{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T07:33:32Z","timestamp":1781336012389,"version":"3.54.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T00:00:00Z","timestamp":1649376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The relatively lower protection rate of the alum-adjuvanted inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines reminds us of the antibody-dependent enhancement (ADE) phenomenon observed in preclinical studies during the development of vaccines for Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1). In this study, using the S1 segment of the SARS-CoV-2 spike protein or inactivated whole SARS-CoV-2 virus as an antigen and aluminum as an adjuvant, the risk of ADE of infection with T helper 2 (Th2)-oriented immune serum from mice (N=6) and humans (N=5) was examined in immune cell lines, which show different expression patterns of Fc receptors. Neither the immune serum from alum-adjuvanted S1 subunit vaccines nor inactivated SARS-CoV-2 vaccination enhanced SARS-CoV-2 S pseudotyped virus infection in any of the tested cell lines <jats:italic>in vitro<\/jats:italic>. Because both of these Th2-oriented immune sera could block SARS-CoV-2 infection without ADE of infection, we speculate that the lower protection rate of the inactivated SARS-CoV-2 vaccine may be attributed to the lower neutralizing antibody titers induced or the pulmonary eosinophilic immunopathology accompanied by eosinophilic infiltration in the lungs upon virus exposure. Adjustment of the immunization schedule to elevate the neutralizing antibody levels and skew adjuvants toward Th1-oriented responses may be considered to increase the efficacies of both inactivated and spike protein-based subunit SARS-CoV-2 vaccines.<\/jats:p>","DOI":"10.3389\/fimmu.2022.882856","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T05:45:37Z","timestamp":1649396737000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Th2-Oriented Immune Serum After SARS-CoV-2 Vaccination Does Not Enhance Infection In Vitro"],"prefix":"10.3389","volume":"13","author":[{"given":"Ning","family":"Luan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxiao","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangyang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunbao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2016.1177688","article-title":"Immunization With Inactivated Middle East Respiratory Syndrome Coronavirus Vaccine Leads to Lung Immunopathology on Challenge With Live Virus","volume":"12","author":"Agrawal","year":"2016","journal-title":"Hum Vaccin Immunother"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e35421","DOI":"10.1371\/journal.pone.0035421","article-title":"Immunization With SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge With the SARS Virus","volume":"7","author":"Tseng","year":"2012","journal-title":"PloS One"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06048-11","article-title":"A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response Upon Challenge","volume":"85","author":"Bolles","year":"2011","journal-title":"J Virol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.6b00006","article-title":"Immunodominant SARS Coronavirus Epitopes in Humans Elicited Both Enhancing and Neutralizing Effects on Infection in Non-Human Primates","volume":"2","author":"Wang","year":"2016","journal-title":"ACS Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00671-11","article-title":"Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH- and Cysteine Protease-Independent FcgammaR Pathway","volume":"85","author":"Jaume","year":"2011","journal-title":"J Virol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.07.090","article-title":"Antibody-Dependent SARS Coronavirus Infection Is Mediated by Antibodies Against Spike Proteins","volume":"451","author":"Wang","year":"2014","journal-title":"Biochem Biophys Res Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-00789-5","article-title":"Antibody-Dependent Enhancement and SARS-CoV-2 Vaccines and Therapies","volume":"5","author":"Lee","year":"2020","journal-title":"Nat Microbiol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa753","article-title":"Severe Acute Respiratory Syndrome Coronavirus 2-Induced Immune Activation and Death of Monocyte-Derived Human Macrophages and Dendritic Cells","volume":"223","author":"Zheng","year":"2021","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.123158","article-title":"Anti-Spike IgG Causes Severe Acute Lung Injury by Skewing Macrophage Responses During Acute SARS-CoV Infection","volume":"4","author":"Liu","year":"2019","journal-title":"JCI Insight"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit504","article-title":"Active Replication of Middle East Respiratory Syndrome Coronavirus and Aberrant Induction of Inflammatory Cytokines and Chemokines in Human Macrophages: Implications for Pathogenesis","volume":"209","author":"Zhou","year":"2014","journal-title":"J Infect Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.3390\/v13091687","article-title":"SARS-CoV-2 Infection: New Molecular, Phylogenetic, and Pathogenetic Insights. Efficacy of Current Vaccines and the Potential Risk of Variants","volume":"13","author":"Rotondo","year":"2021","journal-title":"Viruses"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00983-14","article-title":"Effects of Toll-Like Receptor Stimulation on Eosinophilic Infiltration in Lungs of BALB\/c Mice Immunized With UV-Inactivated Severe Acute Respiratory Syndrome-Related Coronavirus Vaccine","volume":"88","author":"Iwata-Yoshikawa","year":"2014","journal-title":"J Virol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.1128\/JVI.02980-14","article-title":"Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated With Delta Inulin Adjuvants Provide Enhanced Protection While Ameliorating Lung Eosinophilic Immunopathology","volume":"89","author":"Honda-Okubo","year":"2015","journal-title":"J Virol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2010.0028","article-title":"Immunogenicity and Protective Efficacy in Mice and Hamsters of a Beta-Propiolactone Inactivated Whole Virus SARS-CoV Vaccine","volume":"23","author":"Roberts","year":"2010","journal-title":"Viral Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2622-0","article-title":"SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness","volume":"586","author":"Corbett","year":"2020","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024671","article-title":"Evaluation of the mRNA-1273 Vaccine Against SARS-CoV-2 in Nonhuman Primates","volume":"383","author":"Corbett","year":"2020","journal-title":"N Engl J Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.immuni.2020.07.019","article-title":"A Single Immunization With Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses Against SARS-CoV-2 in Mice","volume":"53","author":"Laczko","year":"2020","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2022483","article-title":"An mRNA Vaccine Against SARS-CoV-2 - Preliminary Report","volume":"383","author":"Jackson","year":"2020","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2027906","article-title":"Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates","volume":"383","author":"Walsh","year":"2020","journal-title":"N Engl J Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2020.10.064","article-title":"NVX-CoV2373 Vaccine Protects Cynomolgus Macaque Upper and Lower Airways Against SARS-CoV-2 Challenge","volume":"38","author":"Guebre-Xabier","year":"2020","journal-title":"Vaccine"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2026920","article-title":"Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine","volume":"383","author":"Keech","year":"2020","journal-title":"N Engl J Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/s41467-020-20653-8","article-title":"SARS-CoV-2 Spike Glycoprotein Vaccine Candidate NVX-CoV2373 Immunogenicity in Baboons and Protection in Mice","volume":"12","author":"Tian","year":"2021","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/s41541-018-0089-x","article-title":"Optimizing the Utilization of Aluminum Adjuvants in Vaccines: You Might Just Get What You Want","volume":"3","author":"HogenEsch","year":"2018","journal-title":"NPJ Vaccines"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.3822780","article-title":"Efficacy and Safety of a COVID-19 Inactivated Vaccine in Healthcare Professionals in Brazil: The PROFISCOV Study","author":"Palacios","year":"2021","journal-title":"Soc Sci Res Net"},{"key":"B25","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1001\/jama.2021.8565","article-title":"Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial","volume":"326","author":"Al Kaabi","year":"2021","journal-title":"JAMA"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01429-X","article-title":"Efficacy and Safety of an Inactivated Whole-Virion SARS-CoV-2 Vaccine (CoronaVac): Interim Results of a Double-Blind, Randomised, Placebo-Controlled, Phase 3 Trial in Turkey","volume":"398","author":"Tanriover","year":"2021","journal-title":"Lancet"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107715","article-title":"Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile","volume":"385","author":"Jara","year":"2021","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1126\/science.abc1932","article-title":"Development of an Inactivated Vaccine Candidate for SARS-CoV-2","volume":"369","author":"Gao","year":"2020","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.cell.2020.06.008","article-title":"Development of an Inactivated Vaccine Candidate, BBIBP-CorV, With Potent Protection Against SARS-CoV-2","volume":"182","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2020.1852059","article-title":"Low Toxicity and High Immunogenicity of an Inactivated Vaccine Candidate Against COVID-19 in Different Animal Models","volume":"9","author":"Wang","year":"2020","journal-title":"Emerg Microbes Infect"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg7996","article-title":"Immunological and Pathological Outcomes of SARS-CoV-2 Challenge Following Formalin-Inactivated Vaccine in Ferrets and Rhesus Macaques","volume":"7","author":"Bewley","year":"2021","journal-title":"Sci Adv"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2021.1976598","article-title":"SARS-CoV-2 Infection and Disease Outcomes in Non-Human Primate Models: Advances and Implications","volume":"10","author":"Yuan","year":"2021","journal-title":"Emerg Microbes Infect"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00083-06","article-title":"Antigenic and Immunogenic Characterization of Recombinant Baculovirus-Expressed Severe Acute Respiratory Syndrome Coronavirus Spike Protein: Implication for Vaccine Design","volume":"80","author":"He","year":"2006","journal-title":"J Virol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2020.06.066","article-title":"Recombinant SARS-CoV-2 Spike S1-Fc Fusion Protein Induced High Levels of Neutralizing Responses in Nonhuman Primates","volume":"38","author":"Ren","year":"2020","journal-title":"Vaccine"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00298","article-title":"Subunit Vaccines Against Emerging Pathogenic Human Coronaviruses","volume":"11","author":"Wang","year":"2020","journal-title":"Front Microbiol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3452","DOI":"10.1016\/j.cell.2021.05.032","article-title":"An Infectivity-Enhancing Site on the SARS-CoV-2 Spike Protein Targeted by Antibodies","volume":"184","author":"Liu","year":"2021","journal-title":"Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5752","DOI":"10.1038\/s41467-020-19568-1","article-title":"Characterization of Neutralizing Antibody With Prophylactic and Therapeutic Efficacy Against SARS-CoV-2 in Rhesus Monkeys","volume":"11","author":"Wang","year":"2020","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","first-page":"108699","DOI":"10.1016\/j.celrep.2021.108699","article-title":"Enhancement Versus Neutralization by SARS-CoV-2 Antibodies From a Convalescent Donor Associates With Distinct Epitopes on the RBD","volume":"34","author":"Zhou","year":"2021","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1703","article-title":"Randomized, Double-Blinded and Placebo-Controlled Phase II Trial of an Inactivated SARS-CoV-2 Vaccine in Healthy Adults","volume":"73","author":"Che","year":"2021","journal-title":"Clin Infect Dis"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.3390\/vaccines9111261","article-title":"An Established Th2-Oriented Response to an Alum-Adjuvanted SARS-CoV-2 Subunit Vaccine Is Not Reversible by Sequential Immunization With Nucleic Acid-Adjuvanted Th1-Oriented Subunit Vaccines","volume":"9","author":"Cao","year":"2021","journal-title":"Vaccines (Basel)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3390\/vaccines9040310","article-title":"Immunogenicity of Varicella-Zoster Virus Glycoprotein E Formulated With Lipid Nanoparticles and Nucleic Immunostimulators in Mice","volume":"9","author":"Cao","year":"2021","journal-title":"Vaccines (Basel)"},{"key":"B42","doi-asserted-by":"publisher","first-page":"222","DOI":"10.3390\/vaccines9030222","article-title":"Natural and Synthetic Saponins as Vaccine Adjuvants","volume":"9","author":"Wang","year":"2021","journal-title":"Vaccines (Basel)"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.12.6915-6920.2003","article-title":"Th1-Directing Adjuvants Increase the Immunogenicity of Oligosaccharide-Protein Conjugate Vaccines Related to Streptococcus Pneumoniae Type 3","volume":"71","author":"Lefeber","year":"2003","journal-title":"Infect Immun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3024.1994.tb00306.x","article-title":"The Profile of IgG1 and IgG2a Antibody Responses in Mice Exposed to Schistosoma Mansoni","volume":"16","author":"Mountford","year":"1994","journal-title":"Parasite Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0394-5","article-title":"Quantification of SARS-CoV-2 Neutralizing Antibody by a Pseudotyped Virus-Based Assay","volume":"15","author":"Nie","year":"2020","journal-title":"Nat Protoc"},{"key":"B46","doi-asserted-by":"publisher","first-page":"4203","DOI":"10.1016\/j.cell.2021.06.021","article-title":"In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies","volume":"184","author":"Li","year":"2021","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02015-19","article-title":"Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry","volume":"94","author":"Wan","year":"2020","journal-title":"J Virol"},{"key":"B48","first-page":"25","article-title":"Antibody-Dependent Enhancement of SARS Coronavirus Infection and Its Role in the Pathogenesis of SARS","volume":"22","author":"Yip","year":"2016","journal-title":"Hong Kong Med J"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2021.03.067","article-title":"The Role of Multiple SARS-CoV-2 Viral Antigens in a Vaccine-Induced Integrated Immune Response","volume":"39","author":"Zhang","year":"2021","journal-title":"Vaccine"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N Engl J Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107659","article-title":"Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine","volume":"385","author":"Heath","year":"2021","journal-title":"N Engl J Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N Engl J Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2021.2002670","article-title":"Waning Antibodies From Inactivated SARS-CoV-2 Vaccination Offer Protection Against Infection Without Antibody-Enhanced Immunopathology in Rhesus Macaque Pneumonia Models","volume":"10","author":"Li","year":"2021","journal-title":"Emerg Microbes Infect"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1016\/j.immuni.2021.06.018","article-title":"COVID-19 Vaccine mRNA-1273 Elicits a Protective Immune Profile in Mice That is Not Associated With Vaccine-Enhanced Disease Upon SARS-CoV-2 Challenge","volume":"54","author":"DiPiazza","year":"2021","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00070-0","article-title":"Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine, BBV152: Interim Results From a Double-Blind, Randomised, Multicentre, Phase 2 Trial, and 3-Month Follow-Up of a Double-Blind, Randomised Phase 1 Trial","volume":"21","author":"Ella","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"B56","doi-asserted-by":"publisher","first-page":"102298","DOI":"10.1016\/j.isci.2021.102298","article-title":"Th1 Skewed Immune Response of Whole Virion Inactivated SARS CoV 2 Vaccine and its Safety Evaluation","volume":"24","author":"Ganneru","year":"2021","journal-title":"iScience"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1038\/s41467-021-21634-1","article-title":"S-Trimer, a COVID-19 Subunit Vaccine Candidate, Induces Protective Immunity in Nonhuman Primates","volume":"12","author":"Liang","year":"2021","journal-title":"Nat Commun"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00241-5","article-title":"Safety and Immunogenicity of S-Trimer (SCB-2019), a Protein Subunit Vaccine Candidate for COVID-19 in Healthy Adults: A Phase 1, Randomised, Double-Blind, Placebo-Controlled Trial","volume":"397","author":"Richmond","year":"2021","journal-title":"Lancet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.882856\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T05:45:43Z","timestamp":1649396743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.882856\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,8]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2022.882856"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.882856","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,8]]},"article-number":"882856"}}