Molecular profiling consortium: biomarker identification and interaction analysis of EPI vaccines

Vaccines work by stimulating immune responses which fight against the vaccine disease if the person is exposed to it in the future. Despite years of successful vaccination campaigns there is still relatively little understanding of how vaccines work. Live vaccines (e.g. measles vaccine) consist of weakened live organisms, and killed vaccines consist of dead bits of organisms or toxins they produce. There is increasing evidence that the order in which live and killed vaccines are administered is important. Specifically, live vaccines provide beneficial effects other than protecting against the target pathogen, but killed vaccines cancel these beneficial effects sometimes leading to an increase in deaths. As our understanding of immunology advances it has become clear that the response to immune challenge, including vaccination, involves a complex network of responses. Until now our ability to investigate immune responses to vaccines in detail has been limited by the small volumes of blood that can be collected and the lack of suitable tests. This study proposes to use state of the art technology to look at the response of the whole human genome before and after giving vaccines to babies. We hope to identify easily measurable substances in the blood that can explain the non-specific effects of vaccines. We will then test these in big studies that are ongoing in Guinea-Bissau that are trying to understand the same things. Understanding interactions between commonly used vaccines will ultimately lead to recommendations regarding safer practices in the future, and provide vital information for the introduction of new vaccines.

The introduction of routine vaccination in infants in the form of the expanded program on immunisation (EPI) was one of the most successful public health interventions of the 20th Century. However, the current EPI schedules were recommended 20 years ago, and the WHO Strategic Advisory Group of Experts agree that it may be time to revise current immunization schedules. Indeed, it is somewhat surprising that despite years of successful vaccination campaigns, there is still relatively little understanding of how vaccines work. Most studies have focused on the induction of vaccine specific antibodies, although in many cases cellular responses are likely to be as or more important. In the developing world routine vaccines are frequently missed or administered in the wrong order, but there is increasing evidence that the order in which live and killed vaccines are administered is important. Specifically, live vaccines (e.g. measles vaccine (MV)) provide beneficial effects other than protecting against the target pathogen, whereas co-administration of killed vaccines (e.g. diphtheria, tetanus, pertussis (DTP)) seems to negate these beneficial effects leading to increased all cause mortality. These non-specific effects of vaccination are set to become more important as vaccine preventable diseases are controlled and their incidence declines. As our understanding of immunology advances, it has become clear that the response to immune challenge involves a complex signalling and cytokine network. Until now the ability to investigate the immune response to vaccines in detail has been limited by the volumes of blood that can be collected and the lack of assays to look at the immune response as a whole. This study proposes to use whole genome microarray analysis pre- and post vaccination in order to assess the systemic immune response pathway to vaccination at the transcriptome level. We will further assess the impact of combining certain EPI vaccines on these responses. A detailed bioinformatic analysis approach will be employed to identify key vaccine induced changes that might explain the described non-specific effects. Identified biomarkers will then be tested for correlations with clinical outcomes using samples from large scale studies being carried out in Guinea Bissau. If unique immune response pathways can be established this opens the door to applying this methodology to other vaccine studies, including new generation vaccines. Furthermore, the results will contribute to the scientific framework for recommending safe EPI practices, and will provide essential data for those considering introducing new vaccines into the EPI schedule.