Immunity (Cambridge, Mass.), 2019-10, Vol.51 (4), p.735-749.e8
2019
Details
- Autor(en) / Beteiligte
- Titel
- Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus
- Ist Teil von
- Immunity (Cambridge, Mass.), 2019-10, Vol.51 (4), p.735-749.e8
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Antibody paratopes are formed by hypervariable complementarity-determining regions (CDRH3s) and variable gene-encoded CDRs. The latter show biased usage in human broadly neutralizing antibodies (bnAbs) against both HIV and influenza virus, suggesting the existence of gene-endowed targeting solutions that may be amenable to pathway amplification. To test this, we generated transgenic mice with human CDRH3 diversity but simultaneously constrained to individual user-defined human immunoglobulin variable heavy-chain (VH) genes, including IGHV1-69, which shows biased usage in human bnAbs targeting the hemagglutinin stalk of group 1 influenza A viruses. Sequential immunization with a stalk-only hemagglutinin nanoparticle elicited group 1 bnAbs, but only in IGHV1-69 mice. This VH-endowed response required minimal affinity maturation, was elicited alongside pre-existing influenza immunity, and when IGHV1-69 B cells were diluted to match the frequency measured in humans. These results indicate that the human repertoire could, in principle, support germline-encoded bnAb elicitation using a single recombinant hemagglutinin immunogen. [Display omitted] •Generated mice with user-defined human antibody VH genes and humanized CDRH3 diversity•IGHV1-69 use enables elicitation of IgG against a “universal” site on influenza•A single flu immunogen elicited gene-encoded broadly neutralizing antibodies•The response was achieved when IGHV1-69 B cells were titrated to human frequency Human broadly neutralizing antibodies (bnAbs) against influenza virus can be biased for VH gene usage, suggesting gene-encoded development pathways. Sangesland et al. show that human IGHV1-69 B cell receptors impart natural affinity for a “universal” vaccine target, enabling rapid bnAb responses in mice that were elicited using a rationally designed influenza immunogen.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613eISSN: 1097-4180DOI: 10.1016/j.immuni.2019.09.001Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6801110
- Format
- –
- Schlagworte
- Acquired immune deficiency syndrome, Affinity, AIDS, Amplification, Animals, Antibodies, Antibodies, Viral - genetics, Antibodies, Viral - metabolism, Antibody Affinity, Antigens, B-Lymphocytes - immunology, BCR, Binding sites, Broadly Neutralizing Antibodies - genetics, Broadly Neutralizing Antibodies - metabolism, Complementarity, Complementarity Determining Regions - genetics, conserved site of vulnerability, Gene expression, Germ-Line Mutation - genetics, Hemagglutinin Glycoproteins, Influenza Virus - immunology, Hemagglutinins, HIV, Human behavior, Human immunodeficiency virus, Humans, Immunity, Humoral, Immunization, Immunization, Secondary, Immunoglobulin Heavy Chains - genetics, Immunoglobulins, Influenza, Influenza A, Influenza A virus - physiology, Influenza Vaccines - immunology, Influenza, Human - immunology, innate-like, Lymphocytes B, Mice, Mice, Transgenic, Nanoparticles, Neutralizing, Protein Engineering, rational vaccine, Receptors, Antigen, B-Cell - genetics, Scholarships & fellowships, Software, Statistical analysis, Transgenic animals, Transgenic mice, universal, Vaccines, Viruses