'Designer virus' is first new oral polio vaccine in 50 years

Phase 1 trial shows promise for completion of stalled eradication effort; offers lessons for COVID-19 vaccine development.

Virologists report promising Phase 1 clinical results for the first new oral polio vaccine in 50 years, which they have designed to be incapable of evolving the ability to cause disease in humans.

Before being halted due to the COVID-19 pandemic, a relentless vaccination campaign had nearly succeeded in eradicating polio from the world. Between 2000 and 2017, the World Health Organization (WHO) estimated that its campaign had reduced the burden of the disease by 99 percent, preventing more than 13 million children from becoming infected and risking potentially debilitating paralysis.

But in recent years, the eradication effort has been plagued by outbreaks of vaccine-derived polio -- in which the weakened virus used in oral polio vaccines evolved the ability to escape from vaccinated individuals and spread in communities with poor vaccination rates.

Now, with support from the Bill and Melinda Gates Foundation, UC San Francisco virologist Raul Andino, PhD and Andrew Macadam, PhD, of the UK's National Institute for Biological Standards and Control (NIBSC) report promising Phase 1 clinical results for the first new oral polio vaccine in 50 years, which they have designed to be incapable of evolving the ability to cause disease in humans.

In a 2017 study, Andino and colleagues discovered that in every vaccine-derived polio outbreak they studied, the virus had used the same three evolutionary steps to mutate from harmless vaccine into a regional menace.

In their new study, Andino, Macadam, and colleagues at the Gates Foundation, the Center for Vaccine Innovation and Access in Seattle, and the Centre for the Evaluation of Vaccination at the University of Antwerp have employed clever genetic wizardry based on decades of study of the poliovirus's biology to redesign the vaccine to ensure that is incapable of following this three-step pathway to re-evolve virulence. Specifically, they stabilized a region of the viral genome that is required for it to re-evolve the ability to infect humans, and ensured that the virus could not get rid of this modification even by exchanging genetic material with related viruses.

The trial found that the new designer polio vaccine was both more stable and more effective than the 50-year old Sabin vaccine from which it was derived. Specifically, the new vaccine caused participants to generate plentiful antibodies against the poliovirus, and despite shedding viral particles in their stool, those particles were unable to infect or cause paralysis in mice. In contrast, previous studies have found that when mice are exposed to viral samples shed by people vaccinated with the standard Sabin oral polio vaccine, as many as 90 percent develop paralysis.

See: Ming Te Yeh, Erika Bujaki, Patrick T. Dolan, Matthew Smith, Rahnuma Wahid, John Konz, Amy J. Weiner, Ananda S. Bandyopadhyay, Pierre Van Damme, Ilse De Coster, Hilde Revets, Andrew Macadam, Raul Andino. Engineering the Live-Attenuated Polio Vaccine to Prevent Reversion to Virulence. Cell Host & Microbe, 2020; DOI: 10.1016/j.chom.2020.04.003

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

FDA - Q3D(R1) Elemental Impurities

FDA has now published this final guidance. Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits.

See: https://www.fda.gov/media/135956/download

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Communities of microbes found to have working memory

Biologists studying communities of bacteria have discovered that these so-called simple organisms feature a robust capacity for memory. Using light, researchers were able to encode complex memory patterns and visualize cells with memory. The discovery reveals surprising parallels between low-level single-celled organisms and sophisticated neurons that process memory in the human brain. The finding also provides a starting path for scientists to one day design basic computing systems with living organisms such as bacteria.

Following recent discoveries by the Süel lab that bacteria use ion channels to communicate with each other, new research suggested that bacteria might also have the ability to store information about their past states. In the new study, the researchers were able to encode complex memory patterns in bacterial biofilms with light-induced changes in the cell membrane potential of Bacillus subtilis bacteria. The optical imprints, they found, lasted for hours after the initial stimulus, leading to a direct, controllable single-cell resolution depiction of memory.

The ability to encode memory in bacterial communities, the researchers say, could enable future biological computation through the imprinting of complex spatial memory patterns in biofilms.

See:

Chih-Yu Yang, Maja Bialecka-Fornal, Colleen Weatherwax, Joseph W. Larkin, Arthur Prindle, Jintao Liu, Jordi Garcia-Ojalvo, Gürol M. Süel. Encoding Membrane-Potential-Based Memory within a Microbial Community. Cell Systems, 2020; DOI: 10.1016/j.cels.2020.04.002

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

FDA - Safety testing of drug metabolites

This guidance provides recommendations to industry on when and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated. Drug metabolites may need to be determined in nonclinical studies when they are disproportionate drug metabolites, that is, metabolites identified only in humans or present at higher plasma concentrations in humans than in any of the animal species used during standard nonclinical toxicology testing.

See: https://www.fda.gov/media/72279/download

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

New insight into bacterial structure to help fight against superbugs

Scientists have produced the first high-resolution images of the structure of the cell wall of bacteria, in a study that could further understanding of antimicrobial resistance.

The findings set a new framework for understanding how bacteria grow and how antibiotics work, overturning previous theories about the structure of the outer bacterial layers.

The images give unprecedented insight into the composition of the bacterial cell wall and will inform new approaches to developing antibiotics in order to combat antibiotic resistance. There are no other examples of studies of the cell wall in any organism at comparable resolution, down to the molecular scale.

The team used an advanced microscopy technique called Atomic Force Microscopy (AFM), which works by using a sharp needle to feel the shape of a surface and build an image similar to a contour map, but at the scale of individual molecules.

See:

L. Pasquina-Lemonche, J. Burns, R. D. Turner, S. Kumar, R. Tank, N. Mullin, J. S. Wilson, B. Chakrabarti, P. A. Bullough, S. J. Foster, J. K. Hobbs. The architecture of the Gram-positive bacterial cell wall. Nature, 2020; DOI: 10.1038/s41586-020-2236-6 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Technological developments with wound treatment dressings

Dressings are long-established in the medical field for keeping wounds clean and preventing secondary infections. Dressings are essential for reducing infection risk; more recent advancements have seen dressings developed to promote wound healing.

In relation to this, Tim Sandle has written an article for Infectious Disease Hub. Here is an extract:

Wound healing refers to a specific biological process related to the general phenomenon of growth and tissue regeneration. Wounds heal by the control of moisture and by a process of staving off infection; while dressings have addressed the former over centuries, with the latter specialized dressings are being developed. Dressings to aid wound healing have been used for several decades, such as the use of hydrocolloid dressings to help treat burns and with the application of hydrogels for wounds that are leaking little or no fluid. However, it is in more recent years that antimicrobial compounds have been incorporated.

This involves the addition of physical or chemical processes designed to kill any pathogenic microorganisms that might be present, and which pose a risk of triggering a disease such as sepsis (where the chemicals that body’s immune system releases into the bloodstream to combat an infection trigger inflammation throughout the entire body) or delay the rate of wound healing (one of the causes of delayed wound healing is the presence of microorganisms in the wound). This article examines some of these developments, and also considers an additional development in the form of color-changing dressings for signaling the presence of antimicrobial-resistant bacteria.

The article can be accessed here.

The reference is:

Sandle, T. (2020) Technological advances with dressings for wound treatment and detection, Infectious Disease Hub, published on 19^th February 2020. At: https://www.id-hub.com/2020/02/20/technological-advances-with-dressings-for-wound-treatment-and-detection/

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Tetanus vaccines

The Ph. Eur Commission adopted 16 revised monographs on tetanus vaccines, following a reassessment of toxicity testing requirements. The revisions include the suppression of three tests and the harmonisation, as far as possible, of the Ph. Eur.’s toxicity testing requirements for tetanus vaccines for human and veterinary use. The Ph. Eur. Commission is committed to phasing out the use of animal tests by continuously reviewing in vivo tests described in Ph. Eur. texts and applying, whenever possible, the 3Rs principles set out in the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS No. 123). The reassessment of toxicity testing requirements for tetanus vaccines and the decision to delete three animal tests is an illustration of this commitment.

See: https://www.edqm.eu/en/news/european-pharmacopoeia-tetanus-vaccines-rationalising-toxicity-testing-requirements

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Plastic eating bacterium offers pollution hope

German scientists have found a small solution to this big problem – plastic-eating bacteria.

This newly identified strain of Pseudomonas bacteria was discovered by a team consisting of researchers from Helmholtz Centre for Environmental Research (Leipzig, Germany), Freiberg University of Mining and Technology (Germany) and Helmholtz Centre for Infection Research (Braunschweig, Germany), who have demonstrated its ability to break down polyurethane, a toxic type of plastic that is particularly hard to recycle.

In 2015 alone, polyurethane accounted for 3.5 million tons of the plastic produced in Europe. Its lightweight, insulating and flexible properties make it suitable for use in many products, from shoes and refrigerators to kitchen sponges. However, it’s incredibly difficult and energy-intensive to recycle, so most ends up on landfill sites where it releases toxic, often carcinogenic, chemicals.

Most bacteria are unable to withstand the toxic fumes released by the plastic, but, as demonstrated in a recent study published in Frontiers in Microbiology, this newly discovered strain is able to not only withstand and survive in the harsh environment, but also degrade some of the chemical building blocks of polyurethane and use these for energy.

For further details, see Biotechniques: https://www.biotechniques.com/microbiology-virology/a-tiny-solution-for-plastic-pollution-scientists-discover-polyurethane-feeding-bacteria  

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

TB eradication update – WHO

There’s an interesting article in Biotechniques, looing at progress with the World Health Organizations tuberculosis eradication strategy. Here is an extract:

Active TB infection is defined by the presence of clinical symptoms, such as cough, fever and weight loss, as well as positive microbial cultures for acid-fast bacteria. Due to widespread dissemination throughout the body, patient infection is defined as pulmonary or extra-pulmonary TB infection.

Globally, 3.4% of all new cases, and 18% of previously treated TB patients, possess drug-resistant bacteria. Therefore, active TB infection is also classified by the degree to which the bacteria are resistant to antibiotic combinations. Quick identification of antibiotic resistance is key in preventing the development of further antibiotic resistance and restricting the morbidity associated with active TB infection. Furthermore, rapid initiation of treatment helps to limit the spread.

Early diagnosis and universal drug susceptibility testing are considered two of the main priorities of the WHO’s End TB Strategy. The current ‘gold standard’ rapid diagnostic test for TB is Xpert MTB/RIF (Cepheid Inc., CA, USA). The diagnostic utilizes real-time PCR technologies via a cartridge-based system. Samples of varying types, including sputum, lymph node aspirate and cerebrospinal fluid, can be taken to diagnose both pulmonary and extrapulmonary infection, with the results detecting both the bacteria and ripanfacin-resistance – the surrogate marker for multi-drug resistant TB. Xpert MTB/RIF is cost-effective and also has proven utility for targeted testing of individuals, for example in prisons where TB burden and risk of cross-infection is high.

The article can be viewed here: https://www.biotechniques.com/microbiology-virology/diagnosing-tb-infection-developments-in-addressing-a-global-threat  



Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

EMA publishes ICH guideline Q12

This guideline provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner. A harmonised approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance and improving supply of medicinal products.

The concepts outlined in prior ICH Quality Guidelines (ICH Q8(R2), Q9, Q10 and Q11) provide opportunities for science-and risk based approaches for use in drug development and regulatory decisions. These guidelines are valuable in the assessment of Chemistry, Manufacturing and Controls (CMC) changes across the product lifecycle. ICH Q8(R2) and Q11 guidelines focus mostly on early stage aspects of the product lifecycle (i.e., product development, registration and launch). This guideline addresses the commercial phase of the product lifecycle (as described in ICH Q10); and it both complements and adds to the flexible regulatory approaches to post-approval CMC changes described in ICH Q8(R2) and Q10 Annex 1.

For details, see: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-q12-technical-regulatory-considerations-pharmaceutical-product-lifecycle-management_en.pdf

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

How Pharma Manufacturers Can Cut Costs and Improve Productivity Now

Time and money are the two most precious humanmade resources. For pharmaceutical companies — especially those on the front lines fighting infectious diseases and treating stubborn ailments — making the most of these resources is especially critical.

By Megan R. Nichols 

The following recommendations can help pharmaceutical manufacturers of all sizes retool their enterprises to save both time and money and become an even more indispensable part of the world's health care community:

1. Adopt Predictive Maintenance Systems

Run-to-failure is no longer an option in a modern manufacturing setting. Preventive maintenance improved on that model, but current technologies can take things to another level. That new level is called predictive maintenance.

Pharmaceutical manufacturing is even more vulnerable to downtime and maintenance lapses than other fields. Failure to keep machines clean, stable and efficient invites contamination, product defects, costly downtime and more expensive maintenance over the lifetime of critical devices.

Deploying predictive maintenance using the Industrial Internet of Things (IIoT) allows manufacturers to capture ongoing metrics and measurements for their equipment. Sensors and edge computing technology work together to monitor assets, catch malfunctions before they impact the product or halt the production line and communicate findings automatically with managers and engineers.

These technologies ensure machines stay in optimal condition for as long as possible, without the costly wear-and-tear of running equipment until it fails.

2. Improve Inventory Management to Boost Margins

According to McKinsey, the average pharmaceutical company holds around 180 days' worth of inventory at any given time. Companies identified as "top performers" tend to shave this down to 100 days. However, available research supports even leaner inventory management practices.

Consumer goods manufacturers target 60 days on average as the optimal amount of inventory to keep on hand. Pharmaceuticals are often time-sensitive and life-saving, so McKinsey points to an optimal window of between 80 and 100 days instead. Targeting this window during inventory management could help pharmaceutical companies free up around $25 billion in operational capital, making their businesses leaner and more financially stable over the long term.

3. Automate Repetitive Tasks Such as Compliance

The pharmaceutical industry consistently ranks among the most heavily regulated industries on the planet. Dealing with multiple regulatory environments across states and territories only compounds these challenges.

From sales reports and quality checks to compliance documentation, pharmaceutical companies have many reasons to adopt automation tools. Repetitive tasks and those requiring frequently changing data from multiple sources are error-prone time sinks.

Automated documentation and reporting tools equipped with machine learning can populate frequently used forms and templates with accurate information, leading to fewer errors and less wasted human effort as documents move between different workflows, facilities or partners.

4. Become a Multi-Product Facility

Manufacturing facilities of all kinds can no longer rely on churning out the same couple of products each year. This issue is especially true in the pharmaceutical industry, thanks to more substantial competition, more frequent calls for small-batch manufacturing and emerging health crises. Each of these factors requires more agile and efficient manufacturers and facilities.

There is a clear need for pharmaceutical manufacturers to become more flexible and adaptable. Becoming a multi-product pharma manufacturing plant requires strong segregation between steps in the fabrication process, cross-contamination protocols and the ability to retool production lines quickly to meet small-batch requirements.

Newer technologies can help with this, including continuous flow chemistry reactors. Static batch reactor systems don't provide the efficiency or speed required by multi-product facilities. In contrast, continuous flow reactors offer more safety and scalability and result in cleaner and more consistent product batches.

5. Hire for Soft Skills and Embrace a Growth Mindset

Every pharmaceutical manufacturer needs to embrace a growth mindset if they want to boost productivity, save money and become more efficient and competitive. For many companies, these objectives must start at the beginning with hiring and recruiting.

Factory managers, supply chain managers, quality control specialists and many other critical positions rely on learned skills. As a result, the hiring process tends to focus on subject matter knowledge. This quality is important, undoubtedly. But campaigns to improve productivity need soft skills, too — as well as driven, thoughtful, out-of-the-box individuals to embrace change, growth and ongoing improvement.

Some of the soft skills required to adopt this mindset include open communication, the ability to engage with employees, leadership skills and, of course, an inventive spirit.

Companies that foster a growth mindset through hiring for soft skills will find it much easier to adopt a systematic approach to improvement, including Lean Six Sigma and others. There are several tenets of Six Sigma that offer substantial value to the pharma industry, including:

· Reducing fulfillment time.

· Finding and eliminating sources of error.

· Making supply chains more responsive and resilient.

· Reducing waste in time, materials and labor.

· Keeping the company organized.

Every workplace inevitably finds different ways to redesign their processes for productivity and eliminate redundancies — but the goal of ongoing improvement begins with finding the right people.

It's hard to understate the importance of pharmaceutical manufacturing. It's how we take ongoing breakthroughs in biotechnology and bring them into the global marketplace, where they improve medical outcomes and enhance human life.

The global pharmaceutical industry is set to reach $1.5 trillion by 2023, with a compound annual growth rate (CAGR) of between 3% and 6%. That's a lot of opportunity for companies that make wise investments in technologies, personnel and forward-thinking, cost-cutting process improvements.

The World Needs More Cost-Effective and Efficient Pharma Manufacturers

Pharma manufacturers can make significant gains within the industry if they adopt more time-saving and cost-effective techniques and processes. By doing so, they can usher in a new era of pharmaceutical practice that's much more productive than its predecessor.
Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Coronavirus: geospatial tool to analyze and visualize the capacities of intensive care beds

The technology allows authorities and hospital operators to identify risk areas and take action before shortages arise. It can be rolled out across nations and applied to other medical capacity questions as well as different areas, such child care facilities, schools and public transport.

The technology has been developed by, a Targomo is a Berlin-based analytics company, using AI and location intelligence to convert complex geospatial research into actionable insights.

The geospatial tool to analyze and visualize the capacities of intensive care bed units in the face of the coronavirus pandemic. Built on Targomo’s Location Intelligence platform, the technology allows authorities and hospital operators to identify risk areas and take action before shortages arise. It can be rolled out across nations and applied to other medical capacity questions as well as different areas, such child care facilities, schools and public transport.



Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Royal College of Nursing opens up its information hub

The Royal College of Nursing (RCN), the world’s largest nursing union and professional body, has partnered with digital preservation specialist Preservica to ensure vital medical and clinical guidance is made available online and preserved for its 450,000 members during the COVID-19 pandemic.

The information is critical to supporting front-line NHS nurses, midwives, student and newly qualified nurses, support workers and retired nurses “returning to duty” at this unprecedented time. The initiative is helping reassure RCN staff and senior decision-makers that records documenting decisions and actions of the RCN, as well as advice given to members, are being actively collected. Actions include the RCN lobbying the UK government on the availability of testing and PPE (Personal Protective Equipment) for its members.

Led by the RCN’s archives team, the college has already made more than a thousand historical clinical guidance publications available online through a secure members portal. The very latest information on tackling infectious diseases and a full summary of all UK government advice and statements is available on the RCN website.

The team is also actively capturing and preserving RCN website bulletins related to COVID-19, and working with the RCN’s comms team to harvest testimonials of front-line nurses that have been shared on social media. The aim is to document the contribution of the college and its members for future generations and enable the RCN to supply evidence that demonstrate its role and actions during the pandemic.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Laboratory Techniques with Applicability in Routine Practice

A new book of interest has been published, focusing on key techniques for those working in bioscience laboratories and students. The reference is:

Chesca, A., Abdulina, G. and Sandle, T. (2020) Laboratory Techniques with Applicability in Routine Practice, Lambert Academic Publishing, Mauritius, IBSN 978-620-056942-4

Tim Sandle as contributed two chapters, which are:

Abstract:

Gram-staining remains the fundamental method for determinative bacteriology, dividing bacteria into Gram-positive and Gram-negative organisms. This test provides information as to the origin of any contamination and is a pre-requisite for many microbial identification methods. Despite the longevity of the test, the test is highly reliant upon analyst technique and therefore errors occur. While there are a few studies looking at errors in the clinical context, research has not been extended to the pharmaceutical and healthcare context. In this study, we present a review of over 6,000 Gram-stains and establish an error rate of around 3%, with the most common reason for error being an over-decolourisation step resulting in organisms that should be Gram-positive appearing as Gram-negative. The analysis enables others to benchmark their facilities against.

Sandle, T. (2020) Assessing Gram-stain error rates in the healthcare context. In Chesca, A., Abdulina, G. and Sandle, T. (2020) Laboratory Techniques with Applicability in Routine Practice, Lambert Academic Publishing, Mauritius, pp7-20

With the second chapter, the abstract reads:

In order to improve the efficiency and detectability of disease, and to streamline services, pathology services have been undergoing a digital transformation. Areas of application extend from the automated scanning of slides to the use of artificial intelligence to aid with the interpretation of data. Furthermore, the implementation of digital workflows, which includes integration between systems and software, is key to achieving widespread adoption and driving improvements. This chapter assesses the main changes taking place and looks at the impact upon the workstream of the pathology function. In doing so, the chapter also considers the advantages and disadvantages that such new technology comes with.

The chapter reference is:

Sandle, T. (2020) Advances in pathology services for diagnosing disease. In Chesca, A., Abdulina, G. and Sandle, T. (2020) Laboratory Techniques with Applicability in Routine Practice, Lambert Academic Publishing, Mauritius, pp21-38

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Understanding sepsis - a film about sepsis for young people

To know what sepsis is and recognize the symptoms is important. This film aims to give everyone an understanding of sepsis, but especially young people. The film demonstrates how the body’s immune system works and explains what happens when you get sepsis.

This video comes from the Sewdish Sepsisfonden Sepsisfonden

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)