April Spotlight April 2017

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WHO’s Most-Wanted List: Deadliest Bacteria

In February, the World Health Organization (WHO) published its first-ever list of “priority pathogens,” a catalogue of 12 families of bacteria that pose the greatest threats to human health. In particular this list highlights the threat of gram-negative bacteria that are resistant to multiple antibiotics. It is intended to guide and promote research and development (R&D) of new antibiotics.

“This is a new tool to ensure R&D responds to urgent public health needs,” said Marie-Paule Kieny (WHO’s assistant director-general for health systems and innovation). “Antibiotic resistance is growing, and we are fast running out of treatment options. If we leave it to market forces alone, the new antibiotics we most urgently need are not going to be developed in time.”

The WHO list is divided into three categories according to the urgency of need for new antibiotics: critical, high priority, and medium priority. Most critical are the multidrug-resistant bacteria that cause trouble in hospitals, nursing homes, and among patients using devices such as ventilators and blood catheters. Acinetobacter, Pseudomonas, and various Enterobacteriaceae (including Klebsiella, Escherichia coli, Serratia, and Proteus) can cause severe and often deadly lung and bloodstream infections. They have become resistant to many antibiotics, including the best available drugs for treating multidrug-resistant bacteria.

The second and third tiers of the list contain other increasingly drug-resistant bacteria that cause more common diseases such as gonorrhoea and food poisoning. Despite its growing resistance to traditional treatments, Mycobacterium tuberculosis was not included on the list because it already is targeted by dedicated programs. Less-resistant bacteria were not included (e.g., Streptococcus and Chlamydia) because they do not pose as significant a public health threat.

In advance of a February G20 meeting in Berlin, Hermann Gröhe (Germany’s federal minister of health) said, “We need effective antibiotics for our health systems. We have to take joint action today for a healthier tomorrow. Therefore, we will discuss and bring the attention of the G20 to the fight against antimicrobial resistance. WHO’s first global priority pathogen list is an important new tool to secure and guide research and development related to new antibiotics.”

The list is intended to spur governments to incentivize basic science and advanced R&D by both publicly funded agencies and the private sector. It will provide guidance to new initiatives such as WHO’s Drugs for Neglected Diseases initiative (DNDi) global antibiotic R&D partnership that is engaging in not-for-profit development of new antibiotics. The list was developed in collaboration with the University of Tübingen’s infectious disease division in Germany using a multicriteria decision analysis technique vetted by international experts.

Criteria in selecting pathogens for the list included how deadly infection is; whether treatment requires long hospital stays; how frequently bacteria resist antibiotics; how easily they spread among species and from person to person; whether infection can be prevented; how many treatment options remain; and whether new antibiotics to treat them are already in development.

“New antibiotics targeting this priority list of pathogens will help to reduce deaths due to resistant infections around the world,” said Evelina Tacconelli (head of University of Tübingen’s division of infectious diseases). More R&D is vital, but it cannot solve the problem alone. Improved prevention of infections and appropriate use of existing antibiotics in both humans and animals are also important, as is rational use of new antibiotics as they emerge.

Find the full list online here: http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en.

ESCMID and ASM Explore Ways to Fight Antimicrobial Resistance

In October 2016, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the American Society for Microbiology (ASM) met at a joint conference in Vienna, Austria. Their goal was to shed light on challenges associated with antimicrobial resistance and help researchers accelerate development of new antimicrobials. Key presentations highlighted important issues in the field: optimization of drug development, strategies to overcome regulatory hurdles, public–private partnerships, innovative trial design, approaches to decrease resistance in new molecules, and better access to safe and effective treatments for special populations, including children and pregnant women.

Regulation of Innovative Approaches to Tackle Resistance: Widespread drug resistance to antibiotics was the central theme of the conference. John Rex (chief strategy officer at AstraZeneca) stressed that all future clinical trials need to be designed with antimicrobial resistance in mind. Wild-type bacteria susceptible to most antibiotics have become rare, whereas those that have developed usual drug resistance (UDR) are more common. Rex warned that UDR bacteria have the potential to evolve into multiple-drug resistant (MDR) bacteria or microorganisms with extensive multidrug resistance. Driving an organism back into the less dangerous UDR category requires application of new antimicrobials, and development of new antibiotics is challenging in the context of widespread resistance. New clinical trial designs and strategies need to be devised and made to work, Rex suggested.

Edward Cox (director of the FDA’s Office of Antimicrobial Products) explored some issues that contribute to a lack of new antimicrobial products in development. Despite progress with a few recent approvals, tough scientific and economic hurdles keep most new molecules in phase 1 clinical trials from ever making it to phase 2. Although innovation is difficult to achieve in such a mature technological field, innovative approaches are needed to help companies develop antimicrobials that meet the challenge of resistance.

Cox’s European counterpart is Marco Cavaleri (head of antiinfectives and vaccines at the European Medicines Agency). He outlined recent progress in regulatory standards for approval of new antimicrobials in the European Union. In particular, Cavaleri elaborated on current unmet needs, new guidelines on pharmacokinetics (PK) and pharmacodynamics (PD) of antibacterial agents, alternative therapies, and harmonization efforts.

University of Florida professor Arnold Louie then presented a roadmap of PK/PD principles for decreasing the chance for pathogens to develop resistance to antimicrobials. He suggested combating resistance for single-drug regimens by hitting bacteria “hard and fast.” That would include using higher dosages over shorter treatment durations to rapidly reduce a patient’s total microbial population and cut the use of antibiotics overall.

Women and Children Don’t Come First: Antimicrobial drugs behave very differently in newborn and adult organ systems, so clinical trial results cannot be extrapolated. John van den Anker (professor at the University Children’s Hospital in Basel, Switzerland) explained that it is also difficult to predict how a pregnant woman and her unborn child will react to emergency antimicrobial therapy. Standard clinical trials fail to provide data on drug toxicity and efficacy in children and pregnant women because it is unethical to enroll them in trials. The professor also highlighted the irony that not only are infants and children excluded from most antimicrobial clinical trials, but they are also unable to access orphan drugs because of clauses restricting the use of such products. The International Neonatal Consortium (established in 2015) called for increased sharing of knowledge and expertise to advance innovation in antimicrobials for very young patients.

John Bradley (professor at the University of California, San Diego) elaborated on challenges that clinicians and researchers face when treating neonates who have severe infections. Premature babies often can weigh only 500 g, which makes calculation of dosage “per kilogram of body weight” difficult. Bradley emphasized the dilemma faced by pediatric investigators and parents when making treatment decisions based on very scant published evidence.

New Positive Initiatives Emerging: University College London professor Mike Sharland confirmed the lack of global consensus on how to conduct clinical trials for children with severe infections. He pointed to a paucity of guidance on how to develop and test new antibiotics for use in children and neonates. However, he reported that promising studies are now emerging, including strategic trials to reevaluate older antibiotics for children. Sharland called for new initiatives in Europe and the United States to recognize a need for detailed data on newly developed antibiotics and on older drugs that were not tested for use in children.

Professor William Hope (University of Liverpool, UK) was on the organizing committee for the conference. “Although discussions have centered on the issues and challenges surrounding antimicrobials,” he remarked, “we have presented strategies to overcome the hurdles and develop new innovative approaches to tackle antimicrobial resistance. The conference provides solutions to some issues outlined by the recent high-level United Nations meeting on antimicrobial resistance. ESCMID will continue to support researchers, specialists, and policy makers with events providing evidence-based results aimed at improving prevention, diagnosis, and treatment of infections in all patient populations, including the most vulnerable such as pregnant women and neonates.”

Ebola Vaccine Protects

According to results published in The Lancet in December, an experimental vaccine has proved highly protective against the deadly Ebola virus. Since the virus was first identified in 1976, sporadic outbreaks have occurred in Africa. But the 2013–2016 West African outbreak caused more than 11,300 deaths and threatened to spread around the world, heightening the need for a vaccine.

This project is led by the World Health Organization (WHO), Guinea’s Ministry of Health, Medecins sans Frontieres, and the Norwegian Institute of Public Health, with other international partners. In Guinea, the vaccine (rVSV-ZEBOV) was studied in 2015, with 11,841 volunteers participating in the coastal region of Basse-Guinée, where new Ebola cases were still being identified at the time. Among 5,837 people who received the vaccine, no Ebola cases were recorded 10 days or more after vaccination. By comparison, 23 cases were diagnosed 10 days or more during the same time period among those who did not receive it.

The vaccine works by replacing a gene from the harmless vesicular stomatitis virus (VSV) with one encoding an Ebola surface protein, so it contains no live Ebola viruses. Earlier trials showed it to be protective in animals and safe for humans as well as inducing an immune response.

The trial used a “ring vaccination” approach, the same method used to eradicate smallpox. When a new Ebola case was diagnosed, researchers traced all people who may have been in contact with that patient (and his or her clothes or linens) over the previous three weeks. This method identified 117 clusters (rings) of infection averaging 80 people each. Initially, those rings were randomized into two groups of adults who either received the vaccine immediately or after a three-week delay. After published interim results showed the vaccine’s efficacy, all rings were offered the vaccine immediately, and the trial was opened to children six years and older.

In addition to showing high efficacy among those vaccinated, the trial appeared to show that unvaccinated people in the rings were protected indirectly (so called “herd immunity”). However, the authors note that the trial was not designed to measure that effect, so more research will be needed. Additional studies are assessing the vaccine’s safety in children and other vulnerable populations such as people with HIV. It is being made available through “compassionate use,” which enables use of a vaccine after informed consent. Meanwhile, the manufacturer (Merck, Sharpe and Dohme) and WHO’s partners are working to compile data for license applications. For faster regulatory review, the product has received breakthrough therapy designation from the US Food and Drug Administration and PRIME status from the European Medicines Agency.

“Ebola left a devastating legacy in our country,” said KeÏta Sakoba, coordinator of the Ebola response and director of the National Agency for Health Security in Guinea. “We are proud that we have been able to contribute to developing a vaccine that will prevent other nations from enduring what we endured.”

This vaccine was originally developed by the Public Health Agency of Canada, then licensed to NewLink Genetics, which in turn licensed it to Merck. Its rapid development has contributed to the development of WHO’s R&D Blueprint strategy to fast-track effective tests, vaccines, and medicines during epidemics.

“While these compelling results come too late for those who lost their lives during West Africa’s Ebola epidemic,” said the study’s lead author Marie-Paule Kieny (WHO’s assistant director-general for health systems and innovation), “they show that when the next Ebola outbreak hits, we will not be defenseless.”

Antimicrobial Peptides Could Take Over Where Antibiotics Leave Off

In fall 2016, a team of researchers reported engineering an antimicrobial peptide that can destroy several types of bacteria, including some that are resistant to most antibiotics. A recent UK study estimated that if no new drugs are developed, antibiotic-resistant bacterial infections will kill 10 million people per year by 2050. Some scientists are turning toward naturally occurring antimicrobial peptides that kill bacteria, viruses, and fungi.

“One of our main goals is to provide solutions to try to combat antibiotic resistance,” said Massachusetts Institute of Technology postdoctoral researcher Cesar de la Fuente. His team’s peptide represents an alternative for treating resistant infections, which are predicted to kill more people annually than any other cause of death.

De la Fuente is corresponding author of this study published in Scientific Reports, with coauthors Osmar Silva (postdoctoral researcher at the University of Brasilia in Brazil) and Evan Haney (postdoctoral researcher at the University of British Columbia in Canada). MIT associate professor Timothy Lu is also an author of the paper.

Antimicrobial peptides are produced by higher organisms as part of their immune defenses. They kill microbes in several different ways, such as poking holes in the invaders’ cell membranes. Once inside, these peptides can disrupt DNA, RNA, and proteins inside the microbial cells. Another critical ability sets these peptides apart from traditional antibiotics: They can recruit their host’s immune system by summoning leukocytes to secrete chemicals that help kill invading microbes.

Scientists have been working for several years to develop such peptides as alternatives to antibiotics. Naturally occurring peptides are made from 20 different amino acids, which creates much variation in their structures. “You can tailor their sequences to tune them for specific functions,” de la Fuente said. “We have the computational power to generate therapeutics that can make it to the clinic and have an impact on society.”

In their study, the researchers began with a naturally occurring antimicrobial peptide called clavanin-A, which was originally isolated from the tunicate, a marine animal. The original form of the peptide kills many types of bacteria, but the researchers engineered it to improve its effectiveness. Antimicrobial peptides have a positively charged region that pokes through bacterial cell membranes and a hydrophobic stretch that enables interaction with and translocation into across those membranes. In hopes of improving their killing ability, the researchers added a sequence of five amino acids to make the peptides even more hydrophobic. The resulting molecule, which they called clavanin-MO, is very potent against a number of bacterial strains. Tested in mice, it killed strains of Escherichia coli and Staphylococcus aureus that are resistant to most antibiotics.

Another key advantage of antimicrobial peptides is that even as they recruit immune cells to combat infection, they also suppress overactive inflammatory responses that can cause life-threatening sepsis. “In this single molecule,” de la Fuente pointed out, “you have a synthetic peptide that kills microbes — both susceptible and drug-resistant — and acts as an antiinflammatory mediator to enhance protective immunity.”

The team also found that their peptide can destroy certain biofilms, which are thin layers of bacterial cells that form on surfaces. That raises the possibility of using it to treat infections such as Pseudomonas aeruginosa affecting the lungs of cystic fibrosis patients. Or they could be embedded into surfaces such as tabletops to make them resistant to microbial growth. Other possible applications for include antimicrobial coatings for catheters and ointments for treating skin infections caused by S. aureus or other species.

If antimicrobial peptides are developed for therapeutic use, the researchers anticipate that they could be used either in stand-alone therapy or together with traditional antibiotics, which would make it more difficult for bacteria to evolve drug resistance. The team is investigating what makes the engineered peptides more effective than the naturally occurring ones, with hopes of making them even better.

Improving Global Access to Protein Medicines

In December 2016, the Bill & Melinda Gates Foundation awarded a grant to DuPont Industrial Biosciences for creating new biological production systems to make protein-based medications such as monoclonal antibodies (MAbs). DuPont will apply its capabilities in protein engineering, pathway engineering, and “cell factories” to the field of protein drugs. The company is known for manufacturing industrial proteins. Applying its approach to pharmaceutical protein production could enable rapid scale-up and lower costs at high volumes, making protein drugs more affordable to people around the world.

“We cannot underestimate the complexity of this challenge,” said William Feehery (president of DuPont Industrial Biosciences). “At the same time, we cannot turn our backs on the possibility of improving access and affordability of life-saving medications for communities around the world. This is cutting-edge science. We are honored to work with a leading organization like The Gates Foundation to tackle this type of issue.” He emphasized that no single company or entity can go it alone.

The Gates Foundation recognizes that solving the world’s greatest health and development issues is a long-term effort. It seeks ideas and solutions from diverse fields, investing in discovery research through a range of mechanisms. In a time when public-funded research is diminishing, companies such as DuPont are engaging with stakeholders across the public and private sectors in new ways to tackle large societal challenges.