Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

• Published in: Cell Vol. 166; no. 3; pp. 609 - 623
• Main Authors: Joyce, M. Gordon, Wheatley, Adam K., Thomas, Paul V., Chuang, Gwo-Yu, Soto, Cinque, Bailer, Robert T., Druz, Aliaksandr, Georgiev, Ivelin S., Gillespie, Rebecca A., Kanekiyo, Masaru, Kong, Wing-Pui, Leung, Kwanyee, Narpala, Sandeep N., Prabhakaran, Madhu S., Yang, Eun Sung, Zhang, Baoshan, Zhang, Yi, Asokan, Mangaiarkarasi, Boyington, Jeffrey C., Bylund, Tatsiana, Darko, Sam, Lees, Christopher R., Ransier, Amy, Shen, Chen-Hsiang, Wang, Lingshu, Whittle, James R., Wu, Xueling, Yassine, Hadi M., Santos, Celia, Matsuoka, Yumiko, Tsybovsky, Yaroslav, Baxa, Ulrich, Mullikin, James C., Subbarao, Kanta, Douek, Daniel C., Graham, Barney S., Koup, Richard A., Ledgerwood, Julie E., Roederer, Mario, Shapiro, Lawrence, Kwong, Peter D., Mascola, John R., McDermott, Adrian B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.07.2016; Elsevier
• Subjects: Adult; Amino Acid Sequence; antibodies; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Viral - chemistry; Antibodies, Viral - genetics; Antibodies, Viral - immunology; B-lymphocytes; B-Lymphocytes - immunology; data collection; epitopes; Epitopes, B-Lymphocyte; Female; Gene Rearrangement, B-Lymphocyte, Heavy Chain; genes; germ cells; hemagglutinins; Humans; Immunologic Memory; influenza; Influenza A virus; Influenza A virus - immunology; Influenza A Virus, H5N1 Subtype - immunology; Influenza Vaccines - immunology; Male; Middle Aged; Models, Molecular; neutralization; Protein Structure, Tertiary; Structure-Activity Relationship; vaccination; vaccines; Young Adult
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.06.043

Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and—in half the subjects—multidonor-class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies. [Display omitted] •Isolation of group 1 and group 2 influenza A-neutralizing antibodies from H5N1 vaccinees•Discovery of three classes of broadly neutralizing antibodies directed to the HA stem•Delineation of sequence signatures specific for broadly neutralizing antibodies•Antibody quantification by NGS to guide the development of a universal vaccine Quantifying B cells capable of producing broadly neutralizing antibodies against influenza serves as a metric to guide the development of a universal influenza vaccine.