Design and Engineering of Deimmunized Vaccinia Viral Vectors

Vaccinia viral (VV) vectors are increasingly used in oncolytic virus therapy and vaccine development for cancer and infectious diseases. However, their effectiveness is hindered by the strong anti-viral immune response induced by the viral vector. In this review, we discuss the strategies to deimmunize vaccinia viral vector. One approach is to mask the virus from the neutralization antibody responses by mapping and eliminating of B-cell epitopes on the viral membrane proteins. The recombinant VVs contain one or more viral glycoproteins with mutations in the neutralizing antibody epitopes, resulting in viral escape from neutralization. In addition, a regulator of complement activation (e.g., CD55) can be expressed on the surface of the virus particle, leading to increased resistance to complement-mediated neutralization.

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Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env

Vaccines ◽

10.3390/vaccines9030239 ◽

2021 ◽

Vol 9 (3) ◽

pp. 239

Author(s):

Christopher A. Gonelli ◽

Hannah A. D. King ◽

Charlene Mackenzie ◽

Secondo Sonza ◽

Rob J. Center ◽

...

Keyword(s):

Neutralizing Antibody ◽

Antibody Responses ◽

Neutralization Activity ◽

Virus Like Particles ◽

Antibody Isotypes ◽

Immunodeficiency Virus ◽

Proline Substitution ◽

Membrane Bound ◽

Antibody Epitopes ◽

Hiv 1

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice. The incorporation of Env into mVLPs was increased by replacing the Env transmembrane and cytoplasmic tail domains with those of influenza haemagglutinin (HA-TMCT). Furthermore, Env was stabilized on the VLP surface by introducing an interchain disulfide and proline substitution (SOSIP) mutations typically employed to stabilize soluble Env trimers. The resulting mVLPs efficiently presented neutralizing antibody epitopes while minimizing exposure of non-neutralizing antibody sites. Vaccination of mice with mVLPs elicited a broader range of Env-specific antibody isotypes than Env presented on immature VLPs or extracellular vesicles. The mVLPs bearing HA-TMCT-modified Env consistently induced anti-Env antibody responses that mediated modest neutralization activity. These mVLPs are potentially useful immunogens for eliciting neutralizing antibody responses that target native Env epitopes on infectious HIV-1 virions.

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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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Cross-reactive Neutralizing Antibody Responses to Enterovirus 71 Infections in Young Children: Implications for Vaccine Development

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0002067 ◽

2013 ◽

Vol 7 (2) ◽

pp. e2067 ◽

Cited By ~ 36

Author(s):

Mei-Liang Huang ◽

Pai-Shan Chiang ◽

Min-Yuan Chia ◽

Shu-Ting Luo ◽

Luan-Yin Chang ◽

...

Keyword(s):

Young Children ◽

Vaccine Development ◽

Enterovirus 71 ◽

Neutralizing Antibody ◽

Antibody Responses

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

Viruses ◽

10.3390/v12111324 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1324

Author(s):

Kenneth Lundstrom

Keyword(s):

Neutralizing Antibodies ◽

Viral Vectors ◽

Vaccine Development ◽

Viral Vector ◽

Recombinant Protein Expression ◽

Surface Proteins ◽

Viral Particles ◽

Preclinical Animal Models ◽

Viral Surface ◽

Lethal Doses

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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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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Development of a Norovirus P Particle Platform for Eliciting Neutralizing Antibody Responses to the Membrane Proximal External Region of Human Immunodeficiency Virus Type 1 Envelope

Protein and Peptide Letters ◽

10.2174/0929866521666140616120955 ◽

2014 ◽

Vol 21 (12) ◽

pp. 1230-1239

Author(s):

Yang Zang ◽

Jinpeng Bi ◽

Dongchuan Du ◽

Xintao Liu ◽

Yan Zhang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

External Region ◽

Membrane Proximal External Region ◽

Immunodeficiency Virus ◽

Hiv 1

Eliciting efficient broadly neutralizing antibodies (BnAbs) is an important goal that has yet to be achieved for human immunodeficiency type 1 (HIV-1) vaccine development, although they are rarely produced in virus-infected individuals. In particular, inducing specific neutralizing antibodies to the gp41 membrane proximal external region (MPER) has proven a difficult task. In this study, we introduce Norovirus P particles as a new platform to display the MPER epitope of HIV-1 as a vaccine with the aim of enhancing immune responses. The results showed that HIV-1 chimeric P particles were capable of inducing MPER-specific antibody responses in immunized guinea pigs, although only weakly neutralizing activity could be detected. These findings are consistent with other previous studies which have also focused on the well-studied 2F5 and 4E10 BnAbs. Our findings provide an alternate strategy for design of vaccines against HIV-1. However, great challenges remain in the effort to develop vaccines that can induce efficient HIV-1 neutralizing antibodies.

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Optimization of Flow-Cytometry Based Assay for Measuring Neutralizing Antibody Responses against Each of the Four Dengue Virus Serotypes

Vaccines ◽

10.3390/vaccines9111339 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1339

Author(s):

Pragati Sharma ◽

Kaustuv Nayak ◽

Elluri Seetharami Reddy ◽

Humaira Farooqi ◽

Kaja Murali-Krishna ◽

...

Keyword(s):

Public Health ◽

Flow Cytometry ◽

Dengue Virus ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Neutralization Assay ◽

Antibody Responses ◽

Health Concern ◽

Dengue Virus Serotypes ◽

Focus Reduction

Dengue is an important public health problem worldwide, with India contributing nearly a third of global dengue disease burden. The measurement of neutralizing antibody responses is critical for understanding dengue pathophysiology, vaccine development and evaluation. Historically, dengue virus neutralization titers were measured using plaque reduction neutralization tests (PRNTs), which were later adapted to focus reduction neutralization tests (FRNTs). Given the slow and laborious nature of both these assays, there has been interest in adapting a high-throughput flow cytometry based neutralization assay. However, flow cytometry based assays typically underestimate neutralization titers, and in situations where the titers are low they can even fail to detect neutralization activity. In this study, by evaluating graded numbers of input Vero cell numbers and viral inoculum, we optimized the flow cytometry based neutralization assay in such a way that it is sensitive and scores titers that are in concordance with focus reduction neutralization tests for each of the four dengue virus serotypes (p < 0.0001). Given that dengue is a global public health concern, and several research groups are making efforts to understand its pathophysiology and accelerate vaccine development and evaluation both in India and worldwide, our findings have timely significance for facilitating these efforts.

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