Advancing chikungunya vaccine development through regulatory science

Abstract

The escalating global spread of chikungunya virus, exemplified by the 2025 local outbreak in Guangdong Province, China, underscores the urgent need for effective vaccination strategies. This paper discusses advancements in chikungunya vaccine development through the lens of regulatory science. We reviewed recent progress in vaccine platforms, including the live-attenuated IXCHIQ^® and VLP-based Vimkunya^®, as well as the emerging mRNA candidates, highlighting their immunogenicity and safety profiles. We further addressed unique challenges in chikungunya vaccine development, such as viral genetic diversity, intermittent outbreaks, and ethical and practical barriers to conducting traditional efficacy trials. To overcome these, we proposed innovative regulatory strategies to accelerate approval, including: (1) surrogate endpoints based on neutralizing antibodies supported by animal challenge models; (2) streamlined chemistry, manufacturing, and controls and nonclinical/ clinical study requirements through platform technology leveraging; and (3) integrated lifecycle risk management with enhanced postmarketing surveillance. Drawing on experience with platform-based vaccine regulation, we emphasize the importance of regulatory agility, international collaboration, and science-driven policy to facilitate the rapid development and deployment of safe, effective, and broadly protective chikungunya vaccines against future arbovirus threats.

Keywords

Chikungunya vaccine / Regulatory science / Platform technology / Accelerated approval / Lifecycle risk management

Conflict of interest statement

No potential conflicts of interest are reported by the authors. The views expressed in this article are the personal views of the authors and might not reflect the position of the regulatory authorities.

Data availability statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Funding

This study was supported by State Key Laboratory of Drug Regulatory Science Foundation grant (Grant No GZNL2025A01001).

Authors’ contributions

X.L. and X.Z. drafted the manuscript, edited a summary of the legal and regulatory frameworks, S.G., S.G., Y.P., M.X. and Q.Z. commented and assisted in manuscript refinement, and T.W., M.L. supervised this paper. All authors have read and agreed to the published version of the manuscript.

Publisher’s note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Edited by Zhang Q, Lei Y, Pan Y

Acknowledgments

We express our sincere gratitude to all departments of the Center for Drug Evaluation, National Medical Products Administration for their invaluable support.

References

[1] Chang AY, Encinales L, Porras A, Pacheco N, Reid SP, Martins KAO, et al. Frequency of chronic joint pain following chikungunya virus infection: A Colombian cohort study. Arthritis Rheumatol 2018; 70(4): 578-584. doi: 10.1002/art.40384.

[2] Tritsch SR, Encinales L, Pacheco N, Cadena A, Cure C, McMahon E, et al. Chronic joint pain 3 years after chikungunya virus infection largely characterized by relapsing-remitting symptoms. J Rheumatol 2020; 47(8): 1267-1274. doi: 10.3899/jrheum.190162.

[3] De Roo AM, Vondeling GT, Boer M, Murray K, Postma MJ. The global health and economic burden of chikungunya from 2011 to 2020: A model-driven analysis on the impact of an emerging vector-borne disease. BMJ Glob Health 2024; 9(12): e016648. doi: 10.1136/bmjgh-2024-016648.

[4] Huerta Albarrán R, Weber A, Avilés Robles M, Appendino JP. Chikungunya virus infection: A scoping review highlighting pediatric systemic and neurologic complications. Semin Pediatr Neurol 2025; 54: 101213. doi: 10.1016/j.spen.2025.101213.

[5] Maure C, Khazhidinov K, Kang H, Auzenbergs M, Moyersoen P, Abbas K, et al. Chikungunya vaccine development, challenges, and pathway toward public health impact. Vaccine 2024; 42(26): 126483. doi: 10.1016/j.vaccine.2024.126483.

[6] Montalvo Zurbia-Flores G, Reyes-Sandoval A, Kim YC. Chikungunya virus: Priority pathogen or passing trend. Vaccines (Basel) 2023; 11(3): 568. doi: 10.3390/vaccines11030568.

[7] Guangdong Provincial Center for Disease Control and Prevention. Chikungunya fever prevention. [Online]. Available from: https://cdcp.gd.gov.cn/ywdt/zdzt/yfjkkyr/. [Accessed on 31 January 2026].

[8] Liu Q, Shen H, Gu L, Yuan H, Zhu W. Chikungunya virus in Europe: A retrospective epidemiology study from 2007 to 2023. PLoS Negl Trop Dis 2025; 19(3): e0012904. doi: 10.1371/journal.pntd.0012904.

[9] World Health Organization. Chikungunya virus disease-global situation. 2025. [Online]. Available from: https://www.who.int/emergencies/disease-outbreak-news/item/2025-DON581. [Accessed on 31 January 2026].

[10] Shaikh MS, Faiyazuddin M, Khan MS, Pathan SK, Syed IJ, Gholap AD, et al. Chikungunya virus vaccine: A decade of progress solving epidemiological dilemma, emerging concepts, and immunological interventions. Front Microbiol 2024; 15: 1413250. doi: 10.3389/fmicb.2024.1413250.

[11] Weaver SC, Osorio JE, Livengood JA, Chen R, Stinchcomb DT. Chikungunya virus and prospects for a vaccine. Expert Rev Vaccines 2012; 11(9): 1087-1101. doi: 10.1586/erv.12.84.

[12] World Health Organization. Generating high-quality evidence on existing vaccines for chikungunya in response to outbreaks. 2025. [Online]. Available from: https://www.who.int/news-room/events/detail/2025/04/08/default-calendar/generating-high-quality-evidence-on-existing-vaccines-for-chikungunya-in-response-to-outbreaks. [Accessed on 23 September 2025].

[13] Li X, Jin S, Guo S, Yang D, Sai W, Qiu X, et al. Platform technology in global vaccine regulation: Development, applications, and regulatory strategies with insights from China. Vaccines (Basel) 2024; 12(12): 1436. doi: 10.3390/vaccines12121436.

[14] Jiang S, Li H, Zhang L, Mu W, Zhang Y, Chen T, et al. Generic diagramming platform (GDP): A comprehensive database of high-quality biomedical graphics. Nucleic Acids Res 2025; 53(D1): D1670-D1676. doi: 10.1093/nar/gkae973.

[15] De Souza WM, Lecuit M, Weaver SC. Chikungunya virus and other emerging arthritogenic alphaviruses. Nat Rev Microbiol 2025; 23(9): 585601. doi: 10.1038/s41579-025-01177-8.

[16] Krambrich J, Mihali F, Gaunt MW, Bohlin J, Hesson JC, Lundkvist A, et al. The evolutionary and molecular history of a chikungunya virus outbreak lineage. PLoS Negl Trop Dis 2024; 18(7): e0012349. doi: 10.1371/journal.pntd.0012349.

[17] Rama K, De Roo AM, Louwsma T, Hofstra HS, Gurgel do Amaral GS, Vondeling GT, et al. Clinical outcomes of chikungunya: A systematic literature review and meta-analysis. PLoS Negl Trop Dis 2024; 18(6): e0012254. doi: 10.1371/journal.pntd.0012254.

[18] Oliveira Lima JP, Alexandre Roberto CH, Nunes da Rocha M, Moreira de Oliveira V, Freire RM, Santos-Oliveira R, et al. Phenol and chromone compounds for in silico inhibition of nsP2 and nsP3 of chikungunya virus. Pharm Sci Adv 2025; 3(1): 100084. doi: 10.1016/j.pscia.2025.100084.

[19] Song H, Zhao Z, Chai Y, Jin X, Li C, Yuan F, et al. Molecular basis of arthritogenic alphavirus receptor MXRA8 binding to chikungunya virus envelope protein. Cell 2019; 177(7): 1714-1724.e12. doi: 10.1016/j.cell.2019.04.008.

[20] Lucas CJ, Sheridan RM, Reynoso GV, Davenport BJ, McCarthy MK, Martin A, et al. Chikungunya virus infection disrupts lymph node lymphatic endothelial cell composition and function via MARCO. JCI Insight 2024; 9(4): e168917. doi: 10.1172/jci.insight.168917.

[21] Liu Y, Wang J, Han Y, Xia X, Zeng R, Fan X, et al. Cryo-EM reveals a double oligomeric ring scaffold of the CHIKV nsP3 peptide in complex with the NTF2L domain of host G3BP1. mBio 2025; 16(5): e0396724. doi: 10.1128/mbio.03967-24.

[22] Lin D, Tang C, Wang J, Yang Y, Yang H, Zhou Y, et al. Multiorgan proteomic analysis of infected animal models predict potential host factors for chikungunya virus. MedComm (2020) 2025; 6(1): e70013. doi: 10.1002/mco2.70013.

[23] Jin J, Liss NM, Chen DH, Liao M, Fox JM, Shimak RM, et al. Neutralizing monoclonal antibodies block chikungunya virus entry and release by targeting an epitope critical to viral pathogenesis. Cell Rep 2015; 13(11): 2553-2564. doi: 10.1016/j.celrep.2015.11.043.

[24] Kosulin K, Brasel TL, Smith J, Torres M, Bitzer A, Dubischar K, et al. Cross-neutralizing activity of the chikungunya vaccine VLA1553 against three prevalent chikungunya lineages. Emerg Microbes Infect 2025; 14(1): 2469653. doi: 10.1080/22221751.2025.2469653.

[25] Ahola T, Merits A. Functions of chikungunya virus nonstructural proteins. In: Okeoma CM, ed. Chikungunya virus: Advances in biology, pathogenesis, and treatment. Cham: Springer; 2016, p. 75-98. doi: 10.1007/978-3-319-42958-8_6.

[26] Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, Das T, Li-Pat-Yuen G, Dassa B, et al. Persistent chronic inflammation and infection by chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol 2010; 184(10): 5914-5927. doi: 10.4049/jimmunol.0900255.

[27] Schneider M, Narciso-Abraham M, Hadl S, McMahon R, Toepfer S, Fuchs U, et al. Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: A double-blind, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2023; 401(10394): 2138-2147. doi: 10.1016/S0140-6736(23)00797-0.

[28] World Health Organization. Global vector control response 20172030. [Online]. Available from: https://www.who.int/publications/i/item/9789241512978. [Accessed on 8 September 2025].

[29] World Health Organization. Global arbovirus initiative: Preparing for the next pandemic by tackling mosquito-borne viruses with epidemic and pandemic potential. 2024. [Online]. Available from: https://www.who.int/publications/i/item/9789240088948. [Accessed on 8 September 2025].

[30] World Health Organization. Global strategic preparedness, readiness and response plan for dengue and other Aedes-borne arboviruses. 2024. [Online]. Available from: https://www.who.int/singapore/news/detail-global/03-10-2024-who-launches-global-strategic-plan-to-fight-rising-dengue-and-other-aedes-borne-arboviral-diseases. [Accessed on 8 September 2025].

[31] Bartholomeeusen K, Daniel M, LaBeaud DA, Gasque P, Peeling RW, Stephenson KE, et al. Chikungunya fever. Nat Rev Dis Primers 2023; 9(1): 17. doi: 10.1038/s41572-023-00429-2.

[32] U . S. Food and Drug Administration. Approval letter-IXCHIQ (chikungunya vaccine, live) 2023. [Online]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-vaccine-prevent-disease-caused-chikungunya-virus. [Accessed on 11 August 2025].

[33] European Medicines Agency. Ixchiq: EPAR-public assessment report. 2024. [Online]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/ixchiq-epar-public-assessment-report_en.pdf. [Accessed on 26 January 2026].

[34] European Medicines Agency. Ixchiq-H-C-005797-II-0001: EPAR assessment report-variation (extension of indication). 2025. [Online]. Available from: https://www.ema.europa.eu/en/documents/variation-report/ixchiq-h-c-005797-ii-0001-epar-assessment-report-variation_en.pdf. [Accessed on 25 January 2026].

[35] U . S. Food and Drug Administration. FDA update on the safety of IXCHIQ (chikungunya vaccine, live) 2025. [Online]. Available from: https://www.drugoffice.gov.hk/eps/upload/eps_news/55872/GB/1/News%20Bulletin%207%20Aug%202025%20(Ixchiq).pdf. [Accessed on 7 August 2025].

[36] U . S. Food and Drug Administration. FDA suspends IXCHIQ biologics license 2025. [Online]. Available from: https://www.fda.gov/safety/medical-product-safety-information/fda-update-safety-ixchiq-chikungunya-vaccine-live-fda-suspends-biologics-license-fda-safety. [Accessed on 25 August 2025].

[37] European Medicines Agency. EMA starts review of IXCHIQ live attenuated chikungunya vaccine. 2025. [Online]. Available from: https://www.ema.europa.eu/en/news/ema-starts-review-ixchiq-live-attenuated-chikungunya-vaccine. [Accessed on 25 January 2026].

[38] European Medicines Agency. IXCHIQ: Temporary restriction on vaccinating people 65 years and older to be lifted. 2025. [Online]. Available from: https://www.ema.europa.eu/en/news/ixchiq-temporary-restriction-vaccinating-people-65-years-older-be-lifted. [Accessed on 25 January 2026].

[39] U . S. Food and Drug Administration. Approval letter-Vimkunya (chikungunya vaccine, recombinant, virus-like particle) 2025. [Online]. Available from: https://www.fda.gov/media/185478/download. [Accessed on 11 August 2025].

[40] European Medicines Agency. European public assessment report-Vimkunya (chikungunya vaccine, recombinant, virus-like particle). 2025. [Online]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/vimkunya. [Accessed on 11 August 2025].

[41] Shaw CA, August A, Bart S, Jackson Booth PG, Knightly C, Brasel T, et al. A phase 1, randomized, placebo-controlled, dose-ranging study to evaluate the safety and immunogenicity of an mRNA-based chikungunya virus vaccine in healthy adults. Vaccine 2023; 41(26): 3898-3906. doi: 10.1016/j. vaccine 2023.04.064.

[42] Liang X, Zhou Y, Yang Y, Li Q, Wang J, Li B, et al. CHIKV mRNA vaccines encoding conserved structural/envelope proteins confer broad cross-lineage protection against infection. Signal Transduet Target Ther 2025; 10(1): 98. doi: 10.1038/s41392-025-02182-2.

[43] Schmitz KS, Comvalius AD, Nieuwkoop NJ, Geers D, Weiskopf D, Ramsauer K, et al. A measles virus-based vaccine induces robust chikungunya virus-specific CD4⁺ T-cell responses in a phase II clinical trial. Vaccine 2023; 41(43): 6495-6504. doi: 10.1016/j.vaccine.2023.09.022.

[44] Folegatti PM, Harrison K, Preciado-Llanes L, Ramos Lopez F, Bittaye M, Kim YC, et al. A single dose of ChAdOx1 Chik vaccine induces neutralizing antibodies against four chikungunya virus lineages in a phase 1 clinical trial. Nat Commun 2021; 12(1): 4636. doi: 10.1038/s41467-021-24906-y.

[45] García-Arriaza J, Cepeda V, Hallengård D, Sorzano CÓS, Kümmerer BM, Liljestrom P, et al. A novel poxvirus-based vaccine, MVA-CHIKV, is highly immunogenic and protects mice against chikungunya infection. J Virol 2014; 88(6): 3527-3547. doi: 10.1128/JVI.03418-13.

[46] World Health Organization. Strategic advisory group of experts on immunization (SAGE) working group on chikungunya vaccines. 2025. [Online]. Available from: https://www.who.int/groups/strategic-advisory-group-of-experts-on-immunization/working-groups/chikungunya. [Accessed on 8 September 2025].

[47] Ghattas M, Dwivedi G, Lavertu M, Alameh MG. Vaccine technologies and platforms for infectious diseases: Current progress, challenges, and opportunities. Vaccines (Basel) 2021; 9(12): 1490. doi: 10.3390/vaccines9121490.

[48] Li YD, Chi WY, Su JH, Ferrall L, Hung CF, Wu TC. Coronavirus vaccine development: From SARS and MERS to COVID-19. J Biomed Sci 2020; 27(1): 104. doi: 10.1186/s12929-020-00695-2.

[49] U . S. Food and Drug Administration. Code of federal regulations, Title 21, Part 601, Subpart E-Accelerated approval of biologics 2023. [Online]. Available from: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-601/subpart-E. [Accessed on 8 September 2025].

[50] Cherian N, Bettis A, Deol A, Kumar A, Di Fabio JL, Chaudhari A, et al. Strategic considerations on developing a CHIKV vaccine and ensuring equitable access for countries in need. NPJ Vaccines 2023; 8(1): 123. doi: 10.1038/s41541-023-00722-x.

[51] Rao S, Erku D, Mahalingam S, Taylor A. Immunogenicity, safety and duration of protection afforded by chikungunya virus vaccines undergoing human clinical trials. J Gen Virol 2024; 105: 001965. doi: 10.1099/jgv.0.001965.

[52] U . S. Food and Drug Administration; Centers for Disease Control and Prevention. FDA and CDC recommend a pause in use of IXCHIQ in individuals 60 years of age and older 2025. [Online]. Available from: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-and-cdc-recommend-pause-use-ixchiq-chikungunya-vaccine-live-individuals-60-years-age-and-older. [Accessed on 23 September 2025].

[53] Richardson JS, Anderson DM, Mendy J, Tindale LC, Muhammad S, Loreth T, et al. Chikungunya virus virus-like particle vaccine safety and immunogenicity in adolescents and adults in the USA: A phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2025; 405(10487): 1343-1352. doi: 10.1016/S0140-6736(25)00345-9.

[54] Freedman DO. A new non-live chikungunya vaccine for travellers. J Travel Med 2025; 32(5): taaf039. doi: 10.1093/jtm/taaf039.

[55] World Health Organization. Considerations for the design of clinical trials of vaccines for epidemic and pandemic diseases. 2017. [Online]. Available from: https://www.who.int/docs/default-source/blue-print/working-group-for-vaccine-evaluation-(4th-consultation)/ap1-guidelines-online-consultation. [Accessed on 28 August 2025].

[56] Hills SL, Sutter RA, Miller ER, Asturias EJ, Chen LH, Bell BP, et al. Surveillance for adverse events following use of live-attenuated chikungunya vaccine, United States, 2024, and the associated public health response in 2024 and 2025. Euro Surveill 2025; 30(32): 2500543. doi: 10.2807/1560-7917.ES.2025.30.32.2500543.

[57] Prasad V, Kaslow DC, Yang S. Pausing chikungunya vaccination and accelerated approval. JAMA 2025; 334(5): 385-386. doi: 10.1001/jama.2025.9393.

[58] Prasad V, Makary MA. US FDA safety labeling change for mRNA COVID-19 vaccines. JAMA 2025; 334(11): 945-946. doi: 10.1001/jama.2025.12675.

[59] Zhang K, Yang X, Wang Y, Yu Y, Huang N, Li G, et al. Artificial intelligence in drug development. Nat Med 2025; 31(1): 45-59. doi: 10.1038/s41591-024-03434-4.

[60] Mapalagamage M, Weiskopf D, Sette A, De Silva AD. Current understanding of the role of T cells in chikungunya, dengue and zika infections. Viruses 2022; 14(2): 242. doi: 10.3390/v14020242.

[61] May M. How mRNA is powering a personalized vaccine revolution. Nat Med 2024; 30(8): 2097-2098. doi: 10.1038/d41591-024-00052-y.

[62] Chen LH, Fritzer A, Hochreiter R, Dubischar K, Meyer S. From bench to clinic: The development of VLA1553/IXCHIQ, a live-attenuated chikungunya vaccine. J Travel Med 2024; 31(7): taae123. doi: 10.1093/jtm/taae123.