FDA-Patented Invention Earns 2016 Patents for Humanity Award for Impact on Global Public Health

By: Carolyn A. Wilson, Ph.D., and Alice Welch, Ph.D. 

In 2003, two scientists in FDA’s Office of Vaccines Research and Review within the Center for Biologics Evaluation and Research (CBER) developed a pivotal step in the manufacture of a vaccine now called MenAfriVac. This vaccine has since protected more than 235 million lives against recurring meningitis outbreaks in sub-Saharan Africa. The patented chemical method devised by these two researchers, Dr. Robert Lee and Dr. Carl E. Frasch, enabled the production of the inexpensive and highly effective MenAfriVac vaccine, earning FDA a 2016 Patents for Humanity Award from the U.S. Patent and Trademark Office.

Carolyn A. Wilson

Carolyn A. Wilson, Ph.D., Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

FDA’s scientific research doesn’t often grab headlines. But FDA’s research program is a critical part of the work we do to protect public health and speed innovations that make safe and effective medicines available. And sometimes FDA scientists make significant discoveries that are patentable inventions. When they do, FDA’s Technology Transfer program facilitates the transfer of such technologies to the private sector so they can become useful solutions to public health challenges. The MenAfriVac vaccine is a stellar example of such an FDA invention.

So it was with particular pride and satisfaction that we joined Drs. Lee and Frasch this past November as the U.S. Patent and Trademark Office honored them with a Patents for Humanity Award, in recognition of the critical contribution the patented technique made to the development of the MenAfriVac vaccine.

The story began in late 2003, when Dr. Lee devised a set of chemical reactions for a technique called “conjugation.” It is a method for efficiently linking one ingredient of a potential vaccine with a molecule that supercharges that ingredient’s ability to stimulate the immune system. That chemical joining, along with the collaboration with Dr. Frasch, became the basis of the FDA patent.

At the time, it was just another quiet development in the quest to make the production of certain types of vaccines more efficient. Little did the two researchers know that this patent would later help the Bill & Melinda Gates Foundation-supported non-profit PATH save tens of thousands of lives in the African meningitis belt.

Alice Welch

Alice Welch, Ph.D., Director of FDA’s Technology Transfer Program.

Just a couple of years earlier in 2001, the Meningitis Vaccine Project (MVP), a World Health Organization (WHO) and PATH partnership, had received Gates Foundation funding. Their goal was to produce an inexpensive, safe, and effective vaccine so that the affected countries could afford mass group A meningitis vaccination programs.

But MVP lacked access to a technique that was simple, efficient, and produced meningitis vaccines inexpensively. Thanks to the scientific accomplishment of these two scientists, CBER was able to provide its new technique to MVP via PATH, through a technology transfer agreement made with help from the National Institutes of Health. CBER also developed reagents to evaluate the performance and safety of the vaccine as well as methods to monitor the manufacturing process. And in December 2003, scientists from the Serum Institute of India Limited came to CBER to learn how to use the technique to make the vaccine on MVP’s behalf. The resulting vaccine didn’t need to be refrigerated, which greatly simplified deployment of this product in sub-Saharan Africa.

Awards Ceremony

Alice Welch holds the 2016 Patent for Humanity Award from the US Patent and Trademark Office.
Also in attendance for the ceremony were (left to right) Carolyn Wilson, Carl Frasch, and Robert Lee.

Early in December 2010, MVP initiated its vaccination campaign using MenAfriVac, first in Burkina Faso, then Mali, and then Niger. A year later, MVP extended the campaign to Cameroon, Chad, and Nigeria.

WHO is now helping countries transition from mass campaigns to routine immunization to establish sustainable disease control in the region. By 2020 the vaccine is expected to have protected more than 400 million people, preventing 100 million cases of meningitis A, 150,000 deaths, and 250,000 cases of severe disability.

In an era when established and emerging infectious disease outbreaks affect the lives of more people worldwide than ever before, the American public and the global community will increasingly depend on FDA to provide the kind of scientific research and expertise that have led to the successful development of medical countermeasures and vaccines like MenAfriVac.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

Alice Welch, Ph.D., is Director of FDA’s Technology Transfer Program.

CBER Laboratories in the Life Sciences-Biodefense Complex

By: Carolyn A. Wilson, Ph.D.

Wise management of research programs means more than selecting projects that will yield the most scientific information but also making sure that we are making wise use of the dollars we allot for research.

Carolyn A. WilsonThat’s why FDA’s Center for Biologics Evaluation and Research (CBER) thinks strategically when it plans research programs by the more than 70 principal investigators who work in our two-year-old laboratories in the Life Sciences-Biodefense Complex at FDA’s White Oak campus.

We ask ourselves how we can most efficiently – and cost-effectively – obtain the answers to our scientific questions that our regulators will need to achieve their mission of ensuring the safety, purity, and potency of biological products.  Products regulated by CBER include vaccines, allergenics (allergy diagnostics and treatments), cellular, tissue, and gene therapy products, and blood and blood products.

To sharpen our research planning we recently undertook a major evaluation of our center’s scientific and administrative strategies and programs with the assistance of an outside consulting firm.

The findings have enabled us to refine  our strategies for wringing the most new knowledge from every dollar we spend on regulatory science – the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products. These refinements to CBER’s research strategy include:

  • A Resource Committee that manages CBER’s annual budget, as well as a Regulatory Science Council that develops center-wide goals, guides office-level objectives, and oversees all research activities. These two councils will increase overall transparency of decision-making, make sure that research is prioritized, and aim to make budget planning more timely and responsive to our mission.
  • More direct control of funds by individual CBER offices and earlier allocation of that funding, and annual peer review of 25 percent of existing and new projects to ensure accountability for how they are run.
  • Systems to increase the transparency of CBER research and research funding, enhance management decisions, and facilitate tracking of funding allocated to activities and projects.
  • Elevating the culture of science through monthly presentations highlighting the public health impact and mission relevance of CBER research; biannual CBER-wide Science Symposium, providing opportunities for communication and potentially improved collaboration across all CBER research projects; and, enhanced prominence of CBER research fellows in the research enterprise.
jars of vegetables

Faulty home food preservation is one potential source of botulism. FDA scientists are developing methods that will help manufacturers to make a vaccine that will prevent this bacterial illness.

These research and administration refinements are helping us better identify and prepare for tomorrow’s needs.  And when you consider the approximately 70-80 research programs we have underway, we’re doing a lot. A few examples include:

  • Studying botulism toxoids (inactivated illness-causing chemicals released by bacteria) to support development of the first vaccine to prevent this potentially fatal infection. CBER scientists are designing new tests to predict what vaccine approaches may be protective. These tests may also help screen vaccines that protect against other toxins such as those from anthrax, as well as the plant-derived toxin ricin.
  • Determining the critical immune events that provide protective immunity to intracellular microbes (bacteria and parasites that live inside human cells). Based on this, FDA scientists will develop new measurements to predict protection that may help evaluate new vaccines for these microbes.

    Girl sneezing in a field of flowers.

    Allergies can turn nature walks into annoying sneezing fits. FDA scientists are developing new tools to help manufacturers produce more potent allergy shots and enhance their safety.

  • Developing new tools and data to help manufacturers produce more potent allergy shots and enhance their safety.
  • Helping to develop a test for cow intestine to ensure heparin harvested from this tissue is not contaminated with the agent causing the bovine transmissible spongiform encephalopathy (TSE, also known as “mad cow disease”), a known risk to humans. This would help to ensure a safe, reliable, domestic source of heparin, which is now obtained mostly from China.
  • Developing new methods and technologies for rapid-testing detection and characterization of emerging infectious pathogens that threaten the safety of tissue and tissue-based products. In the course of developing these technologies, the lab has found previously unidentified microbial contaminants in archived tissues used for these studies. These findings provide preliminary evidence to support the potential for application of rapid test technologies in evaluation of emerging infectious disease transmission risks associated with the implantation, transplantation, infusion, or transfer of human tissue.

As CBER continues to advance regulatory science in its Life Sciences-BioDefense Complex, our projects will adapt to new challenges that the science of biologics will inevitably pose to FDA. And CBER will address those challenges, keeping in mind both the public health and our fiduciary responsibility to make every research dollar count.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research

FDA’s giant NMR magnet puts more imaging power into our regulatory science

By: Carolyn A. Wilson, Ph.D.

Carolyn A. WilsonThe word spin might make you think of someone trying to influence your opinion. But in physics, spin refers to an intrinsic property of certain subatomic particles that make some nuclei act like small magnets. That kind of spin is key to a powerful laboratory technique scientists use to study complex, carbon-based biological products at the atomic and molecular level.

This technique, called nuclear magnetic resonance (NMR), uses a strong, external magnetic field and radio waves to trigger the release of electromagnetic energy from atoms with nuclei that have spin. Computers convert these data into contour plots that resemble topographic land maps. Scientists use these data to determine the locations of atoms in relation to each other in molecules. This enables them to create three-dimensional models they can hold in their hands and study, or 3D images they can rotate on a computer screen.

Scientists in FDA’s Center for Biologics Evaluation and Research (CBER) are using NMR to study two types of molecules relevant to the vaccines against bacterial and viral disease that we regulate: polysaccharides (long chains of sugar molecules), which occur in either the cell wall or the capsule surrounding some disease-causing bacteria, and shorter chains of sugars called oligosaccharides. Oligosaccharides are found in viruses and are also part of bacterial vaccines.


Scientists at FDA discuss construction of the facility that will house the new NMR. From left to right: Hugo F. Azurmendi (CBER), Kang Chen (CDER), Darón I. Freedberg (CBER) & Marcos D. Battistel (CBER). Get this and other FDA photos on Flickr.

The microbes need these molecules to cause disease, so CBER scientists are using NMR to study how the structure of such polysaccharides and oligosaccharides triggers production of antibodies against the microbes that carry these molecules. The methods developed by CBER scientists will allow evaluation of licensed and investigational polysaccharide vaccines by using NMR to determine if those vaccines were developed in a manner consistent with these insights into how the structure of these molecules triggers antibody production. In addition, the outcomes of these studies might provide information that manufacturers could use to design novel polysaccharide vaccines that are safe and effective.

Insights into the structures of polysaccharides that play critical roles in generating protective immune responses would be especially useful in confronting dangerous pathogens for which there are no vaccines. Two such pathogens, the bacteria Neisseria meningitidis B and Escherichia coli K1, cause meningitis (a potentially fatal inflammation of the brain and spinal cord). The capsules surrounding these bacteria contain a polysaccharide called polysialic acid. This molecule is unusual because it doesn’t trigger antibody production when injected by itself into adult humans, but people infected with bacteria that have polysialic acid in their cell walls or capsules do produce antibodies against it. One logical explanation for this difference is that “free” polysialic acid has a somewhat different structure than polysialic acid on bacterial cell walls. But, using NMR, CBER scientists found that polysialic had the same structure whether free or as part of the pathogen. Figuring out why only bound polysialic acid triggers antibody production might help researchers develop much needed vaccines for these bacteria. Soon they will have a new NMR facility at the White Oak campus that could help them solve that puzzle.

NMR "Stick" Model; NMR studies at CBER are providing insights into the atomic and molecular ins and outs of polysialic acid, a molecule found on the surface of bacteria, including some that cause meningitis. This work is aimed at helping researchers develop safe and effective vaccines against such bacteria that are based polysialic acid. Using the NMR data from their studies, the CBER scientists created two models of polysialic acid, a “stick” model and a “solid spheres” model, shown in the two short animated videos (above and below).

NMR “Stick” and “Solid Spheres” Models: NMR studies at CBER are providing insights into the atomic and molecular ins and outs of polysialic acid, a molecule found on the surface of bacteria, including some that cause meningitis. This work is aimed at helping researchers develop safe and effective vaccines against such bacteria that are based polysialic acid. Using the NMR data from their studies, the CBER scientists created two models of polysialic acid, a “stick” model (above) and a “solid spheres” model (below), shown in these two short animations.


NMR “Solid Spheres” Model

The NMR spectrometer in the new facility will have a magnet that is much stronger than those previously used at FDA. The stronger the magnet, the more precise the data generated by NMR and the more precise the models that can be developed from this data.

To put this into perspective, the clinical application of NMR, called magnetic resonance imaging (MRI), uses magnets with strengths of 1.5 to 3 units of magnetic power called Tesla. The strength of NMR magnets at CBER is now about 16.4 Tesla (700 megahertz). The new NMR facility at White Oak will have a strength of 19.9 Tesla (850 megahertz)—about 6 times that of hospital MRI machines. In fact, the magnet is so powerful that the machine is isolated in a special room with walls thick enough to block its magnetic field from pulling unsecured metallic objects toward it. In the photograph you can see the NMR team visiting the facility as it is being prepared for the arrival of the machine.

CBER will share the new NMR spectrometer with the Center for Drug Evaluation and Research (CDER), which will use it to do extremely sensitive assessments of the purity of heparin and of the structures and properties of protein therapeutics.

This powerful magnetic molecular “microscope” is one way that FDA incorporates new technology into its regulatory science work to protect and promote the nation’s health.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

Developing new tools to support regulatory use of “Next Gen Sequencing” data

By: Carolyn A. Wilson, Ph.D.

When you’re thirsty, you don’t want to take a drink from a fire hose. And when scientists are looking for data they don’t want to be knocked over with a flood of information that overwhelms their ability to analyze and make sense of it.

Carolyn WilsonThat’s especially true of data generated by some types of both human and non-human genome research called Next Generation Sequencing (NGS). This technology produces sets of data that are so large and complex that they overwhelm the ability of most computer systems to store, search, and analyze it, or transfer it to other computer systems.

The human genome comprises about 3 billion building blocks called nucleic acids; much medical research involves analyzing this huge storehouse of data by a process called sequencing—determining the order in which the nucleic acids occur, either in the entire genome or a specific part of it. The goal is often to find changes in the sequence that might be mutations that cause specific disease. Such information could be the basis of diagnostic tests, new treatments, or ways to track the quality of certain products, such as vaccines made from viruses.

NGS is a complicated technique, but basically it involves cutting the genome into millions of small pieces so you can use sophisticated chemical tricks and technologies to ignore the “junk” you don’t need, and then make up to hundreds of copies of each of the pieces you want to study. This enables additional techniques to identify changes in the sequence of nucleic acids that might be mutations. NSG enables scientists to fast-track this process by analyzing millions of pieces of the genome at the same time. For comparison, the famous human genome sequencing and analysis program that took 13 years to complete and cost $3 billion could now be completed in days for a few thousand dollars.

Man with HIVE Computer

The Center for Biologics Evaluation and Research (CBER) supported the development of High-Performance Integrated Virtual Environment (HIVE) technology, a private, cloud-based environment that comprises both a storage library of data and a powerful computing capacity being used to support Next Generation Sequencing of genomes.

In order to prepare FDA to review and understand the interpretation and significance of data in regulatory submissions that include NGS, the Center for Biologics Evaluation and Research (CBER) supported the development of a powerful, data-hungry computer technology called High-Performance Integrated Virtual Environment (HIVE), which can consume, digest, analyze, manage, and share all this data. HIVE is a private cloud-based environment that comprises both a storage library of data and a powerful computing capacity. One specific algorithm (set of instructions for handling data) of HIVE that enables CBER scientists to manage the NGS fire hose is called HIVE-hexagon aligner. CBER scientists have used HIVE-hexagon in a variety of ways; for example, it helped scientists in the Office of Vaccines Research and Review study the genetic stability of influenza A viruses used to make vaccines. The scientists showed that this powerful tool might be very useful for determining if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections, or even worse, cause infections.

There’s another exciting potential to HIVE-hexagon research: the more scientists can learn about variations in genes that alter the way they work—or make them stop working–the more they can help doctors modify patient care to reflect those very personal differences. These differences can affect health, disease, and how individuals respond to treatments, such as chemotherapy and influenza vaccines. Such knowledge will contribute to advances in personalized medicine.

Team members at work in FDA's HIVE server room.

CBER scientists showed that HIVE might help scientists determine if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections or cause infections. Genome studies supported by HIVE will also contribute to advances in personalized medicine.

Because CBER’s HIVE installation has been so successful we are now collaborating with FDA’s Center for Devices and Radiological Health (CDRH) to provide a second installation with greater capacity and computer power that takes advantage of the high-performance computing capacity there. When ready and approved by FDA for use, we will use this powerful, CBER-managed, inter-center resource to handle regulatory submissions.

HIVE-hexagon and its innovative NGS algorithms are just one major step CBER has taken recently as it continues its pioneering work in regulatory research to ensure that products for consumers are safe and effective. I’ll tell you about other exciting breakthroughs in my next update on CBER research.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

For more HIVE photos go to Flickr

Supporting Innovative Research Through Regulatory Science

By: Carolyn A. Wilson, Ph.D.

In my last blog post I discussed aspects of regulatory science, that is, how scientists in FDA’s Center for Biologics Evaluation and Research (CBER) help to turn innovative medical research into life-saving or life-enhancing biological products. I also described how FDA scientists help determine if potential health problems are linked to the use of a particular medical product. In this post, I’ll discuss two more studies that made important contributions to public health.

Carolyn WilsonSometimes CBER research changes the way scientists look at a problem so their research is more efficient. For example, in the field of gene therapy, a strain of the common cold virus called an adenovirus, is used as a vector – delivering therapeutic genes to treat both inherited and non-inherited conditions. However, success of this therapeutic approach has been hampered in part by the finding that an immune response to the adenovirus may prevent efficient delivery of the therapeutic genes to their targets, such as cancer cells. The problem appeared to be that once inside the body, the adenovirus attaches a blood clotting protein called FX to itself and binds to liver cells. As a result the vector doesn’t reach the desired target cells where it would deliver the therapeutic gene.

Some scientists thought that altering the virus so it couldn’t bind FX would let it avoid the liver, making it a more efficient vector. However, scientists in the Office of Cellular, Tissue and Gene Therapies (OCTGT) discovered that adenovirus commandeers the FX protein to use as a shield to evade attack by the immune system. So removing it would likely enable the immune system to attack and disable the adenovirus and block treatment. This new knowledge that the adenovirus needs FX to disguise itself from the immune system will help guide researchers to design gene therapy vectors that survive in the bloodstream and reach their desired target cells.

Another group of scientists, in the Office of Blood Research and Review (OBRR), has contributed to our understanding of why African Americans are significantly more likely than whites to produce antibodies against a drug used to treat hemophilia A. People with hemophilia A carry a mutation in the gene for the protein Factor VIII (FVIII) – a protein that plays an essential role in clotting and preventing blood loss. This mutation either eliminates or greatly reduces the amount of Factor VIII in the blood. Fortunately, there is a therapeutic form of FVIII made through biotechnology that is used to replace faulty or missing, natural FVIII. But unfortunately, some African Americans with hemophilia A make antibodies against therapeutic FVIII. These antibodies attack it and disrupt treatment. The FDA scientists discovered certain genetic variations in the gene for Factor VIII made by these individuals that appear to be responsible for this immune system attack. The discovery is an important step in developing ways to predict which patients will develop antibodies against this complication. And that is an important step toward developing a personalized-medicine approach to hemophilia A by custom-designing medical responses to this life-threatening disease.

The examples I’ve given of CBER research here and in my previous blog are just a small sample of the important knowledge our scientists are creating that supports efforts of medical researchers striving to develop products that improve public health nationally and globally.  In 2013, CBER scientists published their research findings in over 200 journals and books.

I’ll be back to update you on more exciting research from CBER during 2014.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

Regulatory Science Supports FDA’s Regulatory Mission

By: Carolyn A. Wilson, Ph.D.

You might only think of FDA as a regulatory agency that oversees medical and food products. But FDA scientists, including those in the Center for Biologics Evaluation and Research (CBER), also perform research. In this first of two blog posts, I will describe how regulatory science, as it is called, helps to turn innovative medical research done at FDA and other places into life-saving or life-enhancing biological products.

Carolyn WilsonMost of the discoveries made at CBER support the development of new or improved vaccines, blood and blood products, and tissue, gene and cell therapies. This research also helps CBER make very informed decisions about new products and policies. That’s because many of the same CBER scientists whose research puts them at the cutting edge of science also review potential new products, inspect commercial facilities that make products, and help develop new policies and guidance documents for industry. In the past year, discoveries that CBER scientists have published in research journals have contributed significantly to public health by addressing issues that affect the safety and effectiveness of vaccines, gene therapy, and a treatment for a serious blood disorder.  

For example, scientists in the Office of Vaccines Research and Review (OVRR) took a big step in solving the mystery of why the rates of pertussis (whooping cough) in the United States have been increasing since the 1980s – despite widespread use of a pertussis vaccine. OVRR scientists showed in baboons that even though the vaccine can prevent symptoms of pertussis, animals receiving it still had the bacteria that cause the disease in their airways for up to six weeks.

These animals were then able to spread the bacteria to other animals. This suggests that while the vaccine protects children from getting pertussis symptoms, vaccinated children can still spread the bacteria through coughing to other children for several weeks – especially if those children aren’t vaccinated. This information is important because it can help scientists and public health officials design new vaccines and strategies to reduce the rate of pertussis in the US.

Statisticians and epidemiologists at CBER also make critical contributions to regulatory science. Serious adverse medical events sometimes occur in patients treated with licensed products (i.e., vaccines). When physicians or consumers report such events to the FDA, epidemiologists at the agency work to determine whether these events are actually caused by the licensed product or are just a coincidence. For example, epidemiologists and statisticians in the Office of Biostatistics and Epidemiology (OBE) studied whether getting the vaccine for 2009 H1N1 influenza (the so-called “swine flu”) several years ago increased the risk of developing a nerve disease called Guillain-Barré Syndrome (GBS). GBS can sometimes occur after infections or vaccinations, causing weakness in the arms and legs and reducing reflexes. The concern about the 2009 vaccine was based on the occurrence of GBS over 30 years ago among some people who received the vaccine against a related strain of H1N1 virus in 1976. CBER’s epidemiologists asked whether the more recent vaccine used to protect against the 2009 H1N1 virus also increases this risk. To answer this question, OBE researchers reviewed the medical records of 23 million individuals who received the 2009 H1N1 influenza vaccine during the 2009-2010 influenza outbreak. Their statistical analysis showed that the risk of death or hospitalization from H1N1 infection was about 500 times greater than the risk of developing GBS from the vaccine. 

Studies like these are very important because they help FDA regulators and public health officials to determine whether potential adverse effects are actually linked to the use of a particular product. In this case, confirming the safety of the vaccine was an important public health measure because it reassured the public that this vaccine was safe to take. 

In my next blog post I’ll be discussing important contributions CBER scientists recently made to gene therapy and the treatment of a blood disease called hemophilia. 

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.