Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies.
Adoptive Transfer
Animals
Antibodies, Protozoan
/ metabolism
B-Lymphocyte Subsets
/ immunology
Disease Models, Animal
Epitopes
/ genetics
Genetic Engineering
Humans
Immune Evasion
Immunogenicity, Vaccine
Malaria
/ immunology
Malaria Vaccines
/ immunology
Mice
Mice, SCID
Plasmodium falciparum
/ physiology
Protozoan Proteins
/ genetics
Structure-Activity Relationship
Vaccination
Vaccines, DNA
/ immunology
PfCSP
adoptively transferred B cells
antibody CIS43
circumsporozoite
epitope-focused immunization
in situ vaccination
junctional epitope
malaria
passive protective
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
14 12 2021
14 12 2021
Historique:
received:
10
02
2021
revised:
23
07
2021
accepted:
20
10
2021
pubmed:
18
11
2021
medline:
19
2
2022
entrez:
17
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34788599
pii: S1074-7613(21)00454-4
doi: 10.1016/j.immuni.2021.10.017
pmc: PMC9087378
mid: NIHMS1787883
pii:
doi:
Substances chimiques
Antibodies, Protozoan
0
Epitopes
0
Malaria Vaccines
0
PfCSP DNA vaccine
0
Protozoan Proteins
0
Vaccines, DNA
0
circumsporozoite protein, Protozoan
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2859-2876.e7Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM007198
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AI005022
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AI005107
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests S.K., P.T., R.R., M.R., P.D.K., R.A.S. and F.D.B. have submitted a US Provisional Patent Application describing improved CIS43 antibodies (filed November 5, 2021). B.J.F., R.A.S., A.H.I., and N.K.K. hold patents on CIS43 (International Application No. PCT/US2018/017826; US Patent Application No. 16/485,354; issued June 1, 2021). L.T.W., R.A.S., and J.R.F. have submitted a US Provisional Patent Application describing mAb L9 (62/842,590; filed May 3, 2019). The remaining authors declare no competing interests.
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