{"doi":"10.1101/2025.03.24.25324570","title":"Strain- and vaccine-specific effects of serum antibodies in the protection of intestinal SARS-CoV-2 infection","abstract":"Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a public health challenge worldwide. The gastrointestinal tract has emerged as an important site of infection and has been implicated as a reservoir for long-term infection, particularly for post-acute COVID-19 syndrome. However, whether vaccine-induced systemic antibodies can prevent intestinal infection with SARS-CoV-2 is unclear. Compared to Vero cells commonly used to assess SARS-CoV-2 neutralization, the intestinal epithelium has a functional interferon response and expresses higher levels of ACE2, enzymes, and antibody-binding Fc receptors that may impact SARS-CoV-2 immune elimination. Methods: We evaluated the potential of antibodies from both naturally infected and vaccinated human subjects to inhibit SARS-CoV-2 infection of the intestinal epithelium. Serum samples were collected from human volunteers who had undergone natural infection with SARS-CoV-2 in 2020 (n=5) or who had received the Pfizer BNT162b2 COVID-19 vaccine (n=13). Banked sera collected in 2016 served as negative controls (n=2). SARS-CoV-2 (WA01, Delta or Omicron) was pre-treated with sera and then used to infect iPSC-derived human intestinal organoids (HIO) or Caco-2 colonic epithelial cells, and SARS-CoV-2 infection was quantified by plaque assay, PCR, or immunofluorescence (IF) after 48-96 h. Results: Both HIOs and Caco-2 cells supported robust infection with SARS-CoV-2. In HIOs, pretreatment of SARS-CoV-2 with a high titer post-vaccine serum completely blocked replication of WA01. Similarly, sera from both naturally infected donors collected in 2020 and sera from individuals who had received a BNT162b2 vaccine significantly inhibited replication of the WA01 strain in Caco-2 cells. In contrast, none of the sera significantly inhibited infection with the Delta variant of SARS-CoV-2. For Omicron, only sera from individuals who had received an Omicron-based vaccine significantly inhibited infection with SARS-CoV-2 in the plaque assay. Across all virus types, sera from individuals who had received Omicron-based BNT162b2 boosters were the most effective at reducing infection in Caco-2 cells. Conclusion: Our results suggest that vaccine-induced antibody responses to SARS-CoV-2 are protective in the gut. Our study also supports previous reports indicating that SARS-CoV-2 vaccines need to be adapted to circulating virus strains to convey full protection from infection.","journal":"medRxiv","year":2025,"id":563519,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":527323,"name":"Deann T. Snyder","orcid":"0000-0003-3087-7260","position":1,"is_corresponding":false},{"id":657451,"name":"Barkan Sidar","orcid":"0000-0002-8499-9119","position":2,"is_corresponding":false},{"id":947253,"name":"Karlin Blackwell","orcid":"0000-0002-4711-7842","position":3,"is_corresponding":false},{"id":1466198,"name":"Brittany R. Jenkins","orcid":"0000-0002-3660-5920","position":4,"is_corresponding":false},{"id":269773,"name":"Sha Huang","orcid":"0000-0002-3587-4045","position":5,"is_corresponding":false},{"id":573128,"name":"Thomas A. Sebrell","orcid":null,"position":6,"is_corresponding":false},{"id":527322,"name":"Jodi F. Hedges","orcid":"0000-0002-7461-3972","position":7,"is_corresponding":false},{"id":28520,"name":"Jason R. Spence","orcid":"0000-0001-7869-3992","position":8,"is_corresponding":false},{"id":559570,"name":"Connie B. Chang","orcid":"0000-0001-9555-8223","position":9,"is_corresponding":false},{"id":657453,"name":"James N. Wilking","orcid":"0000-0002-7255-7209","position":10,"is_corresponding":false},{"id":498168,"name":"Seth T. Walk","orcid":"0000-0001-6891-8537","position":11,"is_corresponding":false},{"id":527324,"name":"Mark A. Jutila","orcid":"0000-0002-4120-1349","position":12,"is_corresponding":false},{"id":559567,"name":"Emma K. Loveday","orcid":"0000-0002-1154-7728","position":13,"is_corresponding":false},{"id":412132,"name":"Diane Bimczok","orcid":"0000-0002-8817-7243","position":14,"is_corresponding":false},{"id":502472,"name":"Michelle D. Cherne","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:13.374766Z","pmid":"40196264","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}