Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

Sven Kratochvil; Chen-Hsiang Shen; Ying-Cing Lin; Kai Xu; Usha Nair; Lais Da Silva Pereira; Prabhanshu Tripathi; Johan Arnold; Gwo-Yu Chuang; Eleonora Melzi; Arne Schön; Baoshan Zhang; Marlon Dillon; Brian Bonilla; Barbara J Flynn; Kathrin H Kirsch; Neville K Kisalu; Patience K Kiyuka; Tracy Liu; Li Ou; Marie Pancera; Reda Rawi; Mateo Reveiz; Kareen Seignon; Lawrence T Wang; Michael T Waring; John Warner; Yongping Yang; Joseph R Francica; Azza H Idris; Robert A Seder; Peter D Kwong; Facundo D Batista

doi:10.1016/j.immuni.2021.10.017

Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

Immunity. 2021 Dec 14;54(12):2859-2876.e7. doi: 10.1016/j.immuni.2021.10.017. Epub 2021 Nov 16.

Authors

Sven Kratochvil¹, Chen-Hsiang Shen², Ying-Cing Lin¹, Kai Xu², Usha Nair¹, Lais Da Silva Pereira², Prabhanshu Tripathi², Johan Arnold¹, Gwo-Yu Chuang², Eleonora Melzi¹, Arne Schön³, Baoshan Zhang², Marlon Dillon², Brian Bonilla², Barbara J Flynn², Kathrin H Kirsch¹, Neville K Kisalu², Patience K Kiyuka², Tracy Liu², Li Ou², Marie Pancera⁴, Reda Rawi², Mateo Reveiz², Kareen Seignon¹, Lawrence T Wang², Michael T Waring⁵, John Warner¹, Yongping Yang², Joseph R Francica², Azza H Idris⁶, Robert A Seder⁷, Peter D Kwong⁸, Facundo D Batista⁹

Affiliations

¹ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
² Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
³ Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA; Vaccine Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁶ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rseder@nih.gov.
⁸ Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.
⁹ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Microbiology, Harvard Medical School, Boston, MA, USA. Electronic address: fbatista1@mgh.harvard.edu.

Abstract

Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.

Keywords: PfCSP; adoptively transferred B cells; antibody CIS43; circumsporozoite; epitope-focused immunization; in situ vaccination; junctional epitope; malaria; passive protective.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
Antibodies, Protozoan / metabolism
B-Lymphocyte Subsets / immunology*
Disease Models, Animal
Epitopes / genetics
Epitopes / immunology*
Genetic Engineering
Humans
Immune Evasion
Immunogenicity, Vaccine
Malaria / immunology*
Malaria Vaccines / immunology*
Mice
Mice, SCID
Plasmodium falciparum / physiology*
Protozoan Proteins / genetics
Protozoan Proteins / immunology*
Structure-Activity Relationship
Vaccination
Vaccines, DNA / immunology*

Substances

Antibodies, Protozoan
Epitopes
Malaria Vaccines
PfCSP DNA vaccine
Protozoan Proteins
Vaccines, DNA
circumsporozoite protein, Protozoan

Abstract

Publication types

MeSH terms

Substances

Grants and funding