Tag Archives: Placebo

Microbiology

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

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Reviewed by Lily Ramsey, LLMMay 25 2023

Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

  • Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
  • Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
  • Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
  • Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
  • LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
  • CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
  • CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

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Source:

Fred Hutchinson Cancer Center

Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Microbiology

First clinical trial of GABA/GAD focused exclusively on children with recent onset Type 1 diabetes

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Reviewed by Emily Henderson, B.Sc.Feb 22 2023

For the first time, humans with newly diagnosed Type 1 diabetes, or T1D, have received two treatments called GABA and GAD that have shown promise in animal studies and in isolated human pancreas islets. This investigator-initiated clinical trial, published in Nature Communications, focused exclusively on children with recent onset T1D.

Diabetes is a disease affecting two pancreatic hormones -; insulin and glucagon. In healthy people, insulin helps cells take up glucose from the blood when glucose levels are high. In contrast, glucagon helps the liver release glucose into the bloodstream when glucose levels are low. Thus, levels of blood glucose remain steady.

In T1D, autoantibodies destroy the pancreatic beta cells, insulin release is diminished, and glucagon release is excessive relative to the insulin deficiency. This can cause a vicious cycle of escalating blood glucose levels. Strategies to ameliorate or cure T1D, therefore, target the preservation of insulin-secreting beta cells and/or attenuation of the relative excess of alpha cell glucagon. Most importantly, concerning the inhibition of alpha cell glucagon in this trial by GABA/GAD, recent studies in animals made diabetic have shown that inhibition of glucagon leads to expansion of insulin-secreting beta cells and improvements in hyperglycemia.

Researchers in the study, led by University of Alabama at Birmingham physicians, were able to enroll children within the first five weeks of diagnosis, before the near total eradication of beta cells. Forty percent of the study participants were younger than 10 years old. The study -; which was constrained to lower-dose GABA therapy by the United States Food and Drug Administration because it was the first human trial with GABA -; did not achieve its primary outcome, the preservation of insulin production by beta cells. However, it did meet the clinically relevant secondary outcome of reduced serum glucagon. Significantly, the trial confirmed the safety and tolerability of oral GABA. Additionally, in collaboration with the immunology team of Hubert Tse, Ph.D., at the UAB Comprehensive Diabetes Center, a separate manuscript under review will describe a salutary effect of GABA alone and in combination with GAD on cytokine responses in peripheral blood mononuclear cells from trial participants.

GABA is gamma aminobutyric acid, a major inhibitory neurotransmitter. In the endocrine pancreas, GABA participates in paracrine regulation -; meaning a hormone that acts on nearby cells -; on the beta cells that produce insulin and the alpha cells that produce glucagon. In various mouse model studies, GABA was able to delay diabetes onset, and restore normal blood glucose levels after diabetes had already commenced. GABA treatment also led to significant decreases in the inflammatory cytokine expression that participates in the pathogenesis of T1D.

GAD is glutamic acid decarboxylase, the enzyme that acts on glutamate to form GABA. Animal and pancreatic islet cell studies show that immunization with GAD alone may help preserve beta cells. Both GABA and GAD are highly concentrated in the pancreatic islet, which is the autoimmune target of T1D.

The study, which was conducted between March 2015 and June 2019, screened 350 patients and enrolled 97, whose ages averaged 11 years. Forty-one took oral GABA twice a day; 25 took the oral GABA in combination with two injections of GAD, one at the baseline visit and one at the one-month visit. The remaining 31 children received a placebo treatment. Analysis after one year of treatment included 39 in the GABA group, 22 in the GABA/GAD group and 30 in the placebo group.

Given that GABA reduces immune inflammation at higher doses in several diabetic rodent models, it is plausible that increased GABA doses, or longer-acting preparations, could offer sufficiently prolonged, above-threshold GABA concentrations to preserve islet cells, particularly during stage 1 diabetes.”

Gail Mick, M.D., UAB Professor in the Department of Pediatrics’ Division of Pediatric Endocrinology and Diabetes

Mick and Kenneth McCormick, M.D., who recently retired from UAB Pediatrics, co-led the trial.

Alexandra Martin and Mick, UAB Department of Pediatrics, are co-first authors of the study, “A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes.”

Other authors are Heather M. Choat, Alison A. Lunsford and Kenneth L. McCormick, UAB Department of Pediatrics; Hubert M. Tse, UAB Department of Microbiology; and Gerald G. McGwin Jr., Department of Epidemiology, UAB School of Public Health.

Source:

University of Alabama at Birmingham

Journal reference:

Martin, A., et al. (2022) A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. Nature Communications. doi.org/10.1038/s41467-022-35544-3.

Microbiology

Clinical trial to evaluate antiviral drug for monkeypox begins in the Democratic Republic of the Congo

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Reviewed by Emily Henderson, B.Sc.Oct 12 2022

A clinical trial to evaluate the antiviral drug tecovirimat, also known as TPOXX, in adults and children with monkeypox has begun in the Democratic Republic of the Congo (DRC). The trial will evaluate the drug’s safety and its ability to mitigate monkeypox symptoms and prevent serious outcomes, including death. The National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, and the DRC’s National Institute for Biomedical Research (INRB) are co-leading the trial as part of the government-to-government PALM partnership. Collaborating institutions include the U.S. Centers for Disease Control and Prevention (CDC), the Institute of Tropical Medicine Antwerp, the aid organization Alliance for International Medical Action (ALIMA) and the World Health Organization (WHO).

TPOXX, made by the pharmaceutical company SIGA Technologies, Inc. (New York), is approved by the U.S. Food and Drug Administration for the treatment of smallpox. The drug impedes the spread of virus in the body by preventing virus particles from exiting human cells. The drug targets a protein that is found on both the virus that causes smallpox and the monkeypox virus.

“Monkeypox has caused a high burden of disease and death in children and adults in the Democratic Republic of the Congo, and improved treatment options are urgently needed,” said NIAID Director Anthony S. Fauci, M.D. “This clinical trial will yield critical information about the safety and efficacy of tecovirimat for monkeypox. I want to thank our DRC scientific partners as well as the Congolese people for their continued collaboration in advancing this important clinical research.”

Since the 1970s, monkeypox virus has caused sporadic cases and outbreaks, primarily in the rainforest areas of central Africa, and in west Africa. A multi-continent outbreak of monkeypox in areas where the disease is not endemic, including Europe and the United States, has been ongoing since May 2022 with the majority of cases occurring in men who have sex with men. The outbreak has prompted recent public health emergency declarations from the WHO and the U.S. Department of Health and Human Services. From Jan.1, 2022 to Oct. 5, 2022, the WHO has reported 68,900 confirmed cases and 25 deaths from 106 countries, areas and territories.

According to the WHO, cases identified as part of the ongoing global outbreak are largely caused by monkeypox virus Clade IIb. Clade I, which is estimated to cause more severe disease and higher mortality than Clade IIa and Clade IIb, especially in children, is responsible for infections in the DRC. The Africa Centres for Disease Control and Prevention (Africa CDC) has reported 3,326 cases of monkeypox (165 confirmed; 3,161 suspected) and 120 deaths in the DRC from Jan. 1, 2022 to Sept. 21, 2022.

People can become infected with monkeypox through contact with infected animals, such as rodents, or nonhuman primates or humans. The virus can transmit among humans by direct contact with skin lesions, body fluids, and respiratory droplets, including through intimate and sexual contact; and by indirect contact with contaminated clothing or bedding. Monkeypox can cause flu-like symptoms and painful skin lesions. Complications can include dehydration, bacterial infections, pneumonia, brain inflammation, sepsis, eye infections and death.

The trial will enroll up to 450 adults and children with laboratory-confirmed monkeypox infection who weigh at least 3 kilograms (kg). Pregnant women are also eligible to enroll. The volunteer participants will be assigned at random to receive either oral tecovirimat or placebo capsules twice daily for 14 days, with the dose administered dependent on the participant’s weight. The trial is double-blinded, so participants and investigators do not know who will receive tecovirimat or placebo.

All participants will stay at a hospital for at least 14 days where they will receive supportive care. Study clinicians will regularly monitor participants’ clinical status throughout the study, and participants will be asked to provide blood, throat swab, and skin lesion swab samples for laboratory evaluations. The study is primarily designed to compare the average time to healed skin lesions among those receiving tecovirimat versus those receiving placebo. Investigators will also gather data on multiple secondary objectives, including comparisons of how quickly participants test negative for monkeypox virus in the blood, overall severity and duration of disease, and mortality between groups.

Participants will be discharged from the hospital once all lesions have scabbed over or flaked off, and after they test negative for monkeypox virus in the blood for two days in a row. They will be followed for at least 28 days and will be asked to return for an optional study visit after 58 days for additional clinical and laboratory tests. An independent Data and Safety Monitoring Board will monitor participant safety throughout the duration of the study.

The trial is led by co-principal investigators Jean-Jacques Muyembe-Tamfum, M.D., Ph.D., director-general of INRB and professor of microbiology at Kinshasa University Medical School in Gombe, Kinshasa; and Placide Mbala, M.D., Ph.D., operations manager of the PALM project and head of the Epidemiology Department and the Pathogen Genomic Laboratory at INRB.

“I am happy that monkeypox is no longer a neglected disease and that soon, thanks to this study, we will be able to prove that there is an effective treatment for this disease,” said Dr. Muyembe-Tamfum.

For more information, please visit clinicaltrials.gov and search identifier NCT05559099. The trial timeline will depend on the pace of enrollment. A separate NIAID-supported trial of TPOXX is ongoing in the United States. For information about the U.S. trial, visit the AIDS Clinical Trials Group (ACTG) website and search TPOXX or study A5418.

PALM is short for “Pamoja Tulinde Maisha” a Kiswahili phrase that translates to “together save lives.”  NIAID and the DRC Ministry of Health established the PALM clinical research partnership in response to the 2018 Ebola outbreak in Eastern DRC. The collaboration has continued as a multilateral clinical research program composed of NIAID, the DRC Ministry of Health, INRB and INRB’s partners. PALM’s first study was the randomized controlled trial of multiple therapeutics for Ebola virus disease, which supported the regulatory approvals of the NIAID-developed mAb114 (Ebanga) and REGN-EB3 (Inmazeb, developed by Regeneron) treatments.

Source:

National Institutes of Health

Microbiology

Clinical trial to test the safety, efficacy of bacteriophages for treating P. aeruginosa infections in CF patients

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Reviewed by Emily Henderson, B.Sc.Oct 11 2022

Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs and other organs in the body. Nearly 40,000 children and adults in the United States live with CF, an often difficult existence exacerbated by an opportunistic bacterium called Pseudomonas aeruginosa, which is a major cause of chronic, life-threatening lung infections.

P. aeruginosa infections are not easily treated. The pathogen can be resistant to most current antibiotics. However, an early-stage clinical trial led by scientists at University of California San Diego School of Medicine, with collaborators across the country, has launched to assess the safety and efficacy of treating P. aeruginosa lung infections in CF patients with a different biological weapon: bacteriophages.

Bacteriophages are viruses that have evolved to target and destroy specific bacterial species or strains. Phages are more abundant than all other life forms on Earth combined and are found wherever bacteria exist. Discovered in the early 20th century, they have long been investigated for their therapeutic potential, but increasingly so with the rise and spread of antibiotic-resistant bacteria.

In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used an experimental intravenous phage therapy to successfully treat and cure colleague Tom Patterson, PhD, who was near death from a multidrug-resistant bacterial infection. Patterson’s was the first documented case in the U.S. to employ intravenous phages to eradicate a systemic bacterial infection. Subsequent successful cases helped lead to creation of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first such center in North America.

In 2020, IPATH researchers published data from 10 cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections, all at UC San Diego. In 7 of 10 cases, there was a successful outcome.

The new phase 1b/2 clinical trial advances this work. The trial is co-led by Robert Schooley, MD, professor of medicine and an infectious disease expert at UC San Diego School of Medicine who is co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016.

It will consist of three elements, all intended to assess the safety and microbiological activity of a single dose of intravenous phage therapy in males and non-pregnant females 18 years and older, all residing in the United States.

The dose is a cocktail of four phages that target P. aeruginosa, a bacterial species commonly found in the environment (soil and water) that can cause infections in the blood, lungs and other parts of the body after surgery.

For persons with CF, P. aeruginosa is a familiar and sometimes fatal foe. The Cystic Fibrosis Foundation estimates that roughly half of all people with CF are infected by Pseudomonas. Previous studies have indicated that chronic P. aeruginosa lung infections negatively impact life expectancy of CF patients, who currently live, on average, to approximately 44 years.

In the first stage of the trial, two “sentinel subjects” will receive one of three dosing strengths of the IV bacteriophage therapy. If, after 96 hours and no adverse effects, the second stage (2a) will enroll 32 participants into one of four arms: the three doses and a placebo.

After multiple follow-up visits over 30 days and an analysis of which dosing strength exhibited the most favorable safety and microbiologic activity, i.e. most effective at reducing P. aeruginosa, stage 2b will recruit up to 72 participants to either receive that IV dose or a placebo.

Enrollment will occur at 16 cystic fibrosis clinical research sites in the United States, including UC San Diego. It is randomized, double-blind and placebo-controlled. The trial is being conducted through the Antibacterial Resistance Leadership Group and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, with additional support for the UC San Diego trial site from the Mallory Smith Legacy Fund.

Mallory Smith was born with cystic fibrosis and died in 2017 at the age of 25 from a multidrug-resistant bacterial infection following a double lung transplant.

Mallory’s death was a preventable tragedy. We are supporting the IPATH trial through Mallory’s Legacy Fund because Mark and I deeply believe in the promise of phage therapy to save lives by combatting multidrug-resistant bacteria.”

Diane Shader Smith, Mother

In an article published in 2020 in Nature Microbiology, Schooley and Steffanie Strathdee, PhD, associate dean of global health sciences and Harold Simon Professor in the Department of Medicine and IPATH co-director, describe phages as “living antibiotics.”

As such, said Schooley, researchers need to learn how to best use them to benefit patients through the same systematic clinical trials employed to evaluate traditional antibiotics.

The primary objectives of the new trial are first to determine the safety of a single IV phage dose in clinically stable patients with CF who are also infected with P. aeruginosa, said Schooley.

“Second, it’s to describe the microbiological activity of a single IV dose and third, to assess the benefit-to-risk profile for CF patients with P. aeruginosa infections. This is one study, with a distinct patient cohort and carefully prescribed goals. It’s a step, but an important one that can, if ultimately proven successful, help address the growing, global problem of antimicrobial resistance and measurably improve patients’ lives.”

Estimated study completion date is early 2025.

Source:

University of California – San Diego