster model last year to mimic SARS-CoV-2 infection and mild disease in people. The University of Plymouth in the United Kingdom collaborated on these most recent studies.
The project involved three groups of hamsters: a pre-infection treatment group; a post-infection treatment group; and an untreated control group. For the two treatment groups, scientists administered MK-4482 orally every 12 hours for three days. At the conclusion of the study, the animals in each of the treatment groups had 100 times less infectious virus in their lungs than the control group. Animals in the two treatment groups also had significantly fewer lesions in the lungs than the control group.
The scientists determined the MK-4482 treatment doses for this study based on previous experiments performed in mouse models of SARS-CoV-1 and MERS-CoV. In those studies, MK-4482 was effective at stopping the viruses from replicating.
With funding support from NIAID, Emory University’s Drug Innovation Ventures group in Atlanta developed MK-4482 (also known as molnupiravir and EIDD-2801) to treat influenza. Merck and Ridgeback Biotherapeutics are now jointly developing and evaluating MK-4482 as a potential COVID-19 treatment. The drug is in Phase 2 and 3 human clinical studies.
The emergence of variants of SARS-CoV-2, the virus that causes COVID-19, serve as a powerful reminder that viruses by their very nature mutate, and that the scientific response may need to adapt to remain effective against them, according to COVAX statement on new variants of SARS-CoV-2.
In light of recent news stories regarding the preliminary data on minimal effectiveness of the AstraZeneca/Oxford vaccine at preventing mild to moderate COVID-19 disease caused by the viral variant B.1.351, it is important to note that primary analysis of data from Phase III trials has so far shown – in the context of viral settings without this variant – that the AstraZeneca/Oxford vaccine offers protection against severe disease, hospitalisation and death. This means it is vitally important now to determine the vaccine’s effectiveness when it comes to preventing more severe illness caused by the B.1.351 variant.
Additional studies will also allow us to confirm the optimal vaccination schedule and its impact on vaccine efficacy. CEPI has announced funding for additional clinical research to optimize and extend the use of existing vaccines, which could include “mix-and-match” studies of different vaccines used in combinations that may improve the quality and strength of the immune response. Such studies could be useful in optimizing the use of available vaccines, including the AstraZeneca/Oxford vaccine.
The WHO Strategic Advisory Group of Experts on Immunization (SAGE) convened today to review evidence on the AstraZeneca/Oxford vaccine, including emerging evidence on performance against viral variants, and to consider the demonstrated impact of the product and the risk-benefit assessment for use cases with limited data. These recommendations for use of the AstraZeneca product are being finalised and will be presented to the WHO Director-General on 9 Feb 2021.
Even though this recent news on effectiveness of the AstraZeneca/Oxford vaccine against the B.1.351 variant is based on a limited study size which focused on low-risk participants and used interval doses that were not optimized for immunogenicity, these results confirm we must do everything possible to reduce the circulation of the virus, prevent infections and reduce the opportunities for the SARS-CoV-2 to evolve resulting in mutations that may reduce the efficacy of existing vaccines
National Institutes of Health researchers have isolated a set of promising, tiny antibodies, or “nanobodies,” against SARS-CoV-2 that were produced by a llama named Cormac.
Preliminary results published in Scientific Reports suggest that at least one of these nanobodies, called NIH-CoVnb-112, could prevent infections and detect virus particles by grabbing hold of SARS-CoV-2 spike proteins. In addition, the nanobody appeared to work equally well in either liquid or aerosol form, suggesting it could remain effective after inhalation. SARS-CoV-2 is the virus that causes COVID-19.
“For years TJ and I had been testing out how to use nanobodies to improve brain imaging. When the pandemic broke, we thought this was a once in a lifetime, all-hands-on-deck situation and joined the fight,” said Dr. Brody, who is also a professor at Uniformed Services University for the Health Sciences and the senior author of the study. “We hope that these anti-COVID-19 nanobodies may be highly effective and versatile in combating the coronavirus pandemic.”
A nanobody is a special type of antibody naturally produced by the immune systems of camelids, a group of animals that includes camels, llamas, and alpacas. On average, these proteins are about a tenth the weight of most human antibodies. This is because nanobodies isolated in the lab are essentially free-floating versions of the tips of the arms of heavy chain proteins, which form the backbone of a typical Y-shaped human IgG antibody. These tips play a critical role in the immune system’s defenses by recognizing proteins on viruses, bacteria, and other invaders, also known as antigens.
Because nanobodies are more stable, less expensive to produce, and easier to engineer than typical antibodies, a growing body of researchers, including Mr. Esparza and Dr. Brody, have been using them for medical research. For instance, a few years ago scientists showed that humanized nanobodies may be more effective at treating an autoimmune form of thrombotic thrombocytopenic purpura, a rare blood disorder, than current therapies.
“The SARS-CoV-2 spike protein acts like a key. It does this by opening the door to infections when it binds to a protein called the angiotensin converting enzyme 2 (ACE2) receptor, found on the surface of some cells,” said Mr. Esparza, who is also an employee of the Henry M. Jackson Foundation for the Advancement of Military Medicine and the lead author of the study. “We developed a method that would isolate nanobodies that block infections by covering the teeth of the spike protein that bind to and unlock the ACE2 receptor.”
To do this, the researchers immunized Cormac five times over 28 days with a purified version of the SARS-CoV-2 spike protein. After testing hundreds of nanobodies they found that Cormac produced 13 nanobodies that might be strong candidates.
Initial experiments suggested that one candidate, called NIH-CoVnb-112, could work very well. Test tube studies showed that this nanobody bound to the ACE2 receptor 2 to 10 times stronger than nanobodies produced by other labs. Other experiments suggested that the NIH nanobody stuck directly to the ACE2 receptor binding portion of the spike protein.
Then the team showed that the NIH-CoVnB-112 nanobody could be effective at preventing coronavirus infections. To mimic the SARS-CoV-2 virus, the researchers genetically mutated a harmless “pseudovirus” so that it could use the spike protein to infect cells that have human ACE2 receptors. The researchers saw that relatively low levels of the NIH-CoVnb-112 nanobodies prevented the pseudovirus from infecting these cells in petri dishes.
Importantly, the researchers showed that the nanobody was equally effective in preventing the infections in petri dishes when it was sprayed through the kind of nebulizer, or inhaler, often used to help treat patients with asthma.
“One of the exciting things about nanobodies is that, unlike most regular antibodies, they can be aerosolized and inhaled to coat the lungs and airways,” said Dr. Brody.
The team has applied for a patent on the NIH-CoVnB-112 nanobody.
“Although we have a lot more work ahead of us, these results represent a promising first step,” said Mr. Esparza. “With support from the NIH we are quickly moving forward to test whether these nanobodies could be safe and effective preventative treatments for COVID-19. Collaborators are also working to find out whether they could be used for inexpensive and accurate testing.”
This study was supported by NIH Intramural Research Programs at the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Environmental Health Sciences (NIEHS); Dr. Brody is an employee of the Uniformed Services University of the Health Sciences. The views expressed here do not represent those of the Department of Defense.
Two randomized, placebo-controlled clinical trials funded by the National Institutes of Health (NIH) are expanding enrollment to further evaluate convalescent plasma as a treatment for patients hospitalized with COVID-19.
Preliminary observational studies indicate that convalescent plasma may improve outcomes among severely ill and hospitalized patients with COVID-19. Prospective, well-controlled randomized trials are needed to generate sufficient data on whether convalescent plasma is effective and safe for the treatment of COVID-19.
Convalescent plasma is blood plasma taken from people who have recovered from COVID-19. It contains antibodies that can recognize and neutralize SARS-CoV-2, the virus that causes COVID-19, as well as other components that may contribute to an immune response.
“The evidence on convalescent plasma as a treatment for severe cases of COVID-19 is promising but incomplete. We need to carry out rigorous randomized control clinical trials to determine how this therapy can improve outcomes,” said NIH Director Francis S. Collins, M.D., Ph.D. “While the world waits for an effective vaccine, it is vital that we simultaneously expand the options for available treatments for those currently suffering from the worst effects of this disease.”
The trials expect to enroll hospitalized patients across the country at academic and community-based hospitals. Participants will be randomly assigned to receive the treatment or a placebo. Outcomes will be compared with respect to clinical improvement measures and resource needs, such as ventilators. Both trials currently are enrolling participants and anticipate results as early as this fall.
The trials are receiving $48 million in support through Operation Warp Speed (OWS), a collaborative initiative across federal agencies to advance the development, manufacturing and distribution of COVID‑19 vaccines, therapeutics and diagnostics.
The National Center for Advancing Translational Sciences (NCATS), part of NIH, will oversee the grant awards through its Clinical and Translational Science Awards (CTSA) Program research network. The CTSA’s Trial Innovation Network (TIN) will play a key role in working to add study sites and enroll patients, including those from communities disproportionately affected by COVID-19.
“The rapid expansion of these vital randomized, controlled convalescent plasma clinical trials demonstrates how nimbly the network of CTSA Program hubs and the TIN can respond to the nation’s research needs and shorten the path from discovery to treatment,” said NCATS Director Christopher P. Austin, M.D.
One trial, called Convalescent Plasma to Limit COVID-19 Complications in Hospitalized Patients, was launched in April by NYU Langone Health in New York, with collaboration from the Albert Einstein College of Medicine and Yale University, New Haven, Connecticut, and with funding from NCATS. To increase enrollment in the trial, NYU is partnering with The University of Texas Health Science Center at Houston and the University of Miami in Florida to enroll participants at sites in these states.
With these additional sites, this trial expects to enroll approximately 1,000 hospitalized patients 18 years or older with respiratory symptoms of COVID-19. The trial is primarily assessing clinical improvement at 14 and 28 days and also will be evaluating outcomes based on mortality, intensive care unit admission and patient antibody concentrations. Additional information about this study and participation is available at ClinicalTrials.gov under study identifier NCT04364737.
The trial called Passive Immunity Trial of Our Nation for COVID-19 also is expanding to enroll about 1,000 participants. Vanderbilt University Medical Center in Nashville, Tennessee, which launched the trial in April, will have access to about 50 additional clinical trial sites across the CTSA Program. Participants are 18 years or older with acute respiratory infection symptoms and laboratory-confirmed SARS-CoV-2 infection; they may be hospitalized or in an emergency department and likely to be admitted. The trial primarily will assess clinical improvement at 15 days and also will evaluate ventilation use, supplemental oxygen use, acute kidney injury and cardiovascular events. Additional information about this study and participation is available at ClinicalTrials.gov under study identifier NCT04362176.
NIAID-Led Study of mRNA Vaccine Supports Advance to Phase 3 Human Trials
Two doses of an experimental vaccine to prevent coronavirus disease 2019 (COVID-19) induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2, report scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. SARS-CoV-2 is the virus that causes COVID-19.
The candidate vaccine, mRNA-1273, was co-developed by scientists at the NIAID Vaccine Research Center and at Moderna, Inc., Cambridge, Massachusetts. The animal study results published online today in the New England Journal of Medicine complement recently reported interim results from an NIAID-sponsored Phase 1 clinical trial of mRNA-1273. The candidate mRNA-1273 vaccine is manufactured by Moderna.
In this study, three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. Notably, say the investigators, animals receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19.
The experimental vaccine also induced Th1 T-cell responses but not Th2 responses. Induction of Th2 responses has been associated with a phenomenon called vaccine-associated enhancement of respiratory disease (VAERD). Vaccine-induced Th1 responses have not been associated with VAERD for other respiratory diseases. In addition, the experimental vaccine induced T follicular helper T-cell responses that may have contributed to the robust antibody response.
Four weeks after the second injection, all the macaques were exposed to SARS-CoV-2 via both the nose and the lungs. Remarkably, after two days, no replicating virus was detectable in the lungs of seven out of eight of the macaques in both vaccinated groups, while all eight placebo-injected animals continued to have replicating virus in the lung. Moreover, none of the eight macaques vaccinated with 100 µg of mRNA-1273 had detectable virus in their noses two days after virus exposure. This is the first time an experimental COVID-19 vaccine tested in nonhuman primates has been shown to produce such rapid viral control in the upper airway, the investigators note. A COVID-19 vaccine that reduces viral replication in the lungs would limit disease in the individual, while reducing shedding in the upper airway would potentially lessen transmission of SARS-CoV-2 and consequently reduce the spread of disease, they add.
In a Perspective for the New England Journal of Medicine(link is external), members of the National Institutes of Health’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Vaccines Working Group assess practical considerations and prerequisites for using controlled human infection models (CHIMs), which can be used for human challenge studies, to support SARS-CoV-2 vaccine development.
In the article, the authors determine the timeline for developing robust CHIMs that meet the essential criteria for limiting risk for study volunteers could take one to two years. The authors conclude that large, randomized, controlled trials of SARS-CoV-2 are the fastest and most effective path forward for establishing vaccine safety and efficacy. Parallel development of CHIMs may provide complementary tools to address additional questions such as the duration of immunity and correlates of protection, if such studies can be conducted ethically.
In a CHIM study, participants are intentionally exposed to an infectious agent to help scientists understand the virus or test interventions to prevent or treat infection. CHIMs use well-characterized microorganisms that either do not cause serious disease, are easily treated, or both. In addition, CHIM studies must take place in laboratories with rigorous isolation to ensure that the infection does not spread into the community.
The authors note that ethical evaluation of the risk to participants and the potential value to society are essential to future considerations of whether to conduct CHIM studies for COVID-19; currently there is no highly efficacious treatment for moderate or severe illness. The authors propose that development of a SARS-CoV-2 GMP stock, preferably with attenuating mutations, should proceed along with preparation of facilities and procedures and engagement of a broad set of stakeholders. Additionally, the researchers recommend developing CHIMs for seasonal coronaviruses, which cause about 30% of cases of the common cold and can provide insights into more deadly coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2.
Early data showed that off-label use of a cancer drug reduced respiratory distress and over-reactive immune responses in patients with COVID-19.
Based on these results, researchers have designed a clinical trial to test whether the drug can be used as a safe and effective treatment for patients with COVID-19.
Coronavirus disease 2019 (COVID-19), which is caused by the virus SARS-CoV-2, is a respiratory illness that can bring mild to severe symptoms. These often include fever, cough, and shortness of breath. Some patients with severe COVID-19 have a hyper immune system response. The immune system normally protects your body from microscopic infections, like bacteria and viruses, by attacking the infection. But an exaggerated immune response can damage the function of your organs, such as the lungs.
This dangerous hyperinflammatory state in patients with severe COVID-19 is known as a cytokine storm. Cytokines act as chemical messengers that help to stimulate and direct the immune response. But when large amounts of cytokines are released in the body, it can be dangerous. Currently, there are no proven treatment strategies for this phase of the illness.
The Bruton tyrosine kinase (BTK) protein plays an important role in the immune system response. Macrophages, a type of immune cell, use BTK to produce cytokines and inflammation. BTK inhibitors are approved to treat certain cancers, but they are not approved as a treatment for COVID-19.
A research team led by Drs. Wyndham H. Wilson, Louis M. Staudt, and Mark Roschewski at NIH’s National Cancer Institute (NCI) and Mihalis Lionakis at NIH’s National Institute of Allergy and Infection Diseases (NIAID) tested the off-label use of a BTK inhibitor called acalabrutinib to treat COVID-19. They carried out a clinical study of 19 patients with a confirmed COVID-19 diagnosis who required hospitalization and had low blood-oxygen levels and evidence of inflammation. Of these, 11 had been receiving supplemental oxygen for a median of two days, and eight others had been on ventilators for a median of 1.5 days.
The study, which was funded by NCI and NIAID, was done in collaboration with researchers at the U.S. Department of Defense’s Walter Reed National Military Medical Center and four other hospitals nationally. Results were published on June 05, 2020 in Science Immunology.
Within one to three days after receiving acalabrutinib, the majority of patients receiving supplemental oxygen experienced a substantial drop in inflammation, and their breathing improved. Eight of these 11 patients were able to come off supplemental oxygen and were discharged from the hospital. Four of the eight patients who were on a ventilator were able to come off it, and two were eventually discharged. Two of the patients in this group died.
Blood samples from the patients showed that levels of interleukin-6 (IL-6), a major cytokine associated with hyperinflammation in severe COVID-19, decreased after treatment with acalabrutinib. Counts of lymphocytes, a type of white blood cell, also rapidly improved in most patients. Low lymphocyte counts have been associated with worse outcome for patients with severe COVID-19.
The researchers compared blood cells from healthy volunteers and patients with severe COVID-19 who were not in the study. Those from patients with COVID-19 had higher activity of the BTK protein and greater production of IL-6.
“If these results are confirmed by a randomized, controlled clinical trial, this therapy may play an important role in the control of severe COVID-19,” Wilson says.
“We have been successfully treating lymphoma patients with BTK inhibitors for years and were eager to lend our expertise to help address the global COVID-19 pandemic,” Staudt adds.
The results of this study were used to inform the design of a clinical trial to further investigate the drug’s safety and efficacy.