Tag Archives: Clinical trial

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

Anticoronavirals: the development of COVID-19 therapies and the challenges that remain

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Neha MathurBy Neha MathurMay 8 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in Nature Microbiology, researchers highlighted the pace of development of coronavirus disease 2019 (COVID-19) therapies during the pandemic and the challenges that hinder the widespread availability of anticoronavirals.

Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com
Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com

Background

COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. On the contrary, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic, and by 21 February 2023, it had caused more than 757 million confirmed cases, including >6.8 million deaths worldwide.

Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. Yet, there is a substantial need for more effective therapeutics to treat unvaccinated and immunocompromised patients and those whose vaccine immunity waned over time.

About the study

In this study, the authors highlighted four stages of SARS-CoV-2 infection that require different therapeutic interventions as critical for identifying COVID-19 therapeutic targets. At stage 1, when viral replication begins inside the host, oral or intravenous administration of monoclonal antibodies and antiviral therapies are effective. However, an ideal time for prophylactic administration of vaccines is Stage 0 preceding the infection.

Clinical trials have established that mAbs and antivirals effectively combat COVID-19 when administered up to 10 days after symptom onset and within three to five days following the onset of symptoms, respectively. COVID-19 patients in stage 2 develop viral pneumonia, cough and fever, lung inflammation causing shortness of breath, and lung aberrations, such as ground glass opacities.

The most serious is stage 3 characterized by a hyperinflammatory state or acute respiratory distress syndrome (ARDS). Some patients might also develop coagulation disorders or shock or systemic inflammatory response syndrome (SIRS). Thus, at stage 3, a patient needs antiviral drugs and immunomodulatory therapy.

Stage 4 represents post-COVID-19 conditions when patients experience hyperinflammatory illnesses, e.g., multi-system inflammatory syndrome in children (MISC), following acute SARS-CoV-2 infection. Unfortunately, possible preventative measures and treatment for post-acute sequelae of SARS-CoV-2 (PASC) are not fully understood. It is a growing area of unmet medical need; thus, extensive research efforts are ongoing to classify PASC, which might be a conglomeration of several syndromes, and determine its cause(s).

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The National Institutes of Health (NIH) Treatment Guidelines Panel makes recommendations for the treatment and prevention of COVID-19. Early in the pandemic, clinicians used azithromycin and hydroxychloroquine as a possible COVID-19 treatment for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Later, clinical trials found this combination ineffective. Similarly, the NIH panel did not specify recommendations for empirical antimicrobials.

The NIH rejected giving vitamin/mineral supplements, e.g., zinc, for hospitalized COVID-19 patients. On the contrary, they recommended prompt use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS. In the absence of effective treatments, clinical recommendations by NIH continue to change and evolve.

Early drug repurposing efforts targeted nucleotide prodrugs, e.g., remdesivir (or GS-5734), AT-527, favipiravir, and molnupiravir (or MK-4482). However, only three antivirals received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), remdesivir, molnupiravir, and nirmatrelvir.

Pre-clinical characterization of remdesivir for other coronaviruses, pharmacokinetic and safety evaluation in humans in a failed clinical trial for Ebola virus, all acquired before the beginning of the COVID-19 pandemic, enabled rapid progression of remdesivir.

A phase 3 study conducted among patients in outpatient facilities and nursing facilities showed that remdesevir administration within seven days of symptom onset decreased hospitalization risk by 87%. Thus, its approval extended to high-risk non-hospitalized patients as well. Currently, phase 1b/2a study for inhaled remdesivir, and pre-clinical evaluation of an oral prodrug based on remdesivir is ongoing.

Another randomized phase III trial evaluated ivermectin, metformin, and fluvoxamine, all repurposed drug candidates, for early COVID-19 treatment of overweight or obese adults. Earlier pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients.

Conversely, the MOVe-OUT outpatient study demonstrated that treatment initiated within five days of symptom onset reduced the hospitalization risk or death. Accordingly, molnupiravir attained an EUA in the US on in late 2021 for treatment of mild-to-moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study suggested that molnupiravir might augment SARS-CoV-2 evolution in immunocompromised individuals.

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In the USA, multiple initiatives have been undertaken to identify candidate agents that may be repurposed as COVID-19 drugs. For instance, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, wherein they adopted a three-way approach to test approved drugs, screen drug repositories, and evaluate novel small molecules, including mAbs against SARS-CoV-2.

Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for treating autoimmune diseases, is being tested for COVID-19 in clinical studies. Likewise, multiple clinical trials are ongoing for camostat mesilate, an inhibitor of transmembrane protease serine 2 (TMPRSS2), an approved chronic pancreatitis treatment in Japan.

Among anti-inflammatory and immunomodulating drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab–cilgavimab have received FDA approval. However, as SARS-CoV-2 continues to evolve, changes in the spike protein led to EUAs being withdrawn for all mAb therapies due to loss of efficacy.

Conclusions

There is a vast knowledge gap regarding COVID-19 pathogenesis. Despite the absence of a viral reservoir, severe disease persists for weeks or even months after COVID-19 recovery. Another intriguing area of investigation is why autoantibodies increase over time during COVID-19. In February 2022, the government of the United States of America (USA) started a flagship program, RECOVER, to understand, prevent and treat COVID-19-related long-term health effects.

Amid decreasing vaccine uptake and waning efficacy of mAbs as SARS-CoV-2 mutates, there is a need for new, safe, and effective COVID-19 therapies for population-level deployment and the potential to reduce resistance development. Researchers need to accelerate research targeting small molecule candidates that would mechanistically target the conserved region of SARS-CoV-2 and not become ineffective across mutant strains.

To be prepared for another pandemic, a large repository of small molecules that have already progressed through early pre-clinical and clinical evaluation is needed to develop drugs, like remdesivir, developed in a short span of two years.

More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.

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Journal reference:
Microbiology

GW one of 18 clinical trial sites across the United States testing monkeypox vaccine in adolescents

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Reviewed by Emily Henderson, B.Sc.Apr 19 2023

The National Institutes of Health trial to evaluate the mpox (previously known as monkeypox) vaccine JYNNEOS has now entered the next stage and is studying the immune responses to and the safety of the vaccine in adolescents. The George Washington University is one of 18 clinical trial sites across the United States that have launched this stage testing the JYNNEOS vaccine.

The JYNNEOS vaccine was approved by the U.S. Food and Drug Administration for use in adults in 2019 and, in 2022, was authorized for use in people under 18 years of age on an emergency use basis. The latest stage of the trial, which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will look to see if the vaccine is safe and triggers an immune response in adolescents ages 12 to 17 that is comparable to adults ages 18 to 50 years. GW’s participation is funded through a contract with Frederick National Laboratory for Cancer Research, operated by Leidos Biomedical Research in Frederick, Maryland, which provides scientific support to NIH.

We are excited to have launched the next stage of this clinical trial, which can help determine if this vaccine can be used to protect adolescents should there be another large outbreak in the United States or some other part of the world.”

David Diemert, clinical director, George Washington University Vaccine Research Unit and professor of medicine, GW School of Medicine and Health Sciences

The GW Vaccine Research Unit is a collaboration between the Departments of Medicine and Microbiology, Immunology and Tropical Medicine located at the George Washington University School of Medicine and Health Sciences, and the GW Medical Faculty Associates. The GW Vaccine Research Unit conducts clinical trials of experimental products that are being developed for the prevention of infectious diseases.

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The clinical investigators at GW and the other sites plan to test 135 adults ages 18 to 50 who will serve as a comparison group in this stage of the study. The researchers will also recruit about 315 adolescents ages 12 to 17 years. All of the recruits will get the standard dose of the vaccine delivered subcutaneously, Diemert said.

The trial will last for 13 months and investigators will check for safety and to see if the antibody response in adolescents in the study are comparable to that of adults.

Mpox historically occurs in West and Central Africa, but in 2022, a large outbreak began in the United States and other countries around the world where mpox is uncommon. The virus spreads through close contact with an infected person or animal.

Although kids in the United States rarely get mpox, experts say children and teens can and do get this painful and sometimes deadly disease.

“Having a safe and effective vaccine at the ready would help prepare the United States and other countries for the next outbreak of this disease,” Diemert said.

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Source:

George Washington University

Microbiology

University Hospital Bonn coordinates eWHORM project to combat worm infections in sub-Saharan Africa

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Reviewed by Emily Henderson, B.Sc.Apr 11 2023

African and European partners join forces to enable the World Health Organisation’s (WHO) “Road Map for Neglected Tropical Diseases” (NTDs) and reduce the burden of disease associated with worm infections.

Worm infections (helminthiases) affect around 1.5 billion people worldwide, making them one of the most prevalent infections in humans. Parasitic worms (helminths) are often transmitted through insect bites or contaminated soil in areas with limited access to clean water, sanitation, and healthcare. These infections can cause chronic and debilitating health problems, such as lymphatic filariasis, onchocerciasis (river blindness), loiasis (African eye worm), mansonellosis, and trichuriasis (whipworm infection).

To combat various soil-transmitted helminths (STH) and filarial worms, a new multidisciplinary consortium of research institutes, universities and not-for-profit organisations in sub-Saharan Africa (SSA) and Europe, coordinated by the University Hospital Bonn (UKB) in Germany, will work together to establish a new adaptive clinical trial platform and improve the clinical research infrastructure in several SSA countries. While each partner will bring unique know-how and complementary experience to achieve the project’s objectives, strong representation from the Global South will drive eWHORM activities. eWHORM will be funded with EUR 7.9 million from the European Union’s European and Developing Countries Clinical Trials Partnership (EDCTP3) programme and additional EUR 3.4 million from the Swiss Government over the next five years.

Achieving the ambitious WHO Road Map goals

Despite significant progress in preventing and controlling helminthiases, many existing drugs have proven problematic in terms of efficacy, treatment duration, and safety. In addition, the chronic underinvestment in healthcare in developing countries has led to poor infrastructure and inadequately trained technical staff.

The eWHORM project aims to address these issues by further developing and testing more efficacious and safe treatment options that act across different helminth species. The project will also train healthcare professionals to enable the diagnosis of multiple diseases in four endemic countries: the Democratic Republic of the Congo, the Gabonese Republic, the Republic of Cameroon, and the United Republic of Tanzania.

This major leap will help to achieve two pressing WHO objectives: (1) eliminating filarial and STH infections and (2) building capacity in endemic countries.

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Responding to persisting and future health challenges

Establishing a robust and equitable clinical research infrastructure is crucial to sustaining the progress that will be brought about by eWHORM. To this end, project partners will promote research network building, knowledge exchange, skill sharing, and gender equality awareness. Early career scientists in SSA will be supported through a Master’s and PhD programme, mentorship programme, and dedicated webinars on all aspects of clinical trial conduct and research. This will, in turn, increase effectiveness and preparedness for both current and future health crises and ensure equitable access to treatment, care, and support for all patients.

Cutting-edge clinical trial to end multiple neglected tropical diseases

The broad-spectrum helminth-killing (pan-nematode anthelmintic) drug oxfendazole (OXF) is used since several decades in the veterinary field to treat multiple species of helminths safely and effectively. In the recent drug development initiative “Helminth Elimination Platform” (HELP), a field-applicable formulation of the cost-effective and easy-to-manufacture drug OXF was developed and a bioavailability study was performed in humans. Several partners, who worked towards a superior, pan-nematode anthelmintic in HELP, are now continuing their ground-breaking research in eWHORM.

Our mission in eWHORM is to assess the efficacy of OXF for simultaneous evaluation against onchocerciasis, loiasis, mansonellosis, and trichuriasis. To do this, we plan to set up a state-ofthe-art adaptive basket trial that can test OXF against multiple diseases at once. This will help us to quickly find out if OXF works and get it to patients faster.”

Marc Hübner, project coordinator, professor of translational microbiology at the Institute for Medical Microbiology, Immunology and Parasitology (IMMIP) at the University Hospital Bonn

“The Drugs for Neglected Diseases initiative (DNDi) and Dr. Sabine Specht, Head of Filarial Disease at DNDi, have a long-standing track record in developing and enabling access to more effective and affordable drugs for Neglected Tropical Diseases,” adds Hübner. “Together with some of the most eminent research and development partners and national stakeholders worldwide, we are looking forward to contributing to what can generate a profound change in the treatment and elimination of helminth diseases.”

Next to the University of Buea, the Centre de Recherches M̩dicales de Lambar̩n̩, and the Institut National de Recherche Biom̩dicale, the consortium includes experts from the Bernhard-Nocht-Institute for Tropical Medicine, the Medical University of Vienna, the Erasmus University Medical Center, the Swiss Tropical and Public Health Institute and Eurice РEuropean Research and Project Office GmbH.

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Source:

University Hospital of Bonn (UKB)

Microbiology

Live attenuated nasal vaccine elicits superior immunity to SARS-CoV-2 variants in hamsters

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Reviewed by Emily Henderson, B.Sc.Apr 4 2023

Since the beginning of the COVID-19 pandemic, researchers have been working on mucosal vaccines that can be administered through the nose. Now, scientists in Berlin have developed a live attenuated vaccine for the nose. In “Nature Microbiology”, they describe the special immune protection it induces.

Coronaviruses spread primarily through the air. When infected people speak, cough, sneeze or laugh, they expel droplets of saliva containing the virus. Other people then breathe in these airborne pathogens and become infected themselves. A research team in Berlin decided to try to fight the virus that causes COVID-19 where it first takes hold: the mucous membranes of the nose, mouth, throat, and lungs. To do so, the scientists developed a live attenuated SARS-CoV-2 vaccine that is administered through the nose. In the latest issue of the journal “Nature Microbiology“, the interdisciplinary team describes how this live attenuated vaccine confers better immunity than vaccines injected into muscle.

Already in the fall of last year, two nasal vaccination formulations were approved for use in India and China. These contain modified adenoviruses – which typically cause respiratory or gastrointestinal illnesses – that are self-attenuating, meaning they either replicate poorly or stop replicating altogether, and therefore never trigger disease. Other live nasal vaccines are currently undergoing development and testing around the world.

Protection at the site of infection

The benefits of a nasal vaccine go far beyond just providing an alternative for people afraid of needles. When a vaccine is injected, it infers immunity primarily in the blood and throughout the entire body. However, this means that the immune system only detects and combats coronaviruses relatively late on in an infection, as they enter the body via the mucous membranes of the upper respiratory tract. “It is here, therefore, that we need local immunity if we want to intercept a respiratory virus early on,” explains the study’s co-last author Dr. Jakob Trimpert, a veterinarian and research group leader at the Institute of Virology at Freie Universität Berlin.

“Nasal vaccines are far more effective in this regard than injected vaccines, which fail or struggle to reach the mucous membranes,” emphasizes Dr. Emanuel Wyler, another co-last author. He has been researching COVID-19 since the start of the pandemic as part of the RNA Biology and Posttranscriptional Regulation Lab, which is led by Professor Markus Landthaler at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB).

In an ideal scenario, a live intranasal vaccine stimulates the formation of the antibody immunoglobulin A (IgA) directly on site, thus preventing infection from occurring in the first place. IgA is the most common immunoglobin in the mucous membranes of the airways. It is able to neutralize pathogens by binding to them and preventing them from infecting respiratory tract cells. At the same time, the vaccine stimulates systemic immune responses that help provide effective overall protection from infection.

Memory T cells that reside in lung tissue play a similarly useful role to antibodies in the mucosa. These white blood cells remain in affected tissue long after an infection has passed and remember pathogens they have encountered before. Thanks to their location in the lungs, they can respond quickly to viruses that enter through the airways.” The co-first author draws attention to one of the observations the team made during their study: “We were able to show that prior intranasal vaccination results in the increased reactivation of these local memory cells in the event of a subsequent SARS-CoV-2 infection. Needless to say, we were particularly pleased with this result.”

Dr. Geraldine Nouailles, immunologist and research group leader at the Department of Pneumology, Respiratory Medicine, and Intensive Care Medicine at Charité

Local immunity impedes viral infection

The scientists tested the efficacy of the newly developed intranasal COVID-19 vaccine on hamster models that had been established by Trimpert and his team at Freie Universität Berlin at the beginning of the pandemic. These rodents are currently the most important non-transgenic model organisms for research into the novel coronavirus, as they can be infected with the same virus variants as humans and develop similar symptoms. They found that after two doses of the vaccine, the virus could no longer replicate in the model organism. “We witnessed strong activation of the immunological memory, and the mucous membranes were very well protected by the high concentration of antibodies,” Trimpert explains. The vaccine could therefore also significantly reduce the transmissibility of the virus.

In addition, the scientists compared the efficacy of the live attenuated vaccine with that of vaccines injected into the muscle. To do so, they vaccinated the hamsters either twice with the live vaccine, once with the mRNA and once with the live vaccine, or twice with an mRNA or adenovirus-based vaccine. Then, after the hamsters were infected with SARS-CoV-2, they used tissue samples from the nasal mucosa and lungs to see how strongly the virus was still able to attack the mucosal cells. They also determined the extent of the inflammatory response using single-cell sequencing. “The live attenuated vaccine performed better than the other vaccines in all parameters,” Wyler summarizes. This is probably due to the fact that the nasally administered vaccine builds up immunity directly at the viral entry site. In addition, the live vaccine contains all components of the virus – not just the spike protein, as is the case with the mRNA vaccines. While spike is indeed the virus’s most important antigen, the immune system can also recognize the virus from about 20 other proteins.

Better than conventional vaccines

The best protection against the SARS-CoV-2 was provided by double nasal vaccination, followed by the combination of a muscular injection of the mRNA vaccine and the subsequent nasal administration of the live attenuated vaccine. “This means the live vaccine could be particularly interesting as a booster,” says the study’s co-first author Julia Adler, a veterinarian and doctoral student at the Institute of Virology at Freie Universität Berlin.

The principle of live attenuated vaccines is old and is already used in measles and rubella vaccinations, for example. But in the past, scientists generated the attenuation by chance – sometimes waiting years for mutations to evolve that produced an attenuated virus. The Berlin researchers, on the other hand, were able to specifically alter the genetic code of the coronaviruses. “We wanted to prevent the attenuated viruses from mutating back into a more aggressive variant,” explains Dr. Dusan Kunec, a scientist at the Institute of Virology at Freie Universität Berlin and another co-last author of the study. “This makes our live vaccine entirely safe and means it can be tailored to new virus variants,” stresses Kunec, who was instrumental in developing the vaccine.

The next step is safety testing: The researchers are collaborating with RocketVax AG, a Swiss start-up based in Basel. The biotech company is developing the live attenuated SARS-CoV-2 vaccine and preparing a phase 1 clinical trial in humans. “We are thrilled to be at the forefront of developing and manufacturing the live attenuated SARS-CoV-2 vaccine as a nasal spray at RocketVax. Our goal is to rapidly scale-up production and advance clinical development towards market access to provide protection against post-COVID symptoms for all. We see great potential in the market for seasonal nasal vaccines”, says Dr. Vladimir Cmiljanovic, CEO of RocketVax.

The future will show which nasal vaccine will ultimately provide better protection. The manufacturers of the nasal adenovirus vaccines developed in India and China have not yet applied for approval in Europe. But one thing is clear to the scientists: since they are administered as nasal sprays or drops, nasal vaccines are a good option for use in places with limited access to trained medical staff. They are also inexpensive to produce and easy to store and transport. Last but not least, live attenuated vaccines such as this one have been proven to provide cross-protection against related viral strains, and thus presumably also against future SARS-CoV-2 variants.

Source:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Journal reference:

Nouailles, G., et al. (2023). Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nature Microbiology. doi.org/10.1038/s41564-023-01352-8

Microbiology

Tulane receives up to $16 million to move nasal pneumonia vaccine from the lab to clinical trials

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Reviewed by Emily Henderson, B.Sc.Mar 24 2023

The National Institute of Allergy and Infectious Diseases awarded an up to $16 million contract to Tulane University to bring to phase one clinical trial a nasal spray vaccine university researchers invented to thwart antibiotic-resistant Klebsiella pneumoniae, a leading cause of pneumonia.

Antibiotic-resistant bacteria are on the rise and are a significant cause of infections requiring hospitalization among children and the elderly. As doctors try to find new types of antibiotics to fight these so-called superbugs, Tulane University School of Medicine researchers Elizabeth Norton, PhD, and Jay Kolls, MD, inventors of the vaccine, are working to protect people before they are exposed to the pathogens in the first place.

“Multidrug-resistant bacteria are causing more severe infections and are a growing public health threat. Vaccines targeting these pathogens represent the most cost-effective option, particularly if you can use this vaccine to prevent or treat the infection in high-risk individuals,” said Norton, principal investigator and associate professor of microbiology and immunology. “Right now, there is no vaccine on the market that targets this type of pneumonia.”

Klebsiella pneumoniae is the third leading cause of hospital-acquired pneumonia and the second leading cause of bloodstream infections with the highest incidence of serious infections. It is also a major cause of childhood pneumonia in parts of Asia. The Tulane vaccine would target high-risk populations such as immunocompromised individuals, diabetics or organ transplant recipients.

Norton said that while the vaccine targets the Klebsiella bacteria, its unique design gives it the potential to be cross-reactive to other members of the Enterobacteriaceae family, the antibiotic-resistant bacterial species behind many hospital-acquired infections, including E. coli.

The vaccine, called CladeVax, is designed to efficiently target mucosa in the nose, throat and lungs to protect the area most at risk for infection.

The nasal spray vaccine uses an adjuvant -; a compound that stimulates the immune system -; named LTA1 that Norton developed at Tulane. That adjuvant, which is made using a protein derived from the E. coli bacteria, will be combined with a series of proprietary antigens identified by the Kolls lab that include outer membrane proteins from the target bacteria.

This is an entirely novel vaccine platform, from the use of the adjuvant to the needle-less route of administration. This represents an entirely new class of vaccines for bacteria that elicits protection in two ways -; both antibody and T-cell immunity. All current pneumonia vaccines only elicit antibodies against surface carbohydrates. Our platform has the potential advantage of providing a much broader protection against pneumonia.”

Jay Kolls, co-principal investigator, and the John W. Deming Endowed Chair in Internal Medicine

Tulane researchers will first test vaccine formulations in animal models and nonhuman primates for dosing and safety before advancing to clinical trials. The project will include collaborators at Tulane National Primate Research Center, the School of Public Health and Tropical Medicine, Tulane Clinical Translational Unit, and the University of North Carolina as well as contractors for GMP manufacturing.

“If this succeeds, we will have another arsenal for the growing number of antibiotic resistant sources of pneumonia or bloodstream infections,” Norton said. “And we can hopefully expand this nasal spray delivery platform to other infections, working on a single, combination vaccine that is needle-less and targets several organisms at once.”

Source:

Tulane University

Microbiology

Leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors

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Reviewed by Emily Henderson, B.Sc.Mar 20 2023

Cancer treatment routinely involves taking out lymph nodes near the tumor in case they contain metastatic cancer cells. But new findings from a clinical trial by researchers at UC San Francisco and Gladstone Institutes shows that immunotherapy can activate tumor-fighting T cells in nearby lymph nodes.

The study, published March 16, 2023 in Cell, suggests that leaving lymph nodes intact until after immunotherapy could boost efficacy against solid tumors, only a small fraction of which currently respond to these newer types of treatments.

Most immunotherapies are aimed only at reinvigorating T cells in the tumor, where they often become exhausted battling the tumor’s cancer cells. But the new research shows that allowing the treatment to activate the immune response of the lymph nodes as well can play an important role in driving positive response to immunotherapy.

This work really changes our thinking about the importance of keeping lymph nodes in the body during treatment.”

Matt Spitzer, PhD, investigator for the Parker Institute for Cancer Immunotherapy and Gladstone-UCSF Institute of Genomic Immunology and senior author of the study

Lymph nodes are often removed because they are typically the first place metastatic cancer cells appear, and without surgery, it can be difficult to determine whether the nodes contain metastases.

“Immunotherapy is designed to jump start the immune response, but when we take out nearby lymph nodes before treatment, we’re essentially removing the key locations where T cells live and can be activated,” Spitzer said, noting that the evidence supporting the removal of lymph nodes is from older studies that predate the use of today’s immunotherapies.

Aim for the lymph nodes, not the tumor

Researchers have largely been working under the assumption that cancer immunotherapy works by stimulating the immune cells within the tumor, Spitzer said. But in a 2017 study in mice, Spitzer showed that immunotherapy drugs are actually activating the lymph nodes.

“That study changed our understanding of how these therapies might be working,” said Spitzer. Rather than the immunotherapy pumping up the T cells in the tumor, he said, T cells in the lymph nodes are likely the source for T cells circulating in the blood. Such circulating cells can then go into the tumor and kill off the cancer cells.

Having shown that intact lymph nodes can temper cancer’s hold in mice, Spitzer’s team wanted to know whether the same would prove true in human patients. They chose to design a trial for patients with head and neck cancers because of the high number of lymph nodes in those areas.

The trial enrolled 12 patients whose tumors hadn’t yet metastasized past the lymph nodes. Typically, such patients would undergo surgery to remove the tumor, followed by other treatments if recommended.

Instead, patients received a single cycle of an immunotherapy drug called atezolizumab (anti-PD-L1) that is produced by Genentech, a sponsor of the trial. A week or two later, Spitzer’s team measured how much the treatment activated the patients’ immune systems.

The treatment also included surgically removing each patient’s tumor and nearby lymph nodes after immunotherapy and analyzing how the immunotherapy affected them.

The team found that, after immunotherapy, the cancer-killing T cells in the lymph nodes began springing into action. They also found higher numbers of related immune cells in the patients’ blood.

Spitzer attributes some of the trial’s success to its design, which allowed the team to get a lot of information from a small number of patients by looking at the tissue before and after surgery and running detailed analyses.

“Being able to collect the tissue from surgery shortly after the patients had been given the drug was a really unique opportunity,” he said. “We were able to see, at the cellular level, what the drug was doing to the immune response.”

That kind of insight would be challenging to get from a more traditional trial in patients with later-stage disease, who would not typically benefit from undergoing surgery after immunotherapy.

Metastases inhibit immune response

Another benefit of the study design was that it allowed researchers to compare how the treatment affected lymph nodes with and without metastases, or a second cancer growth.

“No one had looked at metastatic lymph nodes in this way before,” said Spitzer. “We could see that the metastases impaired the immune response relative to what we saw in the healthy lymph nodes.”

It could be that the T cells in these metastatic nodes were less activated by the therapy, Spitzer said. If so, that could explain, in part, the poor performance of some immunotherapy treatments.

Still, the therapy prompted enough T-cell activity in the metastatic lymph nodes to consider leaving them in for a short period of time until treatment ends. “Removing lymph nodes with metastatic cancer cells is probably still important but taking them out before immunotherapy treatment may be throwing the baby out with the bathwater,” said Spitzer.

A subsequent goal of the current trial is to determine whether giving immunotherapy before surgery protects against the recurrence of tumors in the future. Researchers won’t know the answer to that until they’ve had a chance to monitor the participants for several years.

“My hope is that if we can activate a good immune response before the tumor is taken out, all those T cells will stay in the body and recognize cancer cells if they come back,” Spitzer said.

Next, the team plans to study better treatments for patients with metastatic lymph nodes, using drugs that would be more effective at reactivating their immune responses.

Source:

University of California – San Francisco

Journal reference:

Rahim, M. K., et al. (2023). Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. doi.org/10.1016/j.cell.2023.02.021

Microbiology

Avanced genome editing technology could be used as a one-time treatment for CD3 delta SCID

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Reviewed by Emily Henderson, B.Sc.Mar 21 2023

A new UCLA-led study suggests that advanced genome editing technology could be used as a one-time treatment for the rare and deadly genetic disease CD3 delta severe combined immunodeficiency.

The condition, also known as CD3 delta SCID, is caused by a mutation in the CD3D gene, which prevents the production of the CD3 delta protein that is needed for the normal development of T cells from blood stem cells.

Without T cells, babies born with CD3 delta SCID are unable to fight off infections and, if untreated, often die within the first two years of life. Currently, bone marrow transplant is the only available treatment, but the procedure carries significant risks.

In a study published in Cell, the researchers showed that a new genome editing technique called base editing can correct the mutation that causes CD3 delta SCID in blood stem cells and restore their ability to produce T cells.

The potential therapy is the result of a collaboration between the laboratories of Dr. Donald Kohn and Dr. Gay Crooks, both members of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and senior authors of the study.

Kohn’s lab has previously developed successful gene therapies for several immune system deficiencies, including other forms of SCID. He and his colleagues turned their attention to CD3 delta SCID at the request of Dr. Nicola Wright, a pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute in Canada, who reached out in search of a better treatment option for her patients.

CD3 delta SCID is prevalent in the Mennonite community that migrates between Canada and Mexico.

Because newborns are not screened for SCID in Mexico, I often see babies who have been diagnosed late and are returning to Canada quite sick.”

Dr. Nicola Wright, pediatric hematologist and immunologist at the Alberta Children’s Hospital Research Institute

When Kohn presented Wright’s request to his lab, Grace McAuley, then a research associate who joined the lab at the end of her senior year at UCLA, stepped up with a daring idea.

“Grace proposed we try base editing, a very new technology my lab had never attempted before,” said Kohn, a distinguished professor of microbiology, immunology and molecular genetics, and of pediatrics.

Base editing is an ultraprecise form of genome editing that enables scientists to correct single-letter mutations in DNA. DNA is made up of four chemical bases that are referred to as A, T, C and G; those bases pair together to form the “rungs” in DNA’s double-helix ladder structure.

While other gene editing platforms, like CRISPR-Cas9, cut both strands of the chromosome to make changes to DNA, base editing chemically changes one DNA base letter into another -; an A to a G, for example -; leaving the chromosome intact.

“I had a very steep learning curve in the beginning, when base editing just wasn’t working,” said McAuley, who is now pursuing an M.D.-Ph.D. at UC San Diego and is the study’s co-first author. “But I kept pushing forward. My goal was help get this therapy to the clinic as fast as was safely possible.”

McAuley reached out to the Broad Institute’s David Liu, the inventor of base editing, for advice on how to evaluate the technique’s safety for this particular use. Eventually, McAuley identified a base editor that was highly efficient at correcting the disease-causing genetic mutation.

Because the disease is extremely rare, obtaining patient stem cells for the UCLA study was a significant challenge. The project got a boost when Wright provided the researchers with blood stem cells donated by a CD3 delta SCID patient who was undergoing a bone marrow transplant.

The base editor corrected an average of almost 71% of the patient’s stem cells across three laboratory experiments.

Next, McAuley worked with Dr. Gloria Yiu, a UCLA clinical instructor in rheumatology, to test whether the corrected cells could give rise to T cells. Yiu used artificial thymic organoids, which are stem cell-derived tissue models developed by Crooks’ lab that mimic the environment of the human thymus -; the organ where blood stem cells become T cells.

When the corrected blood stem cells were introduced into the artificial thymic organoids, they produced fully functional and mature T cells.

“Because the artificial thymic organoid supports the development of mature T cells so efficiently, it was the ideal system to show that base editing of patients’ stem cells could fix the defect seen in this disease,” said Yiu, who is also a co-first author of the study.

As a final step, McAuley studied the longevity of the corrected stem cells by transplanting them into a mouse. The corrected cells remained four months after transplant, indicating that base editing had corrected the mutation in true, self-renewing blood stem cells. The findings suggest that corrected blood stem cells could persist long-term and produce the T cells patients would need to live healthy lives.

“This project was a beautiful picture of team science, with clinical need and scientific expertise aligned,” said Crooks, a professor of pathology and laboratory medicine. “Every team member played a vital role in making this work successful.”

The research team is now working with Wright on how to bring the new approach to a clinical trial for infants with CD3 delta SCID from Canada, Mexico and the U.S.

This research was funded by the Jeffrey Modell Foundation, the National Institutes of Health, the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, the V Foundation and the A.P. Giannini Foundation.

The therapeutic approach described in this article has been used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The technique is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Kohn and McAuley listed as co-inventors.

Source:

University of California – Los Angeles Health Sciences

Journal reference:

McAuley, G.E., et al. (2023) Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing. Cell. doi.org/10.1016/j.cell.2023.02.027.

Microbiology

Wayne State team discovers a simple technology to detect active TB infection antibodies

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Reviewed by Emily Henderson, B.Sc.Mar 13 2023

A team of faculty from Wayne State University has discovered new technology that will quickly and easily detect active Mycobacterium tuberculosis (TB) infection antibodies. Their work, “Discovery of Novel Transketolase Epitopes and the Development of IgG-Based Tuberculosis Serodiagnostics,” was published in a recent edition of Microbiology Spectrum, a journal published by the American Society for Microbiology. The team is led by Lobelia Samavati, M.D., professor in the Center for Molecular Medicine and Genetics in the School of Medicine. Samavati was joined by Jaya Talreja, Ph.D, and Changya Peng, research scientists in Wayne State’s Department of Internal Medicine.

TB remains a global health threat, with 10 million new cases and 1.7 million deaths annually. According to the latest World Health Organization report, TB is the 13th leading cause of death and the second leading infectious killer after COVID-19. Latent tuberculous infection (LTBI) is considered a reservoir for TB bacteria and subjects can progress to active TB. One-third of the world’s population is infected with TB and, on average, 5 to 10% of those infected with LTBI will develop active TB disease over the course of their lives, usually within the first five years after initial infection.

The gold standard tests to determine whether an infection is active TB are the sputum smear and culture tests. However, these methods require collecting sputum, which is time consuming, expensive, requires trained personnel and lacks sensitivity. The current conventional tests differentiating LTBI from uninfected controls -; such as tuberculin skin tests (TST) and/or interferongamma release assay (IGRA) -; do not differentiate between active TB infection and latent TB. Despite advances in rapid molecular techniques for TB diagnostics, there is an unmet need for a simple inexpensive point-of-care (POC), rapid non-sputum-based test.

Samavati’s research group has worked for more than 15 years to develop technology for detection of antibodies in various respiratory diseases. Her lab has developed a novel non-sputum based technology and has discovered several novel immune-epitopes that differentialy bind to specific immunoglobulin (IgG) in TB-infected subjects. The levels of epitope-specific IgG in seum can differentiate active TB from LTBI subjects, healthy contols and other respiratory diseases. This technology can be used as a simple serum assay non-sputum based serological POC- TB test, which is highly specific and sensitveto diffentiate active TB from LTBI.

“Previously, we developed a T7 phage antigen display platform and after immunoscreening of large sets of serum samples, identified 10 clones that differentially bind to serum antibody (IgG) of active TB patients differentiating TB from other respiratory diseases,” said Samavati. “One of these high-performance clones had homology to the Transketolase (TKT) enzyme of TB bacteria that is an essential enzyme required for the intracellular growth of the bacteria in a host. We hypothesized that abundance of IgG in sera against the identified novel neoantigen that we named as TKTµ may differentiate between active TB, LTBI and other non-TB granulomatous lung diseases such as sarcoidosis. We developed a novel direct Peptide ELISA test to quantify the levels of IgG in serum samples against TKTµ. We designed two additional overlapping M.tb TKT-peptide homologs with potential antigenicity corresponding to M.tb-specific transketolase (M.tb-TKT1 and M.tb-TKT3) and hence standardized three Peptide ELISA (TKTμ, M.tb TKT1 and M.tb TKT3) for the TB serodiagnosis.”

After development and standardization of a direct peptide ELISA for three peptides, the research team tested 292 subjects, and their TKT-peptide ELISA results show that TB patients have significantly higher levels of TKT-specific antibodies compared to patients who were healthy controls and with LTBI. The increased levels of TKT-specific antibodies is presumably associated with growing M.tb bacteria in active TB patients. TKT plays a key role in the switch from the dormancy to proliferative phase and TKT specific IgG may uncover the differences between active TB and LTBI. Thus, IgG-based serodiagnosis of TB with TKT-peptide ELISA is promising.

Currently, commercially available serological TB tests show poor sensitivity and specificity. The ELISA results obtained with the Wayne State team’s discovered TKT peptides yielded high specificity and sensitivity. Their results show that IgG antibodies against transketolase can discriminate active tuberculosis. 

Our TKT peptide ELISA test requires chemically synthesized TKT peptides to coat the wells in the ELISA plate, less than 100µl blood serum sample from patient, detection reagents and an ELISA plate reader. We are extremely enthusiastic about our technology and the fact that with a simple test we can differentiate active TB from LTBI and other respiratory diseases. We believe that our method and TKT peptide ELISA can fit the requirements of the World Health Organization and the Centers for Disease Control and Prevention as a POC screening method.”

Lobelia Samavati, M.D., Professor, Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University

The research team has applied a patent application on its technology and is actively seeking companies interested in investing.

This research was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health, grant numbers 113508 and 148089. The Foundation for Innovative New Diagnostics (FIND, Geneva, Switzerland) provided TB and LTBI samples.

Source:

Wayne State University

Journal reference:

Talreja, J., et al. (2023). Discovery of Novel Transketolase Epitopes and the Development of IgG-Based Tuberculosis Serodiagnostics. Microbiology Spectrum. doi.org/10.1128/spectrum.03377-22.

Microbiology

Clinical trial shows safety and immunogenicity of temperature-stable experimental TB vaccine

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Reviewed by Emily Henderson, B.Sc.Mar 6 2023

A clinical trial testing a freeze-dried, temperature-stable experimental tuberculosis (TB) vaccine in healthy adults found that it was safe and stimulated both antibodies and responses from the cellular arm of the immune system. The Phase 1 trial was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. A non-temperature stable form of the candidate previously had been tested in several clinical trials. However, this was the first clinical trial of any subunit TB vaccine candidate in a temperature-stable (thermostable) form. Results are published in Nature Communications.

The experimental vaccine, ID93+GLA-SE, was developed by Christopher B. Fox, Ph.D., and scientists at the Access to Advanced Health Institute (formerly the Infectious Disease Research Institute) in Seattle. It is a recombinant subunit vaccine made from four proteins of Mycobacterium tuberculosis bacteria combined with GLA-SE, an immune-stimulating adjuvant. The freeze-dried formulation does not require refrigeration and is mixed with sterile water just prior to injection. Thermostable vaccines are desirable in settings where maintaining cold or frozen vaccines for long periods can be costly and difficult.

The current trial investigated whether administering temperature-stable vaccine containing both ID93 and GLA-SE in a single vial would be as effective at inducing an immune response as a regimen in which non-thermostable ID93 and liquid GLA-SE are held in two vials and combined prior to injection. A single-vial presentation of a thermostable vaccine would have clear advantages in ease of storage, transport and administration, the investigators note.

Daniel F. Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine Development, led the single-site trial at the university’s School of Medicine. Twenty-three participants received the thermostable single-vial regimen, while 22 participants received the two-vial, non-thermostable regimen. Both vaccine presentations were safe and well-tolerated. Recipients of the single-vialled thermostable vaccine had robust T-cell responses and produced higher levels of antibodies in the blood than those receiving the non-thermostable two-vial presentation.

The investigators note some limitations in this small trial. For example, no established correlates of protection define what immune responses are required for vaccine-induced protection from TB disease. Therefore, it is not possible to say whether the enhanced immune responses seen in the thermostable vaccine formulation would translate to improved protective vaccine efficacy. Nevertheless, they conclude, results of this trial demonstrate “a proof-of-concept that adjuvant-containing vaccines can be formulated in a freeze-dried single-vial presentation without detrimentally impacting clinical immunogenicity or safety characteristics.”

Source:

National Institutes of Health

Journal reference:

Sagawa, Z.K., et al. (2023) Safety and immunogenicity of a thermostable formulation of the ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults. Nature Communications. doi.org/10.1038/s41467-023-36789-2.