Genome wide association study of vaccine responses in infants living in the Developing World VaccGene Phase II African Cohorts

Human genetic heterogeneity accounts for approximately 70% of the observed variability in
response to common childhood vaccinations. Identifying the elements of this heterogeneity
will enable the development of vaccines which have improved clinical and cost effectiveness
through rational adjuventation approaches, or by targeting particular at-risk or responsive
subgroups. The studies published to date have been limited in terms of the number of vaccine
subtypes analysed, diversity of the populations included, sample sizes and breadth of other
environmental and lifestyle variables which may explain some of the remainder of variation in
the response to each vaccine. Nevertheless, these studies have proposed that the genes
which harbour the variants associated with vaccine responsiveness reside within regions of
the genome associated with immune function such as the HLA locus and FOXP1and ITGAL.
We are proposing one of the largest genome-wide association studies of vaccine response
ever undertaken, which will provide unparalleled power to identify the genetic factors
associated with the response to all of the most commonly used childhood vaccines
worldwide. For the first phase of the project (Prelim I0308) we genotyped ca. 1,400 children
from the Entebbe Mother and Baby (EMaB) study, an ongoing birth cohort in southern
Uganda, using the Illumina HumanOmni2.5-8 chip. Analyses for response to vaccination
against diphtheria, tetanus, pertussis, Haemophilus influenzae, measles, hepatitis B and BCG
are now underway. Working alongside other ongoing studies, we plan for the second phase
of the project to expand sample sizes to up to 7,000 individuals in total. This large cohort will
include 1,500 South African infants, 500 Burkina Faso infants, 1,800 children from Ecuador
and up to 1,800 from a variety of countries (MAL-ED Consortium). The principal measured
phenotypes will be the serological responses at 6 or 12 months of age to the vaccines
administered to all enrolled children as part of expanded programme of immunisation in all
countries. As for the primary Ugandan study the responses will be analysed as quantitative
traits using mixed model (GEMMA) analyses following imputation using a combined 1000
Genome and African Genome Variation Project reference panel. The data will be analysed as
one large discovery mega-analysis to maximise the power of finding the relevant associated
variants. Interim GWAS analyses will be performed on each population to test for population
specific signals. Other phenotypes that will be assessed in the new studies include
quantitative response to BCG, rotavirus and pneumococcal vaccines (South Africa, Ecuador
and Uganda), clinical and immunological response to malaria vaccines (Burkina),
immunological correlates of atopy (Ecuador and Uganda) and malaria infection (Burkina,
Ecuador and Uganda) in addition to non-communicable disease traits such as blood pressure
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[A8] If applicable, provide text (abstract) which will accompany data for this study in the ENA/EGA.
[A9] Does this project use samples?
[A10] Please choose which types of sample you will be using
[A12] Please state the anticipated date (month/year) samples will be available in-house (if known). If samples are
already in-house, type 'in-house' here. Please note that for sequencing, genotyping and microarrays this is essential
for scheduling the work.
[A13] Please state the anticipated project start date (month/year).
[A14] Please state the project duration (months).
[A15] Please read WTSI's Data Sharing Policy and Guidelines, then explain your data sharing plans for the project
[A16] Are the data sharing plans of this project compliant with the Institute's Guidelines?
[A17] Are there any conflicts of interest related to this proposal?
(Uganda).
We are requesting funds to genotype on the Illumina HumanOmni2.5-8 platform 2,000 African
infants recruited through ongoing maternal and child vaccine clinical trials (against
pneumococcus in Soweto, South Africa, and malaria in Banfora, Burkina Faso). The DNA
from the Burkina cohort is at the University of Oxford and ready to be shipped, while the DNA
from the South African cohort will be available by mid-2014. Appropriate consent for genetic
analyses has been acquired for the proposed study cohorts from both local ethics committees
and UK-based Committees.EGA study EGAS00001000918