{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:01:19Z","timestamp":1785416479035,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Thammasat University Hospital","award":["COVID19 1\/2565.1"],"award-info":[{"award-number":["COVID19 1\/2565.1"]}]},{"award":["COVID19 1\/2565.1"],"award-info":[{"award-number":["COVID19 1\/2565.1"]}],"id":[{"id":"https:\/\/ror.org\/02s7hnh67","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Clinical Research Center, Faculty of Medicine, Thammasat University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Our previous study demonstrated that while the third SARS-CoV-2 booster effectively enhanced immunity against the Delta subvariant, its protection declined over time. This study aimed to evaluate and compare the humoral and cellular immune responses, as well as reactogenicity, of the mRNA-1273 vaccine administered as a fourth booster in healthy Thai adults previously vaccinated with two doses of CoronaVac (CV) followed by a third dose of either AZD1222 (AZ) or BNT162b2 (BNT). Methods: Participants received a single 100 \u00b5g (0.5 mL) intramuscular dose of mRNA-1273. Blood samples were collected at baseline (D0), D14, D90, and D180 to assess anti-RBD IgG, conduct a surrogate virus neutralization test (sVNT) against the Delta and Omicron variants, and assess IFN-\u03b3 levels and reactogenicity. Results: Both 2CV\/AZ- and 2CV\/BNT-primed groups exhibited comparable local and systemic reactogenicity. The fourth mRNA-1273 dose markedly increased Delta variant inhibition within 14 days in both groups and remained at high levels at Days 90 and 180. sVNT inhibition against Omicron rose similarly in both groups at Day 14; it declined sharply by Days 90 and 180, with the 2CV\/AZ-primed group showing significantly lower levels than the 2CV\/BNT-primed group. Baseline anti-RBD IgG levels were lower in the 2CV\/AZ group (p = 0.003) but surpassed those of the 2CV\/BNT group by Day 14, with no significant differences at later time points. IFN-\u03b3 responses followed a similar pattern to anti-RBD IgG Conclusions: A heterologous fourth mRNA-1273 booster in both 2CV\/AZ- and 2CV\/BNT-primed groups effectively enhances B-cell and T-cell responses against SARS-CoV-2. However, emerging variants such as Omicron may still pose challenges. The trial was registered with the Thai Clinical Trials Registry: the name of the registry: \u201cThe comparison of immune response to the 4th dose booster with mRNA-1273 COVID-19 vaccine in individuals who had received 2 doses of CoronaVac and booster with ChAdOx-1 or BNT162b2 COVID-19 vaccine\u201d, TCTR20220205002 on 5 February 2022.<\/jats:p>","DOI":"10.3390\/vaccines14040348","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T09:15:59Z","timestamp":1776244559000},"page":"348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparison of Immune Responses and Safety Profiles Following a Fourth Heterologous Dose (Second Booster) with mRNA-1273 in Individuals Previously Vaccinated with Two Doses of CoronaVac and a Booster Dose of Either AZD1222 or BNT162b2"],"prefix":"10.3390","volume":"14","author":[{"given":"Auchara","family":"Tangsathapornpong","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"},{"name":"Research Unit in Infectious and Immunology, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3196-4657","authenticated-orcid":false,"given":"Sira","family":"Nanthapisal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"},{"name":"Research Unit in Infectious and Immunology, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"},{"name":"Clinical Research Center, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waraphon","family":"Fukpho","sequence":"additional","affiliation":[{"name":"Thammasat University Hospital, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pornumpa","family":"Bunjoungmanee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"},{"name":"Research Unit in Infectious and Immunology, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamonbhorn","family":"Neamkul","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanassanan","family":"Pontan","sequence":"additional","affiliation":[{"name":"Thammasat University Hospital, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthit","family":"Boonyarangkul","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supattra","family":"Wanpen","sequence":"additional","affiliation":[{"name":"Thammasat University Hospital, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanokporn","family":"Thongphubeth","sequence":"additional","affiliation":[{"name":"Thammasat University Hospital, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuntila","family":"Tharabenjasin","sequence":"additional","affiliation":[{"name":"Chulabhorn International College of Medicine, Thammasat University, Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peera","family":"Jaru-Ampornpan","sequence":"additional","affiliation":[{"name":"Virology and Cell Technology Research Team, National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueang, Khlong Luang, Pathumthani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","unstructured":"World Health Organization (2022, March 24). Novel Coronavirus\u2014Thailand (ex-China). Available online: https:\/\/www.who.int\/emergencies\/disease-outbreak-news\/item\/2020-DON234."},{"key":"ref_3","unstructured":"WHO (2021). COVID-19 Weekly Epidemiological Update Edition 68, WHO. Available online: https:\/\/www.who.int\/publications\/m\/item\/weekly-epidemiological-update-on-covid-19---30-november-2021."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1016\/j.cell.2022.04.035","article-title":"Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike","volume":"185","author":"Yamasoba","year":"2022","journal-title":"Cell"},{"key":"ref_5","unstructured":"World Health Organization (2020, October 20). Draft Landscape of COVID-19 Candidate Vaccines. Available online: https:\/\/www.who.int\/publications\/m\/item\/draft-landscape-of-covid-19-candidate-vaccines."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1473-3099(20)30843-4","article-title":"Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18\u201359 years: A randomised, double-blind, placebo-controlled, phase 1\/2 clinical trial","volume":"21","author":"Zhang","year":"2021","journal-title":"Lancet Infect Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"875","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":"ref_8","unstructured":"WHO (2021, August 29). Interim Statement on COVID-19 Vaccine Booster Doses 2021 [Updated 10 August 2021]. Available online: https:\/\/www.who.int\/news\/item\/10-08-2021-interim-statement-on-covid-19-vaccine-booster-doses."},{"key":"ref_9","first-page":"269","article-title":"Short-term immune response after inactivated SARS-CoV-2 (CoronaVac(R), Sinovac) and AZD1222nCoV-19 (Vaxzevria(R), Oxford-AstraZeneca) vaccinations in health care workers","volume":"40","author":"Jantarabenjakul","year":"2021","journal-title":"Asian Pac. J. Allergy Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S0140-6736(22)00152-0","article-title":"Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: Results of a systematic review and meta-regression","volume":"399","author":"Feikin","year":"2022","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"taac037","DOI":"10.1093\/jtm\/taac037","article-title":"The effective reproductive number of the Omicron variant of SARS-CoV-2 is several times relative to Delta","volume":"29","author":"Liu","year":"2022","journal-title":"J. Travel. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1056\/NEJMoa2119451","article-title":"Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant","volume":"386","author":"Andrews","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eabn4947","DOI":"10.1126\/science.abn4947","article-title":"Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa","volume":"376","author":"Pulliam","year":"2022","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0140-6736(22)00094-0","article-title":"Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): A phase 4, non-inferiority, single blind, randomised study","volume":"399","author":"Weckx","year":"2022","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100315","DOI":"10.1016\/j.jnha.2024.100315","article-title":"Immunogenicity of BNT162b2 as a first booster after a ChAdOx1 primary series in a Thai geriatric population living with frailty","volume":"28","author":"Niyomnaitham","year":"2024","journal-title":"J. Nutr. Health Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1080\/20477724.2022.2108646","article-title":"Immunogenicity of the BNT162b2 COVID-19 vaccine as a third dose (booster) following two doses of different primary series regimens in Thailand","volume":"116","author":"Wanlapakorn","year":"2022","journal-title":"Pathog. Glob. Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1038\/s41591-021-01449-9","article-title":"Immune responses against SARS-CoV-2 variants after heterologous and homologous AZD1222nCoV-19\/BNT162b2 vaccination","volume":"27","author":"Hammerschmidt","year":"2021","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1016\/S0140-6736(21)02717-3","article-title":"Safety and immunogenicity of seven covid-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or bnt162b2 in the uk (cov-boost): A blinded, multicentre, randomised, controlled, phase 2 trial","volume":"398","author":"Munro","year":"2021","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.15585\/mmwr.mm7044e2","article-title":"The Advisory Committee on Immunization Practices\u2019 Interim Recommendations for Additional Primary and Booster Doses of COVID-19 Vaccines\u2014United States, 2021","volume":"70","author":"Mbaeyi","year":"2021","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.15585\/mmwr.mm7145a2","article-title":"Interim Recommendations from the Advisory Committee on Immunization Practices for the Use of Bivalent Booster Doses of COVID-19 Vaccines\u2014United States, October 2022","volume":"71","author":"Rosenblum","year":"2022","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tangsathapornpong, A., Nanthapisal, S., Pontan, K., Bunjoungmanee, P., Neamkul, Y., Boonyarangkul, A., Wanpen, S., Fukpho, W., Jitpokasem, S., and Tharabenjasin, P. (2023). Immunogenicity and safety of the third booster dose with mRNA-1273 COVID-19 vaccine after receiving two doses of inactivated or viral vector COVID-19 vaccine. Vaccines, 11.","DOI":"10.3390\/vaccines11030553"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"403","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":"ref_23","unstructured":"U.S. Department of Health and Human Services, Department of Health and Human Services, Food and Drug Administration, and CBER (2021, November 30). Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials September 2007, Available online: https:\/\/www.fda.gov\/media\/73679\/download."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zou, Y., Huang, D., Jiang, Q., Guo, Y., and Chen, C. (2022). The vaccine efficacy against the SARS-CoV-2 Omicron: A systemic review and meta-analysis. Front. Public. Health., 10.","DOI":"10.3389\/fpubh.2022.940956"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2021.12.033","article-title":"mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant","volume":"185","author":"Hoelzemer","year":"2022","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4350","DOI":"10.1038\/s41467-022-31929-6","article-title":"Differential neutralization and inhibition of SARS-CoV-2 variants by antibodies elicited by COVID-19 mRNA vaccines","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e063935","DOI":"10.1136\/bmjopen-2022-063935","article-title":"Effectiveness of mRNA COVID-19 vaccines against Omicron and Delta variants in a matched test-negative case-control study among US veterans","volume":"12","author":"Zwain","year":"2022","journal-title":"BMJ Open"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"139","DOI":"10.15585\/mmwr.mm7104e3","article-title":"Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance\u2014VISION Network, 10 States, August 2021\u2013January 2022","volume":"71","author":"Thompson","year":"2022","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"ref_29","first-page":"e2022179","article-title":"Delta Variant: The New Challenge of COVID-19 Pandemic, an Overview of Epidemiological, Clinical, and Immune Characteristics","volume":"93","author":"Samieefar","year":"2022","journal-title":"Acta. Biomed."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chen, L., He, Y., Liu, H., Shang, Y., and Guo, G. (2024). Potential immune evasion of the severe acute respiratory syndrome coronavirus 2 Omicron variants. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1339660"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/s41467-023-35815-7","article-title":"Effectiveness of mRNA-1273 vaccination against SARS-CoV-2 omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5","volume":"14","author":"Tseng","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41586-021-04120-y","article-title":"Immunogenicity and efficacy of heterologous ChAdOx1\u2013BNT162b2 vaccination","volume":"600","author":"Pozzetto","year":"2021","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2411059","DOI":"10.4014\/jmb.2411.11059","article-title":"A Meta-analysis on the immunogenicity of homologous versus heterologous immunization regimens against SARS-CoV-2 Beta, Delta, and Omicron BA.1 VoCs in healthy adults","volume":"35","author":"Ndzouboukou","year":"2025","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1056\/NEJMoa2116414","article-title":"Homologous and heterologous Covid-19 booster vaccinations","volume":"386","author":"Atmar","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1002\/jmv.27572","article-title":"Induction of humoral and cellular immune responses to COVID-19 mRNA and vector vaccines: A prospective cohort study in Bulgarian healthcare workers","volume":"94","author":"Nikolova","year":"2022","journal-title":"Med. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1016\/j.cell.2022.05.022","article-title":"Humoral and cellular immune memory to four COVID-19 vaccines","volume":"185","author":"Zhang","year":"2022","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18684","DOI":"10.1038\/s41598-025-00054-x","article-title":"Prolonged effects of adenoviral vector priming on T-cell cytokine production in heterologous adenoviral vector\/mRNA COVID-19 vaccination regimens","volume":"15","author":"Isogawa","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1056\/NEJMoa2028436","article-title":"Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults","volume":"383","author":"Anderson","year":"2020","journal-title":"N. Engl. J. Med."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/4\/348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T09:29:52Z","timestamp":1776245392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/4\/348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["vaccines14040348"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14040348","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]}}}