mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models.
Xuesong WangChristopher A CottrellXiaozhen HuRashmi RayMaria BottermannPaula Maldonado VillavicencioYu YanZhenfei XieJohn E WarnerJordan Renae Ellis-PughOleksandr KalyuzhniyAlessia LiguoriJordan R WillisSergey MenisSebastian RämischSaman EskandarzadehMichael KubitzRyan TingleNicole PhelpsBettina GroschelSunny HimansuAndrea CarfiKathrin H KirschStephanie R WeldonUsha NairWilliam R SchiefFacundo D BatistaPublished in: Science immunology (2024)
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
Keyphrases
- mouse model
- binding protein
- clinical trial
- antiretroviral therapy
- hiv positive
- human immunodeficiency virus
- hiv infected
- dengue virus
- hepatitis c virus
- hiv testing
- cancer therapy
- machine learning
- fatty acid
- big data
- hiv aids
- men who have sex with men
- cell therapy
- phase iii
- capillary electrophoresis
- south africa
- bone marrow
- artificial intelligence
- protein protein