The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071168
The Journal of Experimental Medicine, Vol. 205, No. 1, 117-131
The Rockefeller University Press, 0022-1007 $30.00
© Giefing et al.
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ARTICLE

 Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies

Carmen Giefing1, Andreas L. Meinke1, Markus Hanner1, Tamás Henics1, Duc Bui Minh1, Dieter Gelbmann1, Urban Lundberg1, Beatrice M. Senn1, Michael Schunn1, Andre Habel1, Birgitta Henriques-Normark2, Åke Örtqvist3, Mats Kalin3, Alexander von Gabain1, and Eszter Nagy1

1 Intercell AG, 1030 Vienna, Austria
2 Department of Bacteriology, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden
3 Department of Infectious Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden

CORRESPONDENCE Eszter Nagy: ENagy{at}intercell.com

Pneumococcus is one of the most important human pathogens that causes life-threatening invasive diseases, especially at the extremities of age. Capsular polysaccharides (CPSs) are known to induce protective antibodies; however, it is not feasible to develop CPS-based vaccines that cover all of the 90 disease-causing serotypes. We applied a genomic approach and described the antibody repertoire for pneumococcal proteins using display libraries expressing 15–150 amino acid fragments of the pathogen's proteome. Serum antibodies of exposed, but not infected, individuals and convalescing patients identified the ANTIGENome of pneumococcus consisting of ~140 antigens, many of them surface exposed. Based on several in vitro assays, 18 novel candidates were preselected for animal studies, and 4 of them showed significant protection against lethal sepsis. Two lead vaccine candidates, protein required for cell wall separation of group B streptococcus (PcsB) and serine/threonine protein kinase (StkP), were found to be exceptionally conserved among clinical isolates (>99.5% identity) and cross-protective against four different serotypes in lethal sepsis and pneumonia models, and have important nonredundant functions in bacterial multiplication based on gene deletion studies. We describe for the first time opsonophagocytic killing activity for pneumococcal protein antigens. A vaccine containing PcsB and StkP is intended for the prevention of infections caused by all serotypes of pneumococcus in the elderly and in children.

Abbreviations used: CHAP, cysteine, histidine-dependent amidohydrolase/peptidase; CPS, capsular polysaccharide; i.n., intranasal(ly); OPK, opsonophagocytic killing; ORF, open reading frame; PASTA, penicillin-binding protein and serine/threonine kinase associated; PcsB, protein required for cell wall separation of group B streptococcus; StkP, serine/threonine protein kinase.

C. Giefing and A.L. Meinke contributed equally to this work.

T. Henics' present address is Max F. Perutz Laboratories, 1030 Vienna, Austria.

D.B. Minh's present address is Icon Genetics GmbH, 06120 Halle/Saale, Germany.

A. Habel's present address is Berna Biotech AG, 3018 Bern, Switzerland.


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