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 A review of Phase I trials of Ebola virus vaccines: what can we learn from the race to develop novel vaccines?

2017 ◽  
Vol 372 (1721) ◽  
pp. 20160295 ◽  
Author(s):  
Teresa Lambe ◽  
Georgina Bowyer ◽  
Katie J Ewer
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Ebola Virus ◽  
Virus Disease ◽  
Safety Data ◽  
Careful Consideration ◽  
Phase I Clinical Trials ◽  
Field Deployment ◽  
Cellular And Humoral Immunity ◽  
Immunological Assays

Sporadic outbreaks of Ebola virus infection have been documented since the mid-Seventies and viral exposure can lead to lethal haemorrhagic fever with case fatalities as high as 90%. There is now a comprehensive body of data from both ongoing and completed clinical trials assessing various vaccine strategies, which were rapidly advanced through clinical trials in response to the 2013–2016 Ebola virus disease (EVD) public health emergency. Careful consideration of immunogenicity post vaccination is essential but has been somewhat stifled because of the wide array of immunological assays and outputs that have been used in the numerous clinical trials. We discuss here the different aspects of the immune assays currently used in the Phase I clinical trials for Ebola virus vaccines, and draw comparisons across the immune outputs where possible; various trials have examined both cellular and humoral immunity in European and African cohorts. Assessment of the safety data, the immunological outputs and the ease of field deployment for the various vaccine modalities will help both the scientific community and policy-makers prioritize and potentially license vaccine candidates. If this can be achieved, the next outbreak of Ebola virus, or other emerging pathogen, can be more readily contained and will not have such widespread and devastating consequences. This article is part of the themed issue ‘The 2013–2016 West African Ebola epidemic: data, decision-making and disease control’.

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.

Clinical Trials in Social Media: Content Analysis of YouTube Videos in Arabic Language (Preprint)

2020 ◽  
Author(s):  
Amal Tabba' ◽  
Linda Kateb ◽  
Maysa Al-Hussaini
Keyword(s):  
Social Media ◽  
Clinical Trials ◽  
Phase I ◽  
Arabic Language ◽  
Phase Iii ◽  
Sources Of Information ◽  
Animal Testing ◽  
Phase I Clinical Trials ◽  
The Public ◽  
Youtube Videos

BACKGROUND Clinical trials are fundamental to the advancement of cancer care; nonetheless, recruitment remains inadequate. A frequently reported barrier to participation is the lack of awareness and knowledge about clinical trials. Research showed that the internet is being used now as a primary source for information on clinical trials. OBJECTIVE We aim in this study to review available videos uploaded on the YouTube, one of the most-visited websites worldwide, about clinical trials in Arabic language and evaluate the comprehensiveness of its content. METHODS YouTube videos were searched using the keywords “clinical trials” and “clinical studies” in Arabic language. Only videos targeting the public were included in the study. Videos targeting medical students/ healthcare professionals, discussing country-specific laws, longer than 30 minutes, or found irrelevant upon viewing were excluded from the analysis. RESULTS Seven videos about clinical trials were included in the final analysis. Only 1 video was related specifically to cancer clinical trials (14.3%). The mean length of videos was 6:43 minutes (range: 1:37-16:53 minutes) with a total number of views of 11,207 (mean 1,601.0, SD ±2,054.6). More than half of the videos (n=4, 57.1%) were created by TV/ Internet Channels and were neutral in tone. Most common presentation style and country of origin were vlog and Saudi Arabia, receptivity (n=3, 42.9% for both). For video-related content, the most frequently mentioned variables were the purpose of clinical trials to test new drug/devices in humans (n=6, 85.7%), animal testing conducted before clinical trials, clinical trials are conducted on several phases, phase I clinical trials and the aim of phase I studies is to assess safety (n=5, 71.5%; for all items). These were followed by mention of phase II and phase III in general (n=4, 57.1%; for both items). CONCLUSIONS This study identified a clear scarcity of YouTube videos about clinical trials in the Arabic language, as well as, potential gaps in the comprehensiveness of the content presented. Viewers’ engagement presented in number of views, likes and dislikes seems to be very low. Stakeholders need to pay more attention to the use of social media in prompting clinical trials and providing comprehensive and reliable sources of information to the public. CLINICALTRIAL None

The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2606-2606
Author(s):  
Jason John Luke ◽  
Larry Rubinstein ◽  
Gary L Smith ◽  
S. Percy Ivy ◽  
Pamela Jo Harris
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase 1 ◽  
Therapeutic Benefit ◽  
Phase Iii ◽  
Phase I Trials ◽  
Toxicity Data ◽  
Phase I Clinical Trials ◽  
Exact Test ◽  
Phase Iii Clinical Trials

2606 Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). Many physicians do not refer to phase I due to perceived limited clinical benefit (CB=CR+PR+SD) and increased toxicity. To understand the actual experience of melanoma patients (pts) in phase I trials, we analyzed the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-2011) and compared them to DTIC. Methods: We queried the CTMS of CTEP for phase I trials in which advanced melanoma pts were treated. Trials were separated into targeted (T), chemo (C) and immunotherapy (I). Pt characteristics, response and toxicity data were collected. Chemotherapy included chemo with targeted or immunotherapy. Toxicity was drug related if attributed possibly, probably or definitely to drug. Fisher’s Exact Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 modern phase III clinical trials (1999-2011). Results: 937 pts (M595:F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 (majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and toxicity data are shown in the Table. Targeted therapy was associated with lower RR (p=.01), immuno with lower CB rate (p<.001) and chemo with higher incidence of G4 toxicity (p<.001) relative to the other groups. Comparing phase 1 to DTIC, RR and CB were not clinically different (phase I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was significantly higher (54% vs. 28%) in phase I (p<.0001). Conclusions: Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had similar therapeutic benefit but more toxicity compared to DTIC naïve pts in modern clinical trials. [Table: see text]

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 Animal and Human Vaccines against West Nile Virus

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1073
Author(s):  
Juan-Carlos Saiz
Keyword(s):  
Clinical Trials ◽  
West Nile Virus ◽  
Vaccine Development ◽  
Phase Iii ◽  
West Nile ◽  
Specific Therapy ◽  
Phase Iii Clinical Trials ◽  
Neuroinvasive Disease ◽  
The Us ◽  
The Status

West Nile virus (WNV) is a widely distributed enveloped flavivirus transmitted by mosquitoes, which main hosts are birds. The virus sporadically infects equids and humans with serious economic and health consequences, as infected individuals can develop a severe neuroinvasive disease that can even lead to death. Nowadays, no WNV-specific therapy is available and vaccines are only licensed for use in horses but not for humans. While several methodologies for WNV vaccine development have been successfully applied and have contributed to significantly reducing its incidence in horses in the US, none have progressed to phase III clinical trials in humans. This review addresses the status of WNV vaccines for horses, birds, and humans, summarizing and discussing the challenges they face for their clinical advance and their introduction to the market.

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