tetano
Editor, Senior Moderator
Immunity. 2019 Sep 20. pii: S1074-7613(19)30372-3. doi: 10.1016/j.immuni.2019.09.001. [Epub ahead of print] [h=1]Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus.[/h]
Sangesland M[SUP]1[/SUP], Ronsard L[SUP]1[/SUP], Kazer SW[SUP]2[/SUP], Bals J[SUP]1[/SUP], Boyoglu-Barnum S[SUP]3[/SUP], Yousif AS[SUP]1[/SUP], Barnes R[SUP]4[/SUP], Feldman J[SUP]1[/SUP], Quirindongo-Crespo M[SUP]4[/SUP], McTamney PM[SUP]5[/SUP], Rohrer D[SUP]4[/SUP], Lonberg N[SUP]4[/SUP], Chackerian B[SUP]6[/SUP], Graham BS[SUP]3[/SUP], Kanekiyo M[SUP]3[/SUP], Shalek AK[SUP]2[/SUP], Lingwood D[SUP]7[/SUP].
[h=3]Author information[/h] 1 The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. 2 The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, 415 Main St, Cambridge, MA 02142, USA. 3 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, 40 Convent Drive, Bethesda, MD 20892-3005, USA. 4 Bristol-Myers Squibb, 700 Bay Road, Redwood City, CA 94063-2478, USA. 5 Medimmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. 6 Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 2425 Camino de Salud, Albuquerque, NM 87106, USA. 7 The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. Electronic address: dlingwood@mgh.harvard.edu.
[h=3]Abstract[/h] 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 (V[SUB]H[/SUB]) 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 V[SUB]H[/SUB]-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.
Copyright ? 2019 Elsevier Inc. All rights reserved.
[h=4]KEYWORDS:[/h] BCR; conserved site of vulnerability; influenza; innate-like; rational vaccine; universal
PMID: 31563464 DOI: 10.1016/j.immuni.2019.09.001
Sangesland M[SUP]1[/SUP], Ronsard L[SUP]1[/SUP], Kazer SW[SUP]2[/SUP], Bals J[SUP]1[/SUP], Boyoglu-Barnum S[SUP]3[/SUP], Yousif AS[SUP]1[/SUP], Barnes R[SUP]4[/SUP], Feldman J[SUP]1[/SUP], Quirindongo-Crespo M[SUP]4[/SUP], McTamney PM[SUP]5[/SUP], Rohrer D[SUP]4[/SUP], Lonberg N[SUP]4[/SUP], Chackerian B[SUP]6[/SUP], Graham BS[SUP]3[/SUP], Kanekiyo M[SUP]3[/SUP], Shalek AK[SUP]2[/SUP], Lingwood D[SUP]7[/SUP].
[h=3]Author information[/h] 1 The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. 2 The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, 415 Main St, Cambridge, MA 02142, USA. 3 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, 40 Convent Drive, Bethesda, MD 20892-3005, USA. 4 Bristol-Myers Squibb, 700 Bay Road, Redwood City, CA 94063-2478, USA. 5 Medimmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. 6 Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, 2425 Camino de Salud, Albuquerque, NM 87106, USA. 7 The Ragon Institute of Massachusetts General Hospital, The Massachusetts Institute of Technology and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA. Electronic address: dlingwood@mgh.harvard.edu.
[h=3]Abstract[/h] 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 (V[SUB]H[/SUB]) 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 V[SUB]H[/SUB]-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.
Copyright ? 2019 Elsevier Inc. All rights reserved.
[h=4]KEYWORDS:[/h] BCR; conserved site of vulnerability; influenza; innate-like; rational vaccine; universal
PMID: 31563464 DOI: 10.1016/j.immuni.2019.09.001