NIH launches clinical trial of universal influenza vaccine candidate

A first-in-human, Phase 1 trial assessing the safety and immunogenicity of an investigational nanoparticle influenza vaccine designed to provide long-lasting protection against multiple flu virus strains has begun at the National Institutes of Health Clinical Center in Bethesda, Maryland.

Healthy participants 18 to 50 years old will receive either a licensed seasonal influenza vaccine or the experimental vaccine, FluMos-v1. Scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) developed FluMos-v1 to stimulate antibodies against multiple influenza virus strains by displaying part of the influenza virus hemagglutinin (HA) protein on self-assembling nanoparticle scaffolds. Alicia T. Widge, M.D., of NIAID’s Vaccine Research Center (VRC), is the principal investigator of the NIAID-sponsored single-site trial. 

“The health and economic burdens of influenza are substantial, and the world badly needs improved flu vaccines,” said NIAID Director Anthony S. Fauci, M.D.  “I am encouraged by the great promise of the VRC nanoparticle vaccine candidate, which so far has performed very well in pre-clinical testing.”

Standard influenza vaccines must be reformulated and administered annually to match changes in the HA protein in the viral strains predicted to dominate in the upcoming influenza season. If the vaccine is not well matched to dominant circulating virus strains, the antibodies elicited may provide sub-optimal protection. So-called universal influenza vaccines are being developed and tested by many research groups and could one day eliminate the need for annual vaccination by generating long-lasting antibodies to protect against many existing or emergent influenza virus strains, including those not represented in the vaccine.

Similar to commercially available flu vaccines, the experimental nanoparticle FluMos-v1 vaccine is designed to elicit antibodies directed against the HA protein from four different virus strains, two influenza type A strains of H1 and H3 subtype and two influenza type B strains. However, unlike conventional flu vaccines, FluMos-v1 displays multiple copies of each of the four HA types. The 20 HA epitopes arrayed in repeating patterns on the nanoparticle scaffolds sent a strong signal to the immune system and prompted a robust antibody response in animal models.

In their recently published animal study, VRC scientists led by Barney S. Graham, M.D., Ph.D., and Masaru Kanekiyo, D.V.M., Ph.D., and their collaborators from the University of Washington tested the investigational nanoparticle vaccine in mice, ferrets and monkeys, and compared the immune responses generated to those made by a commercially available seasonal flu vaccine. FluMos-v1 performed as well as or slightly better than the commercial vaccine in eliciting antibodies matched to the vaccine’s HA components. FluMos-v1 vastly outperformed the seasonal flu vaccine in its ability to elicit protective antibodies to two influenza type A subtypes (H5 and H7) not in the vaccine. 

The clinical trial aims to enroll 35 participants, 15 of whom will receive a single intramuscular injection of an FDA-licensed, quadrivalent seasonal flu vaccine. Five participants will receive one 20-microgram (mcg) dose of the investigational vaccine by intramuscular injection. If there are no safety concerns detected at that dosage, an additional 15 volunteers will receive one 60-mcg dose of the investigational vaccine.

Participants will keep a diary for a week following vaccination in which to report any signs or symptoms, including redness, pain or swelling at the injection site, tiredness, headache, muscle aches or joint pain. All volunteers will record their temperature daily and will measure any swelling or redness at the injection site. Volunteers will return to the NIH Clinical Center periodically for 40 weeks—over one flu season — after inoculation and will provide blood samples. The blood samples will yield information about the safety of the investigational vaccine and also will be assessed to determine levels of HA-directed antibodies produced following vaccination. Participants who receive FluMos-v1 will have oral mucosal samples taken that will be used for research purposes to determine the oral mucosal immune response to the vaccine.

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.

Drug reverses signs of liver disease in people living with HIV

Researchers at the National Institutes of Health and their colleagues at Massachusetts General Hospital (MGH) in Boston report that the injectable hormone tesamorelin reduces liver fat and prevents liver fibrosis (scarring) in people living with HIV.

The study was conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute, both parts of NIH. The findings were published online today in The Lancet HIV

A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes). Dr. David Kleiner, NCI

“Many people living with HIV have overcome significant obstacles to live longer, healthier lives, though many still experience liver disease,” said NIAID Director Anthony S. Fauci, M.D. “It is encouraging that tesamorelin, a drug already approved to treat other complications of HIV, may be effective in addressing non-alcoholic fatty liver disease.”

Non-alcoholic fatty liver disease, or NAFLD, frequently occurs alongside HIV, affecting as many as 25% of people living with HIV in the developed world. However, no effective treatments currently exist to treat the condition, which is a risk factor for progressive liver disease and liver cancer. Investigators led by Colleen M. Hadigan, M.D., senior research physician in NIAID’s Laboratory of Immunoregulation, and Steven K. Grinspoon, M.D., Chief of the Metabolism Unit at MGH, tested whether tesamorelin could decrease liver fat in men and women living with both HIV and NAFLD. Among the participants enrolled, 43% had at least mild fibrosis, and 33% met the diagnostic criteria for a more severe subset of NAFLD called nonalcoholic steatohepatitis (NASH). Thirty-one participants were randomized to receive daily 2-mg injections of tesamorelin, and 30 were randomized to receive identical-looking injections containing a placebo. Researchers provided nutritional counseling to all participants, as well as training in self-administering the daily injections. Researchers then compared measures of liver health in both groups at baseline and 12 months.

After one year, participants receiving tesamorelin had better liver health than those receiving placebo, as defined by reduction in hepatic fat fraction (HFF)—the ratio of fat to other tissue in the liver. The healthy range for HFF is less than 5%. Thirty-five percent of study participants receiving tesamorelin achieved a normal HFF, while only 4% of those on placebo reached that range with nutritional advice alone. Overall, tesamorelin was well-tolerated and reduced participants’ HFF by an absolute difference of 4.1% (corresponding to a 37% relative reduction from the beginning of the study). While nine participants receiving placebo experienced onset or worsening of fibrosis, only two participants in the tesamorelin group experienced the same. Additionally, levels of several blood markers associated with inflammation and liver damage — including the enzyme alanine aminotransferase (ALT) — decreased more among those taking tesamorelin compared to those on a placebo, particularly among those with increased levels at the beginning of the study.

Given these positive results, investigators suggest expanding the indication for tesamorelin to include people living with HIV who have been diagnosed with NAFLD. They also recommend additional research to determine if tesamorelin could contribute to long-term protection against serious liver disease in people without HIV.

“Our hope is that this intervention may help people living with HIV, as well as benefit HIV-negative people with liver abnormalities,” said Dr. Hadigan. “Further research may inform us of the potential long-term benefits of this approach and develop formulations that can benefit everyone with liver disease, regardless of HIV status.”

Egrifta (tesamorelin) was approved in 2010 by the U.S. Food and Drug Administration to reduce excess abdominal fat in HIV patients with lipodystrophy — a complication characterized by an abnormal distribution of body fat initially associated with older classes of HIV medications. The most commonly reported side effects in previous clinical trials evaluating Egrifta included joint pain (arthralgia), skin redness and rash at the injection site (erythema and pruritis), stomach pain, swelling, and muscle pain (myalgia). Worsening blood sugar control occurred more often in trial participants treated with Egrifta than with placebo.

“Because tesamorelin proved effective in treating abnormal fat build-up in the abdomens of people in the context of HIV and related medication use, we hypothesized that the drug might also reduce fat that accrues in the liver and causes damage in a similar population,” said Dr. Grinspoon.

While liver disease is often associated with heavy alcohol use, NAFLD occurs when excess fat builds up in the liver without alcohol as a contributing factor. This condition may progress to liver damage, cirrhosis or cancer that could be life-threatening and necessitate liver transplantation.

Previous studies have found that vitamin E supplements, weight loss and other lifestyle changes can improve outcomes among HIV-negative people with NASH. However, treatment options for NASH and NAFLD are often not tested in people with HIV and none are available for this group. Obesity and type 2 diabetes raise the risk of developing NAFLD regardless of HIV status, and people with HIV are at increased risk of NAFLD because some HIV medications and HIV itself are associated with gaining abdominal fat and may contribute to liver fat build-up.

FDA-approved drug effectively treats rare chronic immune disorder

Small NIH clinical trial conducted in partnership with AstraZeneca.

A drug approved to treat a severe form of asthma dramatically improved the health of people with rare chronic immune disorders called hypereosinophilic syndromes (HES) in whom other treatments were ineffective or intolerable.

Activated eosinophils in the peripheral blood of a patient with idiopathic hypereosinophilic syndrome.NIAID

This finding comes from a small clinical trial led by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted through a partnership with the global biopharmaceutical company AstraZeneca. The results were published online today in the New England Journal of Medicine.

“People living with a rare disease often have few, if any, effective treatment options,” said NIAID Director Anthony S. Fauci, M.D. “This promising treatment advance for people with hypereosinophilic syndromes is just one example of how NIH research responds to the unique medical needs of individuals with rare diseases.”

HES is caused by higher-than-normal numbers of white blood cells called eosinophils(link is external) in the blood, tissues or both. While most people have 0 to 500 eosinophils per microliter (µL) of blood, people with HES typically have more than 1,500 eosinophils/µL. The symptoms of HES vary widely from one patient to the next and can affect the heart, lungs, skin, gastrointestinal tract, central nervous system and other organ systems.

Nearly all existing therapies for HES involve drugs that are not specifically approved for treating the syndromes, have significant side effects and sometimes become less effective over time. The study reported today was only the second randomized, placebo-controlled trial — the gold standard of medical research — to test the effectiveness of a drug specifically for treating HES. The trial was led by Amy Klion, M.D., chief of the Human Eosinophil Section in the NIAID Laboratory of Parasitic Diseases.

The medication tested in this Phase 2 clinical trial is benralizumab, also known by the brand name Fasenra. It consists of an antibody that binds to a protein, called IL-5 receptor a, found on the surface of eosinophils. Scientists hypothesize that once this binding takes place, immune cells called natural killer cells approach and destroy the eosinophils.

In an earlier clinical trial, benralizumab safely improved the symptoms of people who have a form of asthma associated with an excess of eosinophils in the lungs. Subsequently, the U.S. Food and Drug Administration approved the drug for treating this condition, called severe eosinophilic asthma. AstraZeneca developed and manufactures benralizumab and provided it for the HES trial through a cooperative research and development agreement with NIAID.

The NIAID trial involved 20 people with severe forms of HES who had at least 1,000 eosinophils/µL of blood when they enrolled in the study and whose condition had been stable on other HES therapies for at least a month before enrolling. These study participants all lacked a genetic marker associated with a type of HES that responds to treatment with a different drug. All study visits took place at the NIH Clinical Center in Bethesda, Maryland.

The trial had three phases over a period of 48 weeks. At the start of the first phase, which lasted 12 weeks, study participants were assigned at random to receive either 30 mg of benralizumab or a placebo solution through an injection under the skin once every 4 weeks while continuing to take their current HES therapy. Neither the participants nor the investigators knew who was receiving the study drug or what the participants’ eosinophil counts were during this first phase.

In the second phase, which lasted from week 12 to week 24, all study participants were given 30 mg of benralizumab through an injection under the skin once every 4 weeks. Eosinophil counts were revealed beginning at week 13, and participants could taper their original HES therapy if doing so was tolerable.

During the third phase, those participants whose symptoms or eosinophil counts had improved by week 24 could continue receiving benralizumab until week 48.

At the end of the first phase, blood eosinophil levels were undetectable in nine of the 10 participants who received benralizumab and had declined by 50 percent or more in three of the 10 participants who received the placebo. While the use of an immunosuppressive drug explained why eosinophil counts declined in one of the placebo recipients, the reason for the decline in the other two placebo recipients is unknown.

After at least 12 weeks of benralizumab therapy during the first phase, second phase or both, 17 of 19 participants had undetectable levels of eosinophils in the blood and a reduction in HES-related symptoms, with few or no side effects. (One person withdrew from the study at week 6 for logistical reasons.) These beneficial responses lasted through the end of the third phase in 14 of 19 participants, (74 percent). Nine of those 14 participants (64 percent) were able to taper off other HES therapies during the third phase. The 14 participants continued taking benralizumab for another year after completing the third phase.

In addition, eosinophils were undetectable in the bone marrow of nine of the 10 participants in the treatment group in the first phase, and in the tissue of all eight participants whose tissue was tested at the end of the second phase.

A larger placebo-controlled trial of benralizumab for treating HES is needed to confirm these results, according to the study investigators.

“We are grateful for the dedication of our study participants, who gave so generously of their time and were willing to undergo numerous invasive tests to help improve treatment options for the HES community,” said Fei Li Kuang, M.D., Ph.D., lead associate investigator on the study and a clinical fellow in the Human Eosinophil Section of the NIAID Laboratory of Parasitic Diseases.