Q&A: BioNTech vaccine is only ‘mRNA 1.0’. This is just the beginning, say co-founders | Horizon: the EU Research & Innovation magazine

Q&A: BioNTech vaccine is only ‘mRNA 1.0’. This is just the beginning, say co-founders | Horizon: the EU Research & Innovation magazine

  • April 8, 2021

The main question, they say, is which vaccine to prioritise first.

The Pfizer/BioNTech coronavirus vaccine was the first mRNA vaccine ever to be approved for the market. Has the past year fundamentally changed how vaccines will be developed in the future?

Uğur Şahin: The Covid-19 case really shows in different ways the advantages of mRNA vaccines. The first one is that it was the fastest (vaccine) development time ever in medical history. This is one of the key advantages of mRNA vaccines – that they can be manufactured in short production cycles and the time to clinical studies could be as low as a few weeks.

The second is that the data clearly shows that it’s not only the fastest approach, it is also a very effective approach in inducing not only immune responses – antibody and T cell responses – but also in preventing symptomatic disease. New (real world) data emerging also (shows that it is effective at) preventing infection, which is important for controlling the pandemic.

And the third is that we are just seeing that the technology, which was never supplied for global use before, has enabled the delivery of vaccines to many, many millions of people. By the end of this year, we plan to manufacture two billion doses.

And this is just the very beginning. This is mRNA 1.0. It’s the proof of concept for a very new pharmaceutical drug class.

Now that you’ve successfully developed one mRNA vaccine, is it just a case of plugging in other virus or pathogen RNA sequences and creating new vaccines? What other infectious diseases do you have in sight?

Özlem Türeci: That’s one of the important questions now, namely how to prioritise all the opportunities. Having gone all the way to conditional market authorisation for Covid-19 has allowed us to establish the technology for all the stages of clinical development and regulatory submission.

In principle, there are many other infectious diseases and pathogens where we would just need to cut out the Sars-CoV-2 spike protein sequence and insert the genetic information for an antigen from some other virus or pathogen into the same mRNA vector backbone and then basically repeat what we have done. And flu is the most imminent one because we are already working on that. But we have a couple of other infectious disease indications (such as tuberculosis) where we have already started preclinical work and are in the process of assembling the next shortlist.

You mentioned you had already begun working on a flu vaccine prior to last year. Why was the Covid-19 vaccine developed so fast in comparison?

OT: We started our cooperation with Pfizer for the influenza vaccine only in 2018, and we were at the stage of doing the foundational preclinical work (when the pandemic hit). So I would not say that influenza is so much slower.

The fact is, that with Covid-19, we were in a global pandemic, which meant the world’s attention and resources were going into it – all stakeholders, including regulatory authorities and clinical networks had a vested interest. Processes to initiate first-in-human studies or conducting large trials which normally take months due to long waiting periods have been accelerated.

When we now pick up again our flu work, we will be able to leverage all the advantages of mRNA in terms of short manufacturing cycles to adapting to seasonal variants and all the other aspects.

You originally started looking at mRNA vaccines as a way to treat cancer. Why?

OT: Uğur and I are both physicians and we have treated cancer patients. We are also immunologists and fascinated by the immune system. So then we asked the question: how can we serve the medical need as physicians, which the current standard of care cannot? We immediately thought about using immune therapies and activating the immune system.

US: We have been working on mRNA for more than 20 years. The reason why we started was our vision of individualised cancer therapy, based on the observation that the tumour antigens, the antigens on cancer cells, which are recognised by T cells (in the immune system), are unique in every cancer patient.

We understood that a future therapy could be (based on) analysing the patient tumour and finding out which antigens would be suitable and then producing a vaccine based on this information. And this idea requires the right technology – a technology which would allow (us) to induce an immune response against any type of tumour antigen in a potent way and which can be manufactured within a few weeks – because the cancer, of course, might be growing.

When we started, we evaluated DNA, vector-based vaccines, peptides, recombinant proteins – everything that has been tested before as a potential vaccine technology. But then we evaluated mRNA and we understood this could be really powerful. We could see that mRNA could be expressed in dendritic cells, which are the key cells for inducing an immune response. And that was one decisive factor and the ability to manufacture the vaccine fast was another. And that’s why we started to develop mRNA vaccines.

How big a leap was it to refocus this work on infectious diseases?

OT: When we started (our work) many years ago, it was very clear that we had to study the immune system in order to be able to redirect it against cancer.

The immune system has developed mechanisms to protect and defend against pathogens such as viruses. RNA viruses are the most ancient ones, which meant even though we worked on cancer (immunotherapy) for so many years, we had to thoroughly understand those (immune system) mechanisms which were originally against viruses, and also develop methods to mobilise different effectors of the immune system (cells that carry out immune responses) against an antigen. We had to profoundly improve the potency of mRNA vaccines because it is very difficult to mount strong immune responses against self-antigens on cancer cells.

And therefore, it was actually a small step from taking all this and using it (knowledge about the immune system) for what it originally by nature was meant for, namely virus protection.

US: The fundamental principle is the same – it is about engineering and delivering an antigen to dendritic cells to induce an immune response.

When you saw in the clinical trials that your vaccine was 95% effective against Covid-19, were you surprised?

OT: We did not know too much about the biology of the virus when we started (in January 2020). Our objective was to get an ideal immune response, and we knew how to tweak our vaccine to get this immune response. So when we got the data from our phase 1 trial, we clearly saw that we had achieved our objective.

However, what we did not know was how much can this immune response achieve in terms of efficacy. Traditional vaccine efficacies are in general, and typically for influenza vaccines, between 50% and 70%. The 95% was a very positive surprise.

‘We clearly see an era of mRNA vaccines.’

Dr Özlem Türeci, Co-Founder, BioNTech

As the vaccination rollouts accelerate and as we get more data in terms of the effectiveness, the effect on transmission, safety and so on, what in particular are you looking out for in that data?

OZ: Understanding efficacy in the broader population is very important. Data (from real world studies) seems to confirm a high efficacy across the broader population and population subsets.  

We have already shown in our clinical trial that (our vaccine works) irrespective of gender or age. But you cannot include all subpopulations – like immunocompromised patients, or patients with renal disease who get haemodialysis on a regular basis – in a clinical trial at sample sizes which allows you to draw conclusions. This will come with the data from the real world studies and will help us to understand (which) levels and subsets of the population the vaccine protects.

The goal is to achieve herd immunity.

US: At the moment, one of the challenges is people saying: ‘This is new and because this is new I am sceptical, I would like to get the traditional vaccine.’ But this will most likely change fast as we continue to share data. We will continue to explain how these mRNA vaccines work. For the Covid-19 vaccine we had eight publications in less than twelve months. And there’s more to come.

Do you think that one day all our vaccines will be mRNA vaccines?

OZ: I think we can say that we believe that mRNA will be transformational. We clearly see an era of mRNA vaccines. (However) there are borders where, due to the biology of the respective pathogen, mRNA is not the right format.

US: mRNA vaccines so far cannot supply bacterial carbohydrate antigens. So all the pneumococcal vaccines (that help protect against bacteria that cause pneumonitis or meningitis, for example) where you really need these carbohydrates cannot be synthesised by mRNA. Any type of antigen design which is not possible to be encoded by mRNA to be translated to protein by the human cell, can’t be addressed by an mRNA vaccine. So, we believe there will be room for other vaccines.

You received basic research funding from the EU early on in your work – how did that help?

US: The EU funding, and also the funding of the German government allowed us to generate deep scientific understanding of the immune recognition of cancer. The funding has also supported the early stages of our mRNA vaccine research. It helped us to improve our vaccines and generate preclinical and early clinical data for our individualised mRNA cancer vaccine approach. The results obtained from these projects helped us to identify investors who believed in our vision. Pharmaceutical development of new medicines is very costly and compared to the amount we raised, mostly as venture capital, the amount we got from the EU is negligible. However, it is important to understand that innovation development is an iterative process. The clinical findings that we have generated with these mRNA vaccines provoke novel questions and will open up new research areas.

This interview has been edited for clarity and length.

BioNTech received EU funding for the MERIT project and €100 million in financing from the European Investment Bank for its Covid-19 vaccine development. Uğur Şahin received funding from the EU’s European Research Council. If you liked this article, please consider sharing it on social media.

HIV Research is at an Inflection Point, Offering Hope for a Cure

HIV Research is at an Inflection Point, Offering Hope for a Cure

  • April 5, 2021

HIV

HIV research is at an inflection point, where a number of different approaches to attacking the virus are in or are approaching clinical development. Recent advances are giving researchers hope that a functional cure or possibly even complete eradication of the virus is possible.

“Many scientific papers over the years claimed they found a cure for HIV, but none manifest a cure,” Heather Madsen, head of HIV Cure and Bioinformatics at ViiV Healthcare (the only company focused exclusively on HIV), told BioSpace. The London patient and, earlier, the Berlin patient, give us hope the virus can be eradicated.”

These people had very invasive oncology procedures in which the immune system was ablated before a bone marrow transplant. The transplanted cells were resistant to viral infection. After the transplant, HIV was undetectable in their systems.

“This is a very dangerous therapy, and some patients die,” Madsen cautioned, “but it gives a lot of hope to the field.”

Other researchers have reported they could reduce viral reservoirs which are the major barrier to a cure for HIV. That approach is based upon the finding that among some patients who were given antiviral drugs very early in the course of their disease.

“The viral reservoir of infected cells was very, very small. It was years before the virus came out of hiding,” she said. “That gives us confidence we can reach a functional cure.” Madsen defined a functional cure as one in which HIV “is undetectable for two or more years in the absence of treatment,” while noting that “the definition changes all the time.”

“There’s a lot of scientific debate about the best approach to a cure, but what’s widely agreed upon is that a cure will require a multi-pronged approach.

“The HIV virus is extremely stealthy,” Madsen continued. “It has many ways to hide from the host immune system, and to persist in the body. Within the next decade, we should have the clinical tools to test combinations of agents that effectively induce the virus out of hiding, reduce the viral reservoirs and enhance the host immune system.”

Breakthroughs in terms of longer-acting therapies are raising the bar for functional cures, Madsen acknowledged. From once-daily oral pills of modern HIV drug cocktails, the treatment field recently has advanced to interventions that can be given less frequently. ViiV Healthcare’s monthly injectable therapy, for example, recently was approved by the FDA, with an every two-month regimen currently under regulatory review.

“Several companies and academic groups are in clinical studies evaluating long-acting therapeutics that can be given once every three to six months,” she said and some groups are investigating therapeutics (including implants) that may be given only once every 12 or more months. “Those are paradigm-shifting for people living with HIV.”

The goal, though, is to eradicate the virus. “That’s very challenging.”

A lot of progress has been made in latency reversing agents, for example, to wake up the virus more potently and selectively.

Nature listed latency reversal using an inhibitor of apoptosis proteins (IAP) as one of the top 10 scientific discoveries in 2020, and it’s the flagship program at Qura Therapeutics/UNC HIV Cure Center, a collaboration between ViiV and the University of North Carolina at Chapel Hill.

“So far latency reversal agents don’t offer a cure on their own. You also have to kill the HIV-infected cells,” she said.

For that, there are a number of approaches. Researchers at Washington University in St. Louis (WUSTL) this winter, for example, published results of a study focused on cellular behavior, showing it can eradicate HIV within the cells, before it becomes fully active.

“It got a lot of attention in the ‘cure’ community,” Madsen said. “It fits a general theme in advances, in terms of understanding which pathways are involved in recognizing HIV, what changes are made to the cell when it’s infected, and how cellular machinery can be used to recognize those changes.

“Researchers are increasingly turning their focus from how to induce the virus out of hiding to which host pathways are involved and how to intervene to enhance host cell immunity.”

Broadly neutralizing antibodies (bNAbs) also are generating a lot of interest in the ‘cure’ field, she said. bNAbs are direct-acting antivirals that prevent the virus from entering uninfected cells. Because they are antibodies isolated originally from people, they can engage with the host immune system – distinguishing them from other antivirals – and potentially attract the host immune cells to infected cells.

When bNAbs were administered to HIV patients, in a few, the virus remained suppressed long after therapy was withdrawn. ViiV has a bNAb in development, and other companies also have bnAbs in clinical development. It represents a potentially important piece of a cure regimen.

Research published in the New England Journal of Medicine March 18, however, reported unclear results. It provided proof of concept of the potential efficacy of bNAbs, but did not prevent the overall acquisition of HIV1, the authors reported.

HIV vaccines also are coming into play. ClinicalTrials.gov lists more than 800 HIV vaccine studies.

One of the most recent is sponsored by Worcester HIV Vaccine, a biotechnology company dedicated to the development of a vaccine to prevent HIV infections. It received FDA clearance in February to launch Phase I trials. The company hopes to eradicate the disease by breaking the transmission cycle.

Its vaccine, PDPHV, is composed of five DNA plasmids and four gp120 recombinant proteins. The DNA component is used to prime the immune system to receive a boost of HIV proteins, which stimulate the body to produce potent antibodies against HIV.

While cures may be on the horizon, some major challenges remain. The first is the multi-pronged approach itself. “Bringing forward several interventions and testing them, with attention to tolerability will be a big challenge,” Madsen said.

As she explained, “On the therapeutic front, approaches have focused on intervening directly on the virus side. Meanwhile, the ‘cure’ field is trying to intervene on the host side including enhancing the immune system. That can be harder from a safety and tolerability perspective. There must be a balanced approach.

There are nearly 3,000 studies underway involving HIV therapeutics, according to ClinicalTrials.gov. Some, one hopes, will lead to cures. For an overview of the quest for a cure to AIDS and an update on HIV research, see the BioSpace HIV Insight Report.

“I’ve yet to see another herb deliver such powerful results”

“I’ve yet to see another herb deliver such powerful results”

  • April 1, 2021

Schulick told NutraIngredients-USA​ that he is excited to provide a true herbal infusion that takes tea to a new functional category, providing a meaningful serving of key actives with clinically proven results

With at least 32 known polyphenols, Cistus incanus​ is one of the richest sources of polyphenols-phenolic compounds. It also has antioxidant activity and that supports the human immune system. 

The New Chapter founder said the company used its extensive sourcing expertise to locate, test, and validate potent ingredients to develop this phytoactive-rich cistus formulation.

Schulick said Cistus incanus​ is the most important discovery he has yet encountered in his 40+ years working in the natural products industry. 

“In my entire career, I’ve yet to see another herb deliver such powerful results,” ​said Schulick. “The people of the Halkidiki peninsula in Greece have been drinking Cistus incanus as tea for thousands of years. To this day, people in this region are known for living beyond the age of 100 more than in other parts of the world and Cistus incanus is, in my opinion, one of the key reasons why.” 

Rapid immune response

Modern clinical studies have demonstrated that Cistus leaf extractives have powerful antibacterial, antifungal, antiviral, and biofilm-breaking qualities. In a 24-week animal study​, Cistus was shown to prevent both the Ebola virus and HIV from attaching to host cells. No resistant HIV viruses were found against Cistus in the study. The research also suggests that the multiple antiviral components in Cistus are what make it effective against Ebola.

Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

  • March 30, 2021

NEW YORK and BETHESDA, Maryland, March 30, 2021 — The Cancer Research Institute (CRI), a nonprofit organization dedicated to the discovery and development of powerful immunotherapies for all cancers and RevImmune, Inc., a privately held biotech company focused on T-cell technology and development, announced today the dosing of the first patient in a new study designed to assess the therapeutic benefit of interleukin-7 (IL-7) in cancer patients with COVID-19. This stems from a new understanding that patients with severe COVID-19 have low levels of T cells and exhausted T cells, and these patients benefit from therapies that focus on augmenting the cellular immune response, rather than solely therapies that dampen the immune system.

The Phase 2 multi-center clinical trial called “ILIAD-7-US-O” will evaluate the clinical benefit of RevImmune’s product candidate CYT107 in approximately 48 patients living with cancer. CYT107 is a therapeutic form of the master growth factor for human T cells, IL-7, and this is the first study to test an IL-7 drug specifically in people with cancer who also have COVID-19. The clinical trial is funded by CRI’s Clinical Accelerator, a program that supports and coordinates early-phase clinical trials of promising immuno-oncology combination therapies.

“This partnership allows CRI to apply RevImmune’s promising IL-7 agent in a novel setting of patients with both cancer and COVID-19, potentially offering a way to strengthen the immune system’s ability to fend off the SARS-CoV-2 coronavirus, mitigate symptoms of COVID-19, and improve overall outcomes for people living with cancer and COVID,” said Jay Campbell, managing director of CRI’s Venture Fund and Anna-Maria Kellen Clinical Accelerator.

Common cancer treatment regimens can compromise a patient’s immune system, including reductions in lymphocyte counts, such as T cells, a condition known as lymphopenia. Similarly, COVID-19 can lead to dysregulation of the adaptive immune system, which can also result in patients becoming lymphopenic. The profound and protracted lymphopenia experienced in COVID-19 patients has been correlated with increased secondary infections and death. Furthermore, surviving lymphocytes have severely impaired anti-viral function and are exhausted, ultimately resulting in immune system collapse.

IL-7 has been shown to provide a rapid and durable restoration of functional immune cells, predominantly CD4+ and CD8+ T cells, which are able to fight the primary viral infection and secondary infections. In previous clinical studies, CYT107 has demonstrated the ability to quickly restore immune function, such as increasing the number and diversity of T cells in patients, including those with low and exhausted T cell levels. CYT107 has been shown to be safe and well-tolerated and patients experienced durable long-lasting responses.

Researchers involved in the ILIAD-7 study hope CYT107 will provide the same benefit to cancer patients with COVID-19, with the aim of reducing risk of progressing to severe stages of COVID-19.

“The medical community has learned a great deal about COVID-19 as a disease this past year and has come to realize that patients who develop severe COVID-19 symptoms have impaired immune systems, including exhausted and depleted T-cells,” said Michel Morre, D.V.M., M.Sc., chief scientific officer at RevImmune. “Therapies like IL-7 reinvigorate and expand the cellular immune response to the infection, and we are excited for the opportunity to continue to follow the science and evaluate a potential treatment option for those affected by both COVID-19 and cancer.”

About the ILIAD-7-US-O Study
The ILIAD-7-US-O study tests RevImmune’s recombinant interleukin-7 product, CYT107, on patients with cancer and lymphopenic (with low lymphocyte counts) COVID-19. The trial aims to compare the effects of CYT107 versus placebo at producing immune reconstitution by restoring lymphocyte function and increasing lymphocyte proliferation in oncology patients, where their cancer is being or has been treated with standard of care therapies. The trial hopes to observe a possible clinical improvement as patients with restored lymphocyte counts should better eliminate invading pathogens such as SARS-CoV-2. Approximately 48 patients will be randomized 1:1 to receive either CYT107 or placebo at two trial sites: Memorial Sloan Kettering Cancer Center in New York City and The University of Texas MD Anderson Cancer Center in Houston, Texas, with Stephen Pastores, M.D., and Cristina Gutierrez, M.D., as Principal Investigators, respectively. The clinical trial is funded by the CRI Anna-Maria Kellen Clinical Accelerator, a program that supports and coordinates early-phase clinical trials of promising immuno-oncology combination therapies.

About the Cancer Research Institute
The Cancer Research Institute (CRI), established in 1953, is a top-rated U.S. nonprofit organization dedicated exclusively to saving more lives by fueling the discovery and development of powerful immunotherapies for all cancers. Guided by a world-renowned Scientific Advisory Council that includes four Nobel laureates and 27 members of the National Academy of Sciences, CRI has invested $445 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. To learn more, go to cancerresearch.org.

About the CRI Anna-Maria Kellen Clinical Accelerator
CRI’s clinical program, the Anna-Maria Kellen Clinical Accelerator, is a unique academia-nonprofit-industry collaboration model that serves as an “incubator” that delivers multi-center clinical trials for promising new immunotherapy combinations. CRI’s venture philanthropy fund supports clinical trials within this program, which fosters a collaborative environment that enables scientists to advance their most ambitious research ideas and accelerates studies that one group or company could not do alone. To learn more about the CRI Anna-Maria Kellen Clinical Accelerator, go to cancerresearch.org/clinical-accelerator.

About RevImmune
RevImmune is a privately held biotech company based in France, the U.S. and the U.K. RevImmune is in multiple Phase II trials with CYT107 for treatment of sepsis, certain infectious diseases, and certain cancers. Over 500 patients have been treated with CYT107 in RevImmune’s prior and current trials for multiple different viral diseases and sepsis. CYT107 showed an excellent safety profile and encouraging results in those trials. To learn more, go to revimmune.com.

Media Contacts:
For Cancer Research Institute: Brian Brewer, +1-212-688-7515 x242, bbrewer@cancerresearch.org
For RevImmune: Michel Morre, +33 6 03 35 70 60, mmorre@revimmune.com

 

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Plant-based RG-I ingredient may support immune function, modulate the microbiota: Study

Plant-based RG-I ingredient may support immune function, modulate the microbiota: Study

  • March 25, 2021

Data published in Nutrients​ indicated that RG-I from bell pepper and carrot offered similar immune- and microbiota modulatory potential in vitro, while a proof-of-concept trial in humans showed that RG-I from bell pepper (bpRG-I) was well tolerated and enhanced innate immune responsiveness.

“RG-I enriched extracts prime innate immune responses and display a dual mode of action by exerting (1) an immunomodulatory effect on phagocytosis, a biomarker previously shown in some studies with ginseng-PS to be associated with protective effects against respiratory infections, and (2) a microbiota modulatory effect, with concomitant enhanced production of SCFA [short chain fatty acids],” ​wrote the researchers.

BeniCaros

The ingredients are being developed and commercialized by Netherlands-based NutriLeads. The privately held company was founded in 2012 and is and backed by investors including Icos Capital, Goeie Grutten, DSM Venturing, Oost NL, SHIFT Invest and Thuja Capital.

The company’s lead ingredient, BeniCaros, is extracted from carrot pomace, which itself is a side stream from carrot juice production. This ingredient is expected to be available in the US for the formulation of dietary supplements and functional foods in the second half of 2021.

Commenting on the publication and the expected impact of the findings, Ruud Albers, PhD, CEO of NutriLeads, said: “We are delighted to share these new data, demonstrating the immunomodulatory effects of plant-based RG-I, which have the potential to bring health benefits to us all. We are particularly pleased that we can successfully derive RG-I from sustainable and widely available sources.

Repurposed heart and flu drugs that protect platelets improve survival of septic mice

Repurposed heart and flu drugs that protect platelets improve survival of septic mice

  • March 25, 2021

Despite continued improvements in antibiotics and hospital intensive care, staph sepsis -; a bloodstream infection caused by Staphylococcus aureus bacteria -; still causes severe illness or death in 20 to 30 percent of patients who contract it.

Rather than continue to throw more antibiotics at the problem, University of California San Diego researchers want to boost the other side of the equation: the patient’s own immune system.

The team recently discovered a battle that occurs between staph bacteria and platelets -; blood cells known better for their role in clotting than in immune defense. In some sepsis cases, they found, the bacteria win out and platelet levels plummet. Patients with fewer platelets were more likely to die of staph sepsis than patients with higher platelet counts.

The researchers also determined that two currently available prescription medications, approved by the U.S. Food and Drug Administration (FDA) for other uses, protect platelets and improve survival in mouse models of staph sepsis. The two repurposed drugs were ticagrelor (Brilinta), a blood thinner commonly prescribed to prevent heart attack recurrence, and oseltamivir (Tamiflu), prescribed to treat the flu.

The study publishes March 24, 2021 in Science Translational Medicine.

In many cases, the antibiotics we give these patients should be able to kill the bacteria, based on lab tests, yet a significant number of patients are not pulling through. If we can reduce mortality in staph sepsis by 10 or 20 percent by arming or protecting the immune system, we can likely save more lives than discovering an additional new antibiotic that may still not cure the sickest patients.”


Victor Nizet, MD, Senior Author, Distinguished Professor at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences

The study started with a group of 49 University of Wisconsin patients with staph sepsis. The team collected the patients’ blood, bacteria samples, and demographic and health information. To their surprise, it wasn’t white blood cell counts (immune cells) that correlated with patient outcomes -; it was the platelet count. Low platelet counts, defined in this case as fewer than 100,000 per mm3 blood, were associated with increased risk of death from staph sepsis. Approximately 31 percent of patients with low platelet counts died from the infection, compared to less than 6 percent of patients with platelets above the threshold.

In laboratory experiments, the researchers worked out what’s likely happening: Platelets secrete antimicrobial peptides that help the immune system destroy staph bacteria. At the same time, staph release an alpha-toxin that’s detrimental to platelets. In addition to poking holes in platelets, the bacteria’s alpha-toxin convinces the blood cells to produce an enzyme that trims off sugar molecules that decorate their own surfaces. The platelet’s new look is recognized by another molecule in the liver called the Ashwell-Morell receptor, which pulls “bald” platelets out of circulation.

Once Nizet and team had an idea of what might be happening in the patients who are less likely to survive staph sepsis, they turned to mouse models of the disease to find ways to tip the balance of what they call the “toxin-platelet-receptor” axis back in favor of the human patient.

The researchers tested several classes of drugs known to be safe in humans and known to act on platelets. Most drugs they tested had no effect, but two drugs made a big difference. Ticagrelor blocks staph’s alpha-toxin so it can’t injure platelets or stimulate its sugar-removing enzyme. Oseltamivir inhibits the platelet sugar-removing enzyme so the cells don’t go bald and aren’t cleared by the liver, even when staph’s alpha-toxin is around.

Mice with staph sepsis and treated with either ticagrelor or oseltamivir maintained more platelets and had less bacteria in their blood. Ultimately, approximately 60 percent of treated mice survived 10 days following infection, compared to 20 percent of untreated mice.

Side effects of these medications may include nausea, diarrhea and nosebleeds, and ticagrelor may cause uncontrollable bleeding. While new clinical trials specifically designed to test the drugs’ safety and efficacy for patients with staph sepsis would be ideal, Nizet said there’s little financial incentive for pharmaceutical companies to do so with an already profitable drug.

Still, repurposing commercially available drugs has many advantages.

“Discovering a new drug is tremendously expensive and takes many, many years,” said Nizet, who is also faculty lead for the Collaborative to Halt Antibiotic-Resistant Microbes (CHARM) at UC San Diego. “But if we look around at what we already have, what we already know to be safe, we may find many opportunities to improve patient outcomes.”

Sepsis can be caused by several types of bacteria in addition to staph, including Streptococcus pyogenes, Klebsiella, E. coli and Pseudomonas aeruginosa. According to the Centers for Disease Control and Prevention, each year at least 1.7 million adults in the U.S. develop sepsis and nearly 270,000 die as a result. One in three patients who die in a hospital has sepsis. And it’s one of the costliest of all diseases -; in 2013, for example, the Department of Health and Human Services reported that sepsis management added up to more than $24 billion in hospital expenses, or 13 percent of total U.S. hospital costs.

Source:

Journal reference:

Sun, J., et al. (2021) Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia. Science Translational Medicine. doi.org/10.1126/scitranslmed.abd6737.

Health Perks, Research, and Recipes

Health Perks, Research, and Recipes

  • March 24, 2021

Black garlic. It sounds like something occultish or a fancy-pants artisanal variety. But nope — it’s just regular old garlic that has been fermented.

This transformative preparation turns the meaty part of the garlic a shocking, oily, charcoal-y ebony. But does it provide any health benefits? According to some research, yes.

Fermentation changes the taste and texture of the garlic, making it sweet and sorta creamy. Yu-uum! This is probably why home cooks (bored of baking sourdough?) and pro chefs alike are concocting eats and drinks with it left, right, and center.

Though black garlic is probably Korean or Chinese in origin, its umami flavor lends itself well to everything from party dips and pasta dishes to cocktails and cookies.

Black garlic is also ahead of the wellness curve. It’s loaded with complex nutrition that may provide benefits for your whole body. As wonderful as raw white garlic is for you, black garlic may be even better.

Let’s peel back the skin and see what’s so special about these inky-colored cloves.

What are the benefits of black garlic?

Research is still underway. But black garlic has shown the following possible health effects:

Not bad, black garlic. Not bad at all.

Yes, individual cloves of black garlic can look like turd pellets, wrinkled cured olives, or weird-looking gelatinous blobs. But there’s a reason it’s called black gold — it’s got a whole lotta goodness!

So, look beyond its unusual appearance to its true wellness-bolstering value. According to a 2017 review, black garlic has a slew of healthful and therapeutic effects in cells throughout your body. Doesn’t that make each one of those little dark nuggets a true gem?

(Keep in mind that many of these studies use concentrated black garlic supplements. The benefits from the black garlic in your stir-fry might be less pronounced, but they still rock.)

Black garlic health benefits

We’ve already alluded to the plethora of positive effects black garlic can have on your bod. Don’t take our garlic-breathy word for it, though. Here’s just some of what researchers have to say:

Black garlic benefits for hair

Black garlic shampoos are, like, a thing. But are they any better for you than regular shampoo?

After scouring the interwebs for any scientific data or fact-backed info on black garlic for hair troubles, we came up with almost nothing specific to black garlic. A 2012 review made a vague reference to aged garlic preventing hair loss in a study using mice. Don’t pull your hair out over this.

For lustrous locks

There are bottles and bottles of black garlic shampoos, hair oils, and more in the marketplace. The marketing claims suggest that this hero ingredient can improve the luster and resilience of your tresses.

Whether they actually work is completely up in the air.

Preventing hair loss

Researchers have looked at the effectiveness of regular garlic (and onion juice) as a treatment for various kinds of hair loss, both from the perspective of preventing loss and of regrowing hair. Garlic has shown some encouraging results.

In a small 2007 study, 95 percent of participants who received a topical garlic gel as part of their treatment regimen for hair loss had “good to moderate” results in just a few months.

But this study had only 44 participants, and the garlic gel was used in combination with a steroid cream, which could have affected the results. More research is needed on this topic.

Black garlic benefits for skin

Garlic has been used in natural topical treatments for skin woes for ages. The skin benefits of black garlic include:

The terms “black garlic” and “aged garlic” are largely used synonymously. Some studies interchange the terms, while others make a slight distinction between them. Yeah — it’s a tad confusing.

Aged black garlic health benefits

Aged garlic is simply garlic that has gone through the full fermentation process.

If it doesn’t sit and pickle in the target heat and humidity conditions for long enough, it won’t turn black. Instead, it’ll end somewhere on the spectrum between raw white garlic and fully fermented black garlic.

Its health benefits also sit at the midpoint between those of regular and black garlic. (It’s the Kermit the Frog of therapeutic garlic, if you will.)

Because it has transformed a little, its chemical properties will also have changed — just not all the way. This means it might have certain effects that are more like those of raw garlic and some that are more similar to those of black garlic.

Fermented black garlic benefits

Some sources say black garlic is a subtype of aged garlic. This is likely because it has matured for an extended period during fermenting. If raw white garlic is at one end of a spectrum, black garlic is at the other.

The amount of time garlic needs to go from being a raw, white caterpillar to a black butterfly is up for debate. Some guidelines call for 40 to 45 days.

But an academic study regarding the commercialization of black garlic determined that the optimal time can be as little as 13 days. It asserts that, in the proper processing conditions, the garlic will blacken and develop its pharmacological and nutritional benefits in this significantly shorter time.

Garlic and black garlic are considered safe functional foods. Black garlic, in particular, is noted for lacking toxicity.

Negative reactions to black garlic (when it’s eaten or applied topically) are rare. But in a few cases, side effects have been reported:

  • Allergic reaction. A 2017 review notes that one woman developed pneumonia as a delayed-onset allergic reaction to black garlic.
  • Blood thinning. Using black garlic a whole bunch can produce an anticoagulant effect, which may be an issue for some people who already have blood clotting problems or take anticoagulant medications. It can also result in excessive bleeding after surgery.
  • Interactions or contraindications with other meds. Black garlic may amplify or interfere with other drugs, including blood thinners and meds for blood pressure and HIV.
  • Other complaints. Too much of a good thing can become a bad thing. Consuming lots of garlic can lead to bad breath, skin odor, and stomach discomfort.

But since black garlic is mellower than raw garlic, it may have milder side effects as well.

Black garlic is a complex but versatile ingredient. It may have its roots in Asian cuisine, but it works well in countless other culinary cultures.

Where to find black garlic

You can find black garlic in some grocery and specialty shops, as well as in Asian markets. You can also order black garlic from online retailers. It’s available in several forms, including whole bulbs, peeled cloves, and powder.

Your other option is to make your own black garlic. It’s incredibly easy to do, and there are tons of instructions online (such as this handy video).

How to use black garlic

Here are some simple, everyday ways to add black garlic to your daily menu:

Get creative and go garlicky-gaga!

Recipes with black garlic

Are you ready for your mouth to water? Check out these black garlic recipes you’re gonna (c)love!

Main dishes

Sides and snacks

Desserts and drinks

Black garlic is just fermented white garlic. This preparation turns the cloves black and jelly-like and gives them a sweet-tart flavor. It also transforms the chemical makeup of this mighty bulb.

Black garlic and other members of the onion clan have long been used to treat many health concerns, including heart, brain, and liver conditions. The available research supports many of black garlic’s benefits.

Black garlic is a safe functional food. There are few reports of adverse reactions to it. But it can mess with certain medications, so if you currently take any meds, consult your doc before starting a garlic supplementation routine.

You can find black garlic in stores or online. It’s versatile, and you can use it in a whole bunch of foods and beverages.

Sargramostim drug can also improve memory in people with mild-to-moderate Alzheimer's disease

Sargramostim drug can also improve memory in people with mild-to-moderate Alzheimer’s disease

  • March 24, 2021

A new study suggests that Sargramostim, a medication often used to boost white blood cells after cancer treatments, is also effective in treating and improving memory in people with mild-to-moderate Alzheimer’s disease. This medication comprises of a natural human protein produced by recombinant DNA technology (yeast-derived rhu GM-CSF/Leukine®).

The study, from the University of Colorado Alzheimer’s and Cognition Center at the University of Colorado Anschutz Medical Campus (CU Anschutz), presents evidence from their clinical trial that shows that Sargramostim may have both disease-modifying and cognition-enhancing activities in Alzheimer’s disease patients. It was published online today by Alzheimer’s & Dementia: Translational Research and Clinical Interventions, an open access journal of the Alzheimer’s Association.

“The goal of the clinical trial was to examine the impact of a natural human protein called granulocyte-macrophage colony stimulating factor (GM-CSF) on people living with Alzheimer’s disease. We tested GM-CSF because people with rheumatoid arthritis tend not to get Alzheimer’s disease and we had previously found this protein, which is increased in the blood of people with rheumatoid arthritis, reduced amyloid deposition in Alzheimer’s mice and returned their poor memory to normal after a few weeks of treatment. Thus, naturally increased levels of GM-CSF in people with rheumatoid arthritis may be one reason that they are protected from Alzheimer’s disease,” said Huntington Potter, PhD, director of the CU Alzheimer’s and Cognition Center, who together with Jonathan Woodcock, Timothy Boyd and collaborators carried out the new trial.

“Human GM-CSF is the active compound in the known human drug Sargramostim, and we are the first to study its effect on people with Alzheimer’s disease.”

GM-CSF/Sargramostim is used to stimulate the bone marrow to make more white blood cells of a particular kind called macrophages and granulocytes, as well as progenitor cells that repair blood vessels. These white blood cells circulate throughout the body and remove cells, bacteria and amyloid deposits that aren’t supposed to be there, as well as promoting repair to damaged blood vessels and to the brain.

The researchers carried out a randomized, double-blind, placebo-controlled phase II trial to test the safety and efficacy of Sargramostim treatment in participants with mild-moderate Alzheimer’s disease.

Study participants who met eligibility criteria were randomized to receive injections of either Sargramostim (20 participants took a standard FDA dosage 250 mcg/m2/day subcutaneous injection for five days a week for three weeks) or placebo (20 participants took saline for five days a week for three weeks). The majority of the participants from the study were recruited and treated at CU Anschutz with a few from the University of South Florida.

The CU Anschutz researchers then conducted and studied multiple neurological, neuropsychological, cell, cytokine, Alzheimer’s pathology biomarkers and neuroimaging assessments.

They found that short-term Sargramostim treatment increased innate and other immune cells, modulated cytokine measures, and was safe and well-tolerated by participants. They also found cognition memory improved by almost two points in the 30 point Mini-Mental State Exam. Measures of blood biomarkers of Alzheimer’s disease–brain amyloid, tangles, and neurodegeneration–all improved toward normal.

These results suggest that short-term Sargramostim treatment leads to innate immune system activation, cognition and memory improvement, and partial normalization of blood measures of amyloid and tau pathology and neuronal damage in participants with mild-to-moderate Alzheimer’s disease.


This surprising finding that stimulating the innate immune system and modulating inflammation may be a new treatment approach and induced us to start a larger trial of Sargramostim in Alzheimer’s disease with more participants treated over a longer time.”


Huntington Potter, PhD, Director of CU Alzheimer’s and Cognition Center

This new trial will be funded by the Alzheimer’s Association/Part The Cloud, the University of Colorado, the Global Down Syndrome Foundation and by a large grant recently awarded from the National Institute on Aging.

Iron-binder DFX improves the effect of new TB antimicrobial, research shows

Iron-binder DFX improves the effect of new TB antimicrobial, research shows

  • March 23, 2021

Although Tuberculosis, or TB, killed nearly as many people as COVID-19 (approx. 1.8 million) in 2020, it did not receive as much media and public attention. The pandemic has proven that transmissible infection is indeed a global issue. TB remains a serious public health concern in Ireland, particularly with the presence of multi-drug resistant types and the numbers of complex cases here continuing to rise, with cases numbering over 300 annually.

Science tells us that iron is crucial for daily human function, but it is also an essential element for the survival of viruses and bacteria. For some time, scientists have known that depriving infections of iron can limit bacterial burden and help improve patient outcomes. Now scientists at Trinity College and St James’s Hospital have recently applied such a trick (of binding iron to support the immune system) to the treatment of TB, along with a new TB antimicrobial called Bedaquiline. The findings have been published (Thursday, 18th March 2021) in the prestigious journal, the International Journal of Molecular Sciences: https://bit.ly/3bXNBcd .The research is led by Professor Joseph Keane and Dr James Phelan.

Bedaquiline has been in use for less than 10 years for multi-drug resistant TB, yet last year Ireland saw its first case of TB that was Bedaquiline-resistant. We know that even as new antituberculosis drugs are introduced, the TB bacteria will become increasingly resistant.

For some time, Dr Phelan has been looking at how to support the immune system to improve treatment effectiveness. He has previously demonstrated how an iron-binding drug, called Desferrioxamine, or DFX, supports lung immunity against TB infection by driving the activation of a key metabolic pathway called ‘glycolysis’. The process of glycolysis helps immune cells make energy to fight infection which in turn drives several signals that improve the patient macrophages’ (white blood cells) ability to address TB infection. Recent data has shown that a large fraction of people suffering from TB lack this glycolytic response. DFX could compensate for this metabolic defect.

As an extension of this work, the research team has now demonstrated that immune macrophage cells infected with TB bacteria, and treated with the drug Bedaquiline, do a better job of killing the bacteria, if they are also treated with this iron-binder DFX. In addition, this approach also drives a panel of cytokines, or immune messengers, that could also help the macrophages to eliminate the pathogen.

The use of these antimicrobials has been the mainstay for TB treatment for almost half a century now; now is the time to make these antimicrobials function better for the patient. DFX, and other iron binders, could be one of the answers to this. The use of iron binders could help pave the way for the development of new host-directed-therapies; instead of targeting the pathogen, host-directed-therapies directly target infected cells and help them kill the pathogen. Therefore, the use host-directed-therapies as a treatment strategy could drastically improve the treatment and clinical care for patients suffering with tuberculosis and other devastating infectious diseases”.


Dr James Phelan, Department of Clinical Medicine, Trinity College and Study Senior Author

Source:

Journal reference:

Cahill, C., et al. (2021) The Iron Chelator Desferrioxamine Increases the Efficacy of Bedaquiline in Primary Human Macrophages Infected with BCG. International Journal of Molecular Sciences. doi.org/10.3390/ijms22062938.

Bacteria residing within tumor cells can boost cancer immunotherapy

Bacteria residing within tumor cells can boost cancer immunotherapy

  • March 22, 2021

Cancer immunotherapy may get a boost from an unexpected direction: bacteria residing within tumor cells. In a new study published in Nature, researchers at the Weizmann Institute of Science and their collaborators have discovered that the immune system “sees” these bacteria and shown they can be harnessed to provoke an immune reaction against the tumor.

The study may also help clarify the connection between immunotherapy and the gut microbiome, explaining the findings of previous research that the microbiome affects the success of immunotherapy.

Immunotherapy treatments of the past decade or so have dramatically improved recovery rates from certain cancers, particularly malignant melanoma; but in melanoma, they still work in only about 40% of the cases.

Prof. Yardena Samuels of Weizmann’s Molecular Cell Biology Department studies molecular “signposts” – protein fragments, or peptides, on the cell surface – that mark cancer cells as foreign and may therefore serve as potential added targets for immunotherapy. In the new study, she and colleagues extended their search for new cancer signposts to those bacteria known to colonize tumors.

Using methods developed by departmental colleague Dr. Ravid Straussman, who was one of the first to reveal the nature of the bacterial “guests” in cancer cells, Samuels and her team, led by Dr. Shelly Kalaora and Adi Nagler (joint co-first authors), analyzed tissue samples from 17 metastatic melanoma tumors derived from nine patients. They obtained bacterial genomic profiles of these tumors and then applied an approach known as HLA-peptidomics to identify tumor peptides that can be recognized by the immune system.

The research was conducted in collaboration with Dr. Jennifer A. Wargo of the University of Texas MD Anderson Cancer Center, Houston, Texas; Prof Scott N. Peterson of Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Prof Eytan Ruppin of the National Cancer Institute, USA; Prof Arie Admon of the Technion – Israel Institute of Technology and other scientists.

The HLA peptidomics analysis revealed nearly 300 peptides from 41 different bacteria on the surface of the melanoma cells. The crucial new finding was that the peptides were displayed on the cancer cell surfaces by HLA protein complexes – complexes that are present on the membranes of all cells in our body and play a role in regulating the immune response.

One of the HLA’s jobs is to sound an alarm about anything that’s foreign by “presenting” foreign peptides to the immune system so that immune T cells can “see” them. “Using HLA peptidomics, we were able to reveal the HLA-presented peptides of the tumor in an unbiased manner,” Kalaora says. “This method has already enabled us in the past to identify tumor antigens that have shown promising results in clinical trials.”

It’s unclear why cancer cells should perform a seemingly suicidal act of this sort: presenting bacterial peptides to the immune system, which can respond by destroying these cells. But whatever the reason, the fact that malignant cells do display these peptides in such a manner reveals an entirely new type of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut microbiome affects immunotherapy. Some of the bacteria the team identified were known gut microbes. The presentation of the bacterial peptides on the surface of tumor cells is likely to play a role in the immune response, and future studies may establish which bacterial peptides enhance that immune response, enabling physicians to predict the success of immunotherapy and to tailor a personalized treatment accordingly.

Moreover, the fact that bacterial peptides on tumor cells are visible to the immune system can be exploited for enhancing immunotherapy. “Many of these peptides were shared by different metastases from the same patient or by tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to produce immune activation,” Nagler says.

In a series of continuing experiments, Samuels and colleagues incubated T cells from melanoma patients in a laboratory dish together with bacterial peptides derived from tumor cells of the same patient. The result: T cells were activated specifically toward the bacterial peptides.

Our findings suggest that bacterial peptides presented on tumor cells can serve as potential targets for immunotherapy. They may be exploited to help immune T cells recognize the tumor with greater precision, so that these cells can mount a better attack against the cancer. This approach can in the future be used in combination with existing immunotherapy drugs.”


Yardena Samuels, Professor, Molecular Cell Biology Department, Weizmann Institute of Science

capsimmunesystem.org