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We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201\u20131215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33.<\/jats:p>","DOI":"10.1128\/jvi.02152-12","type":"journal-article","created":{"date-parts":[[2012,11,15]],"date-time":"2012-11-15T03:38:40Z","timestamp":1352950720000},"page":"1569-1585","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["Unusual Features of Vaccinia Virus Extracellular Virion Form Neutralization Resistance Revealed in Human Antibody Responses to the Smallpox Vaccine"],"prefix":"10.1128","volume":"87","author":[{"given":"Mohammed Rafii-El-Idrissi","family":"Benhnia","sequence":"first","affiliation":[{"name":"Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Maybeno","sequence":"additional","affiliation":[{"name":"Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Blum","sequence":"additional","affiliation":[{"name":"Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowena","family":"Aguilar-Sino","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Matho","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangzhi","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Head","sequence":"additional","affiliation":[{"name":"DNA Array Core Facility and Consortium for Functional Glycomics, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip L.","family":"Felgner","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of California, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk M.","family":"Zajonc","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilia","family":"Koriazova","sequence":"additional","affiliation":[{"name":"Kyowa Hakko Kirin California, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichiro","family":"Kato","sequence":"additional","affiliation":[{"name":"Kyowa Hakko Kirin California, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis R.","family":"Burton","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"James E.","family":"Crowe","sequence":"additional","affiliation":[{"name":"Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjoern","family":"Peters","sequence":"additional","affiliation":[{"name":"Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Crotty","sequence":"additional","affiliation":[{"name":"Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Smallpox and its eradication.","author":"Fenner F","year":"1988","unstructured":"FennerF HendersonDA AritaI JezekZ LadnyiID. 1988. 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