New molecule shows promise in HIV vaccine design

Researchers at the University of Maryland and Duke University have designed a novel protein-sugar vaccine candidate that, in an animal model, stimulated an immune response against sugars that form a protective shield around HIV. The molecule could one day become part of a successful HIV vaccine.

“An obstacle to creating an effective HIV vaccine is the difficulty of getting the immune system to generate antibodies against the sugar shield of multiple HIV strains,” said Lai-Xi Wang, a professor of chemistry and biochemistry at UMD. “Our method addresses this problem by designing a vaccine component that mimics a protein-sugar part of this shield.”

Wang and collaborators designed a vaccine candidate using an HIV protein fragment linked to a sugar group. When injected into rabbits, the vaccine candidate stimulated antibody responses against the sugar shield in four different HIV strains. The results were published in the journal Cell Chemical Biology on October 26, 2017.

The protein fragment of the vaccine candidate comes from gp120, a protein that covers HIV like a protective envelope. A sugar shield covers the gp120 envelope, bolstering HIV’s defenses. The rare HIV-infected individuals who can keep the virus at bay without medication typically have antibodies that attack gp120.

Researchers have tried to create an HIV vaccine targeting gp120, but had little success for two reasons. First, the sugar shield on HIV resembles sugars found in the human body and therefore does not stimulate a strong immune response. Second, more than 60 strains of HIV exist and the virus mutates frequently. As a result, antibodies against gp120 from one HIV strain will not protect against other strains or a mutant strain.

To overcome these challenges, Wang and his collaborators focused on a small fragment of gp120 protein that is common among HIV strains. The researchers used a synthetic chemistry method they previously developed to combine the gp120 fragment with a sugar molecule, also shared among HIV strains, to mimic the sugar shield on the HIV envelope.

Next, the researchers injected the protein-sugar vaccine candidate into rabbits and found that the rabbits’ immune systems produced antibodies that physically bound to gp120 found in four dominant strains of HIV in circulation today. Injecting rabbits with a vaccine candidate that contained the protein fragment without the sugar group resulted in antibodies that primarily bound to gp120 from only one HIV strain.

“This result was significant because producing antibodies that directly target the defensive sugar shield is an important step in developing immunity against the target and therefore the first step in developing a truly effective vaccine,” Wang said.

Although the rabbits’ antibodies bound to gp120, they did not prevent live HIV from infecting cells. This result did not surprise Wang, who noted that it usually takes humans up to two years to build immunity against HIV and the animal study only lasted two months.

“We have not hit a home run yet,” Wang noted. “But the ability of the vaccine candidate to raise substantial antibodies against the sugar shield in only two months is encouraging; other studies took up to four years to achieve similar results. This means that our molecule is a relatively strong inducer of the immune response.”

The researchers’ next steps will be to conduct longer-term studies in combination with other vaccine candidates, hone in on what areas of gp120 the antibodies are binding to and determine how they can increase the antibodies’ effectiveness at neutralizing HIV.

TapImmune’s T-Cell Cancer Vaccine for Worldwide Eradication of Women’s Cancers

Early proof of efficacy, scalability with cost effective manufacturing, and testability in large Phase III FDA trials are the reasons why TapImmune (TPIV) is the leading T-cell cancer vaccine company and will dominate this space. World class collaborators including the Mayo Clinic, AstraZeneca (AZN), Sloan Kettering and Phase II trial funding from the U.S. Department of Defense prove this point.

Vaccines have eradicated numerous infectious diseases. Cancer is vaccine’s next target, powered by T-cells. White blood cells that are responsible for detecting foreign or abnormal cells including cancerous ones, T-cells specialize in seeking, attaching to, and destroying cancer cells with the help of the rest of the immune system.

Cunning cancer cells often find ways to con the immune system though, making them invisible to T-cells. TapImmune’s effective T-cell cancer vaccine activates cytotoxic T cells and directs them to see and attack specific types of cancer.  TapImmune’s vaccines are superior to other T-cell based cancer treatment candidates due to their powerful and unique combination of proprietary peptide antigens.

Stimulating both killer T-cells (CD8) and helper T-cells (CD4) creates sustained and long lasting tumor cell killing.  Roche’s (ROG:VS) Herceptin, a monoclonal antibody isn’t even designed to kill tumor cells, but in a market desperate for a solution, it has become standard of care by merely slowing down tumor growth. 2015 Herceptin sales exceeded $6.6 billion. If slowing down cancer makes Herceptin a blockbuster, then TapImmune’s cancer killing T-cell vaccine should become an uber-blockbuster and command sales far higher than Herceptin.

Early efficacy results in Phase I trials conducted at the prestigious Mayo Clinic show immune response to TapImmune’s T-cell vaccine in between 75% and 100% of patients treated. These impressive data were published in the Journal of Clinical Oncology and presented at oncology’s top scientific conference, ASCO, as well as at the San Antonio Breast Cancer Symposium.

Beyond efficacy, off-the-shelf platform technology is what sets TapImmune apart in the market and gives its T-cell cancer vaccines the dominant position.

While other cancer vaccines have shown promise, they have for the most part been autologous – meaning doctors take tumor cells from a specific person, process those cells into a vaccine, and reinsert this one-person-specific vaccine into that same person. This kind of personalized medicine is very expensive and difficult to run through large Phase III studies given the way FDA trials are conducted today.

TapImmune’s T-cell vaccines have been specifically designed for high efficacy, high scalability, cost effectiveness, and are ideally suited for large scale FDA testing. This makes them more likely to get FDA approved and reimbursed once on the market.

Today, TapImmune is testing its lead cancer vaccine TPIV-200 in two Phase II studies and is set to begin enrollment any day in two more Phase II studies. Should any of these four trials show promise, TapImmune will charge into larger scale Phase IIIs, armed with an off-the-shelf, consistently manufactured, low cost cancer vaccine that can be used as a therapeutic and prophylactic (preventative).

Indications are ovarian cancer and triple negative breast cancer, two of the hardest women’s cancers to treat. The breast cancer treatment market will top $20 billion by 2024 and ovarian cancer will be $1.4 billion by 2021 according to Decision Resources.

Instead of creating a specific vaccine for each person, TapImmune has selected excellent cancer targets including folate receptor alpha and HER2/neu, which are expressed on the surface of majority of tumor target cells. Deploying TapImmune’s proprietary antigen expression system, these antigens were selected from immune responses in patients to broadly stimulate T-helper cells, T-killer cells and T-memory cells.

Blockbuster Herceptin can only be used in 15-20% of the HER2/neu positive breast cancer population. Besting this by far, TapImmune’s T-cell cancer vaccine is applicable to over 50% of the HER2/neu patient population.

TapImmune vaccines cover about 85% of genotypes, offering broad population coverage from one easy to manufacture vaccine. With this effective formula, TapImmune can mass manufacture cancer vaccines that can be used on any person who needs it. No custom tailoring needed here.

HER2/neu is a valuable cancer target for both ovarian and colorectal cancer, both diseases where there are very few therapeutic options. In breast cancer as well, HER2/neu is overexpressed in ~ 30% of patients.

An equally powerful target is folate receptor alpha, overexpressed in 90% of ovarian cancer cells, over 80% of triple negative breast cancer, and 80% non-small cell lung cancer patients. In the US, approximately 30,000 ovarian cancer and 40,000 triple negative breast cancer patients are newly diagnosed every year. The only treatment options for these patients are surgery, radiation and chemotherapy. With time to recurrence being relatively short, survival prognosis is extremely poor after recurrence.

Fast Track and Orphan Drug designations have been granted by the U.S. FDA to TapImmune’s TPIV 200 in the treatment of ovarian cancer. There is every reason in the world for Fast Track to also be granted for a cancer vaccine to prevent recurrence in the breast cancer population.

Big pharma and the world’s leading medical institutions have independently vetted TapImmune’s technology.

A joint AstraZeneca-TapImmune Phase II ovarian cancer trial is now enrolling patients at the prestigious Sloan Kettering Institute. The trial is testing a combination therapy – TapImmune’s TPIV 200 and AstraZeneca’s durvalumab an anti-PD-L1 antibody, in 40 women who have high-grade ovarian cancer and have not been responsive to platinum chemotherapy, currently the standard of care for advanced ovarian cancer.

Reports Preclinical Data Showing LEAPS Vaccine is Successful in Treating Rheumatoid Arthritis

Rheumatoid Arthritis is a chronic inflammatory disease that mainly targets the synovial membrane, cartilage and bone. It affects about 1% of the global population and is associated with significant morbidity and increased mortality. Non-steroidal, as well as steroidal anti-inflammatory medicines and now more commonly the use of anti-TNFα related therapies are the current standard treatment of patients with advanced RA, but information suggests that over half of the RA patients treated do not respond to current anti-TNFα drugs such as etanercept (Enbrel®) and infliximab (Remicade®).

New preclinical data presented by CEL-SCI demonstrated that its investigational new drug candidate CEL-4000 has the potential for use as a therapeutic vaccine to treat rheumatoid arthritis. CEL-4000 has been developed using CEL-SCI’s patented LEAPS (Ligand Epitope Antigen Presentation System) technology. Data were presented by Daniel Zimmerman, Ph.D., CEL-SCI’s Senior Vice President of Research, Cellular Immunology, at the American College of Rheumatology’s Annual Meeting in Washington DC. The poster presentation titled, “A Therapeutic Peptide Vaccine Reduces Pro-inflammatory Responses and Suppresses Arthritis in the Cartilage Proteoglycan G1 Domain-induced Mouse Model of Rheumatoid Arthritis,” was presented earlier this month.

This study was supported in part by funding of a Phase I Small Business Innovation Research (SBIR) grant in the amount of $225,000 from the National Institute of Arthritis Muscoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH). The study was conducted in collaboration with Drs. Katalin Mikecz and Tibor Glant, and their research team at Rush University Medical Center in Chicago, IL.

“These findings, in conjunction with the results from earlier animal studies with LEAPS vaccines, support the potential that LEAPS vaccines may be useful as a therapeutic treatment for different types of rheumatoid arthritis. LEAPS vaccines may be advantageous to other therapies because they appear to act early on the immune system and inhibit the production of disease-promoting inflammatory cytokines. This is a significant step forward in the development of the LEAPS technology,” said Dr. Zimmerman.

This efficacy study evaluated the LEAPS vaccine’s effect in both the Proteoglycan (PG) induced arthritis (PGIA) and the closely related recombinant huG1 domain of PG (GIA) both in animal models of rheumatoid arthritis (RA) having a dominant T helper 1 (Th1) cytokine profile. These animal models were developed and have been studied extensively in Dr. Glant’s laboratory for over 25 years and are closely related to the human condition of many RA patients. The PGIA and GIA model also exhibits rheumatoid factor (Rf), RA-specific antibodies ACPA (anti citrulline peptide antibodies) and tend to develop spondylitis not usually seen in other RA models.

Disease severity, as determined based on the Arthritis Index and histopathology, was suppressed in mice treated with the LEAPS vaccine when compared to controls. As initially reported based on preliminary data in the PGIA model only, the reduction in disease (RA) severity following LEAPS vaccination with CEL-4000 (DerG-PG70 treatment) correlated with up-regulation of T regulatory cells (Treg) and Th2 cytokines (IL-10, IL-4 and TGF-β), reduced proliferation of PG specific T lymphocytes, and decreases in the production of Th1 and Th17 cytokines (IFN-γ and IL-17).

Scientists Uncover Why Hepatitis C Virus Vaccine Has Been Difficult To Make

Researchers have been trying for decades to develop a vaccine against the globally endemic hepatitis C virus (HCV). Now scientists at The Scripps Research Institute (TSRI) have discovered one reason why success has so far been elusive.

Using a sophisticated array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body’s antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection.

“Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go,” said co-senior author TSRI Associate Professor Mansun Law.

“We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses,” said co-senior author Ian A. Wilson, TSRI’s Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.

The report, published online ahead of print by the Proceedings of the National Academy of Sciences the week of October 24, 2016, is likely to lead to new and better HCV vaccine designs.

A Great Need

A working vaccine against this liver-infecting virus is needed desperately. HCV infection continues to be a global pandemic, affecting an estimated 130 to 150 million people worldwide and causing about 700,000 deaths annually from liver diseases including cancer. Although powerful antiviral drugs have been developed recently against HCV, their extremely high costs are far beyond the reach of the vast majority of people living with HCV infection. Moreover, antiviral treatment usually comes too late to prevent liver damage; HCV infection is notorious for its ability to smolder silently within, producing no obvious symptoms until decades have passed.

The Law and Wilson laboratories have been working together in recent years to study HCV’s structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells.

Because this receptor-binding site on E2 is crucial to HCV’s ability to infect its hosts, it has an amino-acid sequence that is relatively invariant from strain to strain. The receptor-binding site is also relatively accessible to antibodies, and indeed many of the antibodies that have been found to neutralize a broad set of HCV strains do so by targeting this site.

For all these reasons, HCV’s receptor-binding site has been considered an excellent target for a vaccine. But although candidate HCV vaccines mimicking the E2 protein have elicited high levels of antibodies against the receptor-binding site, these antibody responses—in both animal models and human clinical trials—have not been very effective at preventing HCV infection of liver cells in laboratory assays.

Enormous Flexibility

To understand why, the Law and Wilson laboratories teamed up with TSRI Associate Professor Andrew Ward and used electron microscopy and several other advanced structural analysis tools to take a closer look at HCV’s E2 protein, in particular the dynamics of its receptor binding site. Their investigations focused on the “recombinant” form of the E2 protein, produced in the lab and therefore isolated from the rest of the virus. Recombinant E2 is a prime candidate for HCV vaccine design and is much easier to purify and study than E2 from whole virus particles.

One finding was that recombinant E2, probably due to its many strong disulfide bonds, has great structural stability, with an unusually high melting point of 85°C. However, the TSRI scientists also found evidence that, within this highly buttressed construction, the receptor binding site portion is extraordinarily loose and flexible in the recombinant protein.

“It adopts a very wide range of conformations,” said study first author Leopold Kong, of TSRI at the time of the study, now at the National Institutes of Health.

Prior studies have shown that HCV’s receptor binding site adopts a narrow range of conformations (shapes) when bound by virus-neutralizing antibodies. A vaccine that elicited high levels of antibodies against only these key conformations would in principle provide effective protection. But this study suggests that the E2 protein used in candidate vaccines displays far too many other binding-site conformations—and thus elicits antibodies that mostly do nothing to stop the actual virus.

Law and Wilson and their colleagues plan to follow up by studying E2 and its receptor binding site as they are presented on the surface of the actual virus. They also plan to design a new version of E2 or even an entirely different scaffold protein, on which the receptor binding site is stabilized in conformations that will elicit virus-neutralizing antibodies.

Improved Pneumonia Treatment Focus Of Current MSU Research

Streptococcus pneumoniae likely is not a term immediately recognizable by most individuals, even if they have had unpleasant run-ins with the common bacterium. However, experts at Mississippi State University are pioneering pathways to new treatment options.

Primarily affecting those at opposite ends of a typical lifespan, it can cause ear infections in young children and serious cases of pneumonia in adults over 65. While illnesses caused by the bacterium can be treated with antibiotics, the infection may evolve into sepsis—a serious blood disorder—if a case of pneumonia is not responded to quickly.

For those at any age, it is a common complication of influenza.

That’s the bad news.

The good news is that help may be on the way from Mississippi State University’s College of Veterinary Medicine.

Dr. Bindu Nanduri, an associate professor in CVM’s basic sciences department, has discovered new information about the genes in the bacterium and how changes in them can enable better treatment and vaccination options.

In explaining her investigation, Nanduri began with the interior of human nasal cavities where the bacteria live and can spread when a body’s immune system is compromised.

She used the example of a child suffering with the common cold who is unable to fight off infection. In that scenario, the bacteria forms in the middle ear, becomes an infection that takes the form of any of 90 different strains and becomes a challenge to cure.

While a number of vaccines are available, Nanduri said none can “carry all of the strains and, because of that, treatment and limiting the infection is very difficult.”

Medication overuse leading to antibiotic resistance is an additional complication. “The bacteria cannot survive without a host, and, in these cases, the hosts are humans,” she said.

Nanduri holds a master’s degree in biosciences from the University of Roorkee in India and a doctorate in biochemistry and microbiology from the University of Arkansas for Medical Sciences in Little Rock. She is a widely sought authority in bioinformatics, the development of computer software to better understand biological data.

At the MSU veterinary college, “We are removing certain genes in the bacteria that make it impossible for it to survive in the host” and “creating treatments that remove those integral genes so that survival in the body is not possible,” she said.

Dr. Stephen Pruett, basic sciences department head, said Nanduri’s research in pathogen-host interactions has helped multidisciplinary centers at the land-grant institution earn a major grant from the National Institutes of Health’s Centers of Biomedical Research Excellence. COBRE grants are highly competitive, he emphasized.

Designed to support a framework for their investigations of pathogen-host interactions, the federal grant covers Nanduri’s CVM research and that of colleagues at the campus institutes of Genomics, Biocomputing and Biotechnology, and Imaging and Analytical Technologies.

Pruett said Nanduri’s discoveries are providing pathways to new treatment options.
“These ‘mutants’ that Dr. Nanduri produces by removing components are much more easily contained by human immune systems,” he said. “Thus, the medications that would produce this change in the bacteria and block their movement are an entirely new category of treatments.”

According to public health officials, pneumonia causes approximately 1.1 million hospital admissions in the U.S. each year—and 53,000 deaths.

Q&A with TapImmune CEO Dr. Glynn Wilson, on a Vaccine to Prevent Cancer Recurrence, in Multiple Phase II Trials

A vaccine that can prevent the recurrence and metastasis of cancer would save countless lives. In the past century, vaccines have virtually eradicated life threatening diseases including polio and tuberculosis. Medical science may soon be at the point of delivering a cancer vaccine.
Scientists at TapImmune are working closely with leading institutions and a big pharma collaborator including the Mayo Clinic, Memorial Sloan Kettering Cancer Center, the U.S. Department of Defense, and AstraZeneca, to bring such a cancer vaccine to market.
TapImmune’s lead cancer vaccine candidate, TPIV 200 is slated for four Phase II trials this year. Outstanding Phase I results from previous studies conducted at the Mayo Clinic are the impetus for Phase II trials in ovarian and breast cancer.
The Bio Connection recently spoke with TapImmune CEO Dr. Glynn Wilson about TPIV 200.

Q: Tell us about TPIV 200 and what makes it a vaccine, rather than a drug or a treatment?

TPIV 200 works much like vaccines that target other disease such as polio and tuberculosis because it stimulates the body’s cellular immune system to recognize and fight the disease. In this case, TPIV 200 targets cancer cells and in particular, it targets metastatic cancer, which is the biggest threat to survival. TPIV 200 broadly stimulates T-cells to recognize, remember, and attack specific targets (antigens) on tumor cells throughout the body.
TPIV 200 is also an off-the-shelf product, like most other vaccines today. It has been formulated and manufactured as a lyophilized (frozen) product with a long shelf life that can be administered via injection, without having to customize it for a specific person’s cancer cells.
Our clinical trials are designed to test TPIV 200’s efficacy in preventing cancer from recurring in people who have already been diagnosed with, and treated for, cancer, thus serving as a vaccine against cancer recurrence.

Q: Would TPIV 200 only be used in people who have already had cancer? What about people using it in a preventative way?

Since a majority of cancer deaths are caused by cancer recurrence and metastasis, not the original tumor, we see this as the area of greatest need. Indeed, in our target indications, ovarian and triple negative breast cancer, patients are at a high risk of cancer recurrence following standard treatments. That’s why we are evaluating the efficacy of TPIV 200 in preventing or delaying recurrence and metastasis.
We certainly see the possibility of developing a prophylactic, or preventative vaccine, for people who have not had cancer, but to do this you will normally need to demonstrate efficacy in a therapeutic setting. There is growing evidence, in preclinical studies, that a preventive vaccine may be viable. We are currently exploring additional studies in this area. A prophylactic cancer vaccine may potentially be developed based on either the TPIV 200 or TPIV 110 platforms. Or, our own in-house developed PolyStart platform also shows great promise for this.

Q: For a company your size, conducting four simultaneous Phase II trials is really impressive. How are you managing this strategy and why four at the same time?

Two of our upcoming Phase II trials are being conducted and financed in collaboration with world-class organizations. These reduce our clinical development costs significantly and they bring on board some of the top minds in immuno-oncology to work on TPIV 200.
With a $13.3 million grant, the U.S. Department of Defense is fully funding a double-blinded, placebo controlled Phase II study of TPIV 200 in 280 patients with triple negative breast cancer to be conducted at the Mayor Clinic in Jacksonville, Florida.
TapImmune is also collaborating with AstraZeneca on a Phase II trial in 40 patients with platinum resistant ovarian cancer, for a combination therapy of TPIV 200 with AstraZeneca’s anti-PD-L1 checkpoint inhibitor, durvalumab (MEDI4736). This study has begun enrollment and is being conducted at the Memorial Sloan Kettering Cancer Center in New York.
Two other Phase II studies are being funded and conducted by us. We recently dosed the first patient in our Phase II trial of TPIV 200 in triple negative breast cancer. This study, which will enroll 80 patients, is being conducted and funded by TapImmune. Later this year, we plan to commence another company conducted and funded Phase II trial in platinum sensitive ovarian cancer patients. Because we are conducting and funding these trials ourselves, we have greater control over the timing and pace of the trial. This is very helpful in terms of seeing data in the relative near term, and advancing our development timeline.
Our strategy is to move TPIV 200 along on multiple fronts via both our own company sponsored trials and by collaborating with others, to reduce our development costs.

Q: Why do you think AstraZeneca, which can partner with just about anyone chose TapImmune’s TPIV 200? Do you see this collaboration with AstraZeneca expanding into something more?

The collaboration started with the Principal Investigator at Memorial Sloan Kettering, Dr. Jason Konner, who saw the potential of combining a leading checkpoint inhibitor with a T-cell vaccine in ovarian cancer patients. Clinicians at AstraZeneca then reviewed the technical and clinical data on TPIV 200, resulting in the current collaboration. They are a big believer in testing combination therapies and are conducting over a dozen clinical trials of their checkpoint inhibitor durvalumab in combination with other compounds.
It’s premature to say anything about a deepening relationship AstraZeneca at this point, but we are very pleased they saw enough promise in TPIV 200 to conduct a collaborative trial with us. If favorable data emerges from the Phase II trial, that may be the impetus for us to discuss an expanded relationship with AstraZeneca.

Q: Can you tell us more about your other cancer vaccine, TPIV 110?

We plan to initiate a Phase II clinical trial of TPIV 110 at the start of 2017. TPIV 110 is a proprietary HER2neu vaccine technology. The HER2neu antigen is a well-established therapeutic target and plays a role in breast, ovarian and colorectal cancer. Each of these is a potential indication for this vaccine. Like TPIV 200, TPIV 110 was originally developed at the Mayo Clinic and TapImmune has a worldwide exclusive license on these technologies. The Mayo Clinic successfully concluded a Phase I trial in HER2neu breast cancer patients that evaluated TPIV 100, a precursor to TPIV 110 which has 4 Class II antigens. TPIV 100 was found to be safe, well-tolerated, and provided a robust immune response across a broad patient population. 19 out of 20 patients showed a robust T-cell response to two antigens and 15 out of 20 patients showed a response to all four antigens. TPIV 110 has been formulated with an additional 5th antigen, which is a Class I antigen, expected to make it more potent than TPIV 100. We believe TPIV 110 shows great promise and it helps round out our cancer vaccine portfolio.
For more information on TapImmune visit (Ticker: TPIV)

FDA Approves Vaccine for Cholera

In a milestone that was years in the making, a vaccine to prevent cholera, invented and developed by researchers at the University of Maryland School of Medicine’s Center for Vaccine Development, was approved today by the U.S. Food and Drug Administration (FDA).

The vaccine, Vaxchora, is the only approved vaccine in the U.S. for protection against cholera. Its licensure allows for use in people traveling to regions in which cholera is common, including travelers, humanitarian aid workers, and the military.

PaxVax, a global biotechnology company based in California, received marketing approval from the FDA for Vaxchora, a single-dose oral, live attenuated cholera vaccine that is indicated for use in adults 18 to 64 years of age. Vaxchora is the only vaccine available in the U.S. for protection against cholera and the only single-dose vaccine for cholera currently licensed anywhere in the world.

The vaccine was invented in the 1980s at Center for Vaccine Development (CVD). Since 2009, CVD researchers have worked closely with PaxVax to develop the vaccine and secure FDA licensure approval.

“This important FDA decision is the culmination of years of dedicated work by many researchers,” said Myron M. Levine, MD, DTPH, the Simon and Bessie Grollman Distinguished Professor at the University of Maryland School of Medicine (UM SOM). “For travelers to the many parts of the world where cholera transmission is occurring and poses a potential risk, this vaccine helps protect them from this disease. It is a wonderful example of how public-private partnerships can develop medicines from bench to bedside.” Dr. Levine is co-inventor of the vaccine, along with James B. Kaper, PhD, Professor and Chairman of the UM SOM Department of Microbiology and Immunology, and the senior associate dean for academic affairs at the school.

Cholera is an acute intestinal diarrheal infection acquired by ingesting contaminated food or water. Globally, cholera cases have increased steadily since 2005 and, millions of people are affected by this disease each year. Cholera can cause severe dehydration and death in less than 24 hours, if left untreated. While some cholera cases are rarely acquired in the U.S. from ingestion of uncooked seafood from the Gulf of Mexico, the vast majority of cases of domestic cholera cases occur in travelers to areas with epidemic or endemic cholera (for example, parts of Africa, Asia, or the Caribbean). A report from the U.S. Centers for Disease Control and Prevention suggests that the true number of cholera cases in the U.S. is at least 30 times higher than observed by national surveillance systems. The currently recommended intervention to prevent infection is to avoid contaminated water and food. But studies have shown that 98 percent of travelers do not follow these precautions.

Vaxchora is expected to be commercially available later this year. The FDA approval is based on results from a phase 1 safety and immunogenicity trial, a phase 3 efficacy trial, and a phase 3 trial to test manufacturing consistency. The first two of these trials were led by Wilbur H. Chen, MD, MS, associate professor of medicine at UM SOM, and chief of the CVD’s Adult Clinical Studies section. The pivotal efficacy trial, which demonstrated protection from cholera of more than 90 percent at 10 days and 80 percent at 3 months after vaccination, is the first instance the FDA has based the decision to approve a product on a human experimental challenge model. Therefore, the licensure of Vaxchora marks a significant regulatory milestone. The most common adverse reactions to Vaxchora in the clinical trials were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea.

Cholera is chiefly a disease of poverty, poor sanitation, and lack of access to safe drinking water, so the global health burden of cholera rests on those populations residing in vulnerable developing countries. The World Health Organization estimates the burden of cholera to be between 1.4 and 4.3 million cases per year globally. Dr. Chen said that the next steps for this cholera vaccine are to explore formulations that could be developed into successful strategies to prevent and control cholera in countries where cholera is common. These future activities would involve immunizing young children in developing countries; this group has the highest risk of dying from cholera.

“The FDA approval of a new vaccine for a disease for which there has been no vaccine available is an extremely rare event. The approval of Vaxchora is an important milestone for PaxVax and we are proud to provide the only vaccine against cholera available in the U.S.,” said Nima Farzan, chief executive officer and president of PaxVax. “We worked closely with the FDA on the development of Vaxchora and credit the agency’s priority review program for accelerating the availability of this novel vaccine. In line with our social mission, we have also begun development programs focused on bringing this vaccine to additional populations such as children and people living in countries affected by cholera.”

“This approval is an excellent example of how our researchers are entering into public-private partnerships to help further science in tangible ways,” said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also the vice president for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. “This vaccine shows once again that work by scientists here has an impact not only nationally, but globally.”

St. Jude Researchers Reveal How Two Types of Immune Cells Can Arise From One

The fates of immune cells can be decided at the initial division of a cell. Researchers at St. Jude Children’s Research Hospital have discovered that the production of daughter cells with different roles in the immune system is driven by the lopsided distribution of the signaling protein c-Myc. Nudging c-Myc in one direction or the other could make vaccines more effective or advance immunotherapies for cancer treatment. The research appears online today in the scientific journal Nature.

Asymmetric cell division generates two types of cells with distinct properties. This type of cell division is essential for producing various cell types and plays an important role in development. Rather than producing two identical daughter cells, the cells undergoing asymmetric division produce daughter cells that are fated for vastly different roles. In the case of activated T cells, researchers knew that one daughter cell became the rapidly dividing effector T cells that launch the immediate attack on infectious agents and other threats. The other daughter cell became the slowly dividing memory T cells that function like sentries to provide long-term protection against recurring threats. Until now, the mechanism underlying the process was unknown.

“Our study shows that the way in which the regulatory protein c-Myc distributes during asymmetric cell division directly influences the fate and roles of activated T cells,” said corresponding author Douglas Green, Ph.D., St. Jude Department of Immunology chair. “We also show how this asymmetry is established and sustained.”

The researchers worked with cells growing in the laboratory and in mice. Scientists showed that during asymmetric cell division of activated T cells, high levels of c-Myc accumulated in one daughter cell. There, c-Myc functioned like a shot of caffeine to launch and sustain the rapid proliferation of effector T cells, including those in mice infected with the influenza virus. In contrast, the daughter cells with low levels of c-Myc functioned like memory T cells, proliferating to mount an immune response a month later when mice were again exposed to the virus.

Researchers also identified the metabolic and signaling pathways that serve as a positive feedback loop to sustain the high levels of c-Myc that effector T-cells require to maintain their identities and function. The scientists showed that disrupting certain components of the system disturbed c-Myc production, which altered the fate of T cells and caused effector T cells to operate like memory T cells.

“Our work suggests that it may be possible to manipulate the immune response by nudging production of c-Myc in one direction or the other,” Green said. “Potentially that could mean more effective vaccines or help to advance T-cell immune therapy for cancer treatment.”

c-Myc is an important transcription factor that regulates expression of a variety of genes and plays a pivotal role in cell growth, differentiation and death via apoptosis (programmed cell death). Excessive or inappropriate production of c-Myc is a hallmark of a wide variety of cancers. Previous research from Green and his colleagues showed that c-Myc also drives metabolic changes following T cell activation. The metabolic reprogramming fuels proliferation of effector T cells. “Activated T cells divide every four to six hours. There is no other cell in adults that can divide that fast, not even cancer cells,” Green explained.

In this study, the researchers observed several metabolic changes that arose from the way c-Myc partitioned in the cell. These metabolic changes help regulate the way the cells divide, proliferate and differentiate. In a series of experiments, researchers showed how manipulating that system could affect T cell fate following asymmetric cell division by modifying production of c-Myc. “While daughter cells of activated T cells seem to have very different fates, we showed their behavior could be altered by manipulating these metabolic and regulatory pathways to increase or decrease c-Myc levels.” Green said.

Asymmetric cell division is an important driver of other fundamental processes in cells, including early embryonic development and the self-renewal of stem cells.

“Similar control mechanisms exist in other cells that divide asymmetrically, including stem cells in the digestive and nervous systems,” he added.