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Vaccines
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Strategies of Viral Vectors for Vaccine Development
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Strategies of Viral Vectors for Vaccine Development

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Attenuated/Inactivated/Live and Vectored Vaccines".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 11818

Special Issue Editor

Dr. Kathleen Hefferon

E-Mail Website
Guest Editor
Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 1A1, Canada
Interests: plant made pharmaceuticals; public health; sustainability; molecular farming; food security
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viral vectors have long been explored as potential tools in medicine. As these vectors grow more and more sophisticated, their applications have expanded. Viral vectors can be used to carry drugs, express heterologous proteins, and even target cancer cells. The scope of this Special Issue will include the development of animal, plant and bacterial virus vectors as a means to produce safe, efficacious and inexpensive vaccines. I/We look forward to receiving your contributions.

Dr. Kathleen Hefferon
Guest Editor

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 100 words) can be sent to the Editorial Office for announcement on this website.

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
  • viral vector
  • virus-like particles

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Published Papers (7 papers)

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Research

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15 pages, 2145 KiB  
Article
Single-Dose Intranasal Immunization with ChAd68-Vectored Prefusion F Vaccines Confers Sustained Protection Against Respiratory Syncytial Virus in Murine Models
by Jing Miao, Xuejie Li, Yingwen Li, Lingjing Mao, Wenkai Suo and Jiaming Lan
Vaccines 2025, 13(5), 528; https://doi.org/10.3390/vaccines13050528 - 15 May 2025
Viewed by 316
Abstract
Background/Objectives: Respiratory syncytial virus (RSV) poses a substantial global health threat, particularly impacting infants and vulnerable pediatric populations through severe respiratory morbidity. Methods: We developed a novel adenoviral vector vaccine platform utilizing chimpanzee adenovirus 68 (AdC68) to deliver prefusion F (pre-F) antigens from [...] Read more.
Background/Objectives: Respiratory syncytial virus (RSV) poses a substantial global health threat, particularly impacting infants and vulnerable pediatric populations through severe respiratory morbidity. Methods: We developed a novel adenoviral vector vaccine platform utilizing chimpanzee adenovirus 68 (AdC68) to deliver prefusion F (pre-F) antigens from RSV subtypes A and B, generating three vaccine candidates: AdC68-A (subtype A), AdC68-B (subtype B), and AdC68-A+B (bivalent formulation). Results: Single intranasal (i.n.) immunization and prime–boost immunizations via intramuscular (i.m.) routes in BALB/c mice induced robust immune activation, with single i.n. administration conferring durable protection evidenced by an 85% reduction in pulmonary viral loads (p < 0.05) at 134 days post-immunization. All vaccine formulations via i.n. single administration elicited potent subtype-specific IgG responses (geometric mean titers 50–12,800) and Th1-polarized cellular immunity (552–1201 IFN-γ+ spot-forming units/106 PBMCs, IgG2a/IgG1 > 1) in bivalent formulation group, while i.m. boosting enhanced cellular responses 3-fold versus prime immunization alone (p < 0.01). Notably, despite undetectable serum-neutralizing antibodies and absent mucosal IgA in bronchoalveolar lavage at 7 days post-i.n. immunization, the sustained viral control highlights non-neutralizing antibody-mediated protective mechanisms. Conclusions: These findings establish the proof-of-concept for adenoviral-vectored intranasal vaccines against RSV, though optimization of humoral response induction and mucosal immunity duration require further investigation. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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24 pages, 5421 KiB  
Article
Rapid Development of Modified Vaccinia Virus Ankara (MVA)-Based Vaccine Candidates Against Marburg Virus Suitable for Clinical Use in Humans
by Alina Tscherne, Georgia Kalodimou, Alexandra Kupke, Cornelius Rohde, Astrid Freudenstein, Sylvia Jany, Satendra Kumar, Gerd Sutter, Verena Krähling, Stephan Becker and Asisa Volz
Vaccines 2024, 12(12), 1316; https://doi.org/10.3390/vaccines12121316 - 24 Nov 2024
Cited by 1 | Viewed by 1902
Abstract
Background/Objectives: Marburg virus (MARV) is the etiological agent of Marburg Virus Disease (MVD), a rare but severe hemorrhagic fever disease with high case fatality rates in humans. Smaller outbreaks have frequently been reported in countries in Africa over the last few years, and [...] Read more.
Background/Objectives: Marburg virus (MARV) is the etiological agent of Marburg Virus Disease (MVD), a rare but severe hemorrhagic fever disease with high case fatality rates in humans. Smaller outbreaks have frequently been reported in countries in Africa over the last few years, and confirmed human cases outside Africa are, so far, exclusively imported by returning travelers. Over the previous years, MARV has also spread to non-endemic African countries, demonstrating its potential to cause epidemics. Although MARV-specific vaccines are evaluated in preclinical and clinical research, none have been approved for human use. Modified Vaccinia virus Ankara (MVA), a well-established viral vector used to generate vaccines against emerging pathogens, can deliver multiple antigens and has a remarkable clinical safety and immunogenicity record, further supporting its evaluation as a vaccine against MARV. The rapid availability of safe and effective MVA-MARV vaccine candidates would expand the possibilities of multi-factored intervention strategies in endemic countries. Methods: We have used an optimized methodology to rapidly generate and characterize recombinant MVA candidate vaccines that meet the quality requirements to proceed to human clinical trials. As a proof-of-concept for the optimized methodology, we generated two recombinant MVAs that deliver either the MARV glycoprotein (MVA-MARV-GP) or the MARV nucleoprotein (MVA-MARV-NP). Results: Infections of human cell cultures with recombinant MVA-MARV-GP and MVA-MARV-NP confirmed the efficient synthesis of MARV-GP and MARV-NP proteins in mammalian cells, which are non-permissive for MVA replication. Prime-boost immunizations in C57BL/6J mice readily induced circulating serum antibodies binding to recombinant MARV-GP and MARV-NP proteins. Moreover, the MVA-MARV-candidate vaccines elicited MARV-specific T-cell responses in C57BL/6J mice. Conclusions: We confirmed the suitability of our two backbone viruses MVA-mCherry and MVA-GFP in a proof-of-concept study to rapidly generate candidate vaccines against MARV. However, further studies are warranted to characterize the protective efficacy of these recombinant MVA-MARV vaccines in other preclinical models and to evaluate them as vaccine candidates in humans. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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17 pages, 5114 KiB  
Article
Newcastle Disease Virus Expressing Cap Gene of Porcine Circovirus Type 2 Confers Protection in Mice and Induced Long-Lasting Neutralizing Antibodies in Pigs
by Sohini Dey, Rudhreswaran Murugasamy, Lukumoni Buragohain, Ajai Lawrence D’silva, Jayashree Sarma, Arpita Bharali, Saravanan Ramakrishnan, Mani Saminathan, Nagendra Nath Barman, Vikram N. Vakharia and Madhan Mohan Chellappa
Vaccines 2024, 12(11), 1285; https://doi.org/10.3390/vaccines12111285 - 15 Nov 2024
Cited by 1 | Viewed by 1506
Abstract
Background/Objectives: Porcine Circovirus 2 (PCV2) infection poses significant health and economic challenges to the global swine industry. The disease in pigs leads to lymphoid depletion, resulting in immunosuppression and increased susceptibility to co-infections with other bacterial and viral pathogens. This study evaluated [...] Read more.
Background/Objectives: Porcine Circovirus 2 (PCV2) infection poses significant health and economic challenges to the global swine industry. The disease in pigs leads to lymphoid depletion, resulting in immunosuppression and increased susceptibility to co-infections with other bacterial and viral pathogens. This study evaluated the efficacy of two novel recombinant Newcastle disease virus (NDV) strain R2B vectored vaccines that express the cap gene of PCV2 alone and along with the transmembrane and cytoplasmic tail (TMCT) domains of the NDV F gene. The efficacy of the vaccine candidates was studied in mouse and pig models. Methods: Six-week-old BALB/c mice were divided into five groups and immunized intramuscularly three times at 14-day intervals with various vaccine candidates, namely rNDV-R2B-PCVcap-TMCT, rNDV-R2B-PCVcap, and CircoFLEX commercial vaccine, along with controls. Following immunization and PCV2d virus challenge, multiple assays assessed the immune responses in animal trials. In the pig animal trial, pigs were divided into four groups: a control group (PBS), NDV-vectored PCVcap-TMCT group, NDV-vectored-PCVcap group, and CircoFLEX vaccine group. Pigs were immunized intramuscularly twice at 28-day intervals. Blood samples were collected at regular intervals over 70 days to evaluate the humoral and cell-mediated immune responses. Results: Both mice and pigs’ trials indicated that the NDV-vectored PCV2 cap-TMCT vaccine candidate elicited superior immune responses. In mice, the rNDV-R2B-PCVcap-TMCT group showed enhanced humoral and cellular immunity, increased PCV2-specific antibody levels, higher CD4+/CD8+ ratio, elevated IFN-γ and TNF-α levels, decreased IL-10 levels, reduced viral loads, and minimal histopathological changes. In pigs, the NDV-vectored PCVcap-TMCT group demonstrated better antibody responses, cytokine profiles (IFN-γ and IL-10), and higher levels of PCV2-specific neutralizing antibodies against the PCV2a, PCV2b and PCV2d genotypes when compared to other groups. Conclusions: These findings suggest NDV-vectored PCVcap-TMCT vaccine candidate, expressing the cap gene of PCV2 along with the TMCT domain, offers a promising alternative for protecting against PCV2 infection, potentially addressing the challenges posed by emerging PCV2 strains in the swine industry. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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22 pages, 3833 KiB  
Article
Viral Vector-Based Chlamydia trachomatis Vaccines Encoding CTH522 Induce Distinct Immune Responses in C57BL/6J and HLA Transgenic Mice
by Giuseppe Andreacchio, Ylenia Longo, Sara Moreno Mascaraque, Kartikan Anandasothy, Sarah Tofan, Esma Özün, Lena Wilschrey, Johannes Ptok, Dung T. Huynh, Joen Luirink and Ingo Drexler
Vaccines 2024, 12(8), 944; https://doi.org/10.3390/vaccines12080944 - 22 Aug 2024
Viewed by 1595
Abstract
Chlamydia trachomatis remains a major global health problem with increasing infection rates, requiring innovative vaccine solutions. Modified Vaccinia Virus Ankara (MVA) is a well-established, safe and highly immunogenic vaccine vector, making it a promising candidate for C. trachomatis vaccine development. In this study, [...] Read more.
Chlamydia trachomatis remains a major global health problem with increasing infection rates, requiring innovative vaccine solutions. Modified Vaccinia Virus Ankara (MVA) is a well-established, safe and highly immunogenic vaccine vector, making it a promising candidate for C. trachomatis vaccine development. In this study, we evaluated two novel MVA-based recombinant vaccines expressing spCTH522 and CTH522:B7 antigens. Our results show that while both vaccines induced CD4+ T-cell responses in C57BL/6J mice, they failed to generate antigen-specific systemic CD8+ T cells. Only the membrane-anchored CTH522 elicited strong IgG2b and IgG2c antibody responses. In an HLA transgenic mouse model, both recombinant MVAs induced Th1-directed CD4+ T cell and multifunctional CD8+ T cells, while only the CTH522:B7 vaccine generated antibody responses, underscoring the importance of antigen localization. Collectively, our data indicate that distinct antigen formulations can induce different immune responses depending on the mouse strain used. This research contributes to the development of effective vaccines by highlighting the importance of careful antigen design and the selection of appropriate animal models to study specific vaccine-induced immune responses. Future studies should investigate whether these immune responses provide protection in humans and should explore different routes of immunization, including mucosal and systemic immunization. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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13 pages, 4129 KiB  
Article
Vaccination with Adenovirus Type 5 Vector-Based COVID-19 Vaccine as the Primary Series in Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 1/2 Clinical Trial
by Yawen Zhu, Rong Tang, Xiaolong Li, Xiaoqin Chen, Xue Wang, Ying Wang, Ruijie Wang, Fengcai Zhu and Jingxin Li
Vaccines 2024, 12(3), 292; https://doi.org/10.3390/vaccines12030292 - 11 Mar 2024
Cited by 1 | Viewed by 2782
Abstract
This randomized, double-blind, placebo-controlled phase 1/2 trial aimed at evaluating the safety and immunogenicity of Ad5-nCoV via aerosolized or intramuscular or intramuscular–aerosolized routes in SARS-CoV-2-negative adults aged over 18 years. In the phase 1 trial, participants were sequentially enrolled into one of five [...] Read more.
This randomized, double-blind, placebo-controlled phase 1/2 trial aimed at evaluating the safety and immunogenicity of Ad5-nCoV via aerosolized or intramuscular or intramuscular–aerosolized routes in SARS-CoV-2-negative adults aged over 18 years. In the phase 1 trial, participants were sequentially enrolled into one of five regimen cohorts: Low-Dose (two doses of aerosolized Ad5-nCoV with 0.5 × 1010 viral particles [vps] per dose), Middle-Dose (two doses of aerosolized Ad5-nCoV with 1.0 × 1010 vps per dose), High-Dose (two doses of aerosolized Ad5-nCoV with 2.0 × 1010 vps per dose), Mixed (intramuscular Ad5-nCoV with 5.0 × 1010 vps [first dose] and aerosolized Ad5-nCoV with 2.0 × 1010 vps [second dose]), and Single-Dose (one dose of aerosolized Ad5-nCoV with 1.0 × 1010 vps). Eligible participants in the phase 2 trial were stratified by 18–59 years old or ≥60 years old and then were sequentially enrolled into one of six regimen cohorts: Low-Dose, Middle-Dose, High-Dose, Mixed, Single-Dose, and Intramuscular (one dose of intramuscular Ad5-nCoV with 1.0 × 1010 vps). The intervals between the two doses were 56 days. Participants were randomly allocated in 3:1 (phase 1) and 5:1 (phase 2) ratios to receive either Ad5-nCoV or the placebo in each cohort. This study is registered on ClinicalTrials.gov, NCT04840992. Most adverse reactions that occurred during the solicited period were mild and moderate. One serious adverse event (myelodysplastic syndrome) was considered potentially related to the aerosolized Ad5-nCoV. The GMTs of neutralizing antibodies in the Mixed group were the highest with 57.03 (95% CI: 23.95, 135.80) and 97.37 (95% CI: 74.30, 127.59) in phase 1 and 2 trials, respectively, 28 days after the second dose (p < 0.0001), which showed significantly higher immune responses compared to other regimens with aerosolized or intramuscular Ad5-nCoV alone. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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Review

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20 pages, 986 KiB  
Review
Past, Present, and Future of Viral Vector Vaccine Platforms: A Comprehensive Review
by Justin Tang, Md Al Amin and Jian L. Campian
Vaccines 2025, 13(5), 524; https://doi.org/10.3390/vaccines13050524 - 15 May 2025
Viewed by 441
Abstract
Over the past several decades, viral vector-based vaccines have emerged as some of the most versatile and potent platforms in modern vaccinology. Their capacity to deliver genetic material encoding target antigens directly into host cells enables strong cellular and humoral immune responses, often [...] Read more.
Over the past several decades, viral vector-based vaccines have emerged as some of the most versatile and potent platforms in modern vaccinology. Their capacity to deliver genetic material encoding target antigens directly into host cells enables strong cellular and humoral immune responses, often superior to what traditional inactivated or subunit vaccines can achieve. This has accelerated their application to a wide array of pathogens and disease targets, from well-established threats like HIV and malaria to emerging infections such as Ebola, Zika, and SARS-CoV-2. The COVID-19 pandemic further highlighted the agility of viral vector platforms, with several adenovirus-based vaccines quickly authorized and deployed on a global scale. Despite these advances, significant challenges remain. One major hurdle is pre-existing immunity against commonly used vector backbones, which can blunt vaccine immunogenicity. Rare but serious adverse events, including vector-associated inflammatory responses and conditions like vaccine-induced immune thrombotic thrombocytopenia (VITT), have raised important safety considerations. Additionally, scaling up manufacturing, ensuring consistency in large-scale production, meeting rigorous regulatory standards, and maintaining equitable global access to these vaccines present profound logistical and ethical dilemmas. In response to these challenges, the field is evolving rapidly. Sophisticated engineering strategies, such as integrase-defective lentiviral vectors, insect-specific flaviviruses, chimeric capsids to evade neutralizing antibodies, and plug-and-play self-amplifying RNA approaches, seek to bolster safety, enhance immunogenicity, circumvent pre-existing immunity, and streamline production. Lessons learned from the COVID-19 pandemic and prior outbreaks are guiding the development of platform-based approaches designed for rapid deployment during future public health emergencies. This review provides an exhaustive, in-depth examination of the historical evolution, immunobiological principles, current platforms, manufacturing complexities, regulatory frameworks, known safety issues, and future directions for viral vector-based vaccines. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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13 pages, 256 KiB  
Review
Strategic and Technical Considerations in Manufacturing Viral Vector Vaccines for the Biomedical Advanced Research and Development Authority Threats
by Lindsay A. Parish, Shyam Rele, Kimberly A. Hofmeyer, Brooke B. Luck and Daniel N. Wolfe
Vaccines 2025, 13(1), 73; https://doi.org/10.3390/vaccines13010073 - 14 Jan 2025
Viewed by 2353
Abstract
Over the past few decades, the world has seen a considerable uptick in the number of new and emerging infectious disease outbreaks. The development of new vaccines, vaccine technologies, and platforms are critical to enhance our preparedness for biological threats and prevent future [...] Read more.
Over the past few decades, the world has seen a considerable uptick in the number of new and emerging infectious disease outbreaks. The development of new vaccines, vaccine technologies, and platforms are critical to enhance our preparedness for biological threats and prevent future pandemics. Viral vectors can be an important tool in the repertoire of technologies available to develop effective vaccines against new and emerging infectious diseases. In many instances, vaccines may be needed in a reactive scenario, requiring technologies than can elicit rapid and robust immune responses with a single dose. Here, we discuss how viral vector vaccines are utilized in a vaccine portfolio for priority biological threats, some of the challenges in manufacturing viral vector vaccines, the need to strengthen live virus manufacturing capabilities, and future opportunities to capitalize on the use of viral vectors to improve the sustainability of the Biomedical Advanced Research and Development Authority’s vaccine portfolio. Full article
(This article belongs to the Special Issue Strategies of Viral Vectors for Vaccine Development)
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