scholarly journals Self-Amplifying RNA Viruses as RNA Vaccines

2020 ◽  
Vol 21 (14) ◽  
pp. 5130 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Immune Responses ◽  
Viral Vectors ◽  
Ebola Virus ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Rna Viruses ◽  
Emerging Diseases ◽  
Host Cells ◽  
Phase Iii ◽  
Rna Replicon

Single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses and rhabdoviruses are characterized by their capacity of highly efficient self-amplification of RNA in host cells, which make them attractive vehicles for vaccine development. Particularly, alphaviruses and flaviviruses can be administered as recombinant particles, layered DNA/RNA plasmid vectors carrying the RNA replicon and even RNA replicon molecules. Self-amplifying RNA viral vectors have been used for high level expression of viral and tumor antigens, which in immunization studies have elicited strong cellular and humoral immune responses in animal models. Vaccination has provided protection against challenges with lethal doses of viral pathogens and tumor cells. Moreover, clinical trials have demonstrated safe application of RNA viral vectors and even promising results in rhabdovirus-based phase III trials on an Ebola virus vaccine. Preclinical and clinical applications of self-amplifying RNA viral vectors have proven efficient for vaccine development and due to the presence of RNA replicons, amplification of RNA in host cells will generate superior immune responses with significantly reduced amounts of RNA delivered. The need for novel and efficient vaccines has become even more evident due to the global COVID-19 pandemic, which has further highlighted the urgency in challenging emerging diseases.

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

Vaccines ◽  
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.

scholarly journals Self-Replicating RNA Viruses for Vaccine Development Against Infectious Diseases and Cancer

2021 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Clinical Trials ◽  
Infectious Diseases ◽  
Immune Responses ◽  
Measles Virus ◽  
Viral Vectors ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Rna Viruses ◽  
Vaccine Candidates ◽  
Vector Systems

Alphaviruses, flaviviruses, measles viruses and rhabdoviruses are enveloped single-stranded RNA viruses, which have been engineered as expression vector systems for recombinant protein expression and vaccine development. Due to the presence of non-structural genes encoding the replicase complex, a 200,000-fold amplification of viral RNA occurs in the cytoplasm of infected cells 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. The self-replicating RNA viral vectors can be administered as replicon RNA, recombinant viral particles, or layered DNA/RNA replicons. Self-replicating RNA viral vectors have been applied for vaccine development against influenza virus, HIV, hepatitis B virus, human papilloma virus, Ebola virus and recently coronaviruses, especially SARS-CoV-2 the causative agent of the COVID-19 pandemic. Measles virus and rhabdovirus vector-based SARS-CoV-2 vaccine candidates have been subjected to clinical trials. Moreover, RNA vaccine candidates based on self-amplifying alphaviruses have also been evaluated in clinical settings. Various cancers such as brain, breast, lung, ovarian, prostate cancer and melanoma have also been targeted for vaccine development. Robust immune responses and protection have been demonstrated in animal models. 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.

scholarly journals Self-Replicating RNA Viruses for RNA Therapeutics

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3310 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Rna Viruses ◽  
Antibody Responses ◽  
Phase Iii ◽  
Phase I Clinical Trials

Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.

scholarly journals Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

2019 ◽  
Vol 7 (10) ◽  
pp. 402
Author(s):  
Titus Abiola Olukitibi ◽  
Zhujun Ao ◽  
Mona Mahmoudi ◽  
Gary A. Kobinger ◽  
Xiaojian Yao
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Immunological Approach ◽  
Vaccine Approach ◽  
Acquired Immune Responses ◽  
Diverse Virus

In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.

scholarly journals Novel Concepts for HIV Vaccine Vector Design

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
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.

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

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.

scholarly journals Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuai Yuan ◽  
Shravani Balaji ◽  
Ivan B. Lomakin ◽  
Yong Xiong
Keyword(s):  
Immune Responses ◽  
Protein Expression ◽  
Vaccine Development ◽  
Nonstructural Protein ◽  
Global Gene Expression ◽  
Current Data ◽  
Host Protein ◽  
Host Cells ◽  
Live Attenuated Vaccine ◽  
Nonstructural Protein 1

Coronaviruses have brought severe challenges to public health all over the world in the past 20years. SARS-CoV-2, the causative agent of the COVID-19 pandemic that has led to millions of deaths, belongs to the genus beta-coronavirus. Alpha- and beta-coronaviruses encode a unique protein, nonstructural protein 1 (Nsp1) that both suppresses host immune responses and reduces global gene expression levels in the host cells. As a key pathogenicity factor of coronaviruses, Nsp1 redirects the host translation machinery to increase synthesis of viral proteins. Through multiple mechanisms, coronaviruses impede host protein expression through Nsp1, while escaping inhibition to allow the translation of viral RNA. In this review, we discuss current data about suppression of the immune responses and inhibition of protein synthesis induced by coronavirus Nsp1, as well as the prospect of live-attenuated vaccine development with virulence-attenuated viruses with mutations in Nsp1.

scholarly journals RNA viruses and microRNAs: challenging discoveries for the 21st century

2013 ◽  
Vol 45 (22) ◽  
pp. 1035-1048 ◽  
Author(s):  
Gokul Swaminathan ◽  
Julio Martin-Garcia ◽  
Sonia Navas-Martin
Keyword(s):  
Immune Responses ◽  
Rna Viruses ◽  
Cellular Protein ◽  
Host Cells ◽  
Dna Viruses ◽  
The Past ◽  
Complex Interactions ◽  
Viral Interactions ◽  
Cellular Machinery ◽  
Productive Replication

RNA viruses represent the predominant cause of many clinically relevant viral diseases in humans. Among several evolutionary advantages acquired by RNA viruses, the ability to usurp host cellular machinery and evade antiviral immune responses is imperative. During the past decade, RNA interference mechanisms, especially microRNA (miRNA)-mediated regulation of cellular protein expression, have revolutionized our understanding of host-viral interactions. Although it is well established that several DNA viruses express miRNAs that play crucial roles in their pathogenesis, expression of miRNAs by RNA viruses remains controversial. However, modulation of the miRNA machinery by RNA viruses may confer multiple benefits for enhanced viral replication and survival in host cells. In this review, we discuss the current literature on RNA viruses that may encode miRNAs and the varied advantages of engineering RNA viruses to express miRNAs as potential vectors for gene therapy. In addition, we review how different families of RNA viruses can alter miRNA machinery for productive replication, evasion of antiviral immune responses, and prolonged survival. We underscore the need to further explore the complex interactions of RNA viruses with host miRNAs to augment our understanding of host-virus interplay.

scholarly journals Overcoming Immunity to a Viral Vaccine by DNA Priming before Vector Boosting

2003 ◽  
Vol 77 (1) ◽  
pp. 799-803 ◽  
Author(s):  
Zhi-yong Yang ◽  
Linda S. Wyatt ◽  
Wing-pui Kong ◽  
Zoe Moodie ◽  
Bernard Moss ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Vectors ◽  
Ebola Virus ◽  
Viral Vector ◽  
Hemorrhagic Fever ◽  
Viral Immunity ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Viral Vaccine ◽  
Humoral Responses

ABSTRACT Replication-defective adenovirus (ADV) and poxvirus vectors have shown potential as vaccines for pathogens such as Ebola or human immunodeficiency virus in nonhuman primates, but prior immunity to the viral vector in humans may limit their clinical efficacy. To overcome this limitation, the effect of prior viral exposure on immune responses to Ebola virus glycoprotein (GP), shown previously to protect against lethal hemorrhagic fever in animals, was studied. Prior exposure to ADV substantially reduced the cellular and humoral immune responses to GP expressed by ADV, while exposure to vaccinia inhibited vaccine-induced cellular but not humoral responses to GP expressed by vaccinia. This inhibition was largely overcome by priming with a DNA expression vector before boosting with the viral vector. Though heterologous viral vectors for priming and boosting can also overcome this effect, the paucity of such clinical viral vectors may limit their use. In summary, it is possible to counteract prior viral immunity by priming with a nonviral, DNA vaccine.

scholarly journals Investigating the Interaction between Negative Strand RNA Viruses and Their Hosts for Enhanced Vaccine Development and Production

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 59
Author(s):  
Kostlend Mara ◽  
Meiling Dai ◽  
Aaron M. Brice ◽  
Marina R. Alexander ◽  
Leon Tribolet ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Development ◽  
Rna Viruses ◽  
Vaccine Design ◽  
Integrated Approach ◽  
Control Measures ◽  
Effective Control ◽  
Negative Strand ◽  
Zoonotic Pathogens ◽  
Host Pathogen

The current pandemic has highlighted the ever-increasing risk of human to human spread of zoonotic pathogens. A number of medically-relevant zoonotic pathogens are negative-strand RNA viruses (NSVs). NSVs are derived from different virus families. Examples like Ebola are known for causing severe symptoms and high mortality rates. Some, like influenza, are known for their ease of person-to-person transmission and lack of pre-existing immunity, enabling rapid spread across many countries around the globe. Containment of outbreaks of NSVs can be difficult owing to their unpredictability and the absence of effective control measures, such as vaccines and antiviral therapeutics. In addition, there remains a lack of essential knowledge of the host–pathogen response that are induced by NSVs, particularly of the immune responses that provide protection. Vaccines are the most effective method for preventing infectious diseases. In fact, in the event of a pandemic, appropriate vaccine design and speed of vaccine supply is the most critical factor in protecting the population, as vaccination is the only sustainable defense. Vaccines need to be safe, efficient, and cost-effective, which is influenced by our understanding of the host–pathogen interface. Additionally, some of the major challenges of vaccines are the establishment of a long-lasting immunity offering cross protection to emerging strains. Although many NSVs are controlled through immunisations, for some, vaccine design has failed or efficacy has proven unreliable. The key behind designing a successful vaccine is understanding the host–pathogen interaction and the host immune response towards NSVs. In this paper, we review the recent research in vaccine design against NSVs and explore the immune responses induced by these viruses. The generation of a robust and integrated approach to development capability and vaccine manufacture can collaboratively support the management of outbreaking NSV disease health risks.

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