Monoclonal antibody prevents malaria in small NIH trial

One dose of a new monoclonal antibody discovered and developed at the National Institutes of Health safely prevented malaria for up to nine months in people who were exposed to the malaria parasite. The small, carefully monitored clinical trial is the first to demonstrate that a monoclonal antibody can prevent malaria in people. The trial was sponsored and conducted by scientists from the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, and was funded by NIAID. The findings were published today in The New England Journal of Medicine. 

“Malaria continues to be a major cause of illness and death in many regions of the world, especially in infants and young children; therefore, new tools are needed to prevent this deadly disease,” said NIAID Director Anthony S. Fauci, M.D. “The results reported today suggest that a single infusion of a monoclonal antibody can protect people from malaria for at least 9 months. Additional research is needed, however, to confirm and extend this finding.”

According to the World Health Organization(link is external), an estimated 229 million cases of malaria occurred worldwide in 2019, resulting in an estimated 409,000 deaths, mostly in children in sub-Saharan Africa. So far, no licensed or experimental malaria vaccine that has completed Phase 3 testing provides more than 50% protection from the disease over the course of a year or longer.

Malaria is caused by Plasmodium parasites, which are transmitted to people through the bite of an infected mosquito. The mosquito injects the parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply. Then the mature parasite spreads throughout the body via the bloodstream to cause illness. P. falciparum is the Plasmodium species most likely to result in severe malaria infections, which, if not promptly treated, may lead to death.

Laboratory and animal studies have demonstrated that antibodies can prevent malaria by neutralizing the sporozoites of P. falciparum in the skin and blood before they can infect liver cells. The NIAID trial tested whether a neutralizing monoclonal antibody called CIS43LS could safely provide a high level of protection from malaria in adults following careful, voluntary, laboratory-based exposure to infected mosquitos in the United States.

CIS43LS was derived from a naturally occurring neutralizing antibody called CIS43. Researchers led by Robert A. Seder, M.D., chief of the Cellular Immunology Section of the VRC Immunology Laboratory, isolated CIS43 from the blood of a volunteer who had received an investigational malaria vaccine. The scientists found that CIS43 binds to a unique site on a parasite surface protein that is important for facilitating malaria infection and is the same on all variants of P. falciparum sporozoites worldwide. The researchers subsequently modified this antibody to extend the amount of time it would remain in the bloodstream, creating CIS43LS.

After animal studies of CIS43LS for malaria prevention yielded promising results, VRC investigators launched a Phase 1 clinical trial of the experimental antibody with 40 healthy adults ages 18 to 50 years who had never had malaria or been vaccinated for the disease. The trial was led by Martin Gaudinski, M.D., medical director of the VRC Clinical Trials Program, and was conducted at the NIH Clinical Center in Bethesda, Maryland, and the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Maryland.

During the first half of the trial, the study team gave 21 participants one dose of CIS43LS by either an intravenous infusion or an injection under the skin. The infusions ranged from 5 to 40 milligrams per kilogram (mg/kg) of body weight, and the subcutaneous injections were 5 mg/kg. Investigators followed the participants for 6 months to learn whether the infusions and subcutaneous injections of the various doses of the experimental antibody were safe and well tolerated. In addition, they measured the amount of CIS43LS in the blood to determine its durability over time.  

In the second half of the trial, six participants who had received an intravenous infusion during the first half of the trial continued to participate. Four of these participants received a second antibody infusion while the other two did not. In addition, four new participants joined the study and received a single intravenous infusion of CIS43LS. Another seven people joined the study as controls who did not receive the antibody.

All participants in the second half of the trial provided informed consent to be exposed to the malaria parasite in what is known as a controlled human malaria infection (CHMI). In this procedure, volunteers are exposed to P. falciparum through bites of infected mosquitos in a carefully controlled setting, then are closely monitored by medical staff for several weeks and promptly treated if they develop malaria. CHMI has been used for decades to generate information about the safety and protective effect of malaria vaccine candidates and potential antimalarial drugs.

Nine participants who had received CIS43LS and six participants who served as controls voluntarily underwent CHMI and were closely monitored for 21 days. Within that period, none of the nine participants who had received CIS43LS developed malaria, but five of the six controls did. The participants with malaria received standard therapy to eliminate the infection.

Among the nine participants who received CIS43LS and were protected, seven underwent CHMI approximately 4 weeks after their infusion. The other two participants had received their sole infusion during the first half of the study and were infected approximately 9 months later. These results indicate that just one dose of the experimental antibody can prevent malaria for 1 to 9 months after infusion. Collectively, these data provide the first evidence that administration of an anti-malaria monoclonal antibody is safe and can prevent malaria infection in humans.

To build on this finding, a larger Phase 2 clinical trial is underway in Mali to evaluate the safety and efficacy of CIS43LS at preventing malaria infection in adults during a six-month malaria season. The trial is being led by Peter D. Crompton, M.D., M.P.H., chief of the Malaria Infection Biology and Immunity Section in the NIAID Laboratory of Immunogenetics, and Kassoum Kayentao, M.D., M.P.H., Ph.D., a professor at the University of Sciences, Techniques and Technologies of Bamako, Mali. NIAID is sponsoring and funding the trial. Results are expected in early 2022.

In addition, VRC scientists are conducting further research on CIS43LS in the United States to determine the lowest dose that protects people from malaria infection.

“Monoclonal antibodies may represent a new approach for preventing malaria in travelers, military personnel and health care workers traveling to malaria-endemic regions,” said Dr. Seder. “Further research will determine whether monoclonal antibodies can also be used for the seasonal control of malaria in Africa and ultimately for malaria-elimination campaigns.”

NIH launches study of third COVID-19 vaccine dose in kidney transplant recipients

Colorized scanning electron micrograph of a cell (purple) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.NIAID

A pilot study has begun to assess the antibody response to a third dose of an authorized COVID-19 mRNA vaccine in kidney transplant recipients who did not respond to two doses of the Moderna or Pfizer-BioNTech COVID-19 vaccine. The Phase 2 trial is sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The lifelong immunosuppressive therapy that organ transplant recipients must take to prevent organ rejection blunts their immune response to both pathogens and vaccines. Research has shown that many organ transplant recipients do not develop antibodies against SARS-CoV-2, the virus that causes COVID-19, after receiving an authorized COVID-19 vaccine regimen. The purpose of the new study is to determine whether a third dose of one of the mRNA COVID-19 vaccines could overcome this problem for at least some kidney transplant recipients. This is particularly important because this population has a high prevalence of conditions that are risk factors for severe COVID-19, such as cardiovascular disease and diabetes.

The pilot study also aims to identify characteristics that could help distinguish those kidney transplant recipients who would benefit from a third dose of an mRNA vaccine from those who will require a different approach to achieve protection. The pilot study findings will inform a subsequent, larger phase of the trial that includes higher-risk strategies to induce a protective immune response against SARS-CoV-2 in solid organ transplant recipients who do not respond to a third dose of an mRNA vaccine.

The third-dose vaccine intervention was chosen because of the demonstrated safety of the two-dose mRNA vaccine regimen in solid organ transplant recipients as well as the efficacy of additional doses of other vaccines, such as those for hepatitis and influenza, in immunocompromised people.

The pilot study, called COVID Protection After Transplant (CPAT), is being conducted at Johns Hopkins University in Baltimore under the leadership of Dorry Segev, M.D., Ph.D. Dr. Segev is the Marjory K. and Thomas Pozefsky professor of surgery and epidemiology, associate vice chair of the department of surgery, and director of the Epidemiology Research Group in Organ Transplantation at Johns Hopkins University. 

The CPAT study team will enroll up to 200 adults ages 18 years or older who received a kidney transplant a year or more prior to enrollment and have had no recent organ rejection or change in immunosuppression. Between 50 and 100 participants will have had no detectable antibody response to two doses of an mRNA COVID-19 vaccine, and 50 to 100 participants will have had a low response. All participants will receive a third dose of the same COVID-19 vaccine that they received previously. Thirty days later, investigators will measure participants’ antibody response to the third dose. The goal is to determine the proportion of participants who achieve a designated antibody response at the 30-day mark. The study team will follow participants for one year after enrollment. Preliminary results are expected in September 2021.

Adjuvant Developed with NIH Funding Enhances Efficacy of India’s COVID-19 Vaccine

An adjuvant developed with funding from the National Institutes of Health has contributed to the success of the highly efficacious COVAXIN COVID-19 vaccine, which roughly 25 million people have received to date in India and elsewhere. Adjuvants are substances formulated as part of a vaccine to boost immune responses and enhance a vaccine’s effectiveness. COVAXIN was developed and is manufactured in India, which is currently suffering a devastating health crisis due to COVID-19. 

“Ending a global pandemic requires a global response,” said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “I am pleased that a novel vaccine adjuvant developed in the United States with NIAID support is part of an efficacious COVID-19 vaccine available to people in India.” 

The adjuvant used in COVAXIN, Alhydroxiquim-II, was discovered and tested in the laboratory by the biotech company ViroVax LLC of Lawrence, Kansas with support exclusively from the NIAID Adjuvant Development Program. The adjuvant comprises a small molecule attached in a unique way to Alhydrogel, a substance frequently called alum that is the most commonly used adjuvant in vaccines for people. Alhydroxiquim-II travels to lymph nodes, where the small molecule detaches from alum and activates two cellular receptors. These receptors, TLR7 and TLR8, play a vital role in the immune response to viruses. Alhydroxiquim-II is the first adjuvant in an authorized vaccine against an infectious disease to activate TLR7 and TLR8. In addition, the alum in Alhydroxiquim-II stimulates the immune system to search for an invading pathogen.

Molecules that activate TLR receptors stimulate the immune system powerfully, but the side effects of Alhydroxiquim-II are mild. This is because, after COVAXIN is injected, the adjuvant travels directly to nearby lymph nodes, which contain white blood cells that play an essential role in identifying pathogens and fighting infection. Consequently, only a small amount of Alhydroxiquim-II is needed in each dose of vaccine, and the adjuvant does not circulate throughout the body, thereby averting more widespread inflammation and undesirable side effects. 

COVAXIN comprises a disabled form of SARS-CoV-2 that cannot replicate but still stimulates the immune system to make antibodies against the virus. Published results from a Phase 2 trial of the vaccine indicate that it is safe and well tolerated. Safety data from a Phase 3 trial of COVAXIN in 25,800 participants in India will become available later this year. Meanwhile, unpublished interim results from the Phase 3 trial indicate that the vaccine has 78% efficacy against symptomatic disease, 100% efficacy against severe COVID-19, including hospitalization, and 70% efficacy against asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19. Results from two studies of blood serum from people who had received COVAXIN suggest that the vaccine generates antibodies that effectively neutralize the B.1.1.7 (Alpha) and B.1.617 (Delta) variants of SARS-CoV-2, first identified in the United Kingdom and India, respectively. 

The NIAID Adjuvant Program has supported the research of the founder and chief executive officer of ViroVax―Sunil David, M.D., Ph.D.―since 2009. His work has focused on searching for novel molecules that activate innate immune receptors and developing them as vaccine adjuvants. 

The collaboration between Dr. David and the company that makes COVAXIN, Bharat Biotech International Ltd. of Hyderabad, was initiated during a 2019 meeting in India coordinated by the NIAID Office of Global Research under the auspices of NIAID’s Indo-U.S. Vaccine Action Program. A delegation of five NIAID-funded adjuvant investigators including Dr. David; two members of the NIAID Division of Allergy, Immunology, and Transplantation; and the NIAID India representative visited four leading biotechnology companies to learn about their work and discuss potential collaborations. The delegation also attended a consultation in New Delhi co-organized by NIAID and India’s Department of Biotechnology and hosted by India’s National Institute of Immunology.

Among the scientific collaborations sparked by these activities, Bharat Biotech signed a licensing agreement with Dr. David to use Alhydroxiquim-II in their candidate vaccines. This license was expanded during the COVID-19 pandemic to include COVAXIN, which has received Emergency Use Authorization in India and more than a dozen other countries. Bharat Biotech developed COVAXIN in collaboration with the Indian Council of Medical Research ‒ National Institute of Virology. The company conducted extensive safety studies of Alhydroxiquim-II and undertook the complex process of scaling up production of the adjuvant under Good Manufacturing Practice standards. Bharat Biotech expects to produce an estimated 700 million doses of COVAXIN by the end of 2021.

The Clock is Ticking: as TB claims some 1.4 million lives in 2019

More than a century has passed since the March 24, 1882, announcement by Robert Koch that Mycobacterium tuberculosis (Mtb) bacteria cause tuberculosis (TB), but the disease still ranks as one of the world’s great killers, claiming some 1.4 million lives in 2019 alone.

The National Institute of Allergy and Infectious Diseases (NIAID) of the United states on Wednesday joined the World Health Organization and others in acknowledging the need for continued, concerted efforts to combat TB, even as the world stand in the shadow of the COVID-19 pandemic, which threatens to slow or reverse progress in global TB control.

“The 2021 World TB Day theme, The Clock is Ticking, reminds us that time is of the essence. We cannot delay the research needed to identify, develop, test, and deliver new or improved TB diagnostics, treatments, and vaccines. On this World TB Day, NIAID stands with the global health community in a renewed commitment to ending this disease”.

TB-causing bacteria spread through the air and the disease usually affects the lungs, although other organs and parts of the body can be involved. Most people infected with the disease can co-exist with the bacterium for months, years or a lifetime without ever developing symptoms (termed latent TB infection.)

By some estimates, up to a quarter of the world’s population has latent Mtb infection. People with latent TB infection cannot transmit the bacteria to others. However, they have a 5-to-10% lifetime risk of developing active TB. Symptoms of active pulmonary TB disease include cough, fever, and weight loss. Malnourished individuals, smokers, people receiving immunosuppressive therapies, and those with compromised immune systems, including those with untreated HIV infections, are at increased risk of developing active TB.

In collaboration with the Bill and Melinda Gates Foundation, NIAID is funding studies to analyze clinical samples collected in trials of BCG and M72/AS01 E vaccines. These studies aim to define the immunological basis of the observed protection from TB disease. Defining how and which immune responses correlate with high degrees of disease protection allows investigators to design new and improved TB vaccines.

To further advance the development of potential TB vaccines, NIAID established three Immune Mechanisms of Protection Against Mycobacterium tuberculosis (IMPAc-TB) Centers in 2019. Multi-disciplinary research teams in the Centers are elucidating the immune responses involved in preventing initial TB infection, establishing latent TB infection, or transitioning from latent infection to active TB disease. Findings are informing development of novel TB vaccine candidates.

NIAID says the clock is indeed ticking, and on World TB Day 2021, NIAID takes time to reflect on the dedication of scientists, clinicians, trial volunteers, and others who work tirelessly to make TB a disease of the past.

“We stand with global health partners in firm resolve to apply cutting-edge research, investment, and collaboration to make that day come soon.”

Fourth large-scale COVID-19 vaccine trial begins in the United States

A fourth Phase 3 clinical trial evaluating an investigational vaccine for coronavirus disease 2019 (COVID-19) has begun enrolling adult volunteers. The trial is designed to evaluate if the investigational Janssen COVID-19 vaccine (JNJ-78436725) can prevent symptomatic COVID-19 after a single dose regimen.

The Janssen Pharmaceutical Companies of Johnson & Johnson

Up to 60,000 volunteers will be enrolled in the trial at up to nearly 215 clinical research sites in the United States and internationally.

The Janssen Pharmaceutical Companies of Johnson & Johnson developed the investigational vaccine (also known as Ad.26.COV2.S) and is leading the clinical trial as regulatory sponsor. Janssen, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, are funding the trial.

U.S. and international trial sites part of the NIAID-supported COVID-19 Prevention Network(link is external) (CoVPN) will participate in the trial. The CoVPN is composed of existing NIAID-supported clinical research networks with infectious disease expertise and designed for rapid and thorough evaluation of vaccine candidates and monoclonal antibodies for the prevention of COVID-19.

“Four COVID-19 vaccine candidates are in Phase 3 clinical testing in the United States just over eight months after SARS-CoV-2 was identified. This is an unprecedented feat for the scientific community made possible by decades of progress in vaccine technology and a coordinated, strategic approach across government, industry and academia,” said NIAID Director Anthony S. Fauci, M.D. “It is likely that multiple COVID-19 vaccine regimens will be required to meet the global need. The Janssen candidate has showed promise in early-stage testing and may be especially useful in controlling the pandemic if shown to be protective after a single dose.”

The Janssen vaccine candidate is a recombinant vector vaccine that uses a human adenovirus to express the SARS-CoV-2 spike protein in cells. Adenoviruses are a group of viruses that cause the common cold. However, the adenovirus vector used in the vaccine candidate has been modified so that it can no longer replicate in humans and cause disease. Janssen uses the same vector in the first dose of its prime-boost vaccine regimen against Ebola virus disease (Ad26.ZEBOV and MVA-BN-Filo) that was recently granted marketing authorization by the European Commission.

Preclinical findings published in Nature(link is external) show that the investigational Janssen COVID-19 vaccine induced neutralizing antibody responses in rhesus macaques and provided complete or near-complete protection against virus infection in the lungs and nose following SARS-CoV-2 challenge. The safety, reactogenicity and immunogenicity of the investigational vaccine are being evaluated in a Phase 1/2a trial in the United States and Belgium enrolling adult volunteers. Positive interim results from the Phase 1/2a clinical study demonstrated that the safety profile and immunogenicity after a single vaccination were supportive of further development.

“Scientific partners from government, industry and academia are working hand-in-hand to develop safe, effective vaccines to put this pandemic in our rear-view mirror,” said NIH Director Francis S. Collins, M.D., Ph.D. “While administrative steps are being streamlined to speed the process, safety and effectiveness measures are just as rigorous than ever.”

The Phase 3 trial is being conducted in collaboration with Operation Warp Speed(link is external) (OWS), a multi-agency collaboration overseen by HHS and the Department of Defense that aims to accelerate the development, manufacturing and distribution of medical countermeasures for COVID-19. OWS and CoVPN also are assisting with additional COVID-19 preventive candidate vaccines, including mRNA-1273, an investigational vaccine co-developed by NIAID and the Cambridge, Massachusetts-based biotechnology company Moderna, Inc., and AZD1222, a vaccine candidate being developed by United Kingdom-based biopharmaceutical company AstraZeneca.

“To have just one candidate vaccine in Phase 3 trials less than a year after a virus was first reported would be a remarkable accomplishment; to have four candidates at that stage is extraordinary,” said HHS Secretary Alex Azar. “By building a portfolio of candidate vaccines, Operation Warp Speed is maximizing the chances that we will have substantial supplies of a safe and effective vaccine—and maybe multiple vaccine options—by January 2021.”

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership helped to ensure the protocols of all NIH- and OWS-supported Phase 3 trials of investigational vaccines use the same assays and are designed to evaluate the same primary objective: whether the vaccine can prevent symptomatic COVID-19. This approach enables transparent evaluation of the relative performance of each vaccine approach across trials.

Paul A. Goepfert, M.D., director of the Alabama Vaccine Research Clinic at the University of Alabama in Birmingham; Beatriz Grinsztejn, M.D., Ph.D., director of the Laboratory of Clinical Research on HIV/AIDS at the Evandro Chagas National Institute of Infectious Diseases-Oswaldo Cruz Foundation in Rio de Janeiro, Brazil; and Glenda E. Gray, M.B.B.Ch., president and chief executive officer of the South African Medical Research Council and co-principal investigator of the HIV Vaccine Trials Network (HVTN), will serve as principal investigators for the Phase 3 trial of the investigational Janssen COVID-19 vaccine.

Volunteers must provide informed consent to participate in the trial. After providing a baseline nasopharyngeal and blood sample, participants will be assigned at random to receive either a single dose of the investigational vaccine or a saline placebo. The trial is blinded, meaning neither investigators nor participants will know who is receiving the investigational vaccine. Participants will be followed closely for safety and will be asked to provide additional blood samples at specified time points after the injection and over two years. Scientists will analyze the blood samples to detect and quantify immune responses to COVID-19. Of note, specialized assays will be used that can distinguish between immunity as a result of natural infection and vaccine-induced immunity.

The trial is designed primarily to determine if the investigational vaccine can prevent moderate to severe COVID-19 after a single dose. It also aims to understand if the vaccine can prevent COVID-19 requiring medical intervention and if the vaccine can prevent milder cases of COVID-19 and asymptomatic SARS-CoV-2 infection.

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 Operation Warp Speed are overseen by a common DSMB developed in consultation with ACTIV.

Experimental COVID-19 vaccine safe, generates immune response

An investigational vaccine, mRNA-1273, designed to protect against SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), was generally well tolerated and prompted neutralizing antibody activity in healthy adults, according to interim results published online today in The New England Journal of Medicine.

Colorized scanning electron micrograph of a cell heavily infected with SARS-CoV-2 virus particles (yellow), isolated from a patient sample. The black area in the image is extracellular space between the cells. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. NIAID

The ongoing Phase 1 trial is supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The experimental vaccine is being co-developed by researchers at NIAID and at Moderna, Inc. of Cambridge, Massachusetts. Manufactured by Moderna, mRNA-1273 is designed to induce neutralizing antibodies directed at a portion of the coronavirus “spike” protein, which the virus uses to bind to and enter human cells.

The trial was led by Lisa A. Jackson, M.D., MPH, of Kaiser Permanente Washington Health Research Institute in Seattle, where the first participant received the candidate vaccine on March 16. This interim report details the initial findings from the first 45 participants ages 18 to 55 years enrolled at the study sites in Seattle and at Emory University in Atlanta. Three groups of 15 participants received two intramuscular injections, 28 days apart, of either 25, 100 or 250 micrograms (mcg) of the investigational vaccine. All the participants received one injection; 42 received both scheduled injections.

In April, the trial was expanded to enroll adults older than age 55 years; it now has 120 participants. However, the newly published results cover the 18 to 55-year age group only.

Regarding safety, no serious adverse events were reported. More than half of the participants reported fatigue, headache, chills, myalgia or pain at the injection site. Systemic adverse events were more common following the second vaccination and in those who received the highest vaccine dose. Data on side effects and immune responses at various vaccine dosages informed the doses used or planned for use in the Phase 2 and 3 clinical trials of the investigational vaccine.

The interim analysis includes results of tests measuring levels of vaccine-induced neutralizing activity through day 43 after the second injection. Two doses of vaccine prompted high levels of neutralizing antibody activity that were above the average values seen in convalescent sera obtained from persons with confirmed COVID-19 disease.

A Phase 2 clinical trial of mRNA-1273, sponsored by Moderna,  began enrollment in late May. Plans are underway to launch a Phase 3 efficacy trial in July 2020.

Researchers closer to treat severe respiratory distress in patients with COVID-19

Study identifies potential approach to treat severe respiratory distress in patients with COVID-19

Early data from a clinical study suggest that blocking the Bruton tyrosine kinase (BTK) protein provided clinical benefit to a small group of patients with severe COVID-19.

Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, MarylandNIAID

Researchers observed that the off-label use of the cancer drug acalabrutinib, a BTK inhibitor that is approved to treat several blood cancers, was associated with reduced respiratory distress and a reduction in the overactive immune response in most of the treated patients.

The findings were published June 5, 2020, in Science Immunology. The study was led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), in collaboration with researchers from the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health, as well as the U.S. Department of Defense’s Walter Reed National Military Medical Center, and four other hospitals nationally.

These findings should not be considered clinical advice but are being shared to assist the public health response to COVID-19. While BTK inhibitors are approved to treat certain cancers, they are not approved as a treatment for COVID-19. This strategy must be tested in a randomized, controlled clinical trial in order to understand the best and safest treatment options for patients with severe COVID-19.

The BTK protein plays an important role in the normal immune system, including in macrophages, a type of innate immune cell that can cause inflammation by producing proteins known as cytokines. Cytokines act as chemical messengers that help to stimulate and direct the immune response. In some patients with severe COVID-19, a large amount of cytokines are released in the body all at once, causing the immune system to damage the function of organs such as the lungs, in addition to attacking the infection. This dangerous hyperinflammatory state is known as a “cytokine storm.” At present, there are no proven treatment strategies for this phase of the illness. The study was developed to test whether blocking the BTK protein with acalabrutinib would reduce inflammation and improve the clinical outcome for hospitalized patients with severe COVID-19.

This prospective off-label clinical study included 19 patients with a confirmed COVID-19 diagnosis that required hospitalization, as well as with low blood-oxygen levels and evidence of inflammation. Of these patients, 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 (range 1-22) days.

Within one to three days after they began receiving acalabrutinib, the majority of patients in the supplemental oxygen group 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. Although the benefit of acalabrutinib was less dramatic in patients on ventilators, four of the eight patients were able to come off the ventilator, two of whom were eventually discharged. The authors note that the ventilator patient group was extremely clinically diverse and included patients who had been on a ventilator for prolonged periods of time and had major organ dysfunction. Two of the patients in this group died.

Blood samples from patients in the study 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. A low lymphocyte count has been associated with worse outcome for patients with severe COVID-19. The researchers also tested blood cells from patients with severe COVID-19 who were not in the study. In comparison with samples from healthy volunteers, they found that these patients with severe COVID-19 had higher activity of the BTK protein and greater production of IL-6. These findings suggest that acalabrutinib may have been effective because its target, BTK, is hyperactive in severe COVID-19 immune cells.

The results of this study were used to inform the trial design of the CALAVI (acalabrutinib) randomized, controlled clinical trial, sponsored by AstraZeneca, which will examine the safety and efficacy of acalabrutinib in patients with severe COVID-19.