Project Leader:

Dr. Volker Gerdts

A profile of the project Single-dose Vaccines for Neonates
(funded through the Bill & Melinda Gates Foundation's Grand Challenges in Global Health Initiative)

Overview:
Infectious diseases are the main cause of neonatal morbidity and mortality in both humans and animals. Infections are usually vertically transmitted from the mother to the offspring or take place during the first weeks of life when the newborn’s immune system is still developing. Most pathogens gain access to the body via the mucosal surfaces. Thus, the induction of mucosal immunity is essential for protecting the newborn.

So far, vaccination is the most effective form of defence against infectious agents. Successful vaccination of the newborn, however, is often compromised by poor immunogenicity of current vaccines, biases in the immune responses in the newborn and potential interference with maternally derived immunity. Most existing vaccines require multiple immunizations which, especially in developing countries, represent a major challenge. Thus, vaccines are needed that induce a protective immune response even after a single immunization (single shot vaccine). The aim of this project is to develop improved vaccines and vaccine formulations that induce protective mucosal immunity in the newborn with a single immunization.

Background:
Infectious diseases are the main cause of illness and death in newborn humans and animals. Infections with these pathogens are usually vertically transmitted from the mother to the offspring or take place during the first weeks of life when the newborn’s immune system is still developing. Most of the pathogens involved gain access to the body via the mucosal surfaces. Thus, the induction of mucosal immunity is essential for protecting the newborn.

So far, vaccination has been shown to be the most effective form of defense against infectious agents. Successful vaccination of the newborn, however, is often compromised by poor immunogenicity of current vaccines, a bias towards Th2 responses in the newborn and potential interference with maternally derived immunity. Therefore, the aim of this project is to develop improved vaccines and vaccine formulations that induce protective mucosal immunity in the newborn.

We are focusing on a number of diseases in a variety of species including pertussis (whooping cough) in young children. Pertussis is caused by infection with Bordetella pertussis and represents one of the most important diseases in young children worldwide. Although especially important for the developing world, pertussis is re-emerging in developed countries such as Canada. As part of an international network of researchers we are currently developing novel vaccine formulations against pertussis for infants and young children.

Other diseases of interest include Escherichia coli infections in young pigs, respiratory syncytial virus and rotavirus in calves, and herpes simplex virus in mice. We are developing new animal models for these diseases which will allow analysis of vaccine efficacy. Collaboration among VIDO, the Dalhousie Infectious Disease Research Alliance (DIDRA), and the Canadian Association for Immunization Research Evaluation (CAIRE) was formed to develop, monitor, and evaluate these new vaccines post-licensing for their potential use in human infants. This group consists of basic vaccine researchers, infectious disease specialists, clinicians, epidemiologists, public health physicians and biopharmaceutical companies and therefore forms a unique consortium for comprehensive vaccine development.

In addition to developing new disease models, we are also investigating the basic principles of mucosal immunity. These include innate responses at the mucosal surfaces, vaccine delivery and induction of local immunity, and lymphocyte trafficking at the mucosa. We are using a variety of models for these studies including the gut-loop model in large animals, or the cannulation of intestinal lymph to analyze local immunity at the mucosal surfaces. The role of antimicrobial peptides, such as defensins, in the mucosa, and their potential use as immune modulators will also be investigated. The goal of our research is to apply the insights gained from these basic studies directly to the development of mucosal vaccines. To this end we are testing a variety of vaccine formulations and methods of vaccine delivery including viral and bacterial vectors, microparticulate carriers, and lipid-based delivery systems.

Objectives:

1. Develop novel vaccine formulations and delivery strategies for inducing mucosal immunity in neonates.
2. Develop relevant animal models that simulate neonatal immune responses in humans.
3. Develop new concepts for maternal immunization.
4. Determine the relationship between vaccine development and compliance and public acceptance of vaccines.
5. Analyze basic principles of local immunity at the mucosal surfaces.

Progress:

For the first time, we have developed a model for pertussis in newborn piglets. This model allows us to analyze the role of maternal antibodies in disease protection, and more importantly will enable us to test novel vaccine formulations for immunizing infants and young children.

In vitro testing of adjuvant components has progressed using cells derived from adult and neonatal porcine, murine, and human subjects. This testing has allowed us to identify adjuvant components that have stimulatory effects on cells of both the innate and adaptive immune systems. We are beginning to look at using combinations of these components to optimally stimulate both innate and adaptive immune responses in experimental vaccine formulations.

With our collaborators, we are beginning to synthesize and examine novel adjuvant components (new peptides and polyphosphazenes), formulations, and methods of mucosal immunization (e.g., inhalation). These components will be tested in vitro and in vivo both alone and in combination with other components. By determining the effects that these components have on isolated cells of the innate immune system, we are hoping to identify the underlying mechanisms of adjuvant action. This will enable us to synthesize enhanced adjuvants and vaccines.

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