New Vaccines Shift the Course of Childhood Diarrhea-Causing Disease and Could Have Big Global Impact

New vaccines have the potential to prevent or temper epidemics of the childhood diarrhea-causing disease rotavirus, protect the unvaccinated and raise the age at which the infection first appears in children, federal researchers reported in a study today.

The findings were based on changing patterns of rotavirus transmission in the United States, where the disease is rarely fatal, and they have implications for combating epidemics in other countries where the death toll is much higher.

The research, published in the July 17 issue of the journal Science, is based on mathematical modeling that takes into account regional birth rates and predicted vaccination levels and effectiveness. The model suggests that when 80 percent or more of children in a given population are vaccinated, annual epidemics may occur on a less regular basis and more unvaccinated children will be protected. Data from 2007-2008, when vaccination first reached appreciable coverage levels in the United States, validate the model′s predictions.

“Rotavirus vaccines have rapidly and dramatically reduced hospitalizations and emergency room visits for gastroenteritis in American children,” said investigator Umesh D. Parashar, M.B.B.S., M.P.H., of the Centers for Disease Control and Prevention′s National Center for Immunization and Respiratory Diseases. “This research not only explains the effects of the U.S. rotavirus vaccination program, but also lays the foundation for understanding the tremendous life-saving benefits of vaccination in the developing world, where more than half a million children die from rotavirus each year.”

The study showed for the first time that the timing of rotavirus epidemics is dependent on the birth rate in the population because they are driven by infants who have never been infected before. In the United States, winter outbreaks would typically occur sooner in the higher birth rate states of the Southwest and later in the Northeast, where birth rates tend to be lower.

But with the introduction of two vaccines, the first in 2006, rotavirus outbreaks may become less frequent and less pronounced. They also may make their first appearance in children when they are older than the previous norm of less than 5 years of age, according to the research.

In older children, later onset would likely mean fewer cases and less severity of diarrhea.

The modeling and analysis were done by a team of researchers from the Fogarty International Center of the National Institutes of Health, the CDC, the Agency for Healthcare Research and Quality, the Pennsylvania State University, Princeton University and the George Washington University.

“When you can observe the immediate effects of vaccination and compare them to what the model predicted, you have a head start on stopping this preventable disease in countries where rotavirus unnecessarily kills hundreds of thousands of children,” said Roger I. Glass, M.D., Ph.D., one of the study authors and director of the Fogarty Center.

Lead author Virginia Pitzer, Sc.D., of Penn State and the Fogarty Center, said, “Each population is going to have a different demographic makeup, and there may be conditions we cannot predict with certainty, but we believe introducing vaccination in the developing world will decrease the terrible burden of rotavirus.”

Source: CDC, July 16, 2009

In a study funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, Saint Louis University’s Center for Vaccine Development is investigating whether the standard vaccine used in foreign countries against tuberculosis offers better protection as a shot, drink or combination of both.

“The fight against tuberculosis is important because a third of the world is thought to be infected and there are significant problems with drug-resistant TB organisms,” said Daniel Hoft, M.D., Ph.D., principal investigator and director of the division of immunobiology at Saint Louis University School of Medicine.

The “standard” tuberculosis vaccine, bacillus Calmette-Guérin (BCG), is given to infants in foreign countries, and is not currently recommended for use in the U.S.

“Experts believe it provides some protection against TB disease, particularly in children where severe manifestations of TB are averted,” Hoft said. “However, despite widespread use of BCG, TB remains a major cause of death worldwide. The main purpose of this study is to find out if BCG can be used in a more effective way.

“We hope to learn whether a BCG vaccine drink or a combination of a drink and an injection could increase immune responses against tuberculosis lung infection and affect the progression of the disease as it spreads throughout the body.”

The study also will look at whether it is better to give one or two doses of the BCG vaccine.

A total of 70 healthy volunteers who are 18 to 40 years old are needed for the research. The study will last about two years and requires up to 21 scheduled visits. Each visit takes between 30 minutes and three hours, depending upon the procedures being performed. Study participants will be compensated for their time and travel after each completed visit.

Tuberculosis is a deadly disease that strikes developing nations hardest. Each year, nearly 8 million new cases of TB develop, and 2 million persons die from the infectious disease.

Source: Saint Louis University Medical Center, June 12, 2009

Fighting infectious disease, the very heart of public health and the genesis of contemporary nursing, is about more than hand washing and immunizations. It’s about screening and early detection, identifying risk and protective factors, and educating clinicians, facilities and the public. But it all begins with research

Infectious disease rates, stable since the 1918 influenza pandemic, have been on the rise since the mid-1980s. The battle against these illnesses—from HIV/AIDS to MRSA and from STDs to resurgent tuberculosis (TB), and others—has been escalating, and long before the recent emergence of the H1N1 influenza virus earlier this year.

For Johns Hopkins University School of Nursing (JHUSON) nurse researchers, the communities around the corner and around the world are their infectious disease laboratories.

JHUSON faculty research, for example, is shedding light on curbing sexually transmitted infections and their physical and emotional repercussions on college campuses. It also is exploring best practices to curtail the spread of resurgent diseases like tuberculosis and reducing the impact of treatment resistant infections like MRSA both within and beyond the hospital setting.

The community-based inquiry not only is yielding new knowledge but also, when coupled with its translation into clinical education and practice, is helping to save lives today and to be better prepared to save them in an uncertain future.

Infection Detective at Work in High-Risk Environments: JHUSON researcher, Assistant Professor and self-professed “infection control preventionist” Jason Farley, PhD, MPH, ARNP, is working to give nurse colleagues and other health care professionals the research-based tools they need to identify, prevent, and destroy drug-resistant infections in hospitals and in communities from Maryland to South Africa.

Growing rates of drug-resistant infections like tuberculosis and methicillin-resistant staphylococcus aureus (MRSA), coupled with recent H1N1 pandemic concerns, make his work most timely. His MRSA-related research not only has documented its evolution from a hospital problem into a community and public health concern, but also has given health providers.

Farley’s work is as much about transmitting knowledge as it is about curbing infection transmission. In new work supported by the JHU’s Center on Global Health, he is evaluating current tuberculosis infection control practices and strategies in TB hospitals throughout South Africa. With highly drug-resistant TB adding to the significant toll taken by HIV/AIDS in that country, the need to improve infection control is marked. Yet, Farley has found considerable inattention to such issues as segregated care for TB-infected patients, lack of evaluation and testing of health care workers for the disease, and limited use of respirators to combat the spread of this airborne disease.

Farley notes, “Infection control needs to be paramount in our thoughts about patient safety and also in how we avoid infection in health care workers.” His work in South Africa seeks to determine if a trained infection control nurse can help reduce or eliminate these and other gaps in infection control. From a public health perspective, Farley says, “No one knows about infection control better than nurses. It’s where our profession’s evidence-based roots began; nurses will continue to be on the front lines of infection prevention and public education tomorrow.”

Breaking through the Sound of Silence: When the Infection is Sexual—Most sexually transmitted diseases (STDs) can be readily treated and cured; all can be prevented. Yet, in the U.S. alone, as many as 19 million new cases of a sexually transmitted disease (STD) are diagnosed each year, almost half of which are among sexually active teens and young adults.

Many are symptom-free, don’t even know they have an STD, and, as a result, don’t get treated. Others whose STD symptoms are evident, may lack access to care or may be too ashamed, afraid or upset to discuss the illness, much less get treatment for it. In either case, continuing infection and ongoing transmission are likely. Whether well-known STDs like gonorrhea, syphilis and HIV/AIDS or less familiar ones like chlamydia and herpes, the physical repercussions of untreated STDs can be significant, ranging from pelvic disease to infertility, cervical cancer, even death, with attendant health care costs and lost productivity.

The emotional toll can be equally or even more devastating, particularly since so many affected and infected are between the ages of 15 and 24. JHUSON Assistant Professor, Hayley D. Mark, PhD, MPH, RN doesn’t think that’s good for the public health and has been working to change the situation through research.

Drawn to the field of STD research because it “affects the human condition as a whole – health, psychology and social environment,” she noted that certain STDs tend to be passed around within specific closed communities, such as a college campus, the nightclub scene or the correctional facility.

While it is well know that screening reduces the likelihood of transmitting HIV and bacterial STDs, Mark wondered whether wide-scale, voluntary screening also could help reduce the incidence of the transmission of genital herpes, HSV-2, a viral, often silent STD. that puts people at greater risk for HIV infection.

She began her inquiry on a college campus, assessing how to motivate student participation in STD screening and the performance characteristics of the HSV test in college students , reported in the Journal of American College Health and Sexually Transmitted Disease, respectively. Results suggested that to be successful, information about the availability of screening for HSV-2 should be neutral in tone and informative, transmitted broadly by a trusted source such as a student health center. Further, Mark’s finding that a diagnosis of HVS-2 often causes significant emotional and social difficulty (social break-ups, depression, and anxiety) led her to recommend the value of both immediate and follow-up counseling to address both the medical and psychological aspects of infection.

Mark believes nurses are ideally poised to break through the silence that so often surrounds STDs. She notes, “Because we are trained to help people feel comfortable in an uncomfortable medical environment, we can help open the door to STD prevention as well as to screening and treatment. Part of what we do is help people talk about difficult health topics by providing a nonjudgmental environment in which knowledge can be shared. It’s a great model of how nurses work to promote the public health.”

Source: Johns Hopkins University School of Nursing, June 12, 2009

Scientists at the National Institutes of Health (NIH) have gained a major insight into how the rogue protein responsible for mad cow disease and related neurological illnesses destroys healthy brain tissue.

"This advance sets the stage for future efforts to develop potential treatments for prion diseases or perhaps to prevent them from occurring." said Duane Alexander, M.D., Director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), where the study was conducted.

The researchers discovered that the protein responsible for these disorders, known as prion protein (PrP), can sometimes wind up in the wrong part of a cell. When this happens, PrP binds to Mahogunin, a protein believed to be essential to the survival of some brain cells. This binding deprives cells in parts of the brain of functional Mahogunin, causing them to die eventually. The scientists believe this sequence of events is an important contributor to the characteristic neurodegeneration of these diseases.

The findings were published in the current issue of the journal Cell. The study was conducted by Oishee Chakrabarti, Ph.D. and Ramanujan S. Hegde, M.D., Ph.D., of the NICHD Cell Biology and Metabolism Program.

Central to prion diseases like mad cow disease and to many other diseases is the phenomenon known as protein misfolding, Dr. Hegde explained. Proteins are made up of long chains of molecules known as amino acids. When proteins are created, they must be carefully folded into distinct configurations. The process of protein folding is analogous to origami, where a sheet of paper is folded into intricate shapes. Upon correct folding, proteins are transported to specific locations within cells where they can perform their various functions. However, the protein chains sometimes misfold. When this happens, the incorrectly folded protein takes the wrong shape, cannot function properly, and as a consequence, is sometimes relegated to a different part of the cell.

In the case of prion diseases, the culprit protein that misfolds and causes brain cell damage is PrP. Normally, PrP is found on the surface of many cells in the body, including in the brain. However, the normal folding and distribution of PrP can go wrong. If a rogue misfolded version of PrP enters the body, it can sometimes bind to the normal PrP and "convert" it into the misfolded form.

This conversion process is what causes mad cow disease, also known as bovine spongiform encephalopathy. Feed prepared from cattle tissue containing an abnormally folded form of PrP can infect cows. In very rare instances, people eating meat from infected cows are thought to have contracted a similar illness called variant Creutzfeld Jacob disease (vCJD). In other human disorders, genetic errors cause other abnormal forms of PrP to be produced.

"The protein conversion process has been well studied," Dr. Hegde said. "But the focus of our laboratory has been on how — and why — abnormal forms of PrP cause cellular damage."

To investigate this problem, Dr. Hegde’s team has been studying exactly how, when, and where the cell produces abnormal forms of PrP. They had found that many of the abnormal forms of PrP were located in the wrong part of the cell. Rather than being on the cell’s surface, some PrP is exposed to the cytoplasm, the gelatinous interior of the cell. Moreover, several studies from Dr. Hegde’s group and others showed that when too much of a cell’s PrP is exposed to the cytoplasm in laboratory mice, they develop brain deterioration.

"The sum of these discoveries provided us with a key insight," Dr. Hegde said. "We realized that in at least some cases, PrP might be inflicting its damage by interfering with something in the cytoplasm."

In the current study, Drs. Chakrabarti and Hegde sought to determine what went wrong when PrP was inappropriately exposed to the cytoplasm. Their next clue came from a strain of mice with dark mahogany-colored fur. Although these mice develop normally at first, parts of their nervous systems deteriorate with age. Upon autopsy, their brains are riddled with tiny holes, and have the same spongy appearance as the brains of people and animals that died of prion diseases. The gene that is defective in this strain of mice is named Mahogunin.

"The similarity in brain pathology between the Mahogunin mutant mice and that seen in prion diseases suggested to us that there might be a connection," Dr. Hegde said.

To investigate this possible connection, the researchers first analyzed PrP and Mahogunin in cells growing in a laboratory dish. When the researchers introduced altered forms of PrP into the cytoplasm of cells, they saw that Mahogunin molecules in the cytoplasm bound to the PrP, forming clusters. This clustering led to damage in the cell that was very similar to the damage occurring when cells are deprived of Mahogunin.

The researchers found that this damage did not occur in the cell cultures if PrP was confined to the surface of the cell, if the cells were provided with additional Mahogunin, or if PrP was prevented from binding to Mahogunin.

The researchers then studied mice with a laboratory induced version of a human hereditary prion disorder called GSS, or Gerstmann-Straussler-Scheinker Syndrome. This extremely rare disease causes progressive neurological deterioration, typically leading to death between age 40 to 60. Dr. Hegde explained that some GSS mutations result in a form of PrP that comes in direct contact with the cytoplasm. In mice that contain one of these mutations, the researchers discovered that cells in parts of the brain were depleted of Mahogunin. The researchers did not see this depletion if PrP was engineered to avoid the cytoplasm.

The findings, Dr. Hedge said, strongly suggest that altered forms of PrP interfere with Mahogunin to cause some of the neurologic damage that occurs in prion diseases.

"PrP probably interferes with other proteins too," Dr. Hegde said. "But our findings strongly suggest that the loss of Mahogunin is an important factor."

An understanding of how PrP interacts with Mahogunin sets the stage for additional studies that may find ways to prevent PrP from entering the cytoplasm, or to replace Mahogunin that has been depleted.

Source: National Insititutes of Health (NIH), 6/11/2009