The CVD study suggests that developing a broadly protective vaccine for malaria may be challenging because the parasite’s genetic makeup is so variable, constantly changing. If a vaccine targets only a single protein in the parasite, and there are many different versions of that protein, the parasite becomes a moving target for vaccine development.

Drug-resistant malaria has been a major barrier to treating the disease, and this CVD study suggests that “vaccine-resistant” malaria may also become a problem. The study is being published in the Oct. 14 issue of the journal Science Translational Medicine.

Scientists and health officials worldwide have made eradication of the disease a priority, with an effective and broadly protective vaccine a critical step toward that goal. Malaria — a parasite spread to humans through mosquito bites — is prevented by avoiding mosquito bites
using bed nets or by killing mosquitoes with insecticides.

The parasite is treatable using medications, although drug resistance is a relatively common problem. According to the World Health Organization, a child dies of malaria every 30 seconds. There are approximately 300 million malaria cases annually worldwide, resulting in more than one million deaths, most of them African children.

Certain regions within a key parasite protein — a protein targeted by some experimental malaria vaccines — seem to affect the human immune response more than others, and targeting those areas could help develop a better vaccine, according to the study led by Shannon Takala, Ph.D., assistant professor of Medicine at the University of Maryland School of Medicine and a research scientist in the CVD. The study was conducted in collaboration with researchers at the University of Bamako in Mali, West Africa, and at the Center for Bioinformatics and Computational Biology and Department of Biology at the University of Maryland, College Park.

“This brings us one step closer to being able to design a broadly protective malaria vaccine,” says Dr. Takala. “Though there are medications that are used to treat malaria, drug resistance is a recurring problem. An effective vaccine could help us eliminate malaria altogether, a public health goal that is attracting more global support than ever before.”

“In addition to its home campus in Baltimore, the University of Maryland School of Medicine employs hundreds of researchers in 23 countries around the globe,” says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the School of Medicine, vice president for medical affairs of the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor. “This study is an example of how our global footprint allows School of Medicine researchers to study diseases such as malaria in the very regions of the world in which they are devastating to the population.”

A research team of Malian and American scientists at the CVD’s outpost in Mali, West Africa, tested malaria parasites from 100 children in Mali over a three-year period. The children, who had not been vaccinated against the disease, all experienced repeated malaria infections during the three years. The CVD researchers, including Christopher Plowe, M.D., M.P.H., Howard Hughes Medical Institute investigator, professor of medicine and chief of the Malaria Section at the University of Maryland School of Medicine, looked at the genetic diversity in a surface protein of the Plasmodium falciparum — the AMA-1 protein — that is the target of some candidate malaria vaccines.

By tracking the changes in the AMA-1 protein each time a child became infected with malaria, researchers found a surprising amount of genetic diversity. Among more than 500 separate malaria infections the children experienced throughout the study, researchers found 214 distinct types of the AMA-1 protein. The scientists also found that the genetic differences in certain parts of the protein but not others corresponded to whether or not a child got sick the next time they were infected with malaria. It was easier for a child’s immune system to defend itself against illness in a subsequent infection if the protein in the second parasite was genetically similar to the parasite that caused their first illness.

Working with Michael P. Cummings, Ph.D., associate professor of biology at the University of Maryland, the researchers were able to track which variants of the AMA-1 protein were present in each infection and compare that data to the symptoms each child experienced during the infections.
 
“Applying a molecular evolutionary perspective to the study of the malaria parasite gave us new information about why it has been so challenging to develop an effective malaria vaccine,” says Dr. Cummings, who is affiliated with the University of Maryland’s Center for Bioinformatics and Computational Biology. “The genetic diversity we found in the AMA-1 protein was so high that it could potentially thwart the usefulness of any vaccine based on this protein.”

By narrowing their focus to those specific regions of the protein that are recognized as distinct by the immune response, the researchers were able to reduce the number of immunologically important AMA-1 types from 214 to just 25. By targeting those specific regions of the protein, scientists could possibly develop a more broadly protective malaria vaccine.

“The emergence of drug-resistant malaria was one of the main reasons eradication of the disease didn’t work when it was tried 50 years ago,” says senior author Dr. Plowe. “We want people to begin thinking now about the possibility that ‘vaccine-resistant malaria’ could be just as much of a problem for the new global eradication effort. We need to come up with ways to beat vaccine-resistant malaria before we start losing vaccines to resistance the way we have lost so many good drugs.”

The study was supported by grants from the National Institutes of Health and the United States Agency for International Development, as well as a seed grant from the University of Maryland.

For more information on the University of Maryland Center for Bioinformatics and Computational Biology, or to reach Dr. Michael Cummings, please contact Kelly Blake, Director of Communications, College of Chemical and Life Sciences, University of Maryland, at (301) 405-8203, or kellyb@umd.edu.

Thirty-five years after founding the University of Maryland School of Medicine's Center for Vaccine Development (CVD), Dr. Levine is known worldwide for his role in developing vaccines to prevent the spread of diseases such as cholera, typhoid fever, and Shigella dysentery. The CVD currently is working on an H1N1 vaccine, and evaluating one for malaria.

Dr. Davis was recruited from Vanderbilt University School of Medicine in Tennessee. He will lead the University of Maryland School of Medicine’s largest department, with over 300 full-time faculty members of both physicians and scientists. He is an endocrinologist who has devoted his career to research and patient care, focusing on treating adults with diabetes and metabolic disorders, as well as studying the biological basis of certain diabetes-related complications.

“As a renowned physician-scientist, Dr. Davis will be most suited to provide excellent clinical and scientific leadership of the Department of Medicine here at the School of Medicine,” says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the School of Medicine, vice president for medical affairs of the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor. “During his 30-year career, Dr. Davis has balanced his award-winning diabetes research program with providing excellent patient care, while excelling at various leadership roles within his institution and in the international medical community at large. His career is the embodiment of the mission of the University of Maryland School of Medicine — to combine world class patient care with top-tier cutting-edge scientific research. We are very pleased that Dr. Davis will lead our Department of Medicine,” says Dean Reece.

“Dr. Davis has a distinguished reputation as a physician leader, educator and a scientist.  We look forward to working with him as he takes the helm of our largest department, caring for  patients with a full range of complex medical conditions,” says Jeffrey A. Rivest, president and CEO of the University of Maryland Medical Center. “In addition, with Dr. Davis’ expertise in diabetes, he will be a tremendous asset to the Joslin Diabetes Center, one of the most prominent programs within our Department of Medicine, which provides comprehensive care and education for people living with diabetes,” says Rivest.

The Department of Medicine at the University of Maryland School of Medicine was created at the school’s founding 202 years ago. Dr. Davis will be the 13th chairman to lead this nationally recognized department. The department is responsible for training 145 residents and 77 fellows. It has been very successful scientifically and currently receives almost $150 million in annual extramural research funding to support its comprehensive laboratory and clinical research programs.

The department includes 11 divisions and one specialized program: Cardiology; Endocrinology, Diabetes and Nutrition; Gastroenterology and Hepatology; General Internal Medicine; Geographic Medicine; Gerontology and Geriatric Medicine; Hematology/Oncology; Infectious Diseases; Nephrology; Pulmonary and Critical Care Medicine; Rheumatology and Clinical Immunology; and the Occupational Health Program. The Department of Medicine has a global reach, with research programs in many countries, and in regions such as South America and Africa.

A native of the United Kingdom, Dr. Davis earned his medical degree from London University and did his specialty training at the Royal College of Physicians. Dr. Davis joined Vanderbilt University School of Medicine in 1988. He was promoted to Director of the Division of Diabetes, Endocrinology and Metabolism, and professor of medicine, molecular physiology and biophysics. Most recently, he also served as associate director of the General Clinical Research Center at Vanderbilt, and for five years, ending in 2002, he was director of the Nashville Veterans Affairs/Juvenile Diabetes Foundation International Research and Training Center.

He has been recognized with many distinguished awards throughout his career, including the Novartis Award for Diabetes Research in 2000 — considered to be the highest honor in that field of research. He was named a Fellow of the American College of Physicians in 2009, a Fellow of the American College of Endocrinologists in 2008 and a Fellow of the Royal College of Physicians in 2001.

Dr. Davis currently leads research projects with extramural funding totaling $10 million.
His research focuses on the mechanisms that defend against a falling blood glucose level, a condition known as hypoglycemia. “Hypoglycemia is the complication of diabetes that patients fear most,” explains Dr. Davis. “Complications that can be associated with diabetes include blindness, kidney failure and even coma or death.” Some diabetics suffer from frequent episodes of hypoglycemia, even as often as several times each week. Dr. Davis’s laboratory has found areas in the brain that act to blunt the body’s ability to protect itself against hypoglycemia. Each episode of hypoglycemia triggers these areas of the brain to send out signals that make it more difficult for the body to defend itself against subsequent episodes of low glucose levels in the blood. Dr. Davis also has identified promising new treatments and interventions that counteract these mechanisms and stimulate the body’s ability to defend itself against hypoglycemia.    

Dr. Davis also explores the mechanisms that cause increased heart attacks and strokes in diabetic patients, most (65 percent) of whom die from such events. Dr. Davis is the author of more than 110 peer-reviewed articles and 50 textbook chapters and review articles.

“I am honored by the opportunity to take on this leadership role at the University of Maryland School of Medicine, an institution with a distinguished history, including being the first public medical school in the U.S.,” says Dr. Davis. “I want to thank Dean Reece for this great honor. I am also very pleased to be succeeding Dr. Frank Calia who has been an outstanding leader of this department, which has flourished on his watch. I hope to continue that momentum. I am looking forward to leading the Department of Medicine into a new, dynamic era of research and patient care defined by cutting-edge discoveries in emerging areas of science including genomics, stem cell biology and metabolic disorders.”

“Our goal is to offer our patients the finest care and most effective and innovative treatments, and recruiting such top-notch specialists and physician leaders as Dr. Davis enables us to fulfill our mission,” says Robert A. Chrencik, president and chief executive officer of the University of Maryland Medical System. “We believe that Dr. Davis is the right person to lead our Department of Medicine to even greater advances in patient care and research.”

Dr. Davis and his wife, Frances, have three sons — Ian, Stuart and Hugh. 

[For more information about participating in clinical trials at the Center for Vaccine Development, please call 410-706-6156, or visit www.clinicaltrials.gov.]

The University of Maryland School of Medicine’s Center for Vaccine Development will lead one of the nation’s first studies of an experimental vaccine designed to prevent the 2009 H1N1 influenza virus. The Center for Vaccine Development is one of a nationwide network of Vaccine and Treatment Evaluation Units (VTEUs) funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The VTEUs are conducting the trial, which will recruit volunteers and test the vaccine beginning in August.

To view the entire news conference, click here. (Real Player is required.)

The clinical trial will enroll as many as 1,000 healthy adults and children at 10 centers nationwide to evaluate the safety of the vaccine and measure its ability to stimulate immune responses to the H1N1 virus. The research is a first step toward the U.S. government’s stated goal of developing a safe and effective vaccine against the H1N1 strain of influenza and making it available to the public before the flu season begins in the fall.

“The H1N1 flu outbreak has been declared a global pandemic by the World Health Organization and a public health emergency by the U.S. government,” says Karen L. Kotloff, M.D., professor of pediatrics, a lead investigator at the VTEU and a researcher in the Center for Vaccine Development at the University of Maryland School of Medicine. “This virus has the potential to cause significant illness with hospitalizations and deaths during the U.S. flu season this fall and winter. Vaccines have always been a vital tool for controlling influenza. The results of these studies will help to guide the optimal use of the H1N1 vaccines in the U.S. and elsewhere in the world.”

“Our Center for Vaccine Development has been home to one of the NIAID’s Vaccine and Treatment Evaluation Units for more than three decades,” says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the University of Maryland School of Medicine.

“Our VTEU is now one of just eight in the country, and it is the only one in the mid-Atlantic region,” says Dean Reece, who also serves as Vice President for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor at the School of Medicine. “We’re very pleased the NIAID has chosen our top-tier researchers as leaders in the effort to stop the H1N1 pandemic before the 2009 influenza season begins.”

All participants in the trial will receive two doses of vaccine three weeks apart. The response after one dose versus two doses will be compared. The trial also will evaluate two strengths of the vaccine to determine which strength is required to stimulate an immune response that is most likely to protect people against the H1N1 flu. The vaccine will be tested in five different age groups. First, researchers will test the vaccine in healthy adult and elderly volunteers. If the vaccines are well tolerated in those groups, then the researchers will begin testing the vaccine in children. Ultimately, as many as 200 adults, 200 seniors and 600 children may be enrolled in the trials.

“The response to the vaccine may vary in different age groups,” Dr. Kotloff said. “This is because young people have not seen a flu virus like this one before. Older adults might have some immunity to the new H1N1 virus as a result of being exposed to similar flu viruses in the past. As a result, older adults might need fewer doses or a lower strength of the vaccine than younger individuals.”

In addition to involving Dr. Kotloff, the lead investigator, trials at the University of Maryland School of Medicine VTEU also will involve co-investigators Wilbur H. Chen, M.D., assistant professor of medicine, and Ina Stephens, M.D., assistant professor of pediatrics. Individuals will be able to volunteer for the trial at sites in Baltimore, Frederick and Annapolis. In Baltimore, the testing will take place at the University of Maryland Medical Center.

University of Maryland School of Medicine researchers also will participate in future studies of the vaccine that will be led by other members of the NIAID’s nationwide network of Vaccine and Treatment Evaluation Units. Those trials will examine important questions such as how the vaccine works in combination with the seasonal flu vaccine and whether including an adjuvant, which boosts the immune response to vaccines, can make the vaccine work better at lower doses.

The eight VTEU sites that will participate in these H1N1 vaccine trials include the University of Maryland School of Medicine as well as Baylor College of Medicine, Cincinnati Children’s Hospital Medical Center, Emory University, Saint Louis University, Seattle Group Health Cooperative, the University of Iowa, and Vanderbilt University. They will be joined by Children’s Mercy Hospital in Kansas City and Duke University Medical Center.

“Learning the responses of different age groups of people to the vaccine will not only tell
us the best way to use the vaccine in an individual, but we also learn ways to use the vaccine
supply most efficiently to protect the greatest number of people,” says Dr. Kotloff.

“The Center for Vaccine Development is an internationally known facility devoted to the use of vaccination to control of infectious diseases such as typhoid, measles, Hib meningitis, cholera, Shigella dysentery and malaria,” says Myron M. Levine, M.D., D.T.P.H., a professor of medicine, head of the Division of Geographic Medicine and director of the Center for Vaccine Development at the School of Medicine. “We’re delighted to play such a key role in the quest for an effective vaccine for this new, emerging strain of influenza.”

For more information about participating in clinical trials at the Center for Vaccine Development, please call 410-706-6156, or visit www.clinicaltrials.gov.

The School of Medicine currently ranks 19th out of all 129 medical schools in the country in direct grants and contract expenditures. The School of Medicine jumped up to 7th place when compared to all 76 public U.S. medical schools. The school's total revenue, which includes grants, tuition, state funding, faculty practice revenue and philanthropic gifts, was $734.5 million. Its economic impact on the state of Maryland was an impressive $1.5 billion, or a $24 return for every $1 of state investment.

Despite stiff competition for federal funding, grants and contracts to the School of Medicine increased an astounding 9.7 percent in fiscal year 2007 to 2008.  Much of the credit for this achievement goes to a 19 percent increase in the number of grant requests submitted. The dean remarked that the quality of these requests has also improved, thanks to new training initiatives for faculty and fellows.

Despite uncertainty in the U.S. economy, philanthropic gifts to the School of Medicine also increased dramatically. Private gifts to the school increased 6.7 percent, to $49.1 million, and endowments have increased 5.7 percent to $173.8 million. "This is something important," said Dean Reece. "I'm very excited for our faculty, who have been able to secure these funds during this difficult time."

Another high point was a 10.7 percent increase in revenue for the Clincal Practice Plan, which collected more than $194 million. Dean Reece said University Physicians, Inc., is operating more efficiently than ever, with a net collection rate of 99 percent.

The State of the School Address was also an opportunity to look back on an historic year of discovery, success and national recognition for the accomplishments of faculty, staff and students.  For example, the Marlene and Stewart Greenebaum Cancer Center earned the prestigious NCI Cancer Center designation, one of only 64 centers in the U.S. to do so.  Faculty members at the University of Maryland Center for Vaccine Development received important research awards.  Christopher Plowe, MD, PhD, professor and chief of the maleria section, was named a 2007 Howard Hughes Medical Institute Investigator. Kirsten Lyke, MD, assistant professor of medicine, and Miriam Laufer, PhD, assistant professor of pediatrics, each received the Doris Duke Clinical Scientist Development award. Jonas Nelson, Class of 2010, became the School of Medicine's first recipient of the Doris Duke Student Award -  one of only 60 students in the country selected for this honor. 

Among the Other Highlights:

• Thanks to the hard work of faculty and staff, the School of Medicine won a successful eight-year reaccreditation Liaison Committee on Medical Education (LCME).

• The University of Maryland School of Medicine now has a presence in 23 countries around the globe, thanks in large part to its Center for Vaccine Development and Institute of Human Virology.

• The School of Medicine established a new organized research center for Trauma and Anesthesiology Research.

• The Graduate Program in Life Sciences (GPILS) boasted 42 new NIH grant proposals from its trainees: 26 from students and 16 from postdoctoral fellows.

• National media coverage of the School of Medicine increased 85 percent. The total number of story placements increased 55 percent, while print and wire service placements increased 150 percent.

• The total workforce at the School of Medicine continues to grow, increasing 3 percent over the past year. That workforce is a loyal one, with the retention rate for our faculty holding steady at more than 90 percent.

"Malaria remains a major global killer, especially of infants and children, and is a serious threat to travelers," says Christopher V. Plowe, M.D, a professor of medicine at the University of Maryland School of Medicine and co-principal investigator on the study. "In this trial, we tested a blood stage vaccine, which attempts to block the malaria parasite from getting into the blood cell. It isn’t expected to completely prevent the infection, but rather to blunt the parasite’s ability to multiply and cause disease."

"We found that the malaria vaccine was well-tolerated and produced a potent immune response," says Mahamadou Thera, M.D., M.P.H., an associate professor of parasitology at the University of Bamako, and the study’s principal investigator. "In the group of volunteers who received a full-dose of the vaccine, we actually saw more than a six-fold increase in the level of parasite-blocking antibodies produced by the immune system."

Researchers from the University of Bamako’s Malaria Research and Training Center and the University of Maryland School of Medicine’s Center for Vaccine Development enrolled 60 adults between the ages of 18 and 55 in the clinical trial. It was conducted in 2004 at the Bandiagara Malaria Project in Mali’s Dogon Country. The participants were randomly assigned to one of three groups. The study groups received the malaria vaccine in either a half dose or a full dose, and the control group received a licensed vaccine that prevents rabies, which is also prevalent in the area. Both vaccines were given in three administrations about 30 days apart.
 
The volunteers were followed closely for any side effects as well as to measure the vaccine’s ability to produce specific antibodies that attack malaria parasites. At the end of the trial, adults who were given the malaria vaccine were offered the rabies vaccine so that all participants in the study would benefit from protection against rabies.

According to Dr. Thera, the research team is now testing the full dose malaria vaccine in a group of 400 children in Mali to assess its ability to prevent malaria disease. "If the results of that trial are promising, this vaccine could become part of a multi-component vaccine. By combining two or more parasite proteins in the same vaccine, we hope that a high level of protection against malaria disease and death can be achieved," says Dr. Thera.

The vaccine tested was developed by the Walter Reed Army Institute of Research and GlaxoSmithKline Biologicals and was first tested in healthy volunteers at the Army Institute in Maryland before being tested in Mali. The trial was supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, the U. S. Agency for International Development and the U. S. Military Malaria Vaccine Program. GlaxoSmithKline Biologicals provided the proprietary Adjuvant System.

Hundreds gathered in historic Westminster Hall for the final campus-wide event celebrating the bicentennial of the University of Maryland School of Medicine. The reception was held on November 29th, 2007, exactly one year after the bicentennial kick-off, which launched the year-long celebration.

"The close of the bicentennial brings a measure of sadness but provides lasting memories and greater recognition from the multiple audiences we reached," said E. Albert Reece, M.D., Ph.D., M.B.A., dean of the University of Maryland School of Medicine. "I am honored to have presided over this milestone year."

In addition to faculty, staff, student and alumni, special guests included University System of Maryland Chancellor William E."Brit" Kirwan, Ph.D.  "Thanks to the bicentennial year, people across the state and nation have a much better understanding of the incredible contributions this school of medicine has made both within Maryland and around the world," he said.

View a 20 minute video of the event and remarks (Real Video Required).

The reception also included special recognition for the University of Salerno School of Medicine (Scuola Medica Salernitana). The first medical school in the Western world, the University of Salerno School of Medicine closed its doors in the early 1800s, just as the University of Maryland began offering medical classes in historic Davidge Hall. Now, the University of Salerno is reopening its medical school and will collaborate with the University of Maryland. Learn More.

Guests were able to view a slideshow of bicentennial memories with pictures of those who participated in a year long series of bicentennial events. Among them:  Baseball hall of famer Cal Ripken Jr., singer Patti LaBelle, humorist Garrison Keillor, and former U.S. Attorney General Janet Reno. Bicentennial events in 2007 included a special lecture series featuring noted physicians and researchers, who helped shed light on diseases such as diabetes, Parkinson’s disease, and stroke.

The final reception was reminiscent of a party that might have been thrown in 1807 by School of Medicine founder John Beale Davidge, with a menu that included plum pudding and wassail. First-year medical student and pianist Jessica Shiu entertained the crowd with traditional seasonal songs and classical music. The reception featured special displays of bicentennial activities sponsored by many of our 25 departments, such as event photos, departmental histories, posters and journal articles.

Chancellor Kirwan may have summed up the feelings of the participants best.  “The most exciting thing for me is that with this remarkable institution, the best is yet to come," he said.  "The School of Medicine may have its roots in the 1800s, but its future is pure 21st century."

Researchers from the Center for Vaccine Development at the University of Maryland School of Medicine have received a $5.6 million grant from the Bill & Melinda Gates Foundation to develop a faster and more precise molecular test to diagnose the causes of diarrheal disease in developing countries. The funding will also enable the researchers to work on identifying new pathogens that cause these infections, which account for at least 18 percent of deaths in children under the age of five worldwide.

"A major obstacle in designing effective strategies to combat these diseases is the large number of pathogens that can make children sick," says James P. Nataro, M.D., Ph.D., a professor of pediatrics, microbiology & immunology, biochemistry & molecular biology, and medicine at the University of Maryland School of Medicine and associate director of its Center for Vaccine Development. "The current technologies available in third-world countries for establishing the causes of diarrheal diseases are extremely cumbersome. In the United States, we have technologies that offer promise for providing rapid, sensitive and specific diagnoses in Africa and elsewhere, and we hope to adapt those strategies for use in developing countries through this grant."

"In the United States, it is standard practice to send fecal samples to a medical laboratory and to receive a quick and accurate diagnosis of the pathogen making the person ill," Dr. Nataro continues. "A diagnosis requires a large number of tests that can be expensive and require lots of expertise and equipmen. In sub-Saharan Africa those resources are not available, making it much more difficult to appropriately treat diarrheal diseases and understand the broader disease burden."

For the study, Dr. Nataro and his colleagues will use computer-assisted molecular technologies to develop a single test that will detect all of the important organisms involved in diarrheal diseases in developing countries. The researchers will test fecal samples obtained from sites in Bangladesh, Mali and Kenya through a cooperative agreement with other researchers from the Center for Vaccine Development. Most importantly, the samples will not need to be fresh, so tests can be performed at laboratories a great distance from the children affected by the infections. Ultimately, fully-stocked laboratories will be established at regional centers to process fecal samples brought in from outlying areas and to facilitate global surveillance for emerging infectious diseases, such as cholera.

"Our goal is to provide a quantum leap in diagnostic technology for diarrheal diseases, so that for the first time clinicians can quickly, comprehensively and with little on-site expertise ascertain the causes of these diseases in even the most remote of settings," says Dr. Nataro. "If we are successful, we foresee a day when a team of investigators can enter an area with their mobile technology and quickly and accurately determine the pathogenic source of an outbreak, which will undoubtedly lead to more timely treatment and better vaccines for patients."

The research program will also include subcontracts to Illumina, Inc., and Ibis Biosciences, a wholly owned subsidiary of Isis Pharmaceuticals, Inc., biotechnology companies in California.

Christopher V. Plowe, M.D., M.P.H., a professor of medicine at the University of Maryland School of Medicine and chief of the malaria section at its Center for Vaccine Development, has been named a 2007 Howard Hughes Medical Institute (HHMI) Investigator. The appointment will enable Dr. Plowe to further his research on creating a malaria vaccine that protects against genetically diverse forms of the malaria parasite and to develop combination drug therapies for malaria that combat the emergence of drug-resistant parasites. Dr. Plowe is one of only 15 new HHMI Investigators in patient-oriented research. HHMI selected its first group of patient-oriented researchers in 2002.

The new HHMI investigators, who come from 13 institutions across the United States, were selected in a nationwide competition. Once selected, HHMI investigators continue to be based at their home institutions, typically leading a research group of 10-25 students, postdoctoral associates and technicians, but they become HHMI employees.
 
Dr. Plowe joined the faculty of the University of Maryland School of Medicine in 1995 to create a new molecular and field-based malaria research program at the Center for Vaccine Development (CVD), which has a long tradition of malaria research. "Human trials that tested live malaria vaccines delivered by mosquitoes were first pioneered at the CVD in the early 1970s by Dr. David Clyde, who had spent the 1950s studying drug-resistant malaria in Africa," says Dr. Plowe. "I feel like I have followed in his footsteps from the lab to the field and back to the lab. The School of Medicine and the CVD have been a great place to build a clinical translational malaria research program, because I can just walk down the hall and find researchers who span the whole spectrum from very upstream basic molecular research to clinical trials in the tropics involving tens of thousands of people."

Dr. Plowe, who lives in Fulton, Maryland, travels frequently to Mali and Malawi, two African nations plagued by malaria. "Malaria is a mosquito-borne parasite that kills more than 5,000 people every day, 90 percent of whom are children in Africa under the age of five," he says. "Malaria parasites mutate and evolve so quickly that drugs and vaccines are always chasing a moving target."

During his career, Dr. Plowe has developed and validated molecular markers that can be used to monitor the malaria parasite’s resistance to the two most important malaria drugs of the 20th century, chloroquine and sulfadoxine-pyrimethamine. Using that information, Dr. Plowe and his colleagues have created strategies to extend the useful life of those drugs. The rapid molecular tests he has developed to document drug resistance are now being used worldwide. "We are now working on a vaccine that might eventually prevent malaria and eliminate the need to use those therapeutic drugs at all," he says. "If we can understand the impact of diversity on vaccine efficacy in the field, we can go back to the lab and engineer a more broadly protective vaccine."

"In his years at the CVD, Chris has done a magnificent job of building a world class, multi-faceted, internationally recognized malaria research and training operation," says Myrone Levine, M.D., D.T.P.H., the Grollman Distinguished Professor of Medicine and director of the Center for Vaccine Development at the University of Maryland School of Medicine. "He manages to balance his efforts as an innovative, well-funded, productive laboratory researcher, a superb field epidemiologist, an inspiring and dedicated teacher, a superior clinician, a highly effective mentor to junior faculty and a provider of service to the community at large. I and all the faculty, staff and trainees at the CVD are immensely proud of Chris and his extraordinary accomplishments, in particular becoming a member of the Howard Hughes Medical Institute."

"Dr. Plowe is the first Howard Hughes Medical Institute Investigator from the University of Maryland School of Medicine, and we are extremely proud of his achievement," says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and dean of the School of Medicine. "This recognition from HHMI validates Dr. Plowe’s extraordinary efforts to eradicate malarial diseases and will help him translate that work from discoveries made in the laboratory to actual treatments and cures for the millions of people in the world who suffer from this disease."

The Howard Hughes Medical Institute, a non-profit medical research organization that is one of the nation’s largest philanthropies, plays a powerful role in advancing biomedical research and science education in the United States. In the past two decades HHMI has made investments of more than $8.3 billion for the support, training and education of the nation’s most creative and promising scientists.

The new vaccine candidate is intended to do this by blocking the replication of parasites in the blood. Small clinical trials already have been conducted to test the vaccine’s safety and ability to trigger antibody responses in adult volunteers at the Walter Reed Army Institute of Research in the United States and in Malian adults and children.

"Malaria kills millions of African babies and children every year and accounts for up to half of all pediatric hospitalizations in many places," says Christopher V. Plowe, M.D, a professor of medicine at the University of Maryland School of Medicine and co-principal investigator on the study. "This parasite has a devastating effect on families all over sub-Saharan Africa – those children who survive still get terribly sick over and over again until they finally develop partial immunity."
 
Researchers from the University of  Maryland School of Medicine’s Center for Vaccine Development and the University of Bamako’s Malaria Research and Training Center have enrolled 400 children between the ages of one and six in the trial, which is being conducted at the Bandiagara Malaria Project in Mali’s Dogon Country. In Mali, malaria transmission season runs from July through December, with transmission and hospitalizations peaking in September and October. About 85 percent of children in Bandiagara have at least one clinical episode of malaria each season; as many as four episodes in a single season have been documented in some children.
 
Children participating in the study are randomly assigned to one of two groups. The study group is receiving the malaria vaccine, and the control group is getting a licensed vaccine that prevents rabies, which is also prevalent in the area. Both vaccines are given in three doses about 30 days apart. The children are monitored for an hour immediately after receiving each dose and will be followed closely for any side effects, as well as to measure the vaccine’s ability to prevent malaria episodes. At the end of the trial, children who were given the malaria vaccine will be given the rabies vaccine so that all children in the study will benefit from protection against rabies. 

"In this trial we are testing a blood stage vaccine, which attempts to block the malaria parasite from getting into the blood cell," says Dr. Plowe. "It doesn’t prevent the infection, but blunts the parasite’s ability to multiply and cause disease. We hope it allows natural immunity to occur during the first five years of life while preventing malaria. If so, we should be able to see a prolonged time before the first documented case of malaria in these children," says Dr. Plowe.

"The Bandiagara Malaria Project is conducting this trial according to the highest international clinical and ethical standards," says Ogobara Doumbo, M.D., professor of parasitology at the University of Bamako and director of the Malaria Research and Training Center. "This is possible only because of long-term commitment by the National Institutes of Health, the University of Maryland School of Medicine and the government of Mali."

The vaccine candidate being evaluated was created by the Walter Reed Army Institute of Research and GlaxoSmithKline Biologicals. The trial is being supported by the National Institutes of Allergy and Infectious Diseases, part of the National Institutes of Health, the U. S. Agency for International Development and the U. S. Military Malaria Vaccine Program.

Mahamadou Thera, M.D., M.P.H., an associate professor of parasitology at the University of Bamako, is the study’s principal investigator. 

Dr. Fraser-Liggett comes to the School of Medicine from The Institute for Genomic Research (TIGR) in Rockville, MD, where she has served as president and director since 1998. During her tenure at TIGR, federal funding to the organization tripled to $60 million per year. At TIGR, Dr. Fraser-Liggett led research teams that sequenced the genomes of many microbial organisms and helped to initiate the era of comparative genomics. She has been the most highly cited scientist in the field of microbiology for the past 10 years.

"Dr. Fraser-Liggett is a true pioneer in the effort to sequence and analyze the genomes of a large number of organisms, and we are thrilled to have her world-class expertise at the University of Maryland," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs, University of Maryland and Dean of the School of Medicine. "Dr. Fraser-Liggett is expected to bring a team of scientists and staff members with her. This major recruitment initiative will fuel the expansion of genomic research at the School of Medicine."

As an expert in the field of microbial genomics, one aspect of Dr. Fraser-Liggett’s current research is to understand the communities of bacteria in the human body, especially the microorganisms that reside in the digestive tract. These bacterial cells far outnumber the human cells that make up our bodies and are vital to good health. By comparing DNA sequences from these microbes, researchers have already determined the biological function of some beneficial bacteria. The research could lead to new ways to promote health and novel vaccines to prevent disease.

"I am extremely excited about the opportunity to build a new genomics institute within the School of Medicine," says Dr. Fraser-Liggett. "The School of Medicine has a rich history in medical and graduate education and an outstanding faculty in both basic and clinical research, many of whom are current or past collaborators with TIGR."

Dr. Fraser-Liggett has overseen the genome sequencing of important human pathogens, including bacterial infections that cause cholera and anthrax, and parasitic infections responsible for malaria and other devastating diseases in the developing world. Her work also includes the study of influenza and other viruses. These studies have provided a strong foundation for the development of new diagnostics, therapeutics and vaccines. At the University of Maryland, Dr. Fraser-Liggett will build on her impressive body of work while collaborating with physician-scientists in an environment that fosters translational medicine.

"One of the most important challenges over the next two decades will be integrating new insights from the past 10 years of genomics studies into the clinical environment to impact human health," says Dr. Fraser-Liggett. "There is no better place to be working toward these goals than in a large academic medical center like the University of Maryland School of Medicine."

"The University of Maryland School of Medicine’s Institute for Genome Sciences will provide countless opportunities for multi-disciplinary collaboration," says Bruce E. Jarrell, M.D., Vice Dean for Research and Academic Affairs. "Institute faculty will have opportunities for clinical research and benefit from the School of Medicine’s strong international programs, such as the Center for Vaccine Development, headed by Dr. Myron Levine; the Institute of Human Virology, led by Dr. Robert Gallo; and the Department of Microbiology and Immunology, chaired by Dr. James Kaper."
 
Dr. Fraser-Liggett has been continuously supported by federal funding, including the National Institutes of Health (NIH). She currently serves on the National Science Advisory Board for Biosecurity and the National Research Council's Committee on Metagenomics. She is a member of the editorial boards of The Journal of Biological Chemistry and The Journal of Bacteriology. She has published more than 220 articles in scientific journals and is a reviewer for nine journals. In addition to three honorary doctoral degrees, she has received the E.O. Lawrence Award, the highest award presented by the Department of Energy; the New York Academy of Science's Diversity in Science Award for Leadership and Scientific Excellence (2005): the Society for Industrial Microbiology's Charles Thom Award (2005); and the Promega Biotechnology Award (2005). She has been elected as a Fellow of the American Academy of Microbiology (2005) and the American Association for the Advancement of Science (2005). She also received Maryland's Top 100 Women Circle of Excellence Award (2004). In 2006, Dr. Fraser-Liggett was elected to the board of directors of Becton, Dickinson and Company.

"Malaria remains a major cause of disease and death worldwide, killing millions of people each year," says Shannon L. Takala, Ph.D., a post-doctoral fellow in the Center for Vaccine Development who is lead author on the study. "Researchers are trying to develop a vaccine based on proteins on the surface of the malaria parasite. The problem is that these proteins have many genetic variants, making it difficult to create one vaccine that works against all types of parasites. Our study provides data that will guide researchers as to which variants to include in future vaccine formulations, and will allow for a more accurate way to determine the effectiveness of current vaccines being tested in clinical trials."

For this study, 2,309 blood samples were taken from 100 volunteers enrolled in a field study conducted from 1999 to 2001 in Bandiagara, Mali, where the parasite Plasmodium falciparum accounts for 97 percent of malaria infections. The samples were collected monthly during each year’s malaria season and at every diagnosis of clinical malaria in the study population. Those samples underwent genetic tests to determine which forms of a malaria protein used to make malaria vaccines were present in people’s infections.

"We found that the majority of malaria parasites at this site have a different form of the protein than that contained in the leading vaccine candidate," says Takala. "If the vaccine protects only against infections with parasites from the same strain as the vaccine, then it may be less effective in this population. By looking at the relationship between specific genetic changes in the malaria parasite and the risk of malaria illness, we identified parts of the protein that may be important to consider in designing a vaccine that will be effective against multiple strains of the parasite."

"One way to think about this study is to compare it to the development of the polio vaccine" says Christopher V. Plowe, M.D., a professor of medicine at the University of Maryland School of Medicine, who served as Dr. Takala’s faculty advisor on the project. "A critical breakthrough in the development of that vaccine was the identification of the three strains of polio that needed to be included in the vaccine to protect all individuals from the multiple forms of polio," explains Dr. Plowe. "There are similar challenges in developing an effective malaria vaccine, because we don’t know if a vaccine based on a specific malaria strain would provide protection only against similar strains of the parasite. This study has identified genetic variations in malaria parasites in their natural environments, information that we hope can be used by vaccine developers to decide which strains should be included in a broadly protective malaria vaccine."
 
Funding for this study was provided by the National Institute of Allergy and Infectious Diseases and the United States Agency for International Development.

$1.5 million award will support malaria research in Mali, West Africa

Christopher V. Plowe, MD, MPH, a professor of medicine at the University of Maryland School of Medicine and a researcher at its Center for Vaccine Development, has received the Doris Duke Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation to support malaria research in Mali, West Africa. The $1.5 million award will allow Dr. Plowe to combine molecular studies in the Center for Vaccine Development with clinical trials in Mali to understand how malaria parasites evolve to evade attack from the human immune system.

"Malaria is a mosquito-borne parasite that kills more than 5,000 people every day, 90 percent of whom are children in Africa under the age of five," says Dr. Plowe. "Malaria parasites mutate and evolve so quickly that drugs and vaccines are always chasing a moving target. This award will help us exploit the amazing advances in malaria genomics to improve a malaria vaccine we are currently testing in Mali. We need to beat the malaria parasite at its own game by making a vaccine that helps the body’s defenses recognize malaria parasites whether they are wearing a red parka or a blue blazer."

Dr. Plowe is one of seven outstanding mid-career physician-scientists from across the United States to receive this year’s award. Each recipient will receive $1.5 million to support the translation of the latest scientific advances into clinical applications that will improve human health. Dr. Plowe’s team at the University of Maryland School of Medicine and colleagues at the University of Bamako in Mali hope that learning how the malaria parasite is shaped by both natural and vaccine-induced immunity will lead to a vaccine that protects people against genetically diverse malaria parasites.

The Doris Duke Award will also support research training for medical students and young physicians to work with Dr. Plowe and his team at the University of Maryland School of Medicine and in Africa.

Established in 1996, the Doris Duke Charitable Foundation seeks to improve the quality of people’s lives through grants supporting the performing arts, wildlife conservation, medical research and the prevention of child maltreatment.

U.S. nonprofit medical research institutions were invited to nominate two investigators for the Distinguished Clinical Scientist Award, which was established in 1999. Nominees must demonstrate leadership, a history of excellence in translational clinical research, and a long-term commitment to research. Dr. Plowe was chosen from a field of 65 nominees.

"Opportunities are greater than ever to translate basic discoveries into the prevention, diagnosis, treatment and cure of disease," says Joan E. Spero, president of the Doris Duke Charitable Foundation. "We are extremely pleased to be able to support another group of outstanding physician-scientists devoted to this goal not only through their research, but also through their mentoring activities."

"This award is a great honor for Dr. Plowe and our center," says Myron Levine, MD, DTPH, professor of medicine, microbiology & immunology and pediatrics at the University of Maryland School of Medicine and director of the Center for Vaccine Development. "The Doris Duke awards are highly competitive and extremely prestigious. Everyone at the Center for Vaccine Development is very proud of Dr. Plowe for having been selected as one of this year’s recipients of the Doris Duke Distinguished Clinical Scientist Award."

Researchers at the University of Maryland School of Medicine in Baltimore will begin a clinical trial in January to test the first cell culture-based pandemic influenza vaccine to see if it will provide immunity faster and more reliably than a vaccine produced in eggs. The new study is also the first test in the United States of a whole virus vaccine for avian influenza, which could produce a stronger response by the immune system.

The Center for Vaccine Development at the University of Maryland School of Medicine is seeking healthy volunteers ages 18 to 40 years old to participate.  The trial is funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health.

“Our previous clinical trials have shown that the inactivated pandemic influenza vaccines against the H5N1 avian influenza strain are safe and stimulate an immune response that may protect people from avian flu,” says James Campbell, M.D., an assistant professor of pediatrics at the University of Maryland School of Medicine and principal investigator on the latest study. “This will be our first trial of a cell culture-based vaccine, and we are hopeful that it will provide a faster and more reliable immune response. The use of cell cultures could also provide for a larger manufacturing capacity and provide an option for people with egg allergies.”

The H5N1 influenza vaccines already tested at the University of Maryland School of Medicine and all FDA-approved influenza vaccines available in the United States are manufactured in eggs. “Viruses are grown in eggs before being inactivated (killed) and put into vaccine form,” he says. “People with egg allergies are not eligible to receive these vaccines.”

According to Dr. Campbell, whole virus vaccines like the new H5NI influenza vaccine about to be tested may stimulate better immune responses than traditional vaccines. “With whole vaccines, the viral particle, although not living, is still intact, which means the body’s immune system may respond better since the vaccine more closely resembles the natural virus,” he says. “The drawback is that people may experience a few more minor side effects with this type of vaccine, but it may be worth the additional discomfort if we are able to provoke better immune responses in more people with this version of the pandemic flu vaccine.”

The University of Maryland Center for Vaccine Development was first asked in April 2005 by the NIAID to test an inactivated pandemic influenza vaccine in preparation for a possible pandemic. That trial involved 450 volunteers at three sites across the country and showed that the vaccine was safe and elicited an immune response. Subsequent studies combined the vaccine with a compound called an adjuvant in order to improve immune responses. Results from those trials should be available later this year.

Current pandemic influenza vaccines are aimed at protecting people from infection with H5N1 influenza, an avian flu strain that was first seen in chickens and other birds in Hong Kong in 1997. People who have direct contact with these infected birds can contract the virus and become ill.

“The currently circulating H5N1 strains of avian flu can lead to severe disease in both birds and humans,” says Dr. Campbell. “Since this virus strain was first identified, there have been 258 cases of avian influenza in humans with 154 deaths. We are concerned that if this highly lethal virus becomes as contagious as the seasonal flu virus, it will spread quickly around the globe.”

During the new study, the Center for Vaccine Development will recruit up to 100 healthy adult volunteers between the ages of 18 and 40. Volunteers will have a medical screening, blood drawn several times and receive two vaccinations. Volunteers will be randomly assigned into six different dosage groups – five of the six groups will receive the cell culture-based H5N1 vaccine, and one of the six groups will receive a placebo. Compensation will be provided, and the study will last approximately eight months.

This latest pandemic influenza vaccine is manufactured by Baxter International. Those interested in volunteering for the study should call the Center for Vaccine Development at (410) 706-6156.

In the first of these open letters, I reviewed with you our research vision. I would like to re-emphasize that all mission areas, while unique, are interdependent and are crucial to our success. I appreciate the comments I have received from many of you. We are a team, so I urge you to continue to communicate with me and be full participants in this process.

It is my intention, and I know it is also the intention of the leadership of the University of Maryland Medical System and the University of Maryland Medical Center, to forge and progressively enhance the strongest possible partnership between our organizations. To that end, the School of Medicine and the Medical System will strive to become a magnet hub for many tertiary and quaternary services, and thus develop several new national magnet programs (centers of excellence for which one’s clinical services and expertise are attractive and sought after throughout the state, region and nation).

We are in a unique position as the state’s public medical school. This position requires us to maintain a comprehensive array of medical and surgical programs. The aging of the “baby boomers,” in combination with increasing life expectancies, are creating enormous demands for medical services. Hence, we must continue to strengthen and expand clinical services in this area.

We recognize that the top three causes of death in the U.S. are cardiovascular disease, cancer and stroke (the latter is often related to hypertension). In addition, the fastest growing epidemic in America is obesity, and the complications that it spawns include diabetes and hypertension. We, therefore, have an opportunity to create new magnet programs for these diseases which have such devastating effects. Efforts should be directed toward developing, inter alia, a strong cardiovascular disease magnet program, and a cancer magnet program, which should ultimately result in the creation of a “Comprehensive Cancer Center” designated by the National Institutes of Health. In addition, every effort should be made to evaluate program effectiveness and success using, among others, indices of quality measures and key outcome variables. With this array of clinical opportunities and the accommodating magnet programs, we hope to broaden our patient referral base and raise the level of national recognition for our clinical expertise, patient satisfaction, quality of care and outcomes.

Magnet programs are not only an effective way to marshal talent to efficiently address major disease states, they also enhance the national and international visibility of the institution, and raise the clinical and research profiles as well. In addition, they become an effective marketing tool, since these centers present a cuttingedge image to the public because of their overall excellence. These magnet areas will attract patients and will make the University of Maryland an unequivocal destination for patients seeking superlative clinical expertise and care.

To achieve the prominence required to attract resources and establish our standing among the great academic medical institutions in the nation, we must commit to raise our clinical institutional profile. To this end, each department chair will be asked to develop unique expertise and national excellence in at least one or two magnet areas. Rigorous performance standards will be established so that progress can be measured and acknowledged. Department chairs will be expected to work with their faculty and staff to achieve professional and academic recognition for their respective clinical magnet programs. In addition, diseases in all disciplines associated with high morbidity and mortality rates (such as cardiovascular disease, cancer, neurological disorders, organ failure, etc.) will receive intensified attention. Communication professionals from the School of Medicine and Medical Center’s joint media relations team will issue communiqués to the local and national media on our programs and the available expertise within the School of Medicine and Medical Center.

Patient-centered care and an overall positive patient experience will be emphasized and practiced in our outpatient and inpatient facilities. Hence, our accessibility, courtesy and efficiency will be the envy of others. In order to compete effectively with institutions which do not have the heavy responsibility of education and research as part of their mission, it is imperative that we adopt the aforementioned approach to patient care. We must create effective monitoring instruments and innovative information technology systems to ensure greater efficiency in the delivery of patient care, which would include prompt, available appointments, reduced length of stay, early-day discharges and coordination of medical care. We must progressively bring all departments into a single appointment system where patients can access our services through a single telephone call a one-stop shopping approach.

I appreciate the participation and contributions of the Medical System leadership. The planned construction of the new ambulatory building brings with it unique opportunities for the Medical Center and School of Medicine to work collaboratively to achieve many of the aforementioned goals. We have every reason to be excited and confident about the future of the School of Medicine and our partnership with the Medical System. There will be challenges to achieve these goals but, working together, we will not only meet our goals, we will indeed exceed them.

I look forward with much enthusiasm to working with each of you in our relentless pursuit of excellence, everyday. Thank you for your cooperation and support.

Sincerely yours, 

E. Albert Reece, M.D., Ph.D., M.B.A.
Vice President for Medical Affairs, University of Maryland
John Z. and Akiko K. Bowers Distinguished Professor and Dean, School of Medicine

Myron M. Levine, M.D., D.T.P.H, professor of medicine, microbiology and immunology, and pediatrics, and director of the Center for Vaccine Development (CVD) at the University of Maryland School of Medicine was given the highest level award, the Ordre National du Mali, Grand Officiel rank. Karen L. Kotloff, M.D., professor of pediatrics and medicine and chief of the Community Studies Section at the Center for Vaccine Development at the University of Maryland School of Medicine received the

Ordre National du Mali, Chevaliere rank, the second highest level. Mali was historically part of French West Africa and follows many French traditions. The Ordre National du Mali (National Order of Mali) follows the tradition of the Légion d’Honneur (Legion of Honor) of France. Previous recipients of the Grand Officiel rank of the Ordre National du Mali include former United States President Jimmy Carter and French President Jacques Chirac.

“Although the Ordre du Mali medals were bestowed upon Karen Kotloff and me as individuals, we accept them on behalf of our many colleagues at the Center for Vaccine Development and our CVD-Mali team who have worked together so diligently and effectively to design ways to control certain communicable diseases in Mali,” says Dr. Levine.

"It has been a great opportunity to work in Mali, and I am extremely honored to receive their recognition,” says Dr. Kotloff. “However, the truth of the matter is that the credit for the success of the CVD-Mali goes to our Malian collaborators. They have worked very hard to build an outstanding center for research and training in infectious diseases."

The Center for Vaccine Development has been working with health officials in Mali for more than a decade to develop vaccines and treatments for such childhood illnesses as measles, meningitis, sepsis, typhoid fever and diarrheal diseases, to make immunization services to infants more efficient and to achieve higher levels of vaccination coverage.

In 2000, the Ministry of Health of Mali and the University of Maryland School of Medicine signed a formal agreement to establish the CVD-Mali to provide laboratory space and resources for CVD researchers working in the country and to train Malian scientists and physicians.

Since then, with funding from a $20 million grant from the Bill and Melinda Gates Foundation, the CVD and CVD-Mali have worked to develop a measles vaccine to immunize infants in developing countries who are too young to receive the currently licensed measles vaccine. That candidate vaccine has shown highly promising results in animal models. A field site in Mali has been established and a Malian clinical trials team has been trained to carry out phase 1 and phase 2 clinical trials of the new vaccine. 

In April 2005, the CVD received an additional grant from the Bill and Melinda Gates Foundation for $3.6 million to study the impact of vaccinating children in Mali against the disease-causing bacterium Haemophilus influenzae type b (Hib), which causes fatal meningitis and other serious infections that affect many infants in Mali. A conjugate vaccine routinely given to infants in the United States and Europe since the 1990s can prevent illnesses caused by Hib. CVD-Mali researchers worked with Malian health authorities and helped them apply for a five-year supply of Hib vaccine from the Global Alliance for Vaccines and Immunizations. Distribution of those vaccines began in July 2005.

“Mali is an African country blessed by having a chief of state who is an inspiring, visionary, dynamic leader, with a long-time interest in improving the health of infants and young children in his country,” says Dr. Levine. “Although classified by United Nations standards as among the five least developed countries in the world, Mali is an exciting and inspiring place to work. Despite the poverty, optimism abounds among its people.”

On the day Drs. Levine and Kotloff received their awards, the Prime Minister of Mali and the Malian Minister of Health joined the country’s president in a visit to the CVD site in Mali that included an inauguration of renovated laboratory and informatics facilities and a welcome home to two Malian scientists who recently returned from two years of training at the CVD in Baltimore to lead research activities in the new laboratories.

“These awards to these outstanding investigators serve as an example of the
excellence of the faculty at the University of Maryland School of Medicine,” says Donald E. Wilson, M.D., M.A.C.P, Vice President of Medical Affairs, University of Maryland and Dean of the School of Medicine. “This honor is a testament to the long-standing tradition of our medical school to provide our expertise and assistance throughout the world.”

The University of Maryland School of Medicine’s Center for Vaccine Development (CVD) has received $27.9 million from the Bill & Melinda Gates Foundation to study diarrheal diseases in young children at locations in Africa and Asia. The goal of the project is to generate information that will lead to the development and dissemination of vaccines and other public health measures in order to prevent illness and death from diarrheal diseases in the world’s poorest countries.

“Diarrheal diseases are the second most common cause of death among young children in developing countries,” says Myron Levine, M.D., D.T.P.H, professor of medicine, microbiology & immunology and pediatrics at the University of Maryland School of Medicine and director of the Center for Vaccine Development. Dr. Levine will serve as coordinating investigator on the multi-year project in collaboration with multiple institutions around the world. “Children die in these countries because of a lack of clean

water and proper sanitation and the consumption of contaminated foods. Moreover, the health care infrastructures in the poorest countries typically are not sufficiently developed enough to offer all sick children easy access to care.”

Under the direction of two University of Maryland School of Medicine physicians, Karen Kotloff, M.D., professor of pediatrics and medicine, and James Nataro, M.D., Ph.D., professor of pediatrics and microbiology & immunology, a multi-disciplinary team of researchers will investigate the specific agents that cause diarrhea in children in Mozambique, Gambia, Kenya, Mali, India and Bangladesh.

“Diarrhea-related mortality is almost unheard of in the rich world, but is a fact of life for children in the world’s poorest countries. We hope that this research will help lead to more effective tools to fight diarrheal diseases,” says Regina Rabinovich, M.D., director of the Gates Foundation’s infectious diseases program. 

According to Dr. Levine, diarrheal diseases are particularly difficult to study because they can be caused by a wide variety of bacterial, viral and protozoal pathogens and sub-types of those pathogens. “Once we know what combination of pathogens is causing diarrhea, we are hopeful that existing vaccines can be introduced in these countries to effectively prevent severe illness or that new vaccines can be created to target these pathogens,” says Dr. Levine.

Previous efforts to study diarrheal diseases in developing countries have produced limited data on their apparent causes, but no study to date has investigated them as extensively and systematically as this new effort. To ensure the quality of the datacollected, each site will use the same state-of-the art methodology.

Each of the participating sites will enroll up to 880 children from birth to age five who are suffering from severe diarrhea. Another 880 healthy children without diarrhea will serve as a control group. A parent or guardian for each child will answer a standardized questionnaire about the onset of the illness and its financial implications for the family. Sixty days after enrollment, a field worker will visit the home of each participant to determine the child’s health status, anticipating that certain pathogens may be associated with significant delayed adverse health outcomes. A stool specimen will be collected from each child to identify its specific pathogens. The unique set of pathogens obtained from this global study will be housed in a repository at the University of Maryland School of Medicine’s Center for Vaccine Development for use by investigators in future studies.

“Although diarrheal diseases are recognized to be the second most important killer among children under age five in the poorest developing countries, there is not agreement among scientists and public health practitioners about precisely what pathogens are responsible for this wide range of illnesses,” says Dr. Levine. “It is also not clear whether there are notable geographic differences or differences in urban or rural settings in the distribution of certain pathogens. This study hopes to resolve these controversies.”
As part of the project, economic studies will be conducted to determine the public and private costs of a diarrheal episode, and public perception of the need to prevent
diarrheal diseases in children will be assessed.

This latest grant from the Gates Foundation is the third received by the (CVD) at the University of Maryland School of Medicine. In 2000, the CVD received a $20.4 million grant to develop a new type of measles vaccine that could protect infants in developing countries who are too young to receive the current measles vaccine. In 2005, the CVD received another $3.5 million from the Gates Foundation to vaccinate children in Mali, Africa, against a bacterial pathogen that causes fatal meningitis and other serious infections and to monitor the impact of that vaccine.

The research consortium involved in the project represents most of the major players in the world involved in the diagnosis and treatment of diarrheal diseases and vaccine development. Institutions and organizations participating in the project are:
• The University of Maryland School of Medicine’s Center for Vaccine Development
• Centro de Investigacao em Saude da Manhica in Manhica, Mozambique
• Medical Research Council in Basse, Gambia
• The Centers for Disease Control and Prevention’s Kenya Medical Research Station in Kisumu, Kenya
• The Centre pour le Developpement des Vaccins du Mali in Bamako, Mali
• The National Institute of Cholera and Enteric Diseases in Kolkata, West Bengal, India
• The International Center for Diarrheal Disease Research in Mirzapur, Bangladesh
• Perry Point Veterans Administration Medical Center in Maryland
• The U.S. Centers for Disease Control and Prevention
• The University of Chile
• The University of Virginia School of Medicine
• The International Vaccine Institute in Seoul, Korea
• The Institut Pasteur in Paris, France
• The World Health Organization
• The Center for International Health at the University of Bergen and the Institute of Public Health in Norway
• The University of Goteborg in Sweden
• The Rollins School of Public Health at Emory University in Atlanta
• The Johns Hopkins University Bloomberg School of Public Health

Researchers at the University of Maryland School of Medicine’s Center for Vaccine Development and the University of Malawi have found that a once popular anti-malaria medication used in Malawi has regained its effectiveness at treating the disease that continues to be the leading killer of the world’s poorest children. Chloroquine was removed from government health facilities in Malawi in 1993 after it proved ineffective at treating malaria in more than 50 percent of documented cases. But a new study appearing in the November 9, 2006, edition of the New England Journal of Medicine shows that the drug is once again useful for both preventing and treating malaria. 

“Malaria is a mosquito-borne parasite that kills more than 5,000 people every day, 90 percent of whom are children in Africa under the age of five,” says Miriam K. Laufer, M.D., an assistant professor of pediatrics at the University of Maryland School of Medicine and a researcher at the Center for Vaccine Development who helped lead the study.

“Chloroquine resistance first emerged in Southeast Asia and South America in the late 1950s, and had made its way to the African continent by the late 1970s when the resistance contributed to increased malaria transmissions and death,” adds Dr. Laufer. “Since the drug failed to treat malaria, the Malawian government replaced it in 1993 with another medication, sulfadoxine-pyrimethamine. For 12 years, chloroquine was not used in Malawi. Now, our study shows that the malaria parasite has once again become susceptible to chloroquine, and the medication could potentially be used in combination with other therapies to treat the disease effectively in the future.”

According to Dr. Laufer, chloroquine has many desirable attributes as an anti-malarial drug. It is inexpensive, rapid-acting and long-acting, and safe for all age groups and pregnant women. It is an excellent drug for preventing malaria in travelers and may be an ideal candidate for intermittent preventive treatment, a control strategy in which pregnant women and infants are periodically treated for malaria at routine health visits.  

For the study, Dr. Laufer and colleagues enrolled 210 children between six months and 12 years of age with symptoms of malaria at the Ndirande District Health Centre in Blantyre, Malawi. The children were randomly assigned to one of two study groups: those who received chloroquine and those who received the standard treatment with sulfadoxine-pyrimethamine. The children were closely monitored for 28 days after administration of the medication.
 
“We found that chloroquine was effective at treating the malaria in 99 percent of the children we studied, while sulfadoxine-pyrimethamine was effective only 21 percent of the time,” says Dr. Laufer. “Infection and fever cleared more quickly in chloroquine recipients than in those who received the standard treatment.”

Additionally, blood samples obtained by the study team showed that the genetic mutation that causes chloroquine resistance, which disappeared after the medication was withdrawn from use in Malawi, was completely absent in the parasites which caused malaria infections in the children in the study.

“Chloroquine was the most important malaria drug of the 20th century and the loss of the drug to resistance was a public health catastrophe for Africa,” says Christopher V. Plowe, M.D., M.P.H., a professor of medicine at the University of Maryland School of Medicine and the principal investigator on the study. “Many African nations continue to use chloroquine even after officially switching to newer drugs to treat malaria. For that reason, chloroquine can’t be successfully used again until it is withdrawn throughout Africa as effectively as it was in Malawi. We envision that chloroquine could one day return to sub-Saharan Africa as an effective treatment for malaria when it is used in combination with other therapies.”

The research team expected chloroquine to perform well because genetic studies had shown that parasites carrying the choloroquine resistance mutation had gradually disappeared from the area during the 10 years after the medication was withdrawn in Malawi. “We were still amazed at how quickly these children got better on cholorquine in this clinical study,” says Dr. Plowe.

Similar efforts to bring back other drugs by withdrawing them after microbes have become resistant have not had this dramatic success, the researchers say, but “that’s likely because nobody pulled a drug out of a whole country so completely before, the way that Malawi did,” notes Dr. Plowe. “It would be worthwhile to explore the possibility of rotating drugs for malaria as well as other infections that have become resistant to important drugs.”

Future studies planned by the University of Maryland School of Medicine’s Center for Vaccine Development will test chloroquine in conjunction with other drugs to see which combinations are best at preventing resistance to chloroquine from remerging. 

Funding for this study was provided by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.