High-resolution African HLA resource uncoversHLA-DRB1expression effects underlying vaccine response

Mentzer A, Alexander T Dilthey, Martin Pollard, Deepti Gurdasani, Emre Karakoc, Tommy Carstensen, Allan Muhwezi, Clare Cutland, Amidou Diarra, Ricardo da Silva Antunes, Sinu Paul, Gaby Smits, Susan Wareing, HwaRan Kim, Cristina Pomilla, Amanda Y. Chong, Debora Y.C. Brandt, Rasmus Nielsen, Samuel Neaves, Nicolas Timpson, Austin Crinklaw, Cecilia S. Lindestam Arlehamn, Anna Rautanen, Dennison Kizito, Tom Parks, Kathryn Auckland, Kate E. Elliott, Tara Mills, Katie Ewer, Nick Edwards, Segun Fatumo, Sarah Peacock, Katie Jeffery, Fiona R.M. van der Klis, Pontiano Kaleebu, Pandurangan Vijayanand, Bjorn Peters, Alessandro Sette, Nezih Cereb, Sodiomon Sirima, Shabir A. Madhi, Alison M. Elliott, Gil McVean, Adrian V.S. Hill, Manjinder S. Sandhu
2022 · doi:10.1101/2022.11.24.22282715
preprint OA: gold CC-BY-NC-ND-4.0
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Abstract

How human genetic variation contributes to vaccine immunogenicity and effectiveness is unclear, particularly in infants from Africa. We undertook genome-wide association analyses of eight vaccine antibody responses in 2,499 infants from three African countries and identified significant associations across the human leukocyte antigen (HLA) locus for five antigens spanning pertussis, diphtheria and hepatitis B vaccines. Using high-resolution HLA typing in 1,706 individuals from 11 African populations we constructed a continental imputation resource to fine-map signals of association across the class II HLA observing genetic variation explaining up to 10% of the observed variance in antibody responses. Using follicular helper T-cell assays, in silico binding, and immune cell eQTL datasets we find evidence of HLA-DRB1 expression correlating with serological response and inferred protection from pertussis following vaccination. This work improves our understanding of molecular mechanisms underlying HLA associations that should support vaccine design and development across Africa with wider global relevance. Teaser High-resolution typing of HLA diversity provides mechanistic insights into differential potency and inferred effectiveness of vaccines across Africa.

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License: CC-BY-NC-ND-4.0