NIAID Research Suggests Protective Effects of Vaccination Remain Intact of

While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.    

Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.

When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective.

To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2—the CD8+ T cell—remained active against the virus.

The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the immunomics-focused company, ImmunoScape.

The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination. 

Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response.  CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells. 

Clinical trials of monoclonal antibodies to prevent COVID-19 now enrolling

Two Phase 3, randomized, placebo-controlled, double-blind clinical trials testing whether experimental monoclonal antibodies (mAbs) can prevent infection by SARS-CoV-2 coronavirus are now enrolling healthy adults at clinical trial sites in the United States.

Image of an antibody binding to the surface of a virus, blocking entry into a human cell.Lisa Donohue, CoVPN

Many of the trial sites and study investigators are part of the COVID-19 Prevention Network(link is external) (CoVPN), recently established by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health. SARS-CoV-2 is the virus that causes coronavirus disease 2019 (COVID-19). The trials are enrolling adults who are at risk of infection due to close contact at work or home to persons with SARS-CoV-2 infection.

“The COVID-19 Prevention Network is designed to conduct large-scale trials rapidly and efficiently,” said NIAID Director Anthony S. Fauci, M.D. “This network will allow us to test the safety and efficacy of monoclonal antibodies and other preventive measures to help identify how best to reduce the level of SARS-CoV-2 infection and ultimately end the COVID-19 pandemic.”   

Monoclonal antibodies(link is external) are laboratory-made versions of proteins naturally produced by the immune system in response to invading viruses or other pathogens. Neutralizing antibodies, whether natural or monoclonal, can bind directly to portions of viruses that they use to attach to and enter cells, preventing them from initiating the infection cycle. Monoclonal antibodies may provide short-term protection from SARS-CoV-2 and could serve as important components of the COVID-19 pandemic response until vaccines become available.

One trial is being conducted jointly by NIAID and trial sponsor Regeneron Pharmaceuticals of Tarrytown, New York. It will evaluate Regeneron’s investigational double mAb combination, REGN-COV-2, which is designed to bind to two points on the SARS-CoV-2 spike protein and prevent it from entering healthy cells. The trial will enroll approximately 2,000 asymptomatic adults who are household contacts of persons with SARS-CoV-2 infection. Participants must have been in close contact (typically due to residing at the same address) with the infected person in a 96-hour window preceding administration of either REGN-CoV-2 or placebo. In addition to assessing safety, the trial will seek to define whether REGN-COV-2 can prevent infection or disease symptoms in those already infected. The efficacy assessment will be a one-month period following administration of REGN-COV-2 or placebo. All trial participants will be followed for safety for seven months after efficacy assessment period ends.

COVID-19 a Reminder of the Challenge of Emerging Infectious Diseases

The emergence and rapid increase in cases of coronavirus disease 2019 (COVID-19), a respiratory illness caused by a novel coronavirus, pose complex challenges to the global public health, research and medical communities, write federal scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and from the Centers for Disease Control and Prevention (CDC). Their commentary appears in The New England Journal of Medicine.

This transmission electron microscope image shows SARS-CoV-2—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S. Virus particles are shown emerging from the surface of cells cultured in the lab. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. NIAID-RML

NIAID Director Anthony S. Fauci, M.D., NIAID Deputy Director for Clinical Research and Special Projects H. Clifford Lane, M.D., and CDC Director Robert R. Redfield, M.D., shared their observations in the context of a recently published report on the early transmission dynamics of COVID-19. The report provided detailed clinical and epidemiological information about the first 425 cases to arise in Wuhan, Hubei Province, China.

In response to the outbreak, the United States and other countries instituted temporary travel restrictions, which may have slowed the spread of COVID-19 somewhat, the authors note. However, given the apparent efficiency of virus transmission, everyone should be prepared for COVID-19 to gain a foothold throughout the world, including in the United States, they add. If the disease begins to spread in U.S. communities, containment may no longer be a realistic goal and response efforts likely will need to transition to various mitigation strategies, which could include isolating ill people at home, closing schools and encouraging telework, the officials write.

Drs. Fauci, Lane and Redfield point to the many research efforts now underway to address COVID-19. These include numerous vaccine candidates proceeding toward early-stage clinical trials as well as clinical trials already underway to test candidate therapeutics, including an NIAID-sponsored trial of the experimental antiviral drug remdesivir that began enrolling participants on February 21, 2020. 

“The COVID-19 outbreak is a stark reminder of the ongoing challenge of emerging and re-emerging infectious pathogens and the need for constant surveillance, prompt diagnosis and robust research to understand the basic biology of new organisms and our susceptibilities to them, as well as to develop effective countermeasures,” the authors conclude.

NIH to Test Experimental Drug to Curb Opioid Cravings

A clinical trial of an experimental drug designed to treat cravings associated with opioid use disorder (OUD) has begun in the National Institutes of Health Clinical Center.

A volunteer holds one day’s dose of the experimental drug ANS-6637
Credit: NIAID

The Phase I trial in healthy adults will assess the safety of the experimental compound, ANS-6637, and how it is processed in the body when given with another drug that is processed by the same liver enzyme pathway. The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) is helping to conduct the trial, which is funded through NIH’s Helping to End Addiction Long-Term (HEAL(link is external)) Initiative, a comprehensive program to accelerate research efforts to stem the public health crisis of OUD.

“Opioid drugs play an important role in controlling pain, but have strong potential for misuse, as evidenced by the opioid epidemic gripping every region of the United States. Opioid misuse and addiction are associated with high-risk behaviors that may lead directly or indirectly to infections with HIV or hepatitis C virus, to other illnesses, and to premature death,” said NIAID Director Anthony S. Fauci, M.D. “Because substance use disorders and certain infectious diseases are often intertwined, infectious disease physicians must understand and be prepared to address both issues in order to provide optimal care for their patients.”

Opioid use causes a surge of the neurotransmitter dopamine in the brain, and habitual use ‘rewires’ the brain’s reward system, possibly generating irresistible cravings to both opioids and associated cues, like injecting equipment or drug use partners.

“At this time, there are few pharmacological interventions that specifically target the cravings felt by some patients who have physical dependence or opioid use disorder,” noted Henry Masur, M.D., chief of the Clinical Center’s Critical Care Medicine Department, and a principal investigator in the new trial. “This trial will lay the groundwork for future studies; together these may lead to effective treatments for the drug cravings that impede the pursuit of sobriety.”

ANS-6637 is being developed by Amygdala Neurosciences, Inc. Pre-clinical studies in animals suggest that the compound inhibits the dopamine surge that accompanies opioid use in persons with OUD, without impacting the background levels of dopamine required for normal brain functions.

The trial will enroll up to 50 healthy adults aged 18 through 65 years. Participants will stay in the Clinical Center in Bethesda, Maryland, for 10 days and return for a final outpatient visit after one week. On the first day, volunteers will receive a single dose of the licensed drug midazolam. Midazolam was chosen because its processing by the body is well understood, acting as a template for liver metabolism. They will receive no drug on day two. On study days three through seven, volunteers will receive 600 milligrams of ANS-6637 each day. On day eight, participants will receive midazolam and ANS-6637 together to see how the investigational agent affects midazolam levels. This in turn will help researchers understand how ANS-6637 is processed by the body, setting up the next phase of scientific investigation in patients with OUD.  

“Opioid use disorder is a treatable medical illness that, much like in the early days of HIV, has been held back from scientific advancement by stigma and misconception,” said Sarah Kattakuzhy, M.D., associate investigator and assistant professor at the Institute of Human Virology at the University of Maryland School of Medicine in Baltimore. “With the support of the HEAL Initiative and NIAID, we can now assess a novel potential therapeutic in the treatment of OUD. If proven effective, ANS-6637 could be part of a comprehensive package of services, including harm reduction, opioid agonist therapy and behavioral interventions, enabling us to offer our patients the highest level of evidence-based therapy.” Dr. Kattakuzhy and colleagues are planning further study of ANS-6637 as a treatment for OUD in clinical trials at the University of Maryland School of Medicine.

Scientists Identify Unique Subtype of Eczema Linked to Food Allergy

Children with Both Conditions have Abnormal Skin Near Eczema Lesions, NIH-Funded Research Finds

A researcher demonstrates the minimally invasive collection of skin samples using small, clear tape strips.
Credit: National Jewish Health

Atopic dermatitis, a common inflammatory skin condition also known as allergic eczema, affects nearly 20 percent of children, 30 percent of whom develop food allergies.

Scientists have now found that children with both atopic dermatitis and food allergy have structural and molecular differences in the top layers of healthy-looking skin near the eczema lesions, whereas children with atopic dermatitis alone do not.

Defining these differences may help identify children at elevated risk for developing food allergies, according to research published online today in Science Translational Medicine. The research was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. 

“Children and families affected by food allergies must constantly guard against an accidental exposure to foods that could cause life-threatening allergic reactions,” said NIAID Director Anthony S. Fauci, M.D. “Eczema is a risk factor for developing food allergies, and thus early intervention to protect the skin may be one key to preventing food allergy.” Children with atopic dermatitis develop patches of dry, itchy, scaly skin caused by allergic inflammation.  Atopic dermatitis symptoms range from minor itchiness to extreme discomfort that can disrupt a child’s sleep and can lead to recurrent infections in scratched, broken skin.

A drawing of skin and a hair follicle. In this study, scientists analyzed the outermost layer of the skin, the stratum cornea, highlighted here in yellow.Credit: NIAMS, NIH

The study, led by Donald Y.M. Leung, M.D., Ph.D., of National Jewish Health in Denver, examined the top layers of the skin, known as the stratum corneum, in areas with eczema lesions and in adjacent normal-looking skin. The study enrolled 62 children aged 4 to 17 who either had atopic dermatitis and peanut allergy, atopic dermatitis and no evidence of any food allergy, or neither condition. Investigators collected skin samples by applying and removing small, sterile strips of tape to the same area of skin. With each removal, a microscopic sublayer of the first layer of skin tissue was collected and preserved for analysis. This technique allowed researchers to determine the skin’s composition of cells, proteins and fats, as well as its microbial communities, gene expression within skin cells and water loss through the skin barrier.

Researchers found that the skin rash of children with both atopic dermatitis and food allergy was indistinguishable from the skin rash of children with atopic dermatitis alone. However, they found significant differences in the structure and molecular composition of the top layer of non-lesional, healthy-appearing skin between children with atopic dermatitis and food allergy compared with children with atopic dermatitis alone. Non-lesional skin from children with atopic dermatitis and food allergy was more prone to water loss, had an abundance of the bacteria Staphylococcus aureus, and had gene expression typical of an immature skin barrier. These abnormalities also were seen in skin with active atopic dermatitis lesions, suggesting that skin abnormalities extend beyond the visible lesions in children with atopic dermatitis and food allergy but not in those with atopic dermatitis alone.

“Our team sought to understand how healthy-looking skin might be different in children who develop both atopic dermatitis and food allergy compared to children with atopic dermatitis alone,” said Dr. Leung. “Interestingly, we found those differences not within the skin rash but in samples of seemingly unaffected skin inches away. These insights may help us not only better understand atopic dermatitis, but also identify children most at risk for developing food allergies before they develop overt skin rash and, eventually, fine tune prevention strategies so fewer children are affected.”

Allergy experts consider atopic dermatitis to be an early step in the so-called “atopic march,” a common clinical progression found in some children in which atopic dermatitis progresses to food allergies and, sometimes, to respiratory allergies and allergic asthma. Many immunologists hypothesize that food allergens may reach immune cells more easily through a dysfunctional skin barrier affected by atopic dermatitis, thereby setting off biological processes that result in food allergies. 

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Reference:  D Leung et al. Non-lesional skin surface distinguishes atopic dermatitis with food allergy as unique endotype. Science Translational Medicine DOI: 10.1126/scitranslmed.aav2685 (2019).

NIAID Scientists Investigate How Exercise Exacerbates Symptoms of Rare Disease

People with a rare disease called mastocytosis must do their cardio with caution.

NIAID staff do a warm-up before taking a run or brisk walk.

Mastocytosis occurs when a person has too many mast cells(link is external), a type of white blood cell. Mast cells normally play a healthy role by releasing granules filled with chemicals that cause inflammation, which allows immune cells and other helpful particles in the blood to reach a site of infection or injury more easily. However, having too many mast cells can lead to the release of too much of these inflammatory chemicals, causing symptoms such as flushing, severe itching, abdominal pain, diarrhea, and fainting due to a sudden drop in blood pressure.

Scientists have reported that physical factors including exercise can worsen mastocytosis-related symptoms. To better understand the relationship between exercise and these symptoms, scientists led by NIAID researcher Hirsh Komarow, M.D., explored whether physical exercise triggers the release of mast-cell chemicals in people with mastocytosis. Dr. Komarow is a staff clinician in the NIAID Laboratory of Allergic Diseases.

Dr. Komarow and colleagues focused on two chemicals released by mast cells, histamine and tryptase. In people with mastocytosis, blood-serum levels of these chemicals rose significantly after physical exercise, supporting the hypothesis that physical activity can induce mast cells to release inflammatory chemicals. The increase in histamine and tryptase levels after exercise was significantly greater in people with mastocytosis than in healthy individuals. The scientists also found that the post-exercise increase in blood levels of these chemicals was associated with a worsening of mastocytosis-related symptoms.

Dr. Komarow advises that people with mastocytosis consult their physicians about how to manage any worsening of symptoms during and after exercise, noting that medication such as an antihistamine could potentially help. In addition, Dr. Komarow recommends that people with mastocytosis know how to self-administer epinephrine to treat anaphylaxis, should it occur.

The results of this study were recently published in The Journal of Allergy and Clinical Immunology: In Practice

NIAID Scientists develops a novel treatment for HIV infection

With more than 70 million people reportedly infected with the HIV virus, Scientists at the NIAID Laboratory of Viral Diseases have developed a novel treatment for HIV infection.

HIV-infected T cell. Scanning electron micrograph of an HIV-infected T cell. Credit: NIAID

The scientists developed nucleic acids that encode novel chimeric antigen receptor (CAR) proteins that can be used to specifically kill HIV-infected cells within HIV-infected individuals.

When the CARs are expressed on host T cells (CAR T cells), they can be used to specifically kill HIV-infected cells within HIV-infected individuals. This technology can also be used to protect uninfected cells within HIV-infected individuals by rendering them resistant to infection by HIV.

There is a growing body of in vitro and in vivo data that provides support for the continued development of NIAID’s CAR T-cells as a treatment, and potential cure, for HIV infection

According to the World Health Organization (WHO), more than 70 million have been infected with the HIV virus and about 35 million people have died of HIV.

Since the beginning of the epidemic, more than 70 million people have been infected with the HIV virus and about 35 million people have died of HIV. Globally, 36.7 million [30.8–42.9 million] people were living with HIV at the end of 2016. An estimated 0.8% [0.7-0.9%] of adults aged 15–49 years worldwide are living with HIV, although the burden of the epidemic continues to vary considerably between countries and regions. Sub-Saharan Africa remains most severely affected, with nearly 1 in every 25 adults (4.2%) living with HIV and accounting for nearly two-thirds of the people living with HIV worldwide. – WHO

NIAID scientists say the potential commercial applications include therapy for HIV infection and research on antiretroviral infection while it will also enhance potency for HIV inhibition and does not render transduced CD8T cells susceptible to HIV infection.