Application of Viral Vectors for Vaccine Development with a Special Emphasis on COVID-19

Viral vectors can generate high levels of recombinant protein expression providing the basis for modern vaccine development. A large number of different viral vector expression systems have been utilized for targeting viral surface proteins and tumor-associated antigens. Immunization studies in preclinical animal models have evaluated the elicited humoral and cellular responses and the possible protection against challenges with lethal doses of infectious pathogens or tumor cells. Several vaccine candidates for both infectious diseases and various cancers have been subjected to a number of clinical trials. Human immunization trials have confirmed safe application of viral vectors, generation of neutralizing antibodies and protection against challenges with lethal doses. A special emphasis is placed on COVID-19 vaccines based on viral vectors. Likewise, the flexibility and advantages of applying viral particles, RNA replicons and DNA replicon vectors of self-replicating RNA viruses for vaccine development are presented.

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Self-Replicating RNA Viruses for Vaccine Development against Infectious Diseases and Cancer

Vaccines ◽

10.3390/vaccines9101187 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1187

Author(s):

Kenneth Lundstrom

Keyword(s):

Infectious Diseases ◽

Viral Vectors ◽

Ebola Virus ◽

Tumor Antigens ◽

Vaccine Development ◽

Rna Viruses ◽

Virus Disease ◽

Recombinant Protein Expression ◽

Polymerase Activity ◽

Surface Proteins

Alphaviruses, flaviviruses, measles viruses and rhabdoviruses are enveloped single-stranded RNA viruses, which have been engineered for recombinant protein expression and vaccine development. Due to the presence of RNA-dependent RNA polymerase activity, subgenomic RNA can replicate close to 106 copies per cell for translation in the cytoplasm providing extreme transgene expression levels, which is why they are named self-replicating RNA viruses. Expression of surface proteins of pathogens causing infectious disease and tumor antigens provide the basis for vaccine development against infectious diseases and cancer. Self-replicating RNA viral vectors can be administered as replicon RNA at significantly lower doses than conventional mRNA, recombinant particles, or DNA plasmids. Self-replicating RNA viral vectors have been applied for vaccine development against influenza virus, HIV, hepatitis B virus, human papilloma virus, Ebola virus, etc., showing robust immune response and protection in animal models. Recently, paramyxovirus and rhabdovirus vector-based SARS-CoV-2 vaccines as well as RNA vaccines based on self-amplifying alphaviruses have been evaluated in clinical settings. Vaccines against various cancers such as brain, breast, lung, ovarian, prostate cancer and melanoma have also been developed. Clinical trials have shown good safety and target-specific immune responses. Ervebo, the VSV-based vaccine against Ebola virus disease has been approved for human use.

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Targeting Viral Surface Proteins through Structure-Based Design

Viruses ◽

10.3390/v13071320 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1320

Author(s):

Yogesh B Narkhede ◽

Karen J Gonzalez ◽

Eva-Maria Strauch

Keyword(s):

Public Health ◽

Viral Infections ◽

Respiratory Viruses ◽

Surface Proteins ◽

Host Cells ◽

Viral Fusion ◽

Health It ◽

Viral Particles ◽

Pathogenic Viruses ◽

Viral Surface

The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.

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Recent Advances in Clinical Trials of HCV Vaccines

Journal of Applied Virology ◽

10.21092/jav.v3i1.48 ◽

2014 ◽

Vol 3 (1) ◽

pp. 10 ◽

Cited By ~ 2

Author(s):

Yongneng Luo ◽

Limin Jiang ◽

Zi'an Mao

Keyword(s):

Clinical Trials ◽

Viral Vectors ◽

Vaccine Development ◽

Viral Vector ◽

Core Protein ◽

Therapeutic Vaccine ◽

Hcv Infection ◽

Effective Vaccine ◽

Protein Subunit ◽

Preclinical Development

<p> Hepatitis C virus infects nearly 3% of the global population, and spreads to 3-4 million new people annually. HCV infection is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases and causes liver-related death in more than 300,000 people each year. Unfortunately, there is currently no vaccine for HCV prevention (prophylactic vaccine) or treatment (therapeutic vaccine). Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T- and B-cell epitopes of the virus and induce strong cross-reactive CD4+/CD8+ T-cell and neutralizing antibody responses in preventing or clearing HCV infection. So far, a few of vaccine development approaches are successful and some of the HCV vaccine candidates have reached human clinical trials, including those modalities mainly based on recombinant proteins (envelope proteins and core protein subunit), synthetic peptides, DNA (plasmid) and viral vectors (virosome). Encouraging results were obtained for those HCV vaccine formulations consisting of prime-boost regimen involving a live recombinant viral vector vaccine alone or in combination with DNA or subunit vaccine. Among several other vaccine strategies under preclinical development, the most promising one is virus like particle based vaccine that will be moving into human studies soon.</p>

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Poly-Gamma-Glutamic Acid (γ-PGA)-Based Encapsulation of Adenovirus to Evade Neutralizing Antibodies

Molecules ◽

10.3390/molecules23102565 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2565 ◽

Cited By ~ 15

Author(s):

Ibrahim Khalil ◽

Martin Khechara ◽

Sathishkumar Kurusamy ◽

Angel Armesilla ◽

Abhishek Gupta ◽

...

Keyword(s):

Glutamic Acid ◽

Neutralizing Antibodies ◽

Viral Vectors ◽

Viral Vector ◽

Neutralizing Antibody ◽

Anticancer Therapy ◽

Significant Research ◽

Low Toxicity ◽

Cancerous Cells

In recent years, there has been an increasing interest in oncolytic adenoviral vectors as an alternative anticancer therapy. The induction of an immune response can be considered as a major limitation of this kind of application. Significant research efforts have been focused on the development of biodegradable polymer poly-gamma-glutamic acid (γ-PGA)-based nanoparticles used as a vector for effective and safe anticancer therapy, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. This study aimed to introduce a specific destructive and antibody blind polymer-coated viral vector into cancer cells using γ-PGA and chitosan (CH). Adenovirus was successfully encapsulated into the biopolymer particles with an encapsulation efficiency of 92% and particle size of 485 nm using the ionic gelation method. Therapeutic agents or nanoparticles (NPs) that carry therapeutics can be directed specifically to cancerous cells by decorating their surfaces using targeting ligands. Moreover, in vitro neutralizing antibody response against viral capsid proteins can be somewhat reduced by encapsulating adenovirus into γ-PGA-CH NPs, as only 3.1% of the encapsulated adenovirus was detected by anti-adenovirus antibodies in the presented work compared to naked adenoviruses. The results obtained and the unique characteristics of the polymer established in this research could provide a reference for the coating and controlled release of viral vectors used in anticancer therapy.

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Novel Concepts for HIV Vaccine Vector Design

mSphere ◽

10.1128/msphere.00415-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 8

Author(s):

Quazim A. Alayo ◽

Nicholas M. Provine ◽

Pablo Penaloza-MacMaster

Keyword(s):

Immune Responses ◽

Viral Vectors ◽

Vaccine Development ◽

Viral Vector ◽

Intracellular Pathogens ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Recent Advances ◽

Robust Adaptive ◽

Selection Of

ABSTRACT The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best-characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce.

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Developmental Landscape of Potential Vaccine Candidates Based on Viral Vector for Prophylaxis of COVID-19

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.635337 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rajashri Bezbaruah ◽

Pobitra Borah ◽

Bibhuti Bhushan Kakoti ◽

Nizar A. Al-Shar’I ◽

Balakumar Chandrasekaran ◽

...

Keyword(s):

Viral Vectors ◽

Ebola Virus ◽

Vaccine Development ◽

Viral Vector ◽

World Health ◽

Prolonged Incubation ◽

Vaccine Candidates ◽

Vector Vaccine ◽

Dna And Rna ◽

Viral Vector Vaccine

Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, arose at the end of 2019 as a zoonotic virus, which is the causative agent of the novel coronavirus outbreak COVID-19. Without any clear indications of abatement, the disease has become a major healthcare threat across the globe, owing to prolonged incubation period, high prevalence, and absence of existing drugs or vaccines. Development of COVID-19 vaccine is being considered as the most efficient strategy to curtail the ongoing pandemic. Following publication of genetic sequence of SARS-CoV-2, globally extensive research and development work has been in progress to develop a vaccine against the disease. The use of genetic engineering, recombinant technologies, and other computational tools has led to the expansion of several promising vaccine candidates. The range of technology platforms being evaluated, including virus-like particles, peptides, nucleic acid (DNA and RNA), recombinant proteins, inactivated virus, live attenuated viruses, and viral vectors (replicating and non-replicating) approaches, are striking features of the vaccine development strategies. Viral vectors, the next-generation vaccine platforms, provide a convenient method for delivering vaccine antigens into the host cell to induce antigenic proteins which can be tailored to arouse an assortment of immune responses, as evident from the success of smallpox vaccine and Ervebo vaccine against Ebola virus. As per the World Health Organization, till January 22, 2021, 14 viral vector vaccine candidates are under clinical development including 10 nonreplicating and four replicating types. Moreover, another 39 candidates based on viral vector platform are under preclinical evaluation. This review will outline the current developmental landscape and discuss issues that remain critical to the success or failure of viral vector vaccine candidates against COVID-19.

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Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients

10.1101/2020.06.03.129585 ◽

2020 ◽

Cited By ~ 1

Author(s):

Cristina Andres ◽

Damir Garcia-Cehic ◽

Josep Gregori ◽

Maria Piñana ◽

Francisco Rodriguez-Frias ◽

...

Keyword(s):

Cleavage Site ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Stop Codon ◽

Mutation Rates ◽

Viral Quasispecies ◽

Gene Deletions ◽

Naturally Occurring ◽

Viral Particles ◽

Transmission Capability

ABSTRACTThe SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a “Don’t burn down the house” strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.

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A proof of concept for structure-based vaccine design targeting RSV in humans

Science ◽

10.1126/science.aav9033 ◽

2019 ◽

Vol 365 (6452) ◽

pp. 505-509 ◽

Cited By ~ 65

Author(s):

Michelle C. Crank ◽

Tracy J. Ruckwardt ◽

Man Chen ◽

Kaitlyn M. Morabito ◽

Emily Phung ◽

...

Keyword(s):

Subunit Vaccine ◽

Vaccine Development ◽

Vaccine Candidate ◽

Level Structure ◽

Vaccine Design ◽

Atomic Level ◽

Surface Proteins ◽

Proof Of Concept ◽

Syncytial Virus ◽

Viral Surface

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

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Type-I IFN promotes humoral immunity in viral vector vaccination

Journal of Virology ◽

10.1128/jvi.00925-21 ◽

2021 ◽

Author(s):

Chaojie Zhong ◽

Fengliang Liu ◽

Renee J. Hajnik ◽

Lei Yao ◽

Kangjing Chen ◽

...

Keyword(s):

Humoral Immunity ◽

Viral Vectors ◽

Vaccine Development ◽

Viral Vector ◽

T Cell Response ◽

Innate Immune ◽

Inflammasome Activation ◽

Type I ◽

Type I Ifn ◽

Immune Pathways

Recombinant viral vectors are an important platform for vaccine delivery. Our recent study has demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus vs. poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type-I IFN and inflammasome activation. However, impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we showed that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated type-I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type-I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo . Following vaccination, type-I IFN receptor knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to the wild-type (WT) mice. Consistent with the antibody response, type-I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to those in WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type-I IFN signaling also promoted the generation of vaccine-specific CD4 T-cell response and T follicular helper (Tfh) response in mice. Together, our data indicate a role of type-I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type-I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and its impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, our study reports that type-I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Findings of the present study provide insights not only for basic understanding of host-viral vector interactions, but also for improving vaccine design by potentially modulating type-I IFN and its associated innate immune pathways in viral vector vaccination.

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On the Relationship of Viral Particles and Extracellular Vesicles: Implications for Viral Vector Technology

Viruses ◽

10.3390/v13071238 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1238

Author(s):

Christoph Metzner ◽

Marianne Zaruba

Keyword(s):

Extracellular Vesicles ◽

Biomedical Applications ◽

Viral Vectors ◽

Viral Infections ◽

Viral Vector ◽

Extracellular Vesicle ◽

Viral Particles ◽

Gene Therapy Vectors ◽

Relationship Of ◽

The Relationship

Gene therapy vectors derived from different viral species have become a fixture in biomedicine, both for direct therapeutic intervention and as tools to facilitate cell-based therapies, such as chimeric antigen receptor-based immunotherapies. On the contrary, extracellular vesicles have only recently gained a massive increase in interest and, concomitantly, knowledge in the field has drastically risen. Viral infections and extracellular vesicle biology overlap in many ways, both with pro- and antiviral outcomes. In this review, we take a closer look at these interactions for the most prominent groups of viral vectors (Adenoviral, Adeno-associated and Retro/Lentiviral vectors) and the possible implications of these overlaps for viral vector technology and its biomedical applications.

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