A program of research to optimize public health immunization programs

Vaccines and immunization programs are the best way to prevent infectious diseases, improve child health, and save lives. According to the Public Health Agency of Canada, vaccines have saved the lives of more babies and children than any other medical intervention in the past 50 years. Through immunization, we have eliminated smallpox and have nearly eliminated eight other deadly diseases of childhood, including chickenpox and some kinds of pneumonia and meningitis. We need to continue to immunize all children so that we maintain high levels of protection throughout communities, which will prevent these diseases from re-emerging. Despite having province-wide immunization programs in place, not everyone gets vaccinated, as shown by several disease outbreaks in the past few years.

Dr. Julie Bettinger is working to address key questions about vaccines and immunization programs to ensure optimal disease protection in the population. Her research assesses the effectiveness of existing vaccination programs, evaluates the effectiveness of new vaccines, and also studies the best way to deliver them to children, adults and communities. Her approach uses quantitative and qualitative methods and includes collecting and analyzing surveillance data on select vaccine-preventable diseases and vaccine-adverse events from the Canadian Immunization Monitoring Program Active, an active surveillance network in 12 pediatric centers across Canada.

Dr. Bettinger’s research also focuses on evaluating the safety and effectiveness of vaccines through grant-funded clinical trials and observational studies and promoting improved immunization uptake through qualitative studies that assess the factors affecting vaccine use. Her work is used by local, provincial, and national public health decision makers, other research scientists, health care providers, and the public. This work, which is conducted at the Vaccine Evaluation Center at the Child and Family Research Institute and BC Children's Hospital, will create a centre for applied, population-based immunization research unique to BC and Canada.

Immunological basis for infections in prematurely born infants

Pre-term babies, those born before week 37 weeks of gestation, are more susceptible to invasive infections than full-term babies. The smallest babies born “extremely” premature (those born before 32 weeks, or approximately 1,500 grams or less of birth weight) suffer the greatest burden of infection among all age patient age groups in BC and other developed countries in general. About one in four “extremely” pre-term babies suffers from an invasive infection, which adds up to more than 8,760 new invasive infections in North America each year. In addition to the immediate health risks, such as a major loss of cardiorespiratory function or death, these infections may lead to long-term physical and intellectual handicaps in these children.

The work of Dr. Pascal Lavoie aims to understand why pre-term babies are so vulnerable to infections caused by common micro-organisms. Dr. Lavoie and his team are examining the way that babies’ immune cells work early in life to determine if this differs from the function of mature immune systems. In order to do this in a way that is completely safe to babies, he takes advantage of scavenged blood samples (he uses, for example, placental blood normally discarded at birth) analyzed using sophisticated technologies to extract detailed information about the human immune system.

Dr. Lavoie also aims to understand why the immune system of pre-term babies appears underdeveloped and what impact therapeutic manipulation of the latter may have on diseases such as bronchopulmonary dysplasia: a chronic form of neonatal inflammatory lung disease which appears to be caused by excessive activation of the immune system during infection. Ultimately, Dr. Lavoie hopes that a better understanding of the immune systems of pre-term infants will help researchers and doctors develop better treatments to boost immune defenses and prevent the dreadful consequences of infections in vulnerable newborns.

OCD translational multi-modal research program

According to the World Health Organization, obsessive-compulsive disorder (OCD) is one of the top 10 causes of disability. The disorder often begins in childhood and interferes with normal development. This disabling mental illness affects approximately 2 – 3 percent of British Columbians and, although treatable, is often under diagnosed.

The aim of Dr. S. Evelyn Stewart's research program is to improve the lives of BC children and families living with OCD. Her goal is to improve the evaluation and awareness of pediatric OCD in BC by conducting research to guide scientific and clinical understanding of OCD and its management by health professionals, and by establishing national and international linkages, which will lead to future research collaborations. Dr. Stewart's specific objectives for the first five years are to 1) create a unique research program within the new pediatric OCD clinic at BC Children's Hospital that is closely tied with the community, 2) establish a pediatric OCD DNA and research data site for BC, 3) launch a comprehensive patient-assessment method, and 4) investigate the outcomes and effectiveness of the program itself.

This program is unique, as it pulls together expertise from the clinic, the community and the laboratory. One important feature of Dr. Stewart's program is the effective transfer of new information between the clinic and the research lab in order to help the outcomes of practice inform research. Dr. Stewart anticipates this program will help limit the suffering and health-care costs related to OCD. The program is anticipated to develop into the first North American OCD Centre of Excellence.

Childhood lung diseases: Infectious and inflammatory mechanisms

Lungs are for life. Unfortunately, the most frequent long-term illnesses in children and babies are respiratory system conditions. Children's lungs can be damaged in many ways: bacterial and viral infections, asthma, or faulty genes causing thick mucus to accumulate in the lungs of children with cystic fibrosis. Even the oxygen and artificial ventilation needed to sustain the lives of premature babies can cause lasting lung damage. A feature shared by all these serious childhood lung diseases is that some of the damage is caused by activation of the innate immune system, which is an important part of our immune defense network. The innate immune system is like a “double-edged” sword. While innate immunity is essential for keeping us healthy, it can cause excessive lung-damaging inflammation if the activity is not carefully controlled.

To prevent lung damage, Dr. Stuart Turvey is examining the systems that control the activity of the innate immune system. These control elements are known as negative regulators. His team will study these negative regulators in a variety of childhood lung diseases spanning premature babies and lung infections through to asthma and cystic fibrosis. The unique aspect of this project, and of Dr. Turvey's group in general, is a commitment to translational research focused on people with lung disease. This means research results from the lab bench are applied directly to patient care.

Rather than relying exclusively on laboratory (animal or cell) models of disease, Dr. Turvey’s team plans to examine genetic material donated by people affected by infectious and inflammatory lung diseases. The results of this work will be an exciting starting point for gaining a better understanding of the causes of childhood lung diseases and developing new medicines to safely control the damaging inflammation that occurs in the lungs of so many babies and children.

Socioeconomic status as a predictor of prenatal mental health, use of selective serotonin reuptake inhibitors during pregnancy, and infant outcomes

During pregnancy, approximately 15 per cent of women experience depression requiring medical intervention. Although these conditions are often treated with Serotonin Reuptake Inhibitor (SRI) antidepressants, these drugs are reported to increase the risks of adverse infant outcomes, including preterm birth, small for gestational age (SGA) birth, respiratory distress, and some congenital heart malformations. Infant outcomes are also influenced by other factors, including socioeconomic status, and research has shown that mothers of lower socioeconomic status are at increased risk of preterm birth, SGA birth, stillbirth, and neonatal and infant death. To complicate things further, data shows that mothers of low socioeconomic status are significantly more likely to experience depression during pregnancy and are significantly more likely to use one or more psychotropic medications (including antidepressants) to manage mental illness during pregnancy than women of higher income. The relationships between prenatal depression, socioeconomic status, use of antidepressants, and infant outcomes are complex and poorly understood.

Dr. Gillian Hanley will systematically address questions about the role socioeconomic status plays in maternal depression, antidepressant use, and infant developmental outcomes during the first year of life. She has hypothesized that maternal socioeconomic status accounts for an increased risk of adverse infant outcomes previously attributed to antidepressant exposure during pregnancy. For this study, Dr. Hanley will link a number of BC population-level administrative datasets to build the most comprehensive source of data on pregnant women of its kind in the world. This dataset will include all pregnancies and births in British Columbia between 2002 and 2009 (approximately 300,000 infants) and will provide sufficient sample size to detect differences in rare outcomes, such as congenital anomalies and neonatal/infant death. In this project, socioeconomic status will be studied as a predictor of antenatal maternal depression, antidepressant use, and infant developmental health.

These results will illuminate complex relationships between prenatal depression, antidepressant use, and infant outcomes. Given that it is ethically and medically unadvisable to undertake a randomized trial of prenatal antidepressant exposure, this population-based study will provide an unprecedented opportunity to examine key influences on infant health. Dr. Hanley's findings should help clinicians and mothers make more informed treatment decisions for their health and that of their infants.

Relationship of Neonatal Pain and Early Brain Development of Preterm Infants on Motor Outcomes at 18 months

Between 2005 and 2009, more than 16,000 infants in British Columbia were born prematurely. Prematurely born infants are at increased risk for developing motor problems that, in many cases, significantly interfere with daily life and school performance. This degree of motor difficulty is often referred to as developmental coordination disorder, or DCD. Children with DCD struggle with many typical tasks, such as tying shoes, riding a bike, handwriting or participating in sports. While it was once believed that children with DCD would outgrow their motor difficulties, studies have shown that these difficulties can persist into adolescence and adulthood. In addition to physical concerns, children with DCD experience other issues, including difficulty with social and peer relationships, lower self-worth and self-esteem, anxiety and depression, and other emotional health concerns. Thus, there is an urgent need to develop rehabilitative therapies to prevent these lifelong complications.

Dr. Jill Zwicker's research program focuses on understanding how the process of early brain development influences motor-skill development. Previous work suggests that DCD may be caused by abnormal brain development, but this has yet to be confirmed. Dr. Zwicker, an occupational therapist with a clinical and research interest in DCD, is using different brain-imaging techniques and is collecting information about health and treatments from a group of 175 premature infants. The babies will have a brain scan in the first few weeks after birth and will have a second scan around the time they would have been born, had they made it to full term. Measurement will be used to compare brain development between these two points in time.

Dr. Zwicker suspects there may be a relationship between brain development and exposure to pain, and that these factors may affect motor development, so she will also gather information about the number of skin-breaking procedures (for example, needle pokes) that the infants receive. In addition, her research team will collect information about other factors that may influence brain and motor development, including medications received, days on oxygen, illness severity, infection, and lung disease.

By having a stronger understanding of the factors that contribute to the development of DCD in children born prematurely, Dr. Zwicker hopes her research will help prevent poor motor outcomes and help develop new therapies to improve motor and functional outcomes for children born prematurely.

The use of CpG adjuvants, bio-degradable microparticles, and microneedle technology for the design of novel single-dose vaccines

Vaccines are important in protecting our bodies against potentially deadly infectious diseases. The vaccines developed in the past 200 years have clearly had a great impact on human health by preventing many infectious diseases and eradicating others, such as smallpox. Despite this success, strategies for developing new and better vaccines are urgently needed. Current vaccine technologies are still inadequate to counter persistent infectious disease threats like human immunodeficiency virus (HIV), tuberculosis, and malaria. This is partly due to the limited ability of our body to mount a robust immune response to these vaccines, particularly for immuno-compromised individuals such as children, elders, and individuals on immunosuppressive treatments such as post-transplant patients or patients with autoimmune diseases. Further, during epidemics, vaccine production capacity is often limited. Dr. Jacqueline Lai will be developing/optimizing strategies that will deliver safer, more stable and effective vaccines painlessly through the skin. Dr. Lai will be exploring the use of novel vaccine formulations and delivery technologies. The laboratory in which she will train has previously shown that a DNA adjuvant – a chemical that can modulate the response to a vaccine – enhances vaccination responses when rubbed onto the skin at the time of vaccination. The use of adjuvants may increase the efficacy of small vaccine doses, resulting in the immunization of more individuals with existing vaccine production capacity. As part of her research, she will be developing new DNA adjuvant formulations and administration strategies to explore the possibility of further enhancing vaccine responses. The second part of Dr. Lai’s research involves the evaluation of new vaccine delivery technologies. As the skin serves to protect us from the environment, the outer-most layer of the skin forms a tight barrier that prevents the penetration of most substances, including DNA adjuvants. To circumvent the limited penetration of adjuvants and vaccines through the skin, she will test new hollow microneedles, designed by collaborating material engineers, which allow for the painless delivery of vaccines directly into the skin. In addition, she will evaluate vaccines encapsulated in biodegradable materials to increase the stability and efficacy of the vaccine formulations and to obviate the need for refrigeration of the vaccine during distribution.

The role of ABCA1 and microRNAs in the regulation of beta cell function

Type 2 diabetes currently affects 2.5 million Canadians. Elevated blood cholesterol levels increase the risk of developing diabetes. Scientists are starting to understand the molecular basis of diabetes and have recently discovered that a deficiency of the ABCA1 molecule, a transporter that removes cholesterol from cells, leads to the accumulation of cholesterol in the insulin secreting-beta cells in the pancreas. This cholesterol accumulation leads to impaired insulin secretion and contributes to diabetes. Therefore, influencing the levels of ABCA1 molecules in beta cells may help control both cholesterol and diabetes. The objective of Dr. Nadeeja Wijesekra’s research is to discover new ways to regulate ABCA1 levels in beta cells in order to improve beta cell function and survival. Her project involves the use of small molecules called microRNAs to regulate ABCA1 levels in mouse beta cells. She will identify specific microRNAs that regulate ABCA1 levels in beta cells and determine how they influences beta cell function by measuring insulin secretion and changes in cholesterol levels. Furthermore, these microRNAs will be used in diabetic mouse models to assess whether their disease condition can be improved. Since increased ABCA1 has been shown to have a positive impact on beta cell function, finding ways to increase ABCA1 levels in these cells may be helpful in ameliorating beta cell defects present in diabetes. Thus these studies are the first to outline a therapeutic strategy to modulate cholesterol in beta cells in order to improve whole body glucose homeostasis.

The role of IL-17 in the pathogenesis of type-1 diabetes

Type 1 diabetes, also known as juvenile diabetes, is an autoimmune disease that usually presents in children and young adults. In patients with Type 1 diabetes, the body attacks itself, thus destroying insulin-producing cells in the pancreas that regulate blood sugar (glucose). A diagnosis of Type 1 diabetes currently translates to a lifetime burden of insulin injections and a risk of multiple complications for children in Canada. T-cells are white blood cells and play a key role in the immune system to control infection. In healthy individuals, a type of T-cell, called Th17, provides a strong defense by guiding the immune system to attack bacteria and virus-infected targets within our bodies. A recent discovery of elevated numbers of Th17 cells in children newly diagnosed with Type 1 diabetes suggests that these cells may play a key role in the early development of this disease in young patients. Interestingly, Th17 cells have been associated with other autoimmune diseases, such as Crohn’s disease and multiple sclerosis. Dr. Ashish Marwaha is working to identify novel treatments for Type 1 diabetes by understanding the function of Th17 cells in the course of a child developing Type 1 diabetes. To understand if there is a specific genetic mutation that can predict which children will have high levels of Th17 cells and therefore at risk of developing Type 1 diabetes, he will be analyzing stored blood samples from British Columbian children with this disease. The findings from this study will determine the extent to which Th17 cells are harmful in Type 1 diabetes and may open the door to new treatments for childhood diabetes that target Th17 cells.

Mortality in children under five years of age in Uganda following hospitalization for sepsis: A prospective cohort study

The United Nations Millennium Development Goal number four commits to reducing child mortality by two thirds before 2015. However, worldwide, eight million children under the age of five die annually. The majority of these deaths occur in resource-poor countries and are a result of a condition called sepsis. Sepsis usually occurs following severe infections, when the body’s immune defences begin to cause harm, leading to death if left untreated. Most infectious diseases including pneumonia, diarrheal diseases and malaria, when severe, result in sepsis. Studies from Kenya have shown that among children admitted to hospital with a severe infection, more children die within the two-month period after leaving the hospital than during their hospital stay. While there are a number of studies regarding hospital treatment, no studies have been conducted to investigate predictors of death after leaving the hospital. Knowledge of these predictors can help to identify which children are in the high- and low-risk groups and thus enabling closer monitoring of high-risk children following discharge. These risk predictors can also be used in clinical trial design so that treatments can be developed, tested, and eventually implemented to reduce sepsis-related deaths following hospitalization. The goal of Dr. Matthew Wiens’ research is to identify predictors of child death from sepsis after leaving the hospital. To do this, he will study a group of children under the age of five who were hospitalized for sepsis at two hospitals in the Mbarara district of Uganda (the Mbarara University Hospital and the Holy Innocents Children’s Hospital). During the hospitalization phase he will collect information on a series of characteristics such as the type and severity of infection, nutritional status, maternal education, access to clean water and many other potential predictors. During the six month follow-up phase after hospitalization the health outcomes of these children will be determined. Using these predictors, Dr. Wiens along with his supervisor and team of researchers will create a scoring system that allows doctors to identify children who at high and low risk of death after discharge and intervene accordingly. Understanding the factors that are likely to influence a child’s long-term health outcome after leaving the hospital will help in the development and implementation of effective interventions to reduce childhood mortality in the developing world.