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The historically used formalin\u2010inactivated KFD vaccine showed limited effectiveness in field studies, providing only about 62% protection. This moderate level of protection highlights the need for improved vaccines that offer higher efficacy and longer\u2010lasting immunity for populations living in endemic areas. A major challenge in vaccine development is the limited understanding of immune responses that protect against KFD, along with the lack of preclinical models that fully reflect the disease as it occurs in humans. Existing animal models\u2014including murine systems and limited non\u2010human primate studies \u2010have contributed to understanding viral replication, lethality, viraemia kinetics, and basic immunological responses. However, murine models often fail to reproduce the full spectrum of human immunopathology, particularly haemorrhagic manifestations and complex host immune responses, while non\u2010human primate models remain limited by cost, accessibility, and incomplete characterisation. Furthermore, variability in experimental endpoints and the absence of standardized immunogenicity and neutralisation assays restrict cross\u2010study comparability and hinder identification of immune correlates of protection. This review critically synthesises current knowledge on KFD animal models and host immune responses, identifying key gaps in translational relevance. We propose a prioritised roadmap that includes: (i) development and validation of advanced preclinical models that better mimic human disease progression and immune dysregulation; (ii) systematic\u00a0identification of serological and cellular correlates of protection; and (iii) standardisation of virological, serological, and immunological assays to support regulatory evaluation and vaccine benchmarking. Addressing these challenges through coordinated interdisciplinary efforts will accelerate the development of next\u2010generation KFD vaccines and therapeutics tailored to endemic populations.<\/jats:p>","DOI":"10.1002\/rmv.70177","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:42:42Z","timestamp":1781811762000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Kyasanur Forest Disease: Advances in Experimental Animal Models, Immune Assays, and Challenges in Vaccine Development"],"prefix":"10.1002","volume":"36","author":[{"given":"Sahina","family":"Sidhik","sequence":"first","affiliation":[{"name":"Centre for Immunobiology &amp; Immunotherapy Translational Health Science and Technology Institute NCR\u2010Biotech Science Cluster  Faridabad Haryana India"},{"name":"Institut Pasteur du Cambodge (Pasteur Network)  Phnom Penh Cambodia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7850-5672","authenticated-orcid":false,"given":"Zaigham Abbas","family":"Rizvi","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology &amp; Immunotherapy Translational Health Science and Technology Institute NCR\u2010Biotech Science Cluster  Faridabad Haryana India"},{"name":"Immunology Core Lab Translational Health Science and Technology Institute NCR\u2010Biotech Science Cluster  Faridabad Haryana India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Awasthi","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology &amp; Immunotherapy Translational Health Science and Technology Institute NCR\u2010Biotech Science Cluster  Faridabad Haryana India"},{"name":"Immunology Core Lab Translational Health Science and Technology Institute NCR\u2010Biotech Science Cluster  Faridabad Haryana India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.65228"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/ijph.2024.1606715"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.4103\/ijmr.IJMR_532_21"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1089\/vbz.2023.0040"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinpr.2024.100352"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0011300"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid1509.080759"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00149"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/0470058005.ch5"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/mve.12549"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1029\/2018GH000164"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40249\u2010015\u20100066\u20109"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10493\u2010018\u20100223\u20105"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10661\u2010024\u201012314\u2010w"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms8091406"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijregi.2024.02.002"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.20194"},{"issue":"4","key":"e_1_2_15_19_1","first-page":"272","article-title":"An Outbreak of Kyasanur Forest Disease in Kerala: A Clinico Epidemiological Study","volume":"3","author":"Chandran P.","year":"2016","journal-title":"Indian Journal of Forensic and Community Medicine"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035\u20109203(86)90390\u20101"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13104\u2010020\u201005137\u20108"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens2020402"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201067599\u2010x"},{"key":"e_1_2_15_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj1428"},{"key":"e_1_2_15_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009678"},{"key":"e_1_2_15_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3311"},{"key":"e_1_2_15_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines8010039"},{"key":"e_1_2_15_28_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2018.0105"},{"key":"e_1_2_15_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11071871"},{"key":"e_1_2_15_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/v9050097"},{"key":"e_1_2_15_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.495"},{"key":"e_1_2_15_32_1","first-page":"701","article-title":"Experimental Transmission of Kyasanur Forest Disease Virus by Dermacentor Auratus Supino","volume":"69","author":"Sreenivasan M. 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