Final Report Summary - IMMUNOGENE (Immunogenetics of Severe Bacterial Disease Susceptibility and Vaccine Responses in Humans)
Human genetic diversity plays a significant role in affecting our susceptibility to disease. We set out to understand the impact of such diversity on responses to a range of vaccines including many administered routinely to children worldwide as well as a novel experimental malaria vaccine. In order to ensure that the project was targeted towards populations in most need we worked directly with teams of scientists in three African centres and recruited over 2,500 infants into one of the largest studies investigating the impact of genetics on vaccine responses. Using a set of tailored ethically approved set of protocols we sought to encourage community participation and facilitate understanding of complex genetic principles to ensure valid informed consent in those communities where genetic research has not been previously undertaken. We used a highly accurate and validated multiplex platform to measure antibody responses against eight vaccine antigens and undertook dense whole-genome genotyping before undertaking eight separate genome wide association studies in 2,499 infants recruited from three sites across Africa (Uganda, South Africa and Burkina Faso). We found significant (p < 5 x 10-9) evidence of association between genetic variants in a key region of the genome (the major histocompatibility complex) and responses against five vaccine antigens (pertussis toxin, filamentous haemagglutinin and pertactin; diphtheria toxin; and hepatitis B surface antigen).
We then undertook a comprehensive, systematic review of the MHC region by undertaking HLA typing using state-of-the-art methods in over 1,700 individuals from across 11 sites in Africa to the highest resolution ever completed to create a picture of diversity in this region that is so important for infection susceptibility across African populations. We subsequently used this resource to impute classical HLA alleles at high resolution into our vaccine recipient cohort to enable us to fine-map the genetic variants most likely to be associated with each vaccine response. Our follow-up analyses were most important for pertussis vaccine where we could use our genetic association findings to correlate pertussis toxin antibody responses negatively with susceptibility to whooping cough. These data therefore provided the first evidence that pertussis toxin antibodies are a significant correlate of protection against future disease.
Our applied resources and methods will be valuable for a range of other diseases relevant, not only in Africa, but around the world. We are already applying our HLA imputation panel to a range of other infectious traits including tuberculosis, leprosy and malaria, and excitingly we have applied our approach to a cohort of infants who received an experimental ME-TRAP vaccine targeting severe malaria. Again we found significant evidence of association across the MHC not to antibody levels, but instead to cell-mediated immune endpoints which fits exactly with our current state of knowledge of malaria protection. We are now seeking to replicate these findings and understand the implications that they may have for understanding immunological correlates of protection against diseases such as malaria that are proving so difficult to develop universally effective vaccines against.
This project has served to generate a series of important resources and approaches that should help us develop improved vaccines against a range of important infections in the near future.
We then undertook a comprehensive, systematic review of the MHC region by undertaking HLA typing using state-of-the-art methods in over 1,700 individuals from across 11 sites in Africa to the highest resolution ever completed to create a picture of diversity in this region that is so important for infection susceptibility across African populations. We subsequently used this resource to impute classical HLA alleles at high resolution into our vaccine recipient cohort to enable us to fine-map the genetic variants most likely to be associated with each vaccine response. Our follow-up analyses were most important for pertussis vaccine where we could use our genetic association findings to correlate pertussis toxin antibody responses negatively with susceptibility to whooping cough. These data therefore provided the first evidence that pertussis toxin antibodies are a significant correlate of protection against future disease.
Our applied resources and methods will be valuable for a range of other diseases relevant, not only in Africa, but around the world. We are already applying our HLA imputation panel to a range of other infectious traits including tuberculosis, leprosy and malaria, and excitingly we have applied our approach to a cohort of infants who received an experimental ME-TRAP vaccine targeting severe malaria. Again we found significant evidence of association across the MHC not to antibody levels, but instead to cell-mediated immune endpoints which fits exactly with our current state of knowledge of malaria protection. We are now seeking to replicate these findings and understand the implications that they may have for understanding immunological correlates of protection against diseases such as malaria that are proving so difficult to develop universally effective vaccines against.
This project has served to generate a series of important resources and approaches that should help us develop improved vaccines against a range of important infections in the near future.