Vaccines Against Flaviviruses and Alphaviruses: Recent Advances and Future Challenges—2nd Edition

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines Against Tropical and Other Infectious Diseases".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 18185

Special Issue Editors


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Guest Editor
Instituto Politécnico Nacional (IPN), Av. Luis Enrique Erro s/n, Unidad Adolfo López Mateos, Mexico City 07738, Mexico
Interests: plasmodium vivax; pre-erythrocytic malaria vaccines; flavivirus vaccines; alphavirus-based vaccines; zika vaccines; dengue vaccines; chikungunya vaccines; VLP; recombinant viral vectors; chimpanzee adenovirus (ChAdOx); MVA
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Centre for Human Genetics, Division of Structural Biology, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2. Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford OX3 7LE, UK
Interests: alphaviruses; flaviviruses; bacteria; vaccines; diagnostics; immunology; immunoassays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mosquito-borne viruses, such as Dengue (DENV), Zika (ZIKV), and Chikungunya (CHIKV) viruses, have emerged in recent decades, affecting millions of people worldwide. These flaviviruses and alphaviruses can be classified into a broader category of arboviruses, and they cause significant disease burdens and public health concerns. Vaccine development against arboviruses has experienced swift progress after the sudden (re)emergence of cases of DENV, CHIKV, and ZIKV in the last two decades. A wide range of vaccine platforms, including both classical and new approaches, such as inactivated and attenuated, proteins, virus-like particles (VLPs), viral vectors, DNA, and mRNA, are currently being tested in preclinical studies and in clinical trials, which could lead to the future licensing of vaccines against these arboviruses.

This Special Issue is based on vaccines against flaviviruses and alphaviruses of medical importance in humans, with particular focus on the design, development, and validation of new vaccine candidates and animal models. We welcome the submission of all types of articles, including short reports, original research, and reviews for this Special Issue. We look forward to receiving your contributions.

Dr. Arturo Reyes-Sandoval
Dr. Young Chan Kim
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vaccine
  • arbovirus
  • flavivirus
  • alphavirus
  • vaccines
  • preclinical
  • animal model
  • challenge studies
  • clinical trials

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Related Special Issues

Published Papers (8 papers)

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Editorial

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2 pages, 136 KB  
Editorial
Recent Advances in Vaccine Development for Flaviviruses and Alphaviruses
by Young Chan Kim and Arturo Reyes-Sandoval
Vaccines 2025, 13(8), 808; https://doi.org/10.3390/vaccines13080808 - 30 Jul 2025
Cited by 1 | Viewed by 1586
Abstract
Mosquito-borne viruses such as dengue (DENV), yellow fever (YFV), Zika (ZIKV), and chikungunya (CHIKV) have re-emerged in recent decades, affecting millions of people worldwide [...] Full article

Research

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20 pages, 1417 KB  
Article
Rational Design of a Chimpanzee Adenoviral-Vector Vaccine Against Yellow Fever Through the Modification of Antigen Transmembrane Domains
by Marta Ulaszewska, Ji Ma, Susan J. Morris, Sophie M. Jegouic Goodall, Winnie Kerstens, Hendrik Jan Thibaut, Lotte Coelmont, Kai Dallmeier, Sarah C. Gilbert and Barbara Dema
Vaccines 2026, 14(3), 273; https://doi.org/10.3390/vaccines14030273 - 20 Mar 2026
Viewed by 656
Abstract
Background/Objectives: Chimpanzee adenoviral-vectored vaccines have proven to be both safe and effective, with a manufacturing and distribution pipeline capable of rapid global supply, as demonstrated during the COVID-19 pandemic. Yellow fever is a mosquito-borne viral hemorrhagic disease endemic in parts of Africa [...] Read more.
Background/Objectives: Chimpanzee adenoviral-vectored vaccines have proven to be both safe and effective, with a manufacturing and distribution pipeline capable of rapid global supply, as demonstrated during the COVID-19 pandemic. Yellow fever is a mosquito-borne viral hemorrhagic disease endemic in parts of Africa and Latin America, and although an effective live attenuated vaccine exists, its use is limited by safety and eligibility restrictions. Moreover, large outbreaks continue to expose critical challenges, such as an insufficient vaccine supply, reliance on fractional dosing, and slow and difficult-to-scale manufacturing processes. Here, we report the design, development and in vivo immunogenicity of multiple yellow fever virus (YFV) antigen constructs based on the pre-membrane (prM) and envelope (E) proteins—with or without the transmembrane domain (TM or ΔTM)—delivered using the ChAdOx1 adenoviral vector. Methods: Four ChAdOx1 YF vaccines were developed, and immunogenicity was evaluated. The efficacy of the full-length YF envelope vaccine was also tested in Balb/c mice. Results/Conclusions: In contrast to previously described orthoflavivirus vaccines on the same platform, the full-length antigen elicited superior immunogenicity and conferred protection against intracranial challenge with the YF17D virus in mice. Notably, this protection was comparable to that induced by the licensed YF17D vaccine, highlighting the promise of this platform as a next-generation yellow fever vaccine candidate. Full article
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30 pages, 1958 KB  
Article
CD4+ T Cells Are Key to Shaping a Protective Humoral Immunity in Primary Dengue 2 Virus Infection: Implications for Rational Vaccine Design
by Angel E. Miranda-Santiago, Crisanta Serrano-Collazo, Lorna A. Cruz, Sandra Henein, Laura Alvarez, Teresa Arana, Jorge L. Sánchez-Bibiloni, Melween I. Martinez, Chiara Roman, Armando G. Burgos, Marcos J. Ramos-Benitez, Lourdes M. Caro-Rivera, James D. Brien, Amelia K. Pinto, Aravinda M. de Silva and Carlos A. Sariol
Vaccines 2025, 13(11), 1103; https://doi.org/10.3390/vaccines13111103 - 29 Oct 2025
Viewed by 1360
Abstract
Background: Understanding the immune mechanisms that differentiate protective from pathogenic responses during dengue virus (DENV) infection is critical for effective vaccine development. Objective: To investigate how CD4+ T cell depletion alters viral control and the humoral immune response during primary DENV2 infection [...] Read more.
Background: Understanding the immune mechanisms that differentiate protective from pathogenic responses during dengue virus (DENV) infection is critical for effective vaccine development. Objective: To investigate how CD4+ T cell depletion alters viral control and the humoral immune response during primary DENV2 infection in a non-human primate (NHP) model. Methods: Rhesus macaques were depleted of CD4+ T cells prior to DENV2 infection. Viral kinetics, B cell activation, antibody specificity, and functional outcomes were evaluated longitudinally, including cross-reactivity and antibody-dependent enhancement (ADE) potential. Results: CD4+ T cells were essential for early viral clearance and the generation of robust, type-specific neutralizing antibodies. In their absence, animals exhibited early non-specific polyclonal B cell activation, delayed isotype switching, and an expanded repertoire of cross-reactive antibodies to DENV and Zika virus (ZIKV), with diminished neutralizing capacity. CD4-depleted macaques also showed increased ADE potential, particularly against ZIKV, and elevated anti-NS1 IgG titers that persisted one-year post-infection. Conclusion: CD4+ T cells play a critical role in orchestrating effective, durable, and type-specific antibody responses during primary DENV infection. Their absence leads to delayed antibody maturation, greater cross-reactivity, and higher ADE potential. These findings emphasize the need for DENV and ZIKV vaccines to include CD4+ T cell epitopes that promote high-quality, type-specific antibody responses and minimize ADE risk. Full article
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26 pages, 3044 KB  
Article
Optimization of YF17D-Vectored Zika Vaccine Production by Employing Small-Molecule Viral Sensitizers to Enhance Yields
by Sven Göbel, Tilia Zinnecker, Ingo Jordan, Volker Sandig, Andrea Vervoort, Jondavid de Jong, Jean-Simon Diallo, Peter Satzer, Manfred Satzer, Kai Dallmeier, Udo Reichl and Yvonne Genzel
Vaccines 2025, 13(7), 757; https://doi.org/10.3390/vaccines13070757 - 16 Jul 2025
Cited by 1 | Viewed by 2544
Abstract
Background: Modern viral vector production needs to consider process intensification for higher yields from smaller production volumes. However, innate antiviral immunity triggered in the producer cell may limit virus replication. While commonly used cell lines (e.g., Vero or E1A-immortalised cells) are already compromised [...] Read more.
Background: Modern viral vector production needs to consider process intensification for higher yields from smaller production volumes. However, innate antiviral immunity triggered in the producer cell may limit virus replication. While commonly used cell lines (e.g., Vero or E1A-immortalised cells) are already compromised in antiviral pathways, the redundancy of innate signaling complicates host cell optimization by genetic engineering. Small molecules that are hypothesized to target antiviral pathways (Viral Sensitizers, VSEs) added to the culture media offer a versatile alternative to genetic modifications to increase permissiveness and, thus, viral yields across multiple cell lines. Methods: To explore how the yield for a chimeric Zika vaccine candidate (YF-ZIK) could be further be increased in an intensified bioprocess, we used spin tubes or an Ambr15 high-throughput microbioreactor system as scale-down models to optimize the dosing for eight VSEs in three host cell lines (AGE1.CR.pIX, BHK-21, and HEK293-F) based on their tolerability. Results: Addition of VSEs to an already optimized infection process significantly increased infectious titers by up to sevenfold for all three cell lines tested. The development of multi-component VSE formulations using a design of experiments approach allowed further synergistic titer increases in AGE1.CR.pIX cells. Scale-up to 1 L stirred-tank bioreactors and 3D-printed mimics of 200 or 2000 L reactors resulted in up to threefold and eightfold increases, respectively. Conclusions: Addition of single VSEs or combinations thereof allowed a further increase in YF-ZIK titers beyond the yield of an already optimized, highly intensified process. The described approach validates the use of VSEs and can be instructive for optimizing other virus production processes. Full article
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Review

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34 pages, 1577 KB  
Review
The Yellow Fever Vaccine Journey: Milestones and Future Directions
by Shriyansh Srivastava, Nandani Jayaswal, Pranav Gupta, Sathvik Belagodu Sridhar, Pooja Jaiswal, Mohd. Tariq, G. S. N. Koteswara Rao, Aroop Mohanty, Sanjit Sah, Rachana Mehta, Juan Pablo Hernández-Ovalle, Jaime D. Acosta-España, Lysien Zambrano and Alfonso J. Rodriguez-Morales
Vaccines 2026, 14(1), 65; https://doi.org/10.3390/vaccines14010065 - 5 Jan 2026
Cited by 6 | Viewed by 3513
Abstract
Yellow fever, a mosquito-borne viral hemorrhagic disease, remains a significant public health concern in endemic regions of Africa and South America. The development of the yellow fever vaccine marked a milestone in virology and immunization. In the 1930s, Max Theiler created the 17D [...] Read more.
Yellow fever, a mosquito-borne viral hemorrhagic disease, remains a significant public health concern in endemic regions of Africa and South America. The development of the yellow fever vaccine marked a milestone in virology and immunization. In the 1930s, Max Theiler created the 17D live-attenuated vaccine, a breakthrough that has achieved global recognition and continues to underpin prevention strategies. This review outlines the historical evolution of the yellow fever vaccine, highlighting pivotal scientific advances, technological innovations, and global eradication initiatives. It examines the current landscape of immunization, focusing on the World Health Organization’s Eliminate Yellow Fever Epidemics (EYE) strategy, ongoing efforts to address vaccine supply constraints, and persistent surveillance gaps. Future directions in vaccine development, including next-generation platforms and improved delivery systems, are also discussed, alongside the need for sustained research investment and international collaboration. As yellow fever emerges in previously non-endemic areas due to climate change and globalization, strengthening vaccination programs remains critical to preventing outbreaks and ensuring effective disease control. Full article
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12 pages, 396 KB  
Review
Insect-Specific Flaviviruses Have Potential Applications as a Scaffold for Pathogenic Flavivirus Vaccines
by Jia-Zhen Cui, Xiang-Hua Xiong, Qing-Yang Wang, Hao-Long Dong, Gang Liu and Hui-Peng Chen
Vaccines 2025, 13(7), 769; https://doi.org/10.3390/vaccines13070769 - 21 Jul 2025
Cited by 2 | Viewed by 1818
Abstract
Pathogenic flaviviruses are predominantly the pathogens of emerging and re-emerging infectious diseases, which have caused multiple public health emergencies globally and pose a serious threat to human health and social development. Although significant achievements have been made in vaccine research, issues such as [...] Read more.
Pathogenic flaviviruses are predominantly the pathogens of emerging and re-emerging infectious diseases, which have caused multiple public health emergencies globally and pose a serious threat to human health and social development. Although significant achievements have been made in vaccine research, issues such as limited protective effects and virulence reversion persist, making the development of novel vaccines against pathogenic flaviviruses a current research hotspot and challenge. ISFVs have recently attracted attention due to their high homology with pathogenic flaviviruses and unique inability to replicate in mammalian hosts. Multiple vaccine candidate strains constructed using ISFVs as scaffolds have demonstrated excellent safety and efficacy. This review summarizes the biological characteristics, host restriction factors, current applications in vaccine development, and challenges faced by ISFVs, providing a reference for future research on pathogenic flavivirus vaccines. Full article
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13 pages, 554 KB  
Review
Innate Immune Response to Powassan Virus Infection: Progress Toward Infection Control
by Mohammad Enamul Hoque Kayesh, Michinori Kohara and Kyoko Tsukiyama-Kohara
Vaccines 2025, 13(7), 754; https://doi.org/10.3390/vaccines13070754 - 15 Jul 2025
Cited by 1 | Viewed by 1442
Abstract
Powassan virus is an emerging tick-borne flavivirus that poses a significant threat to human health. The outcome of Powassan virus infection is shaped by both viral factors and the host immune response. While this review aimed to examine the innate immune response, particularly [...] Read more.
Powassan virus is an emerging tick-borne flavivirus that poses a significant threat to human health. The outcome of Powassan virus infection is shaped by both viral factors and the host immune response. While this review aimed to examine the innate immune response, particularly toll-like receptor-mediated immune responses to Powassan virus, data specific to the immune response to Powassan virus remain scarce. Therefore, we focused on toll-like receptor responses to related flaviviruses to infer possible mechanisms of host response. Insights from both in vivo and in vitro studies are critical for guiding the development of effective therapeutic and preventive strategies. Currently, there are no clinically approved treatments or vaccines for Powassan virus, highlighting the urgent need for their development. We also highlight recent progress in POWV vaccine development, with an emphasis on the potential use of toll-like receptor agonists as adjuvants to enhance immunogenicity and improve vaccine efficacy. Full article
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22 pages, 723 KB  
Review
From Antibodies to Immunity: Assessing Correlates of Flavivirus Protection and Cross-Reactivity
by Hannah E. Flores, Eduar Fernando Pinzon Burgos, Sigrid Camacho Ortega, Alonso Heredia and Joel V. Chua
Vaccines 2025, 13(5), 449; https://doi.org/10.3390/vaccines13050449 - 24 Apr 2025
Cited by 4 | Viewed by 4469
Abstract
Flaviviruses are arthropod-borne RNA viruses that can cause a wide range of human diseases, from mild symptoms to severe illness with multiorgan failure and death. Effective prevention of these diseases relies on identifying reliable vaccine targets, typically measured by correlates of protection (CoPs), [...] Read more.
Flaviviruses are arthropod-borne RNA viruses that can cause a wide range of human diseases, from mild symptoms to severe illness with multiorgan failure and death. Effective prevention of these diseases relies on identifying reliable vaccine targets, typically measured by correlates of protection (CoPs), which help indicate host immunity after vaccination. Current vaccines primarily focus on neutralizing antibodies (nAbs) against the viral envelope E protein, though emerging evidence suggests other potential targets may also be effective in disease prevention. Additionally, there is growing evidence of cross-protection between different flaviviruses when immunity to one virus is achieved, although this can be limited by antibody-dependent enhancement. This review examines the current understanding of flavivirus immunity, CoPs, and the potential for cross-protection in the context of existing vaccine strategies. Full article
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