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Vaccines
Volume 13
Issue 9
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Vaccines, Volume 13, Issue 9 (September 2025) – 104 articles

Cover Story (view full-size image): Non-typeable Haemophilus influenzae (NTHi) can cause local infections and invasive diseases such as meningitis and septicemia but vaccines are still lacking. Since these isolates lack a capsule, vaccines should target outer membrane proteins (OMPs). Whole genome sequencing of 1144 H. influenzae genomes identified 514 conserved among all these isolates. We focused on two: OMP5 (P5) and OMP26 (P26). Both proteins are involved in virulence of NTHi. Our findings show that purified, cloned P5 and P26 proteins are immunogenic during human infections. In mice, combined immunization with these proteins conferred both passive and active protection against homologous and heterologous NTHi isolates, indicating potential broad cross-protection. View this paper
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20 pages, 3584 KB  
Article
Heterologous DNA–Adenovirus Prime–Boost Strategy Expressing Bluetongue Virus VP2 and VP7 Proteins Protects Against Virulent Challenge
by Pablo Nogales-Altozano, Laro Gómez-Marcos, Ana Belén Carlón, Andrés Louloudes-Lázaro, Alicia Rivera-Rodríguez, Jaime Larraga, Pedro J. Alcolea, Ana Alonso, Vicente Larraga, Verónica Martín, José M. Rojas and Noemí Sevilla
Vaccines 2025, 13(9), 991; https://doi.org/10.3390/vaccines13090991 - 22 Sep 2025
Viewed by 146
Abstract
Background/Objectives: Bluetongue virus (BTV) is an emerging arbovirus causing significant economic losses in the ruminant industry. Current vaccines offer limited cross-protection against heterologous serotypes and do not enable differentiation between infected and vaccinated animals (DIVA). Subunit-based vaccines provide a potential DIVA-compatible solution. This [...] Read more.
Background/Objectives: Bluetongue virus (BTV) is an emerging arbovirus causing significant economic losses in the ruminant industry. Current vaccines offer limited cross-protection against heterologous serotypes and do not enable differentiation between infected and vaccinated animals (DIVA). Subunit-based vaccines provide a potential DIVA-compatible solution. This study aimed to develop a vaccination protocol expressing BTV structural proteins VP7 or VP2 using antibiotic-resistance-free DNA plasmids and replication-defective adenovirus vectors. Methods: We evaluated homologous DNA prime–boost and heterologous DNA prime–adenovirus boost strategies in a murine model, assessing adaptive immune responses and protection against virulent BTV challenge. Results: The heterologous DNA–adenovirus prime–boost strategy expressing both antigens conferred full protection, preventing viremia, while homologous DNA-DNA prime–boost provided only partial protection. Both VP7 and VP2 elicited cellular and humoral immune responses, but the heterologous strategy significantly enhanced anti-BTV IgG, neutralizing antibody titers, and T cell activation. CD8+ T cell responses showed the strongest correlation with viral load reduction, suggesting that cellular immunity to conserved VP7 could serve as a platform for cross-protection against multiple BTV serotypes. Conclusions: These findings highlight the potential of heterologous DNA–adenovirus vaccination as an effective DIVA-compatible strategy for BTV control. By inducing strong and protective immune responses, this approach could improve disease surveillance and management, ultimately reducing the impact of BTV on livestock industries. Full article
(This article belongs to the Special Issue Animal Diseases: Immune Response and Vaccines)
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28 pages, 569 KB  
Review
What Stage Are We at in the Development of Vaccines Against Tick-Borne Diseases?
by Weronika Stachera, Magdalena Szuba, Arya Taesung Kim, Subin Yu, Jaeuk Choi, Deborah Nzekea, Yen Ching Wu, Adrianna Brzozowska, Marcin Sota, Marianna Misiak and Monika Dybicz
Vaccines 2025, 13(9), 990; https://doi.org/10.3390/vaccines13090990 - 22 Sep 2025
Viewed by 426
Abstract
The increasing prevalence of Lyme disease, tick-borne encephalitis (TBE), and other tick-borne infections such as Babesia, Ehrlichia, Rickettsia, and Anaplasma is a growing public health concern. Existing tick bite prevention strategies are insufficient; therefore, vaccines represent a promising preventive measure. [...] Read more.
The increasing prevalence of Lyme disease, tick-borne encephalitis (TBE), and other tick-borne infections such as Babesia, Ehrlichia, Rickettsia, and Anaplasma is a growing public health concern. Existing tick bite prevention strategies are insufficient; therefore, vaccines represent a promising preventive measure. At the moment, only a vaccine for tick-borne encephalitis is available on the market. A vaccine for Lyme disease, however, is at an advanced stage of clinical trials. In this article, we focus on describing the progress in the invention of vaccines for tick-borne diseases. This article analyzes their development and effectiveness. Full article
(This article belongs to the Special Issue Advancements in Vaccine Research: Epidemiology, Immunogenicity, Effectiveness and Safety)
15 pages, 747 KB  
Review
Advances in Biotechnology and the Development of Novel Human Vaccines
by Ioanna Papadatou and Athanasios Michos
Vaccines 2025, 13(9), 989; https://doi.org/10.3390/vaccines13090989 - 22 Sep 2025
Viewed by 425
Abstract
Recent advances in biotechnology have fundamentally reshaped the landscape of vaccine development, offering innovative strategies to improve immunogenicity, safety and accessibility. This review explores the cutting-edge platforms—including mRNA, DNA, virus-like particles, viral and bacterial vectors, and bacteriophage-based vaccines—that are redefining how vaccine antigens [...] Read more.
Recent advances in biotechnology have fundamentally reshaped the landscape of vaccine development, offering innovative strategies to improve immunogenicity, safety and accessibility. This review explores the cutting-edge platforms—including mRNA, DNA, virus-like particles, viral and bacterial vectors, and bacteriophage-based vaccines—that are redefining how vaccine antigens are delivered to the immune system. We also discuss alternative delivery methods, such as transcutaneous and mucosal immunization, which have the potential to improve vaccine acceptance and distribution, as well as next-generation adjuvants targeting innate immune receptors aiming to further enhance vaccine efficacy, especially in vulnerable populations. By synthesizing these innovations, this review highlights how biotechnology is enabling the design of safer, more efficient, and more adaptable vaccines to address both existing and emerging infectious diseases. Full article
(This article belongs to the Special Issue Biotechnologies Applied in Vaccine Research)
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15 pages, 5640 KB  
Article
Visual Detection of Malaria Parasite-Parasitized Erythroblasts in Peripheral Blood via Immunization-Based Model
by Kumpei Ito, Yuki S. Tateishi, Takashi Imai, Shinya Miyazaki, Yukiko Miyazaki, Wataru Kagaya, Mai Nakashima, Miho Sase, Misato Yoshioka-Takeda, Chikako Shimokawa, Kyoko Hayashi, Kentaro Itokawa, Osamu Komagata, Ha Ngo-Thanh, Aoi Shimo, Tamasa Araki, Takeshi Annoura, Takashi Murakami and Hajime Hisaeda
Vaccines 2025, 13(9), 988; https://doi.org/10.3390/vaccines13090988 - 21 Sep 2025
Viewed by 257
Abstract
Background: Erythroblasts have recently been identified as host cells for malarial parasites, revealing a previously underappreciated host–parasite interaction. However, their extremely low abundance in peripheral blood has hindered progress, especially in elucidating the biological significance of parasitized erythroblasts (pEBs) in vivo. Methods: [...] Read more.
Background: Erythroblasts have recently been identified as host cells for malarial parasites, revealing a previously underappreciated host–parasite interaction. However, their extremely low abundance in peripheral blood has hindered progress, especially in elucidating the biological significance of parasitized erythroblasts (pEBs) in vivo. Methods: Here, we visualized pEBs in a murine model and established a method to increase their number in peripheral blood by immunizing mice with live Plasmodium yoelii 17XNL, followed by challenge with P. berghei ANKA. Results: Immunized mice were protected from cerebral malaria and survived longer, during which pEBs appeared in circulation and were detected using Giemsa-stained smears. All blood-stage parasite forms were identified within pEBs, including enucleating erythroblasts. Conclusions: This model enables in vivo/ex vivo analysis of pEB biology without bone marrow/spleen isolation, thus lowering technical/ethical barriers for the field. Full article
(This article belongs to the Special Issue New Horizons in the Fight Against Vector-Borne Diseases and Parasitic Infestations: From Basic Research to Applied Studies in Vaccines)
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24 pages, 782 KB  
Article
Multilevel Analysis of Zero-Dose Children in Sub-Saharan Africa: A Three Delays Model Study
by Charles S. Wiysonge, Muhammed M. B. Uthman, Duduzile Ndwandwe and Olalekan A. Uthman
Vaccines 2025, 13(9), 987; https://doi.org/10.3390/vaccines13090987 - 21 Sep 2025
Viewed by 413
Abstract
Background: Zero-dose children represent a critical challenge for achieving universal immunization coverage in sub-Saharan Africa. This study applies the Three Delays Model to examine multilevel factors associated with zero-dose children. Methods: We analyzed data from 30,500 children aged 12–23 months across 28 sub-Saharan [...] Read more.
Background: Zero-dose children represent a critical challenge for achieving universal immunization coverage in sub-Saharan Africa. This study applies the Three Delays Model to examine multilevel factors associated with zero-dose children. Methods: We analyzed data from 30,500 children aged 12–23 months across 28 sub-Saharan African countries using demographic and health surveys (2015–2024). Zero-dose status was defined as not receiving the first dose of diphtheria–tetanus–pertussis vaccine. Multilevel logistic regression models examined individual-, community-, and country-level determinants. Results: Overall, zero-dose prevalence was 12.19% (95% confidence interval: 11.82–12.56), ranging from 0.51% in Rwanda to 40.00% in Chad. Poor maternal health-seeking behavior showed the strongest association (odds ratio (OR) 12.00, 95% credible interval: 9.78–14.55). Paternal education demonstrated clear gradients, with no formal education increasing odds 1.52-fold. Maternal empowerment factors were significant: lack of decision-making power (OR = 1.23), financial barriers (OR = 1.98), and no media access (OR = 1.32). Low community literacy and low country-level health expenditure were associated with increased zero-dose prevalence. Substantial clustering persisted at community (19.5%) and country (18.7%) levels. Conclusions: Zero-dose children concentrate among the most disadvantaged populations, with maternal health-seeking behavior as the strongest predictor. Immediate policy actions should integrate antenatal care with vaccination services, target high-parity mothers, eliminate financial barriers, and increase health expenditure to 15% of national budgets. Full article
(This article belongs to the Section Vaccines and Public Health)
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19 pages, 934 KB  
Review
Individualized mRNA Vaccines in Melanoma—Where Do We Stand?
by Ioanna Gazouli, Dimitrios Bafaloukos, Christos Koutserimpas and George Samonis
Vaccines 2025, 13(9), 986; https://doi.org/10.3390/vaccines13090986 - 21 Sep 2025
Viewed by 386
Abstract
Immunotherapy, consisting mainly of immune checkpoint inhibitors, has been successfully employed in the treatment of early and advanced-stage melanoma for more than ten years. Personalized mRNA vaccines represent the next evolutionary step, offering patients a treatment unique to them and their tumor, whilst [...] Read more.
Immunotherapy, consisting mainly of immune checkpoint inhibitors, has been successfully employed in the treatment of early and advanced-stage melanoma for more than ten years. Personalized mRNA vaccines represent the next evolutionary step, offering patients a treatment unique to them and their tumor, whilst putting recent, significant technological and scientific advances into practice. Clinical and preclinical data about mRNA vaccines are now emerging, further encouraging research and spreading enthusiasm among patients and physicians. Nonetheless, a lot remains to be discovered about mRNA vaccines’ mechanisms of action, their actual effect on the immune cells of the patient, and successful mRNA delivery to the host. Full article
(This article belongs to the Special Issue Vaccines Targeting the Tumor Microenvironment: Challenges and Future Prospects)
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13 pages, 1511 KB  
Article
Oral Vaccination with Aeromonas veronii Ghost Against Lethal Bacterial Infection in Cyprinus carpio
by Na Jiang, Zhihong Ma, Jinjing Zhang, Lin Luo, Xingchen Huo, Jufeng Jiang, Jian Gao, Jie Huang and Dongjie Shi
Vaccines 2025, 13(9), 985; https://doi.org/10.3390/vaccines13090985 - 20 Sep 2025
Viewed by 293
Abstract
Background/Objectives: Aeromonas veronii is a significant pathogen affecting aquatic animals and has the potential to infect humans. Vaccination remains the most effective strategy for preventing infections caused by this bacterial strain. Methods: This study aimed to validate the efficacy of bacterial ghosts as [...] Read more.
Background/Objectives: Aeromonas veronii is a significant pathogen affecting aquatic animals and has the potential to infect humans. Vaccination remains the most effective strategy for preventing infections caused by this bacterial strain. Methods: This study aimed to validate the efficacy of bacterial ghosts as an oral vaccine by administering them to Cyprinus carpio and evaluating the resultant innate and acquired immune responses. Following immunization, the vaccinated Cyprinus carpio were exposed to a lethal dose of the wild-type bacterial strain to assess survival rates and relative protection efficiency. Results: Oral vaccination with bacterial ghosts led to the significant enhancement of lysozyme (LZM) and myeloperoxidase (MPO) activity in koi serum. It also resulted in the upregulation of cytokines, such as IL-2 and TNF-α, as well as an increase in both systemic (IgM) and mucosal (IgZs) antibody responses. The immunized group demonstrated reduced cumulative mortality following bacterial challenge. The relative percent survival in the vaccinated group reached as high as 87.50%. Conclusions: The oral immunization of Cyprinus carpio with A. veronii-derived bacterial ghosts confers substantial immune protection, providing a foundational basis for the development of novel vaccines against A. veronii. Full article
(This article belongs to the Special Issue Advances in Aquatic Animal Immunology and Vaccine Development for Disease Prevention)
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10 pages, 1477 KB  
Article
Baseline Anti-SARS-CoV-2 IgG and Protection from Symptomatic Infection: Post Hoc Analysis of the SCTV01E Phase 3 Randomized Trial
by Lixin Yan, Jiang Yi, Dongfang Liu, Jian Li, Adam Abdul Hakeem Baidoo and Liangzhi Xie
Vaccines 2025, 13(9), 984; https://doi.org/10.3390/vaccines13090984 - 19 Sep 2025
Viewed by 246
Abstract
Background: Following SARS-CoV-2 infection, the necessity of vaccination after natural infection remains uncertain. However, many asymptomatic individuals who test negative virologically may nevertheless receive vaccination without being aware of their prior infection. Investigating the implications for vaccine safety and efficacy is crucial. Methods: [...] Read more.
Background: Following SARS-CoV-2 infection, the necessity of vaccination after natural infection remains uncertain. However, many asymptomatic individuals who test negative virologically may nevertheless receive vaccination without being aware of their prior infection. Investigating the implications for vaccine safety and efficacy is crucial. Methods: We analyzed the daily fluctuations in anti-SARS-CoV-2 IgG antibody levels during the enrollment period of a phase 3 randomized, double-blinded, placebo-controlled clinical trial of a tetravalent COVID-19 protein vaccine, SCTV01E. Additionally, we investigated the relationship between baseline IgG levels and their protection against COVID-19 in participants who received placebo. Results: The daily enrolled participants with different baseline IgG levels (<338 BAU/mL, 338–1000 BAU/mL, >1000 BAU/mL) showed dynamic changes with the enrollment date. Among participants with baseline IgG levels < 338 BAU/mL, vaccination conferred a relative protective efficacy of 69.15% (95% CI: 51.14–80.52%) against symptomatic SARS-CoV-2 infection compared with the control group. Conversely, in those with higher baseline IgG levels (≥338 BAU/mL), vaccination did not confer additional benefit. In the placebo group, the relative protection in participants with baseline IgG levels ≥ 338 BAU/mL was 93.79% (87.60%, 96.89%) compared to that of those with baseline IgG levels < 338 BAU/mL. The safety profile of SCTV01E in participants with baseline IgG ≥ 338 BAU/mL was comparable to that in participants with <338 BAU/mL, with favorable safety profiles. Conclusions: During the SCTV01E phase 3 clinical trial, an anti-SARS-CoV-2 IgG antibody IgG level of 338 BAU/mL was suitable for screening individuals in the early phase post-infection alongside virological tests. Vaccinating the infected population was safe and did not compromise efficacy. Clinical Trial: NCT05308576. Full article
(This article belongs to the Section COVID-19 Vaccines and Vaccination)
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12 pages, 524 KB  
Article
Correlates of Meningococcal B Vaccination and Health Behavior Profiles Among MSM in China
by Rongyan Li, Qian Zou, Yi Zhou, Ye Zhang, Dan Wu, Xinyuan Zhang, Fengshi Jing, Jie Fan, Xi He and Weiming Tang
Vaccines 2025, 13(9), 983; https://doi.org/10.3390/vaccines13090983 - 19 Sep 2025
Viewed by 270
Abstract
Background: Meningococcal B (MenB) vaccination offers protection against invasive meningococcal disease and moderate cross-protection against gonorrhea. However, little is known about coverage and behavioral correlates among men who have sex with men (MSM) in China. This study assessed self-reported MenB vaccination uptake and [...] Read more.
Background: Meningococcal B (MenB) vaccination offers protection against invasive meningococcal disease and moderate cross-protection against gonorrhea. However, little is known about coverage and behavioral correlates among men who have sex with men (MSM) in China. This study assessed self-reported MenB vaccination uptake and its associations with sociodemographic and behavioral factors. Methods: We conducted a nationwide cross-sectional survey among 1022 MSM recruited via community-based organizations and online platforms. Vaccination status and recent sexual behaviors were self-reported. Logistic regression identified correlates of uptake, and latent class analysis (LCA) examined behavioral profiles. Results: Participants had a mean age of 29.6 years; most were unmarried (87.7%) and nearly 90% had a college degree or above. Overall, 21.7% reported receiving MenB vaccination. Uptake was positively associated with condomless anal intercourse (aOR = 1.57, 95% CI: 1.08–2.31), group sex (occasionally: aOR = 1.63, 95% CI: 1.01–2.64; frequently: aOR = 3.86, 95% CI: 1.85–8.04), and female partners in the past six months (aOR = 3.69, 95% CI: 2.25–6.10). MSM with multiple casual male partners were less likely to be vaccinated (aOR = 0.55, 95% CI: 0.32–0.93). LCA identified heterogeneous subgroups; notably, the “multi-partner and proactive” group, with high pre-exposure prophylaxis against HIV infection awareness and frequent STI testing, showed low uptake (13.4%). Conclusions: MenB vaccination coverage among MSM in China remained suboptimal. Uptake differed across behavioral subgroups, underscoring the need for stratified, context-specific strategies to inform future vaccine introduction. Full article
(This article belongs to the Special Issue Vaccine Against Sexually Transmitted Diseases)
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1 pages, 127 KB  
Correction
Correction: Hussain et al. Mind the Age Gap: Expanding the Age Window for mRNA Vaccine Testing in Mice. Vaccines 2025, 13, 370
by Muattaz Hussain, Agata Ferguson-Ugorenko, Rebecca Macfarlane, Natalie Orr, Samuel Clarke, Michael J. A. Wilkinson, Linda Horan and Yvonne Perrie
Vaccines 2025, 13(9), 982; https://doi.org/10.3390/vaccines13090982 - 19 Sep 2025
Viewed by 158
Abstract
The authors would like to make the following corrections to the published paper [...] Full article
18 pages, 1696 KB  
Article
A Quantitative Exploration of the Relationship Between Healthcare Accessibility and Mass Media in Nigeria Using the Levesque Framework of Healthcare Access
by Chelsea Gordon, Teresa Paslawski, Thilina Bandara, Shannon Floer and Tayyab Shah
Vaccines 2025, 13(9), 981; https://doi.org/10.3390/vaccines13090981 - 18 Sep 2025
Viewed by 596
Abstract
Background/Objectives: This study investigates the relationship between maternal media access and childhood immunization status in Nigeria using the Levesque Framework for Healthcare Access. Methods: Utilizing data from the 2021 MICS-NICS survey, the study analyzes sociodemographic and media/ICT variables through logistic regression [...] Read more.
Background/Objectives: This study investigates the relationship between maternal media access and childhood immunization status in Nigeria using the Levesque Framework for Healthcare Access. Methods: Utilizing data from the 2021 MICS-NICS survey, the study analyzes sociodemographic and media/ICT variables through logistic regression and geospatial mapping. Results: The results indicate that region is the strongest predictor of immunization status, with significant disparities in access to media and healthcare services across Nigeria. Television exposure was associated with improved immunization outcomes, while mobile phone ownership was not. Conclusions: The findings emphasize the importance of equitable media access and tailored health communication strategies to improve healthcare accessibility. The study highlights the need for region-specific interventions and continued monitoring of media access trends to support universal health coverage goals. Full article
(This article belongs to the Special Issue Inequality in Immunization 2025)
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30 pages, 5835 KB  
Article
GMP Manufacturing and Characterization of the HIV Booster Immunogen HxB2.WT.Core-C4b for Germline Targeting Vaccine Strategies
by Sammaiah Pallerla, Latha Kallur Siddaramaiah, Philipp Mundsperger, Dietmar Katinger, Katharina Fauland, Günter Kreismayr, Robert Weik, Onur Arslan, Mingchao Shen, Gabriel Ozorowski, Wen-Hsin Lee, Andrew B. Ward, Sabyasachi Baboo, Jolene K. Diedrich, John R. Yates III, James C. Paulson, Tracy Blumen, Daniel Craig, Ryan Swoyer, Maoli Yuan and Leonidas Stamatatosadd Show full author list remove Hide full author list
Vaccines 2025, 13(9), 980; https://doi.org/10.3390/vaccines13090980 - 18 Sep 2025
Viewed by 468
Abstract
Background/Objectives: Despite progress in antiretroviral therapy, HIV remains a major global health challenge with over one million new infections annually. An effective vaccine is urgently needed. Germline-targeting immunogens show promise in initiating broadly neutralizing antibody (bNAb) precursors. This study developed a scalable, cGMP-compliant [...] Read more.
Background/Objectives: Despite progress in antiretroviral therapy, HIV remains a major global health challenge with over one million new infections annually. An effective vaccine is urgently needed. Germline-targeting immunogens show promise in initiating broadly neutralizing antibody (bNAb) precursors. This study developed a scalable, cGMP-compliant process to manufacture the HIV vaccine booster immunogen HxB2.WT.Core-C4b, a nanoparticle designed to direct bNAb precursor maturation after priming. Methods: A CHO cell platform was established through single-cell cloning from a high-producing stable pool. Upstream and downstream processes were optimized for scalability and yield. Three scales were tested 10 L, 40 L, and 400 L. Key parameters (pH, temperature, feeding, metabolite profiles) were systematically refined. Analytical characterization included glycosylation profiling, electron microscopy, and antigenicity testing. Viral clearance was evaluated per ICH Q5A guidelines. Results: Optimization ensured consistent yields above 130 mg/L, with titers up to 250 mg/L. The selected clone (4E22) demonstrated strong growth, viability, and reproducibility. Glycan occupancy at 18 N-linked sites, including bNAb epitopes (N276, N332), was stable across scales. Over 70% of self-assembling nanoparticle were fully assembled at the GMP level. Antigenicity and purity met cGMP release criteria. Viral clearance achieved >13-log reduction for enveloped and >7-log for non-enveloped viruses. Conclusions: This work establishes a robust, scalable platform for HIV nanoparticle immunogens. Consistent quality and yield across scales support clinical development of HxB2.WT.Core-C4b and provide a model for other glycosylated nanoparticle vaccines. The immunogen is being evaluated in clinical study HVTN 320 (NCT06796686), enabling early testing of next-generation vaccines designed to elicit broadly neutralizing antibodies. Full article
(This article belongs to the Special Issue Advances in HIV Vaccine Development, 2nd Edition)
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27 pages, 1281 KB  
Review
Novel Strategies for Developing Next-Generation Vaccines to Combat Infectious Viral Diseases
by Fangfeng Yuan and Martin H. Bluth
Vaccines 2025, 13(9), 979; https://doi.org/10.3390/vaccines13090979 - 17 Sep 2025
Viewed by 687
Abstract
The development of viral vaccines faces persistent scientific and logistical challenges, particularly in the wake of the COVID-19 pandemic. This review critically examines emerging strategies to overcome key barriers in viral vaccine design and deployment. We focus on four major areas: (1) structure-guided [...] Read more.
The development of viral vaccines faces persistent scientific and logistical challenges, particularly in the wake of the COVID-19 pandemic. This review critically examines emerging strategies to overcome key barriers in viral vaccine design and deployment. We focus on four major areas: (1) structure-guided antigen engineering to stabilize conformations; (2) the mRNA platform and its delivery system; (3) advanced adjuvant systems that enhance cellular and humoral immunity; and (4) approaches to mitigate immune imprinting and antigenic variability, such as chimeric antigens and glycan shielding. We also explore anti-idiotypic vaccination strategies and the limitations of current animal models in predicting human immune responses. In addition, to address vaccine hesitancy and inequitable access, we advocate for global collaboration in manufacturing, distribution, and public education to ensure inclusive immunization strategies. By integrating molecular insights with platform technologies, we aim to inform the rational design of future vaccines with improved efficacy and public acceptance. Full article
(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)
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32 pages, 3452 KB  
Review
Recent Advancements in Non-Invasive Vaccination Strategies
by Mahek Gulani, Tanisha Arte, Amarae Ferguson, Dedeepya Pasupuleti, Emmanuel Adediran, Yash Harsoda, Andrew Nicolas McCommon, Rikhav Gala and Martin J. D’Souza
Vaccines 2025, 13(9), 978; https://doi.org/10.3390/vaccines13090978 - 16 Sep 2025
Viewed by 737
Abstract
Vaccines remain one of the most powerful tools in modern medicine, having revolutionized public health by preventing millions of deaths and controlling the spread of infectious diseases worldwide. However, conventional needle-based vaccines face several limitations, including pain and discomfort, the need for cold-chain [...] Read more.
Vaccines remain one of the most powerful tools in modern medicine, having revolutionized public health by preventing millions of deaths and controlling the spread of infectious diseases worldwide. However, conventional needle-based vaccines face several limitations, including pain and discomfort, the need for cold-chain infrastructure, reliance on trained healthcare personnel, risk of cross-contamination, and limited accessibility in low-resource settings. These challenges have spurred the development of non-invasive vaccination approaches that promise safer, more accessible, and patient-friendly immunization. Non-invasive immunizations not only eliminate the need for needles but may also enhance compliance and enable mucosal immune responses. To harness the full potential of these innovative delivery routes, a comprehensive understanding of their formulation strategies and mechanism of action is essential. This review aims to comprehensively discuss recent advancements in oral, intranasal, microneedle, buccal, sublingual, and vaginal vaccinations and highlight their underlying immunological mechanisms, formulation strategies in preclinical studies, examples of marketed products, and ongoing clinical trials. Full article
(This article belongs to the Special Issue Innovative Technology in Vaccine Development: Advancing Immunization Strategies)
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22 pages, 7902 KB  
Article
CD63-Mediated SARS-CoV-2 RBD Fusion Neoantigen DNA Vaccine Enhances Antitumor Immune Response in a Mouse Panc02 Model via EV-Targeted Delivery
by Guang Liu, Ziqing Yuan, Ziyi Wu, Qiyv Yang, Tingbo Ding, Ker Yu and Jibin Dong
Vaccines 2025, 13(9), 977; https://doi.org/10.3390/vaccines13090977 - 16 Sep 2025
Viewed by 464
Abstract
Background: Although DNA vaccines offer a flexible platform for tumor immunotherapy, their weak immunogenicity remains a key limitation. This study aimed to improve the immunogenicity of DNA vaccines by enhancing the efficiency of tumor neoantigen delivery through extracellular vesicles (EVs), thereby promoting stronger [...] Read more.
Background: Although DNA vaccines offer a flexible platform for tumor immunotherapy, their weak immunogenicity remains a key limitation. This study aimed to improve the immunogenicity of DNA vaccines by enhancing the efficiency of tumor neoantigen delivery through extracellular vesicles (EVs), thereby promoting stronger dendritic cell (DC) activation and antitumor responses. Methods: A novel DNA vaccine (pCSP) was engineered by fusing tumor-specific neoantigens to the EV-associated protein CD63 and incorporating a SARS-CoV-2 receptor-binding domain (RBD) fragment to facilitate EV uptake by DCs. The resulting EVs were expected to carry neoantigens into the immunoproteasome for major histocompatibility complex I (MHC-I) presentation. The immunological and antitumor effects of pCSP were assessed through in vitro functional assays and in vivo experiments in a murine pancreatic cancer model. Safety was evaluated through histological and biochemical analyses. Results: In vitro, pCSP significantly promoted EV internalization by DCs by approximately twofold and enhanced their immune activation, as evidenced by elevated cytokine production. In vivo, pCSP markedly suppressed tumor growth with a decrease in volume by over 70% relative to controls, boosted CD8+ T cell responses, and increased immune infiltration into the tumor microenvironment. Safety assessments revealed that while liver/kidney function markers were within physiological ranges, mild inflammatory infiltrates were consistently observed in the lungs, indicating a localized safety concern that warrants further monitoring. Conclusions: The pCSP vaccine enhances the immunogenicity of neoantigen DNA vaccines by improving EV uptake and immune activation in DCs. These findings provide a potential strategy for improving DNA vaccine efficacy in the context of cancer immunotherapy while maintaining acceptable safety. Full article
(This article belongs to the Special Issue Advances in ImmunoTherapy of Cancer)
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32 pages, 446 KB  
Review
Messenger RNA and Plasmid DNA Vaccines for the Treatment of Cancer
by Jena E. Moseman, Daeun Shim, Donghwan Jeon, Ichwaku Rastogi, Kaitlyn M. Schneider and Douglas G. McNeel
Vaccines 2025, 13(9), 976; https://doi.org/10.3390/vaccines13090976 - 14 Sep 2025
Viewed by 882
Abstract
Immunotherapy is now an established therapy for nearly a third of patients with cancer. Most therapies, typically using cytokines or checkpoint blockade therapy, rely on global activation of immune effector cells. The ability of vaccines to activate specific populations of cells has led [...] Read more.
Immunotherapy is now an established therapy for nearly a third of patients with cancer. Most therapies, typically using cytokines or checkpoint blockade therapy, rely on global activation of immune effector cells. The ability of vaccines to activate specific populations of cells has led to a renewed interest in their ability to treat cancers, either alone or with other immune therapies or other conventional therapies. The COVID-19 pandemic sparked a new interest in nucleic acid vaccines with the development of new technologies and the short manufacturing time for vaccine implementation. Nucleic acid-based cancer vaccines have been studied for decades, but have shown modest anti-tumor efficacy as monotherapies, as many of these vaccines encode for shared tumor-associated antigens (TAAs) and must overcome immune tolerance. New developments, technologies, routes of delivery, and combination therapies have paved the way for new approaches and clinical trials involving nucleic acid vaccines for the treatment of cancer. Here we review mRNA and pDNA vaccines for the treatment of cancer, including similarities and differences in their mechanisms of action, an overview of these treatment modalities in preclinical and clinical studies, methods to improve these vaccine strategies, and exciting new combination approaches in development. Full article
(This article belongs to the Special Issue New Approaches to Vaccine Development and Delivery)
13 pages, 3262 KB  
Article
Long-Term Follow-Up of T Cell Immunity Against Orthopoxviruses in People Living with HIV After Vaccination and Natural Monkeypox Virus Infection
by Monika Lindemann, Stefanie Sammet, Felix Maischack, Gabriela Graf, Peter A. Horn, Heidi Wiehler, Jessica Wunderling and Stefan Esser
Vaccines 2025, 13(9), 975; https://doi.org/10.3390/vaccines13090975 - 13 Sep 2025
Viewed by 426
Abstract
Background/Objectives: After the 2022 mpox outbreak also outside Africa, risk groups including people living with HIV (PLWH) were vaccinated with the Modified Vaccinia Ankara–Bavarian Nordic vaccine (MVA-BN). Previous data on PLWH showed that two vaccinations induced specific T cell responses in 64% of [...] Read more.
Background/Objectives: After the 2022 mpox outbreak also outside Africa, risk groups including people living with HIV (PLWH) were vaccinated with the Modified Vaccinia Ankara–Bavarian Nordic vaccine (MVA-BN). Previous data on PLWH showed that two vaccinations induced specific T cell responses in 64% of the patients and natural monkeypox virus (MPXV) infection in 100%. The initial T cell response assay took place at a median of approximately 100 days post-vaccination and 300 days post-infection. Methods: This study investigates the durability of T cell immunity in PLWH by retesting patients approximately two years after initial assessment. We were able to retest 27 of 33 vaccinated patients and 7 of 10 patients after MPXV infection. T cells were stimulated with the same orthopoxvirus-derived peptide pools as in the initial study, and interferon (IFN)-γ and interleukin (IL)-2 ELISpot assays were performed. Results: The ELISpot assays showed specific T cell responses in 59% and 86% of twice vaccinated and previously infected patients, respectively. Paired analysis revealed no significant differences between previous and current data (short- and long-term follow-up), with IL-2 ELISpot results showing positive correlations at both time points (r = 0.67, p = 0.0001). Long-term IFN-γ responses after MPXV infection were 4.3 times higher (p < 0.01), and IL-2 responses were 2.9 times higher (p = 0.05) than after vaccination. Conclusions: Our data indicates that T cell responses to Orthopoxviruses remain overall stable for 2–3 years in PLWH, with long-term immunity being stronger after natural MPXV infection than after two vaccinations. Full article
(This article belongs to the Special Issue Strategies for the Monitoring, Treatment, and Prevention of Mpox and Other Poxvirus Infections)
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20 pages, 8567 KB  
Review
Need for Invasive Meningococcal Disease Prevention Through Vaccination for Young Children in the Americas
by Gaurav Mathur, Joseph B. Domachowske, Maria Gabriela Graña, Reena Ladak, Joanne M. Langley, Oluwatosin Olaiya, Alysa Pompeo, Laura Taddei and Rodolfo Villena
Vaccines 2025, 13(9), 974; https://doi.org/10.3390/vaccines13090974 - 13 Sep 2025
Viewed by 740
Abstract
Background: Invasive meningococcal disease (IMD) is an uncommon but potentially life-threatening condition, resulting in life-long sequelae or death in up to 20% of cases. Most IMD cases are caused by Neisseria meningitidis serogroups (Men) A, B, C, W, X, and Y. The highest [...] Read more.
Background: Invasive meningococcal disease (IMD) is an uncommon but potentially life-threatening condition, resulting in life-long sequelae or death in up to 20% of cases. Most IMD cases are caused by Neisseria meningitidis serogroups (Men) A, B, C, W, X, and Y. The highest IMD incidence is among children < 5 years of age (YOA). We reviewed IMD epidemiology data and existing national immunization programs (NIP) in the Americas and identify unmet needs to decrease IMD burden in young children. Methods: Using national surveillance data and published literature from 2006 to 2024, we evaluated the IMD burden and national vaccination strategies for children < 5 YOA in the Americas, focusing on Canada, the United States, Brazil, Chile, Argentina. Results: The highest IMD incidence was among infants, followed by children 1–4 YOA, with MenB infections predominating in both age groups. Chile has both MenACWY (2014) and MenB (2023) infant vaccination in its NIP. Argentina and Brazil’s NIPs include MenACWY (2017) and MenC (2010) vaccinations for infants, respectively. In Canada, MenC (2002) vaccination is recommended at 1 YOA (replaced by MenACWY in 2024 in Manitoba); MenB vaccination is selectively recommended. In each country, the incidence of IMD caused by vaccine-preventable serogroups decreased following the introduction of the respective meningococcal vaccination in the NIP. Conclusions: Comprehensive meningococcal vaccination programs in the Americas have the potential to reduce the IMD burden in children < 5 YOA. National recommendations and NIPs could reduce IMD burden by offering equitable access to protection against IMD, aligning with the WHO roadmap to defeat meningitis by 2030. Full article
(This article belongs to the Section Epidemiology and Vaccination)
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11 pages, 615 KB  
Article
Immunogenicity and Safety of a Live Attenuated Varicella Vaccine in Healthy Children Aged 12 to 15 Months: A Phase III, Randomized, Double-Blind, Active-Controlled Clinical Trial
by Nancy Nazaire-Bermal, Ningning Jia, Maria Angela C. Maronilla, Josemaria F. Lopez, Gang Zeng, Wenbin Wu, Adrielle Bernice C. Nimo, Chunfang Luan and Qianqian Xin
Vaccines 2025, 13(9), 973; https://doi.org/10.3390/vaccines13090973 - 13 Sep 2025
Viewed by 598
Abstract
Objectives: The varicella vaccine (VarV) produced by Sinovac (Dalian) obtained World Health Organization (WHO) prequalification in November 2022. However, no direct comparative studies have been conducted between VarV and other WHO-prequalified varicella vaccines. The study aimed to assess the immunogenicity and safety [...] Read more.
Objectives: The varicella vaccine (VarV) produced by Sinovac (Dalian) obtained World Health Organization (WHO) prequalification in November 2022. However, no direct comparative studies have been conducted between VarV and other WHO-prequalified varicella vaccines. The study aimed to assess the immunogenicity and safety of Sinovac’s VarV compared with Merck Sharp & Dohme’s (MSD) VARIVAX® (Moorgate, London, UK) following a single dose administration. Methods: This Phase III, randomized, double-blind, active-controlled, non-inferiority trial was conducted in the Philippines. Healthy children aged 12 to 15 months were enrolled. Eligible participants were randomly assigned (1:1) to receive a single dose of varicella vaccine either manufactured by Sinovac (Test group) or MSD (Active control group). Immunogenicity was evaluated 6 weeks after vaccination by enzyme-linked immunosorbent assay (ELISA). The primary immunogenicity endpoint was seroresponse rate 6 weeks after vaccination. Seroresponse rate was defined as varicella-zoster virus (VZV) antibody concentration ≥ 10 mIU/mL in participants who were seronegative (antibody concentration < 10 mIU/mL) at baseline. The secondary endpoint was the corresponding geometric mean concentration (GMC). Adverse events (AEs) and serious adverse events (SAEs) were monitored for 6 weeks after vaccination. Results: Among the 484 participants analyzed, the seroresponse rates 6 weeks after vaccination were 98.85% and 98.88% in the Test group and Active control group, respectively, with a difference of −0.03% (95% CI: −3.10%, 2.99%), which exceeded the predefined non-inferiority margin of −10%. The corresponding GMCs were 35.73 mIU/mL and 37.34 mIU/mL, respectively, with the ratio of 0.96 (95% CI: 0.86, 1.06), also exceeding the predefined non-inferiority margin of 0.67. Furthermore, the incidence of adverse reactions (ARs) in the Test group was lower than that in the Active control group (38.08% vs. 55.51%). Conclusions: Sinovac’s VarV demonstrated non-inferior immunogenicity to WHO-prequalified comparator vaccine (VARIVAX®) and favorable safety profile. These findings indicated that VarV (Sinovac, Beijing, China) met WHO standards for varicella vaccine evaluation, supporting its global use consideration. Full article
(This article belongs to the Section Vaccine Advancement, Efficacy and Safety)
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13 pages, 468 KB  
Article
Safety and Immunogenicity of Single-Dose of Adsorbed Tetanus Vaccine in Adults Aged 18–44 Years: Randomized, Double-Blind, Positive-Controlled Phase I/III Clinical Trial
by Zhiqiang Xie, Liyong Yuan, Yaping Qiao, Wangyang You, Yurong Li, Taotao Zhu, Wei Zhang, Lili Huang, Jiebing Tan, Xiaocan Jia, Zhe Li, Feng Xue, Xiaojuan Lian and Yanxia Wang
Vaccines 2025, 13(9), 972; https://doi.org/10.3390/vaccines13090972 - 13 Sep 2025
Viewed by 536
Abstract
Background: The persistence of non-neonatal tetanus (non-NT) highlights the necessity of adult booster vaccines and post-traumatic prophylaxis. This Phase I/III clinical trial aimed to evaluate the safety and immunogenicity of a new adsorbed tetanus vaccine. Methods: A randomized, double-blind, positive-controlled clinical [...] Read more.
Background: The persistence of non-neonatal tetanus (non-NT) highlights the necessity of adult booster vaccines and post-traumatic prophylaxis. This Phase I/III clinical trial aimed to evaluate the safety and immunogenicity of a new adsorbed tetanus vaccine. Methods: A randomized, double-blind, positive-controlled clinical trial was conducted in Henan Province, China. A total of 1258 healthy participants aged 18–44 years (60 in Phase I and 1198 in Phase III) were enrolled, with no history of tetanus infection, or tetanus toxoid-containing vaccines (TTCVs) vaccination within the past 10 years. The participants were randomly assigned at a 1:1 ratio to receive a single dose of either the investigational vaccine or the licensed control vaccine. The Phase III clinical trial was initiated subsequent to the 7-day safety observation period following vaccination in the Phase I trial. The objective of the Phase III clinical trial was to assess the non-inferiority of the seroconversion rate of tetanus antibodies at 30 days post-vaccination with the investigational vaccine compared to the control vaccine. Serum samples were collected prior to and at 30 days post-vaccination. Adverse events were monitored for 30 days, with serious adverse events (SAEs) followed up for 6 months post-vaccination. Results: The investigational group achieved a seroconversion rate of 99.48%, which was non-inferior to that of the control group (99.66%), with a negligible rate difference of −0.17% (95% confidence interval [CI]: −1.20%, 0.78%). The investigational group exhibited a significantly higher geometric mean concentration (GMC) of antibodies (4.721 IU/mL vs. 3.627 IU/mL, p < 0.0001). Among the susceptible participants, the seroconversion rates were 99.78% in the investigational group and 99.79% in the control group, respectively, with a non-inferior rate difference of −0.01% (95%CI: −1.06%, 0.97%). Furthermore, the investigational group showed a low incidence of adverse reactions (ARs) within 30 days post-vaccination (12.26%), which was comparable to that of the control group (13.65%). All the reported ARs were mild or moderate, and no SAEs were associated with the vaccination. Conclusions: The new adsorbed tetanus vaccine demonstrated favorable safety and comparable immunogenicity to the marketed control vaccine, with a significantly higher antibody GMC, supporting its clinical application in tetanus prevention. Full article
(This article belongs to the Special Issue Advancements in Vaccine Research: Epidemiology, Immunogenicity, Effectiveness and Safety)
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15 pages, 2543 KB  
Article
Immunogenicity and Antigenicity of the Recombinant Ectodomain of Rabies Virus Glycoprotein Containing the Human Collagen XVIII Trimerization Domain
by Izat Smekenov, Gulshat Bayandy, Sanzhar Alybayev, Nuraiym Baltakhozha, Zhanat Batanova, Nurlan Akhmetsadykov and Amangeldy Bissenbaev
Vaccines 2025, 13(9), 971; https://doi.org/10.3390/vaccines13090971 - 12 Sep 2025
Viewed by 460
Abstract
Background: Rabies remains a fatal zoonotic disease, necessitating effective and affordable vaccines. While current vaccines are effective, they require multiple doses and may not induce long-lasting immunity in all settings. The rabies virus glycoprotein (RABV-G) is the principal antigen responsible for eliciting [...] Read more.
Background: Rabies remains a fatal zoonotic disease, necessitating effective and affordable vaccines. While current vaccines are effective, they require multiple doses and may not induce long-lasting immunity in all settings. The rabies virus glycoprotein (RABV-G) is the principal antigen responsible for eliciting virus-neutralizing antibodies, but its recombinant monomeric forms often suffer from poor immunogenicity due to misfolding and aggregation. Methods: A recombinant trimeric RABV-G ectodomain (rRABV-G-XVIII) was engineered by fusing it to a human collagen XVIII-derived trimerization domain. The protein was expressed in E. coli, purified under denaturing conditions, and refolded. Trimer formation was verified using size-exclusion chromatography. Mice were immunized with rRABV-G-XVIII, with or without adjuvant, and compared to a monomeric form (rRABV-GE). Antigen-specific antibody responses were measured by ELISA, neutralizing activity was assessed, and protective efficacy was evaluated via intracerebral challenge with the CVS-27 rabies strain. Results: rRABV-G-XVIII formed stable trimers and induced strong humoral immune responses, with high ELISA titers and virus-neutralizing activity comparable to an inactivated rabies vaccine. Mice immunized with rRABV-GE showed lower antibody responses and partial protection, which improved with adjuvant. All rRABV-G-XVIII-immunized mice were fully protected against rabies challenge, independent of adjuvant use. Conclusions: Stabilization of RABV-G in its native trimeric conformation markedly improves immunogenicity and protective efficacy. This approach offers a promising strategy for the development of rabies subunit vac-cines with simplified formulations and potential for cost-effective production in bacterial systems. Full article
(This article belongs to the Section Vaccine Design, Development, and Delivery)
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17 pages, 728 KB  
Review
Engineering Universal Cancer Immunity: Non-Tumor-Specific mRNA Vaccines Trigger Epitope Spreading in Cold Tumors
by Matthias Magoola and Sarfaraz K. Niazi
Vaccines 2025, 13(9), 970; https://doi.org/10.3390/vaccines13090970 - 12 Sep 2025
Viewed by 975
Abstract
The landscape of cancer immunotherapy must shift from personalized neoantigen vaccines toward universal platforms that leverage innate immune activation. This review examines a novel mRNA vaccine strategy that encodes non-tumor-specific antigens, carefully selected pathogen-derived or synthetic sequences designed to transform immunologically “cold” tumors [...] Read more.
The landscape of cancer immunotherapy must shift from personalized neoantigen vaccines toward universal platforms that leverage innate immune activation. This review examines a novel mRNA vaccine strategy that encodes non-tumor-specific antigens, carefully selected pathogen-derived or synthetic sequences designed to transform immunologically “cold” tumors into inflamed therapy-responsive microenvironments. Unlike conventional approaches requiring patient-specific tumor sequencing and 8–12-week manufacturing timelines, this platform utilizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to trigger broad innate immune activation through multiple pattern recognition receptors (PRRs). The key therapeutic mechanism is epitope spreading, where vaccine-induced inflammation reveals previously hidden tumor antigens, enabling the immune system to mount responses against cancer-specific targets without prior knowledge of these antigens. Delivered via optimized lipid nanoparticles (LNPs) or alternative polymer-based systems, these vaccines induce epitope spreading, enhance checkpoint inhibitor responsiveness, and establish durable antitumor memory. This approach offers several potential advantages, including immediate treatment availability, a cost reduction of up to 100-fold compared to personalized vaccines, scalability for global deployment, and efficacy across diverse tumor types. However, risks such as cytokine release syndrome (CRS), potential for off-target autoimmunity, and challenges with pre-existing immunity must be addressed. By eliminating barriers of time, cost, and infrastructure, this universal platform could help democratize access to advanced cancer treatment, potentially benefiting the 70% of cancer patients in low- and middle-income countries (LMICs) who currently lack immunotherapy options. Full article
(This article belongs to the Section Vaccination Against Cancer and Chronic Diseases)
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14 pages, 612 KB  
Article
COVID-19 Vaccination Reduces Lower Limb Amputation Rates and Mortality Rate in Patients with Pre-Existing Peripheral Vascular Disease Based on TriNetX Database
by Shiuan-Tzuen Su, Yu-Hsuan Huang, Jing-Yang Huang and James C.-C. Wei
Vaccines 2025, 13(9), 969; https://doi.org/10.3390/vaccines13090969 - 12 Sep 2025
Viewed by 431
Abstract
Background: Unvaccinated individuals with peripheral arterial occlusive disease (PAOD) are more likely to develop acute limb ischemia (ALI) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We assessed the protective effect of the COVID-19 vaccine in preventing ALI in PAOD patients with [...] Read more.
Background: Unvaccinated individuals with peripheral arterial occlusive disease (PAOD) are more likely to develop acute limb ischemia (ALI) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We assessed the protective effect of the COVID-19 vaccine in preventing ALI in PAOD patients with SARS-CoV-2 infection. Methods: This retrospective cohort study was conducted using the United States TriNetX (Cambridge, MA, USA), using patients with PAOD who were diagnosed with SARS-CoV-2 infection between 1 November 2020 and 31 December 2023. Propensity score matching was performed to adjust for demographic variables, lifestyle factors, medical utilization, and comorbidities. Cox proportional hazards models were used to compare the two matched cohorts. Kaplan–Meier analysis estimated the 3-year cumulative probability of lower limb amputation incidence. We selected 12,948 PAOD patients who received the COVID-19 vaccine and 44,064 PAOD patients who were unvaccinated against COVID-19. Results: A total of 11,822 pairs of COVID-19 vaccinated PAOD patients and unvaccinated individuals were compared. The mean (SD) age was 66.5 (14.1) years; there were 4849 male patients (41%) and 6569 female (55.6%) compared to unvaccinated PAOD patients, and those who received the COVID-19 vaccine had a significantly lower risk of 3-year all-cause mortality (log-rank test, p < 0.001; hazard ratio (HR) was 0.857; 95% CI, 0.796–0.922) and lower limb amputation (log-rank test, p = 0.001, HR = 0.716; 95% CI, 0.587–0.873), though there was no significant difference in ischemic stroke (log-rank test, p = 0.174; HR = 0.958; 95% CI, 0.902–1.019). Conclusions: This study found that patients who received the COVID-19 vaccine had a significantly lower risk of 3-year all-cause mortality and lower limb amputation, though there was no significant difference in ischemic stroke. Full article
(This article belongs to the Special Issue Vaccines and Immunotherapy for Inflammatory Disease)
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14 pages, 1863 KB  
Article
Adjuvant Mucosal Strategies Confer Safe and Effective Immunity Against Mycoplasma pneumoniae and Overcome Vaccine-Associated Enhanced Lung Pathology
by Zhentao Lei, Dandan Gao, Xiaolong Zhang, Han Cao, Jingping Hu, Yifan Zhou, Ning Luan and Cunbao Liu
Vaccines 2025, 13(9), 968; https://doi.org/10.3390/vaccines13090968 - 12 Sep 2025
Viewed by 473
Abstract
Background/Objectives: The global spread of Mycoplasma pneumoniae (MP) poses a significant threat to public health; however, no licensed vaccine for human use is currently available. The development of a safe and effective vaccine is a critical priority. This study systematically evaluated the protective [...] Read more.
Background/Objectives: The global spread of Mycoplasma pneumoniae (MP) poses a significant threat to public health; however, no licensed vaccine for human use is currently available. The development of a safe and effective vaccine is a critical priority. This study systematically evaluated the protective efficacy and safety of an inactivated MP vaccine using different adjuvants and immunization routes. Methods: Mice were immunized with inactivated vaccines via either intramuscular (IM) injection with aluminum hydroxide (alum) or a combination of CpG+QS21 (CQ) or via intranasal (IN) administration of Flagellin from Salmonella Typhimurium (FLA-ST), a potent Toll-like receptor 5 (TLR5) agonist, as a mucosal adjuvant. Vaccine-induced immunogenicity, protective efficacy against MP challenge, and associated lung pathology were assessed. Results: Both IM-vaccinated groups (alum and CQ) exhibited robust systemic immune responses. However, upon subsequent MP challenge, these groups exhibited significant inflammatory pathology in the lung tissues. Notably, the CQ-adjuvanted group displayed severe pulmonary inflammatory infiltration. In stark contrast, compared with the IM-vaccinated group, the IN-immunized group with the FLA-ST mucosal adjuvant achieved significant clearance of MP from the lungs and showed markedly milder histopathological lung damage. Conclusions: Our findings suggest that IM immunization with CQ-adjuvanted inactivated vaccines may represent a suboptimal strategy for MP, given the risk of exacerbating lung immunopathology. Conversely, a mucosal immunization approach using the FLA-ST adjuvant demonstrates considerable promise, offering an effective balance between bacterial clearance and an improved safety profile, highlighting its potential for future MP vaccine development. Full article
(This article belongs to the Section Vaccine Advancement, Efficacy and Safety)
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17 pages, 1008 KB  
Article
Impact of COVID-19 on Mucosal Immunity and Antibody Responses in COVID Vaccinees
by Priya Kannian, Muruganantham Lillimary Eniya, Pasuvaraj Mahanathi, Arul Gracemary, Nagalingeswaran Kumarasamy and Stephen J. Challacombe
Vaccines 2025, 13(9), 967; https://doi.org/10.3390/vaccines13090967 - 12 Sep 2025
Viewed by 442
Abstract
Background and Objectives: SARS-CoV-2 infection initiates at mucosal surfaces, and mucosal immunity may influence the nature and severity of infection. Little is known about the induction of mucosal immunity by vaccination in COVID-19 convalescents. Methods: Sera from 205 healthcare workers were [...] Read more.
Background and Objectives: SARS-CoV-2 infection initiates at mucosal surfaces, and mucosal immunity may influence the nature and severity of infection. Little is known about the induction of mucosal immunity by vaccination in COVID-19 convalescents. Methods: Sera from 205 healthcare workers were collected one month after the first Covishield vaccination and 1/3/6 months after the second vaccination, while paired sera and stimulated whole-mouth fluid (SWMF) was collected 1/3/6 months after the third vaccination (N = 10) and at 0/30/90 days after a COVID-19 episode (N = 8). Anti-SARS-CoV-2 spike antibody detection by ECLIA/ELISA and cytokine detection by ELISA/CBA were performed. Results: One month post-second vaccination, serum antibodies had increased significantly (6-fold) in the COVID-19-naïve group (CNG) but declined (1.5-fold) in the previously COVID-19-exposed group (CEG), who already had high antibody titres. The serum regulatory cytokine IL-10 levels were higher after three antigen exposures (p = 0.0002). New infections (breakthrough infections—BTIs) or reinfections (RIs) with asymptomatic/mild disease occurred in 44% of the CNG and 27% of the CEG (p < 0.01). The mucosal cytokine IL-17 levels were significantly higher in the CEG. Salivary IgG/IgA and secretory IgA antibodies were detectable both after vaccination and COVID-19. Innate cytokines (MIG, MCP-1, IL-8, IL-1β) were higher and sustained in SWMF in contrast to serum. Conclusions: Two vaccinations in the CNG resulted in an antibody boost, but the second vaccination in the CEG induced antibody anergy. Serum/mucosal antibodies declined by six months after vaccination, but the rapid increase at subsequent exposures were indicative of a good T cell/B cell memory response to SARS-CoV-2. A higher percentage of BTI among the CNG than RI among the CEG may indicate better protection due to higher antibody responses in the latter group. Full article
(This article belongs to the Special Issue A One-Health Perspective on Immunization Against Infectious Diseases)
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20 pages, 2143 KB  
Article
Differences in Glycoproteins and the Potential for Early Protection Using LAIV Based on Drift Variants of the A/H1N1pdm09 Influenza Virus
by Yulia Desheva, Irina Mayorova, Andrey Rekstin, Daniil Sokolovsky, Polina Kudar, Nina Kopylova, Danila Guzenkov, Darya Petrachkova, Andrey Mamontov, Andrey Trullioff and Irina Kiseleva
Vaccines 2025, 13(9), 966; https://doi.org/10.3390/vaccines13090966 - 11 Sep 2025
Viewed by 367
Abstract
Background/Objectives: Antigenic drift of influenza A(H1N1pdm09) viruses has led to periodic replacement of vaccine strains. Understanding how structural differences in glycoproteins influence immune protection is crucial for improving vaccine effectiveness. Methods: We conducted a structural analysis of the hemagglutinin (HA) and neuraminidase (NA) [...] Read more.
Background/Objectives: Antigenic drift of influenza A(H1N1pdm09) viruses has led to periodic replacement of vaccine strains. Understanding how structural differences in glycoproteins influence immune protection is crucial for improving vaccine effectiveness. Methods: We conducted a structural analysis of the hemagglutinin (HA) and neuraminidase (NA) glycoproteins from drifted A(H1N1)pdm09 strains: A/South Africa/3626/2008 and A/Guangdong–Maonan/SWL1/2020, as well as their cold-adapted live attenuated vaccine (LAIV) reassortant strains (A/17/South Africa/2013/01(H1N1)pdm09 and A/17/Guangdong–Maonan/2019/211(H1N1)pdm09). We compared their replication in chicken embryo and mammalian cell culture, assessed type I interferon induction, and evaluated post-vaccine protection in mice after homologous and heterogeneous viral challenges. Results: The two vaccine strains had distinct glycosylation patterns for HA and NA. However, they had similar replication capacity in embryonated egg and mammalian cells. In the mouse respiratory tract, both strains replicated similarly. A/17/South Africa/2013/01(H1N1)pdm09 induced significantly higher levels of IFN-α and Mx1 in vitro, and it elicited earlier IgM and IgG response after vaccination in mice. At day 6 after immunization, it provided 70% protection from homologous challenge. A/17/Guangdong–Maonan/2019/211(H1N1)pdm09 did not prevent death, but it reduced viral titer in the lungs. Interestingly, A/17/South Africa/2013/01(H1N1)pdm09 provided full protection from heterologous H5N1 challenge, while A/17/Guangdong–Maonan/2019/211(H1N1)pdm09) only provided partial protection. Conclusions: Differences in HA and NA glycans among A(H1N1)pdm09 strains may influence innate and adaptive immunity, as well as cross-protection. These findings emphasize the importance of glycoprotein structure when selecting vaccine candidates for optimal homologous and cross-protection against influenza. Full article
(This article belongs to the Section Influenza Virus Vaccines)
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22 pages, 2109 KB  
Article
Antibody Responses to SARS-CoV-2 and Common HCoVs in Hemodialysis Patients and Transplant Recipients: Data from the Dominican Republic
by Lisette Alcantara Sanchez, Eloy Alvarez Guerra, Dongmei Li, Samantha M. King, Shannon P. Hilchey, Qian Zhou, Stephen Dewhurst, Kevin Fiscella and Martin S. Zand
Vaccines 2025, 13(9), 965; https://doi.org/10.3390/vaccines13090965 - 11 Sep 2025
Viewed by 785
Abstract
Background: Vaccination against SARS-CoV-2 has been pivotal in controlling the COVID-19 pandemic. However, understanding vaccine-induced immunity in immunocompromised individuals remains critical, particularly how prior exposure to other coronaviruses modulates immune responses. The influence of previous infections with endemic human coronaviruses (HCoVs), such as [...] Read more.
Background: Vaccination against SARS-CoV-2 has been pivotal in controlling the COVID-19 pandemic. However, understanding vaccine-induced immunity in immunocompromised individuals remains critical, particularly how prior exposure to other coronaviruses modulates immune responses. The influence of previous infections with endemic human coronaviruses (HCoVs), such as OC43, on SARS-CoV-2 immunity is not fully understood. This study evaluates antibody responses to COVID-19 vaccination in hemodialysis patients (HD), transplant recipients (TR), and healthy controls (CO), accounting for prior SARS-CoV-2 infection and baseline human coronavirus (HCoV) reactivity. Methods: We obtained longitudinal antibody measurements from 70 subjects (CO: n = 33; HD: n = 13; TR: n = 24) and assessed antibody kinetics across multiple post-vaccination time points using multivariate linear mixed modeling (MLMM). Results: Limited but measurable cross-reactivity was observed between SARS-CoV-2 and endemic HCoVs, particularly the β-coronavirus OC43. Pre-existing immunity in healthy individuals modestly enhanced vaccine-induced anti-spike (S) IgG responses, supported by post-vaccination increases in SARS-CoV-2 IgG. Prior SARS-CoV-2 infection significantly influenced anti-S and nucleocapsid (N) IgG responses but had limited impact on endemic HCoVs responses. Vaccine type and immune status significantly affected antibody kinetics. mRNA vaccination (BNT162b2) elicited stronger and more durable SARS-CoV-2 anti-S IgG responses than the inactivated CoronaVac vaccine, especially in immunocompetent individuals. Immunocompromised groups showed delayed or attenuated responses, with modest anti-S IgG cross-reactive boosting. Elevated anti-N IgG in CoronaVac recipients raised questions about its origin—infection or vaccine effects. MLMM identified key immunological and clinical predictors of antibody responses, emphasizing the critical role of host immune history. Conclusions: These findings highlight a constrained but meaningful role for HCoV cross-reactivity in SARS-CoV-2 immunity and vaccine responsiveness, underscore the need for infection markers unaffected by vaccination, and support development of broadly protective pan-coronavirus vaccines and tailored strategies for at-risk populations. Full article
(This article belongs to the Section COVID-19 Vaccines and Vaccination)
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18 pages, 523 KB  
Systematic Review
Strategies to Increase Vaccinations in Adult Cancer Patients: A Systematic Review
by Giuseppina Lo Moro, Federica Golzio, Sara Claudia Calabrese, Giacomo Scaioli, Alessandro Basile, Roberta Siliquini and Fabrizio Bert
Vaccines 2025, 13(9), 964; https://doi.org/10.3390/vaccines13090964 - 11 Sep 2025
Viewed by 477
Abstract
Background/Objectives: Although vaccinations are a priority for patients with cancer, achieving high coverage remains challenging. Evidence on effective strategies in oncology settings is still limited. This systematic review aimed to identify interventions to improve vaccination uptake or reduce hesitancy among cancer patients. Methods: [...] Read more.
Background/Objectives: Although vaccinations are a priority for patients with cancer, achieving high coverage remains challenging. Evidence on effective strategies in oncology settings is still limited. This systematic review aimed to identify interventions to improve vaccination uptake or reduce hesitancy among cancer patients. Methods: A systematic search was conducted in PubMed, Embase, and Scopus, including studies published up to the end of 2023. The protocol was registered in PROSPERO (CRD42024511008). Results: Out of 10,927 non-duplicate records, 15 studies describing unique interventions were included. All studies were published between 2011 and 2022, primarily conducted in Europe/UK (40%) and in North America (40%). The most common study design was pre-post (60%), and 33.3% included a control group. Most interventions were multi-component (60%) and were classified into three main categories: educational materials/campaigns (46.7%), reminders (40%), and patient counselling (33.3%). Additional components included guideline development in two studies. Some studies also highlighted the importance of specific key figures, such as dedicated professionals, general practitioners, and pharmacists. Interventions mainly targeted patients (40%), with 33.3% addressing both healthcare professionals and patients and 26.7% professionals only. They most frequently concerned vaccinations against influenza and pneumococcal disease (26.7%), pneumococcal disease alone (26.7%), or Coronavirus Disease 2019 (COVID-19) (26.7%). Vaccination uptake was the primary outcome in 86.7% of studies, with 66.7% reporting significant improvements. Conclusions: This review identified a variety of strategies, with education, reminders, and counselling as key components. Multicomponent interventions and those involving both patients and providers were most promising. However, methodological limitations and limited generalizability highlighted the need for more rigorous research. Full article
(This article belongs to the Special Issue Virus Pandemics and Vaccinations)
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16 pages, 1547 KB  
Article
Cord Blood RSV-Neutralizing Antibodies and Risk of Hospitalization for RSV-Associated Acute Respiratory Infection in Vietnamese Children: A Case–Cohort Study
by Michiko Toizumi, Yutaro Yamagata, Hien Anh Thi Nguyen, Hirono Otomaru, Hoang Huy Le, Hiroyuki Moriuchi, Jean-Francois Eleouet, Marie-Anne Rameix-Welti, Makoto Takeda, Hung Thai Do and Lay-Myint Yoshida
Vaccines 2025, 13(9), 963; https://doi.org/10.3390/vaccines13090963 - 11 Sep 2025
Viewed by 461
Abstract
Background: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children, particularly severe during infancy. Maternal RSV-specific neutralizing antibodies (nAbs), transferred via the placenta, may provide protection in early infancy, but the extent and duration of protection remain [...] Read more.
Background: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children, particularly severe during infancy. Maternal RSV-specific neutralizing antibodies (nAbs), transferred via the placenta, may provide protection in early infancy, but the extent and duration of protection remain uncertain. Objective: We investigated the association between cord blood RSV-A nAb levels and the risk of hospitalization due to RSV-associated acute respiratory infection (RSV-ARI) by 24 months of age. Methods: We conducted a case–cohort study nested within a birth cohort in Nha Trang, Vietnam. From the full cohort (n = 1977), a random subcohort of 392 infants and all 66 infants hospitalized for RSV-ARI by age 24 months were included for RSV-A nAb testing. RSV-A nAb titers at birth were categorized into three groups in the subcohort (low: lowest quartile; middle; interquartile; high: highest quartile). Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) for RSV-ARI hospitalization. Results: The incidence of RSV-ARI hospitalization was 17.92 per 1000 person-years by 24 months, and 25.40 per 1000 person-years among infants aged <12 months. Among infants aged <6 months, those in the low nAb group had a significantly higher risk of hospitalization compared to the middle nAb group (adjusted HR: 4.05; 95% CI: 1.51–10.89). Maternal anemia was consistently associated with increased risk. Conclusions: Lower RSV-nAb titers at birth were associated with an increased risk of RSV-ARI hospitalization during early infancy. These findings support the importance of maternal immunization strategies to enhance infant protection against RSV. Full article
(This article belongs to the Special Issue Host Immunity and Vaccines for Respiratory Pathogens)
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Review
Influenza Vaccines: Current Status, Adjuvant Strategies, and Efficacy
by Vijay Reddy Mokalla, Shirisha Gundarapu, Radhey S. Kaushik, Mrigendra Rajput and Hemachand Tummala
Vaccines 2025, 13(9), 962; https://doi.org/10.3390/vaccines13090962 - 11 Sep 2025
Viewed by 1538
Abstract
The influenza virus is one of the major global health concerns, causing significant morbidity and mortality in both humans and animals, with substantial impacts on public health. Vaccination remains the primary strategy for managing influenza virus infections; however, the virus undergoes frequent genetic [...] Read more.
The influenza virus is one of the major global health concerns, causing significant morbidity and mortality in both humans and animals, with substantial impacts on public health. Vaccination remains the primary strategy for managing influenza virus infections; however, the virus undergoes frequent genetic changes through antigenic drift and shift. These mutations lead to new seasonal strains that evade pre-existing immunity. These mutations can potentially result in virulent strains that could trigger future pandemics. Therefore, developing a vaccine capable of providing robust protection despite these genetic changes is essential. Vaccine adjuvants are essential for boosting and directing the immune system’s response, broadening the spectrum of protection, and reducing the amount of antigen required to achieve protection, which is particularly valuable in the face of rapidly evolving strains and during pandemics. Recent advances in adjuvant design and formulation strategies have demonstrated promising improvements in both the overall potency and durability of influenza vaccines, importantly, significant reductions in losses due to influenza infection. This review highlights the current status of different types of influenza virus vaccines, their benefits, and challenges. Further, the review focuses on the role of adjuvants, discussing their advantages, limitations, and methodological approaches, while also considering their potential contribution in developing a universal flu vaccine intended to provide extensive and lasting protection. Full article
(This article belongs to the Section Vaccine Advancement, Efficacy and Safety)
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