{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:16:59Z","timestamp":1765948619533,"version":"3.48.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SK Bioscience Co., Ltd.","award":["Q2208341"],"award-info":[{"award-number":["Q2208341"]}]},{"name":"SK Bioscience Co., Ltd.","award":["Q2208691"],"award-info":[{"award-number":["Q2208691"]}]},{"name":"SK Bioscience Co., Ltd.","award":["Q2208671"],"award-info":[{"award-number":["Q2208671"]}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2023-00249465"],"award-info":[{"award-number":["RS-2023-00249465"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: The COVID-19 pandemic accelerated the development of diverse vaccine platforms, including mRNA, adenoviral vector, and protein subunit vaccines. Given the growing evidence that the gut microbiome modulates vaccine-induced immunity, this study compared the effects of a protein subunit vaccine (NVX-CoV2373), an mRNA vaccine (BNT162b2), and an adenoviral vector vaccine (ChAdOx1) on gut microbiome diversity following booster vaccination. Methods: We conducted a prospective cohort study involving 35 healthy adults who received an NVX-CoV2373 booster. Stool and blood samples were collected before vaccination and three weeks afterward. Gut microbiome profiles were analyzed using 16S rRNA gene sequencing, and the results were compared with our previous cohorts who received BNT162b2 or ChAdOx1 vaccines. Results: The NVX-CoV2373 booster was associated with a significant increase in the Shannon diversity index (p = 0.027), indicating enhanced alpha diversity. This finding contrasts with the decrease or absence of significant short-term change observed following repeated administrations of adenoviral vector and mRNA vaccines, respectively. Notably, NVX-CoV2373 vaccination was accompanied by an increased relative abundance of beneficial taxa such as Bacteroides fragilis and a decrease in Prevotella bivia. In comparison, repeated ChAdOx1 doses resulted in a sustained reduction in alpha diversity, whereas BNT162b2 showed a transient post-booster rise followed by a long-term decline in species richness. Conclusions: In the booster setting, the protein subunit vaccine NVX-CoV2373 exerted a distinct and favorable effect on gut microbiome diversity, increasing alpha diversity in contrast to the patterns observed with mRNA and adenoviral vector booster vaccines.<\/jats:p>","DOI":"10.3390\/vaccines13121248","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T15:52:59Z","timestamp":1765813979000},"page":"1248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vaccine Platform-Dependent Differential Impact on Microbiome Diversity: Potential Advantages of Protein Subunit Vaccines"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5633-7214","authenticated-orcid":false,"given":"Hye","family":"Seong","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Gu","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliel","family":"Nham","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu Jung","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Yun","family":"Noh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"},{"name":"Asia Pacific Influenza Institute, Korea University College of Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee Jin","family":"Cheong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"},{"name":"Asia Pacific Influenza Institute, Korea University College of Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-3880","authenticated-orcid":false,"given":"Woo Joo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"},{"name":"Asia Pacific Influenza Institute, Korea University College of Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sooyeon","family":"Lim","sequence":"additional","affiliation":[{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"},{"name":"Asia Pacific Influenza Institute, Korea University College of Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0148-7194","authenticated-orcid":false,"given":"Joon Young","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea"},{"name":"Vaccine Innovation Center-KU Medicine, Seoul 08308, Republic of Korea"},{"name":"Asia Pacific Influenza Institute, Korea University College of Medicine, Seoul 08308, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1056\/NEJMoa2026920","article-title":"Phase 1\u20132 trial of a sars-cov-2 recombinant spike protein nanoparticle vaccine","volume":"383","author":"Keech","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101569","DOI":"10.1016\/j.eclinm.2022.101569","article-title":"Safety and immunogenicity of a sars-cov-2 recombinant protein nanoparticle vaccine (gbp510) adjuvanted with as03: A randomised, placebo-controlled, observer-blinded phase 1\/2 trial","volume":"51","author":"Song","year":"2022","journal-title":"EClinicalMedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"89","DOI":"10.12701\/jyms.2021.01669","article-title":"Coronavirus disease 2019 (covid-19) vaccine platforms: How novel platforms can prepare us for future pandemics: A narrative review","volume":"39","year":"2022","journal-title":"J. Yeungnam Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chom.2020.06.014","article-title":"The impact of the microbiome on immunity to vaccination in humans","volume":"28","author":"Olin","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.immuni.2014.08.009","article-title":"Tlr5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination","volume":"41","author":"Oh","year":"2014","journal-title":"Immunity"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1093\/infdis\/jiw518","article-title":"Significant correlation between the infant gut microbiome and rotavirus vaccine response in rural ghana","volume":"215","author":"Harris","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.cell.2019.08.010","article-title":"Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans","volume":"178","author":"Hagan","year":"2019","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/s41392-023-01445-0","article-title":"Gut microbiota as a potential key to modulating humoral immunogenicity of new platform covid-19 vaccines","volume":"8","author":"Seong","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41577-021-00554-7","article-title":"Modulation of immune responses to vaccination by the microbiota: Implications and potential mechanisms","volume":"22","author":"Lynn","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2189885","DOI":"10.1080\/21645515.2023.2189885","article-title":"The matrix-m\u2122 adjuvant: A critical component of vaccines for the 21st century","volume":"19","author":"Stertman","year":"2023","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_11","unstructured":"World Medical Association (1964). Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 187, 441\u2013444."},{"key":"ref_12","first-page":"11","article-title":"Optimal alignments in linear space","volume":"4","author":"Myers","year":"1988","journal-title":"Comput. Appl. Biosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1093\/bioinformatics\/btt403","article-title":"Nhmmer: DNA homology search with profile hmms","volume":"29","author":"Wheeler","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2584","DOI":"10.7717\/peerj.2584","article-title":"Vsearch: A versatile open source tool for metagenomics","volume":"4","author":"Rognes","year":"2016","journal-title":"PeerJ"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1099\/ijsem.0.001755","article-title":"Introducing ezbiocloud: A taxonomically united database of 16s rrna gene sequences and whole-genome assemblies","volume":"67","author":"Yoon","year":"2017","journal-title":"Int. J. Syst. Evol. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1093\/bioinformatics\/btr381","article-title":"Uchime improves sensitivity and speed of chimera detection","volume":"27","author":"Edgar","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1080\/01621459.1992.10475194","article-title":"Estimating the number of classes via sample coverage","volume":"87","author":"Chao","year":"1992","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2307\/2531532","article-title":"Estimating the population size for capture-recapture data with unequal catchability","volume":"43","author":"Chao","year":"1987","journal-title":"Biometrics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"927","DOI":"10.2307\/1936861","article-title":"Robust estimation of population size when capture probabilities vary among animals","volume":"60","author":"Burnham","year":"1979","journal-title":"Ecology"},{"key":"ref_20","unstructured":"Magurran, A.E. (2013). Measuring Biological Diversity, John Wiley & Sons."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1023\/A:1026096204727","article-title":"Nonparametric estimation of shannon\u2019s index of diversity when there are unseen species in sample","volume":"10","author":"Chao","year":"2003","journal-title":"Environ. Ecol. Stat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-3207(92)91201-3","article-title":"Conservation evaluation and phylogenetic diversity","volume":"61","author":"Faith","year":"1992","journal-title":"Biol. Conserv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1109\/18.61115","article-title":"Divergence measures based on the shannon entropy","volume":"37","author":"Lin","year":"1991","journal-title":"IEEE Trans. Inf. Theory"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2504(08)60168-3","article-title":"Bray-curtis ordination: An effective strategy for analysis of multivariate ecological data","volume":"14","author":"Beals","year":"1984","journal-title":"Adv. Ecol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1093\/bioinformatics\/bts342","article-title":"Associating microbiome composition with environmental covariates using generalized unifrac distances","volume":"28","author":"Chen","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ismej.2009.97","article-title":"Fast unifrac: Facilitating high-throughput phylogenetic analyses of microbial communities including analysis of pyrosequencing and phylochip data","volume":"4","author":"Hamady","year":"2010","journal-title":"ISME J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ye, Y., and Doak, T.G. (2009). A parsimony approach to biological pathway reconstruction\/inference for genomes and metagenomes. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000465"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/nbt.2676","article-title":"Predictive functional profiling of microbial communities using 16s rrna marker gene sequences","volume":"31","author":"Langille","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R60","DOI":"10.1186\/gb-2011-12-6-r60","article-title":"Metagenomic biomarker discovery and explanation","volume":"12","author":"Segata","year":"2011","journal-title":"Genome Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1038\/s41467-019-09884-6","article-title":"Bacteroides fragilis polysaccharide a induces il-10 secreting b and t cells that prevent viral encephalitis","volume":"10","author":"Ramakrishna","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e003334","DOI":"10.1136\/jitc-2021-003334","article-title":"Gut microbiome is associated with the clinical response to anti-pd-1 based immunotherapy in hepatobiliary cancers","volume":"9","author":"Mao","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2000036","DOI":"10.1002\/mnfr.202000036","article-title":"How microbial food fermentation supports a tolerant gut","volume":"65","author":"Jonas","year":"2021","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3920\/BM2020.0057","article-title":"Short chain fatty acids in human gut and metabolic health","volume":"11","author":"Ellen","year":"2020","journal-title":"Benef. Microbes"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Piero, P., Leonilde, B., Mirco, V., Maria De, A., Ilaria, F., Elisa, L., Mohamad, K., David, Q.H.W., Markus, S., and Agostino Di, C. (2022). Gut microbiota and short chain fatty acids: Implications in glucose homeostasis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031105"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2545421","DOI":"10.1080\/19490976.2025.2545421","article-title":"Commensal bacterial glycosylation at the interface of host-bacteria interactions","volume":"17","author":"Chao","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hou, Y., Li, J., and Ying, S. (2023). Tryptophan metabolism and gut microbiota: A novel regulatory axis integrating the microbiome, immunity, and cancer. Metabolites, 13.","DOI":"10.3390\/metabo13111166"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40168-023-01486-1","article-title":"Il-22 alters gut microbiota composition and function to increase aryl hydrocarbon receptor activity in mice and humans","volume":"11","author":"Mar","year":"2023","journal-title":"Microbiome"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Moyan, L., Max, N., Willem, M.d.V., and Elena, R. (2022). Microbial tryptophan metabolism tunes host immunity, metabolism, and extraintestinal disorders. Metabolites, 12.","DOI":"10.3390\/metabo12090834"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Su, X., Gao, Y., and Yang, R. (2022). Gut microbiota-derived tryptophan metabolites maintain gut and systemic homeostasis. Cells, 11.","DOI":"10.3390\/cells11152296"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/eji.202149401","article-title":"Tryptophan and the innate intestinal immunity: Crosstalk between metabolites, host innate immune cells, and microbiota","volume":"52","author":"Li","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, J., Zhu, N., Su, X., Gao, Y., and Yang, R. (2023). Gut-microbiota-derived metabolites maintain gut and systemic immune homeostasis. Cells, 12.","DOI":"10.3390\/cells12050793"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/s12276-023-01028-7","article-title":"Immune regulation through tryptophan metabolism","volume":"55","author":"Byungsuk","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16003","DOI":"10.1038\/npjbiofilms.2016.3","article-title":"The gut microbiota: A major player in the toxicity of environmental pollutants?","volume":"2","author":"Claus","year":"2016","journal-title":"Npj Biofilms Microbiomes"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Reimer, J.M., Karlsson, K.H., L\u00f6vgren-Bengtsson, K., Magnusson, S.E., Fuentes, A., and Stertman, L. (2012). Matrix-m\u2122 adjuvant induces local recruitment, activation and maturation of central immune cells in absence of antigen. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041451"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/12\/1248\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:12:19Z","timestamp":1765948339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/12\/1248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["vaccines13121248"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13121248","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2025,12,15]]}}}