{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T18:07:57Z","timestamp":1762625277690,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T00:00:00Z","timestamp":1715212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Vienna","award":["945393"],"award-info":[{"award-number":["945393"]}]},{"name":"Institute of Specific Prophylaxis and Tropical Medicine","award":["945393"],"award-info":[{"award-number":["945393"]}]},{"name":"European Union\u2019s Horizon 2020","award":["945393"],"award-info":[{"award-number":["945393"]}]},{"name":"State of Lower Austria","award":["945393"],"award-info":[{"award-number":["945393"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Patients with multiple myeloma (MM) are a heterogenous, immunocompromised group with increased risk for COVID-19 morbidity and mortality but impaired responses to primary mRNA SARS-CoV-2 vaccination. The effects of booster vaccinations and breakthrough infections (BTIs) on antibody (Ab) levels and cross-protection to variants of concern (VOCs) are, however, not sufficiently evaluated. Therefore, we analysed humoral and cellular vaccine responses in MM patients stratified according to disease stage\/treatment into group (1) monoclonal gammopathy of undetermined significance, (2) after stem cell transplant (SCT) without immunotherapy (IT), (3) after SCT with IT, and (4) progressed MM, and in healthy subjects (prospective cohort study). In contrast to SARS-CoV-2 hu-1-specific Ab levels, Omicron-specific Abs and their cross-neutralisation capacity remained low even after three booster doses in a majority of MM patients. In particular, progressed MM patients receiving anti-CD38 mAb and those after SCT with IT were Ab low responders and showed delayed formation of spike-specific B memory cells. However, MM patients with hybrid immunity (i.e., vaccination and breakthrough infection) had improved cross-neutralisation capacity against VOCs, yet in the absence of severe COVID-19 disease. Our results indicate that MM patients require frequent variant-adapted booster vaccinations and\/or changes to other vaccine formulations\/platforms, which might have similar immunological effects as BTIs.<\/jats:p>","DOI":"10.3390\/vaccines12050518","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T03:21:04Z","timestamp":1715311264000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Breakthrough Infections in SARS-CoV-2-Vaccinated Multiple Myeloma Patients Improve Cross-Protection against Omicron Variants"],"prefix":"10.3390","volume":"12","author":[{"given":"Angelika","family":"Wagner","sequence":"first","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5283-0458","authenticated-orcid":false,"given":"Erika","family":"Garner-Spitzer","sequence":"additional","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Auer","sequence":"additional","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-8543","authenticated-orcid":false,"given":"Pia","family":"Gattinger","sequence":"additional","affiliation":[{"name":"Center for Pathophysiology, Infectiology and Immunology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Zwazl","sequence":"additional","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9","family":"Platzer","sequence":"additional","affiliation":[{"name":"Center of Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Orola-Taus","sequence":"additional","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8340-0197","authenticated-orcid":false,"given":"Peter","family":"Pichler","sequence":"additional","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian","family":"Amman","sequence":"additional","affiliation":[{"name":"Center of Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University Vienna, 1090 Vienna, Austria"},{"name":"Research Center for Molecular Medicine of the Austrian Academy of Sciences, CeMM, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0597-1976","authenticated-orcid":false,"given":"Andreas","family":"Bergthaler","sequence":"additional","affiliation":[{"name":"Center of Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University Vienna, 1090 Vienna, Austria"},{"name":"Research Center for Molecular Medicine of the Austrian Academy of Sciences, CeMM, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-8198","authenticated-orcid":false,"given":"Johannes B.","family":"Huppa","sequence":"additional","affiliation":[{"name":"Center of Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6404-4430","authenticated-orcid":false,"given":"Hannes","family":"Stockinger","sequence":"additional","affiliation":[{"name":"Center of Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1440-9013","authenticated-orcid":false,"given":"Christoph C.","family":"Zielinski","sequence":"additional","affiliation":[{"name":"Wiener Privatklinik, and Central European Cooperative Oncology Group (CECOG), Central European Cancer Center, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudolf","family":"Valenta","sequence":"additional","affiliation":[{"name":"Center for Pathophysiology, Infectiology and Immunology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Karl Landsteiner University of Health Sciences, 3500 Krems, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2707-3213","authenticated-orcid":false,"given":"Michael","family":"Kundi","sequence":"additional","affiliation":[{"name":"Center for Public Health, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1302-3223","authenticated-orcid":false,"given":"Ursula","family":"Wiedermann","sequence":"additional","affiliation":[{"name":"Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1178224219868235","DOI":"10.1177\/1178224219868235","article-title":"Multiple myeloma: An overview of management","volume":"13","author":"Bird","year":"2019","journal-title":"Palliat. Care Soc. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1182\/blood.2020008824","article-title":"Outcomes of patients with hematologic malignancies and COVID-19: A systematic review and meta-analysis of 3377 patients","volume":"136","author":"Vijenthira","year":"2020","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ejca.2021.10.014","article-title":"Immunogenicity and risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection after Coronavirus Disease 2019 (COVID-19) vaccination in patients with cancer: A systematic review and meta-analysis","volume":"160","author":"Ferrigno","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"889138","DOI":"10.3389\/fimmu.2022.889138","article-title":"SARS-CoV-2-mRNA Booster Vaccination Reverses Non-Responsiveness and Early Antibody Waning in Immunocompromised Patients-A Phase Four Study Comparing Immune Responses in Patients with Solid Cancers, Multiple Myeloma and Inflammatory Bowel Disease","volume":"13","author":"Wagner","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41408-021-00530-3","article-title":"The neutralizing antibody response post COVID-19 vaccination in patients with myeloma is highly dependent on the type of anti-myeloma treatment","volume":"11","author":"Terpos","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.ccell.2021.06.014","article-title":"Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma","volume":"39","author":"Gleason","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1038\/s41375-021-01354-7","article-title":"Response to mRNA vaccination for COVID-19 among patients with multiple myeloma","volume":"35","author":"Stampfer","year":"2021","journal-title":"Leukemia"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Garner-Spitzer, E., Wagner, A., Gudipati, V., Schoetta, A.M., Orola-Taus, M., Kundi, M., Kunert, R., Mayrhofer, P., Huppa, J.B., and Stockinger, H. (2023). Lower magnitude and faster waning of antibody responses to SARS-CoV-2 vaccination in anti-TNF-alpha-treated IBD patients are linked to lack of activation and expansion of cTfh1 cells and impaired B memory cell formation. EBioMedicine, 96.","DOI":"10.1016\/j.ebiom.2023.104788"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1200\/JCO.2015.61.2267","article-title":"Revised International Staging System for Multiple Myeloma: A Report from International Myeloma Working Group","volume":"33","author":"Palumbo","year":"2015","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1111\/all.15264","article-title":"Omicron: A SARS-CoV-2 variant of real concern","volume":"77","author":"Gattinger","year":"2022","journal-title":"Allergy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabf4063","DOI":"10.1126\/science.abf4063","article-title":"Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection","volume":"371","author":"Dan","year":"2021","journal-title":"Science"},{"key":"ref_12","unstructured":"Austrian Federal Ministry of Social Affairs, Health, Care and Consumer Protection (2024, April 23). COVID-19-Impfungen, Erg\u00e4nzung zum Impfplan \u00d6sterreich 2022, Version 1.1, 28 November 2022. Available online: https:\/\/www.paediatrie.at\/media\/com_acymailing\/upload\/impfplan_2022.pdf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1038\/s41587-022-01387-y","article-title":"Viral variant-resolved wastewater surveillance of SARS-CoV-2 at national scale","volume":"40","author":"Amman","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102040","DOI":"10.1016\/j.eclinm.2023.102040","article-title":"Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): A cohort study","volume":"61","author":"Hofsink","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1158\/2643-3230.BCD-22-0173","article-title":"Impaired SARS-CoV-2 Variant Neutralization and CD8+ T-cell Responses Following 3 Doses of mRNA Vaccines in Myeloma: Correlation with Breakthrough Infections","volume":"4","author":"Azeem","year":"2023","journal-title":"Blood Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ccell.2022.05.003","article-title":"Enhanced but variant-dependent serological and cellular immune responses to third-dose BNT162b2 vaccination in patients with multiple myeloma","volume":"40","author":"Enssle","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Aleman, A., van Kesteren, M., Zajdman, A.K., Srivastava, K., Cognigni, C., Mischka, J., Chen, L.Y., Upadhyaya, B., Serebryakova, K., and Nardulli, J.R. (2023). Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma. EBioMedicine, 98.","DOI":"10.2139\/ssrn.4550619"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.3389\/fimmu.2018.02134","article-title":"CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance","volume":"9","author":"Usmani","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1182\/blood-2015-12-687749","article-title":"Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma","volume":"128","author":"Krejcik","year":"2016","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1182\/bloodadvances.2017006866","article-title":"Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma","volume":"1","author":"Casneuf","year":"2017","journal-title":"Blood Adv."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Verhoeven, D., Grinwis, L., Marsman, C., Jansen, M.H., Consortium, T.B., Van Leeuwen, E.M., and Kuijpers, T.W. (2023). B-cell targeting with anti-CD38 daratumumab: Implications for differentiation and memory responses. Life Sci. Alliance, 6.","DOI":"10.26508\/lsa.202302214"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13045-022-01290-8","article-title":"Risk of SARS-CoV-2 Breakthrough Infection in Vaccinated Cancer Patients: A Retrospective Cohort Study","volume":"15","author":"Rooney","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1111\/bjp.12771","article-title":"Isolation, Loneliness and Aloneness in the Age of COVID-19: Reflections on Clinical Experiences","volume":"38","author":"Goldblatt","year":"2022","journal-title":"Br. J. Psychother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1093\/infdis\/jiad353","article-title":"SARS-CoV-2 Hybrid Immunity: The Best of Both Worlds","volume":"228","author":"Lasrado","year":"2023","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/S1473-3099(22)00801-5","article-title":"Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: A systematic review and meta-regression","volume":"23","author":"Bobrovitz","year":"2023","journal-title":"Lancet. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1182\/blood.2021013429","article-title":"Severe impairment of T-cell responses to BNT162b2 immunization in patients with multiple myeloma","volume":"139","author":"Enssle","year":"2022","journal-title":"Blood"},{"key":"ref_27","first-page":"1280","article-title":"CD8(+) T cells contribute to survival in patients with COVID-19 and hematologic cancer","volume":"27","author":"Bange","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_28","first-page":"81","article-title":"Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma","volume":"4","author":"Greil","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41375-023-02070-0","article-title":"Cytokine-responsive T- and NK-cells portray SARS-CoV-2 vaccine-responders and infection in multiple myeloma patients","volume":"38","author":"Enssle","year":"2024","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.chom.2023.12.010","article-title":"Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant","volume":"32","author":"Muller","year":"2024","journal-title":"Cell Host Microbe"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41577-022-00678-4","article-title":"Milder disease with Omicron: Is it the virus or the pre-existing immunity?","volume":"22","author":"Sigal","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zheng, R., Mieth, K., Bennett, C., Miller, C., Anderson, L.D., Chen, M., and Cao, J. (2023). Clinical Features and Risk Stratification of Multiple Myeloma Patients with COVID-19. Cancers, 15.","DOI":"10.3390\/cancers15143598"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/s41375-023-01920-1","article-title":"Management of patients with multiple myeloma and COVID-19 in the post pandemic era: A consensus paper from the European Myeloma Network (EMN)","volume":"37","author":"Terpos","year":"2023","journal-title":"Leukemia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9825","DOI":"10.1038\/s41598-018-28111-8","article-title":"Age-related differences in humoral and cellular immune responses after primary immunisation: Indications for stratified vaccination schedules","volume":"8","author":"Wagner","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.4049\/jimmunol.2300315","article-title":"Challenges and Prospects in Developing Future SARS-CoV-2 Vaccines: Overcoming Original Antigenic Sin and Inducing Broadly Neutralizing Antibodies","volume":"211","author":"Evans","year":"2023","journal-title":"J. Immunol."},{"key":"ref_36","first-page":"12","article-title":"Vaccine based on recombinant fusion protein combining HBV PreS with SARS-CoV-2 wild-type- and Omicron-derived RBD strongly induces Omicron-neutralizing antibodies in a murine model","volume":"24","author":"Gattinger","year":"2024","journal-title":"Vaccines"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/5\/518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:43:04Z","timestamp":1760107384000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/5\/518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,9]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["vaccines12050518"],"URL":"https:\/\/doi.org\/10.3390\/vaccines12050518","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2024,5,9]]}}}