Grand Challenges in Global Health initiative

Research Goals: Single-dose vaccines for neonates

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• The Bill & Melinda Gates Foundation, in partnership with the Foundation of the National Institutes of Health, established the Grand Challenges in Global Health initiative in 2003 at the World Economic Forum in Davos, Switzerland.
• $450 million US was made available for 14 global health challenges identified through consultation with scientists and public health leaders around the world.
• Two additional funding commitments were made by the Wellcome Trust ($27.1 million), and the Canadian Institutes of Health Research (CIHR) ($4.5 million).
• In June 2005, 43 grant offers were announced out of 1,500 original proposals.
• One of three Canadian teams, VIDO was offered a grant of $5.6 million over five years for the project “Linking innate and specific immunity to develop single dose vaccines for neonates.”

The problem
Infectious diseases are the main cause of neonatal morbidity and mortality in both 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 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). Therefore, 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.

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.

• Childhood vaccination is one of the best ways of reducing sickness and death in infants and young children worldwide. Yet almost 30 million children have no access to immunization, and nearly two million children die each year of vaccine-preventable diseases (World Health Organization).
• Access to immunization varies widely across the world: a child in a developing country is 10 times more likely to die of a vaccine-preventable disease than a child from an industrialized country.
• Due to the unique immune systems of newborns, it is difficult to achieve a strong and balanced immune response with vaccination.
• Most existing vaccines require multiple immunizations (“booster shots”)—a major challenge in countries where it is difficult for families to travel for medical attention. Thus, vaccines are needed that are effective after a single immunization (“single shot vaccine”).
• The template disease for this project is whooping cough (pertussis). Pertussis is still one of the most important diseases of young children, with an estimated global burden of more than 48.5 million cases and up to 300,000 deaths each year. In the developed world, nearly all mortality occurs in infants too young to have been immunized or in un-immunized older children.

The solution

• The VIDO team will create single-dose vaccines by developing new vaccine components called adjuvants that will create a broad and long-lasting immune response with a single immunization.
• Vaccines will be delivered to the mucosal surfaces of the respiratory tract without the use of needles.
• Most disease-causing organisms enter mammals at the mucosal surfaces. By immunizing here, vaccines will be more effective at preventing infection.
• The adjuvants to be tested are relatively inexpensive to produce on a large scale, so can be readily used in developing countries. Each compound has unique characteristics, allowing the team to approach the problem from a number of directions.

The approach

• During these experiments, the team will seek to learn more about how the immune system of newborns works and how effective immune responses in the newborn can be created with a single immunization.
• The team will screen a variety of formulations combining each adjuvant with a template antigen (Bordetella pertussis, the causative agent of whooping cough). Each adjuvant will be tested individually and in combination to assess synergy between the different types of adjuvants.
• All formulations will be screened based on which “marker” genes are up-regulated, or turned on.
• In addition, the team will use microarrays for gene expression analysis to identify genes that are up-regulated by the formulations. These studies will also support comparisons of responses in newborn humans versus young animals.
• The team will investigate the role of antibodies received by the newborn from the mother and possible ways of overcoming the interference of these antibodies with vaccination of the newborn.
• The team will test optimal formulations against whooping cough, or pertussis, and evaluate these formulations for stability and safety.

The outcomes

• The technologies being developed will be “platform technologies;” that is, applicable across species and across diseases.
• There will be applications for enhancing the immunity of newborns to many disease-causing organisms, and significance to numerous vaccines for both newborns and adults, with the potential for profound impact on the health and economic activity of developing countries.

Dr. Luis Barreto, Vice President of Public Affairs, Sanofi Pasteur
Dr. Joost Oppenheim, NCI, Laboratory of Molecular Immunoregulation
Dr. Roy Curtiss III, The Biodesign Institute, Arizona State University
Dr. Gordon Dougan, Sanger Institute, UK

• Elahi, S., Holmstrom, J., and Gerdts, V. 2007. The benefits of using diverse animal models for studying pertussis. Trends in Microbiology, 15(10):462-8.
• Gerdts, V., Littlel-van den Hurk, S.D., Griebel, P.J., Babiuk, L.A. 2007. Use of animal models in the development of human vaccines. Future Microbiology, 2:667-675.
• Mutwiri, G., Benjamin, P., Soita, H., Townsend, H., Yost, R., Roberts, B., Adrianov, A.K., Babiuk, L.A. 2006. Poly[di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP) is a potent enhancer of mixed Th1/Th2 immune responses in mice immunized with influenza virus antigens. Vaccine, 25(7):1204-13.
• Elahi, S., Buchanan, R.M., Attah-Poku, S., Townsend, H.G.G., Babiuk, L.A., and Gerdts, V. 2006. The Host Defense Peptide Beta-Defensin 1 Confers Protection against Bordetella pertussis in Newborn Piglets. Infection and Immunity, 74(4):2338-2352.
• Elahi, S., Buchanan, R.M., Babiuk, L.A., and Gerdts, V. 2006. Maternal Immunity Provides Protection against Pertussis in Newborn Piglets. Infection and Immunity, 74(5):2619-2627.
  

• Rehaume, L.M., D.M.E. Bowdish, Y. Li, J. Yu, and R.E.W. Hancock. Defensins block LPS-induced cytokine production and induce chemokine transcription and release from innate immune cells. (Keystone symposium on Innate Immunity, Banff, Alberta, February 10-15, 2006).

For information on the project, please contact Jim Holmstrom, Project Manager, VIDO.

E-mail: jim.holmstrom@usask.ca

Phone: 306-966-2568

Fax: 306-966-7478

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