{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T03:49:18Z","timestamp":1782013758267,"version":"3.54.5"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hypoallergenic recombinant fold\u2010variants of major allergens have been suggested as safer and more effective AIT candidates. The Bet v 1\u2010fold variant BM41, with confirmed preclinical hypoallergenicity and increased immunogenicity, was proposed for the treatment of birch pollen allergy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a 6\u2010month randomized, double\u2010blind, placebo\u2010controlled first\u2010in\u2010human clinical trial with BM41, a licensed birch pollen extract\u2010based treatment, as the active comparator (AC), and placebo (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200916,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200916, and\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915, respectively). The primary endpoint was safety. Secondary outcomes were Bet v 1\u2010specific (s)IgE, IgG, IgG\n                      <jats:sub>1<\/jats:sub>\n                      , and IgG\n                      <jats:sub>4<\/jats:sub>\n                      responses measured by ImmunoCAP, and sIgE\u2010blocking activity using mediator release and facilitated antigen binding assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Despite SPT\u2010confirmed hypoallergenicity (~50% compared to natural Bet v 1), more adverse events occurred in response to BM41. Although similar sIgG and sIgG\n                      <jats:sub>1<\/jats:sub>\n                      levels were induced, sIgG\n                      <jats:sub>4<\/jats:sub>\n                      levels increased 3\u2010fold more in AC compared to the BM41 group. In AC, the sIgG\n                      <jats:sub>4<\/jats:sub>\n                      \/sIgG\n                      <jats:sub>1<\/jats:sub>\n                      ratio tripled over time, whereas for BM41 it stagnated. BM41 induced efficient serum inhibitory activity for sIgE compared to placebo but was 12%\u201332% less efficient than AC. Both sIgG\n                      <jats:sub>4<\/jats:sub>\n                      and sIgG\n                      <jats:sub>1<\/jats:sub>\n                      contributed to the blocking effect in AC, while in BM41 both sIgG subclasses showed a lowered functional capacity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Preclinically established hypoallergenicity of BM41 did not result in a lower number of adverse events. The reduced induction of sIgG\n                      <jats:sub>4<\/jats:sub>\n                      by the fold variant in the course of the treatment was less efficient in blocking sIgE\u2010mediated responses. This is the first study providing evidence that, instead of a Th1\u2010favored IgG\n                      <jats:sub>1<\/jats:sub>\n                      \u2010dominated response, \u201cmodified Th2\u201d\u2010skewed IgG\n                      <jats:sub>4<\/jats:sub>\n                      \u2010dominated humoral responses are beneficial in AIT vaccine design.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/all.16606","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T03:36:05Z","timestamp":1748835365000},"page":"2018-2030","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Subcutaneous Allergen Immunotherapy With Hypoallergenic Bet v 1 Compared to Conventional Extract: Poorer Blocking Antibody Capacity Dominated by\n                    <scp>\n                      IgG\n                      <sub>1<\/sub>\n                    <\/scp>\n                    Instead of\n                    <scp>\n                      IgG\n                      <sub>4<\/sub>\n                    <\/scp>"],"prefix":"10.1111","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1236-5934","authenticated-orcid":false,"given":"Lorenz","family":"Aglas","sequence":"first","affiliation":[{"name":"Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna  Vienna Austria"},{"name":"Department of Biosciences and Medical Biology University of Salzburg  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4039-5708","authenticated-orcid":false,"given":"Line Kring","family":"Tannert","sequence":"additional","affiliation":[{"name":"Odense Research Center for Anaphylaxis Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9729-3000","authenticated-orcid":false,"given":"Serge A.","family":"Versteeg","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology Amsterdam University Medical Centers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5519-8662","authenticated-orcid":false,"given":"Scott A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1567-3350","authenticated-orcid":false,"given":"Ewa A.","family":"Bartko","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, Allergy Clinic Copenhagen University Hospital\u2010Herlev and Gentofte  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7893-1935","authenticated-orcid":false,"given":"Mario","family":"Wenger","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3792-0487","authenticated-orcid":false,"given":"Amin","family":"Kraiem","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0593-7567","authenticated-orcid":false,"given":"Hannah","family":"Widauer","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  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