{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:45:55Z","timestamp":1776746755525,"version":"3.51.2"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"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. Med."],"abstract":"<jats:p>The continuous evolution of SARS-CoV-2 poses a significant challenge to existing immune barriers, highlighting the limitations of single-modality immunization. Hybrid immunity, shaped by the combination of natural infection and vaccination, induces more potent, broad-spectrum, and durable protective immunity. This review proposes that heterologous vaccination \u2013 the sequential use of vaccines based on different technological platforms \u2013 can serve as an active public health strategy to simulate and optimize hybrid immunity. We systematically elaborate on the synergistic advantages of hybrid immunity at both the humoral and cellular levels, citing evidence from multiple clinical trials that for both convalescent individuals and infection-na\u00efve populations, heterologous vaccination regimens outperform homologous regimens in enhancing the breadth of neutralizing antibodies, strengthening cross-protection, and establishing robust immune memory. By mimicking the antigenic distance effect, heterologous vaccination safely replicates the immunological benefits of natural infection without the associated risks, positioning it as a key strategic tool to counter persistent viral evolution and build a resilient population-wide immune barrier.<\/jats:p>","DOI":"10.3389\/fmed.2026.1828887","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:22:10Z","timestamp":1776745330000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hybrid immunity strategies: heterologous vaccination combined with natural SARS-CoV-2 infection"],"prefix":"10.3389","volume":"13","author":[{"given":"Yuan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Public Health, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Public Health, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruixia","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Public Health, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Public Health, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Public Health, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Public Health, Gansu University of Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Gansu Provincial Hospital","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dehong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion, Gansu Provincial Hospital","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/s41586-021-04389-z","article-title":"Considerable escape of SARS-CoV-2 omicron to antibody 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