Search Results (10)

The recombinant vesicular stomatitis virus-Zaire Ebolavirus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP) was highly effective against Ebola virus disease in a ring vaccination trial conducted during the 2014–2016 outbreak in Guinea and is licensed by regulatory agencies including US FDA, EMA, and prequalified by WHO. Vaccination studies in a nonhuman primate (NHP) model guided initial dose selection for clinical trial evaluation. We summarize two dose-ranging studies with the clinical-grade rVSVΔG-ZEBOV-GP vaccine candidate to assess the impact of dose level on immune responses and efficacy in an NHP Ebola virus (EBOV) challenge model. Forty-six cynomolgus macaques were vaccinated with a wide range of rVSVΔG-ZEBOV-GP doses and challenged 42 days later intramuscularly with 1000 pfu EBOV. Vaccination with rVSVΔG-ZEBOV-GP induced relatively high levels of EBOV-specific IgG and neutralizing antibodies, measured using the same validated assays as used in rVSVΔG-ZEBOV-GP clinical trials. Similar responses were observed across dose groups from 1 × 10⁸ to 1 × 10² pfu. A single vaccination conferred 98% protection from lethal intramuscular EBOV challenge across all dose groups. These results demonstrate that robust antibody titers are induced in NHPs across a wide range of rVSVΔG-ZEBOV-GP vaccine doses, correlating with high levels of protection against death from EBOV challenge. Full article

Viral vectors have been used for a broad spectrum of gene therapy for both acute and chronic diseases. In the context of cancer gene therapy, viral vectors expressing anti-tumor, toxic, suicide and immunostimulatory genes, such as cytokines and chemokines, have been applied. Oncolytic viruses, which specifically replicate in and kill tumor cells, have provided tumor eradication, and even cure of cancers in animal models. In a broader meaning, vaccine development against infectious diseases and various cancers has been considered as a type of gene therapy. Especially in the case of COVID-19 vaccines, adenovirus-based vaccines such as ChAdOx1 nCoV-19 and Ad26.COV2.S have demonstrated excellent safety and vaccine efficacy in clinical trials, leading to Emergency Use Authorization in many countries. Viral vectors have shown great promise in the treatment of chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, hemophilia, β-thalassemia, and sickle cell disease (SCD). Proof-of-concept has been established in preclinical studies in various animal models. Clinical gene therapy trials have confirmed good safety, tolerability, and therapeutic efficacy. Viral-based drugs have been approved for cancer, hematological, metabolic, neurological, and ophthalmological diseases as well as for vaccines. For example, the adenovirus-based drug Gendicine^® for non-small-cell lung cancer, the reovirus-based drug Reolysin^® for ovarian cancer, the oncolytic HSV T-VEC for melanoma, lentivirus-based treatment of ADA-SCID disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease have been approved for human use. Full article

This review describes key aspects of the development of the rVSVΔG-ZEBOV-GP Ebola vaccine and key activities which are continuing to further expand our knowledge of the product. Extensive partnerships and innovative approaches were used to address the various challenges encountered during this process. The rVSVΔG-ZEBOV-GP Ebola vaccine was initially approved by the European Medicines Agency and prequalified by the World Health Organization in November 2019. It was approved by the United States Food and Drug Administration in December 2019 and approved in five African countries within 90 days of prequalification. The development resulted in the first stockpile of a registered Ebola vaccine that is available to support outbreak response. This also provides insights into how the example of rVSVΔG-ZEBOV-GP can inform the development of vaccines for Sudan ebolavirus, Marburg virus, and other emerging epidemic diseases in terms of the types of approaches and data needed to support product registration, availability, and the use of a filovirus vaccine. Full article

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. Full article

Preventative vaccines are considered one of the most cost-effective and efficient means to contain outbreaks and prevent pandemics. However, the requirements to gain licensure and manufacture a vaccine for human use are complex, costly, and time-consuming. The 2013–2016 Ebola virus disease (EVD) outbreak was the largest EVD outbreak to date and the third Public Health Emergency of International Concern in history, so to prevent a pandemic, numerous partners from the public and private sectors combined efforts and resources to develop an investigational Zaire ebolavirus (EBOV) vaccine candidate (rVSVΔG-ZEBOV-GP) as quickly as possible. The rVSVΔG-ZEBOV-GP vaccine was approved as ERVEBO^TM by the European Medicines Authority (EMA) and the United States Food and Drug Administration (FDA) in December 2019 after five years of development. This review describes the development program of this EBOV vaccine, summarizes what is known about safety, immunogenicity, and efficacy, describes ongoing work in the program, and highlights learnings applicable to the development of pandemic vaccines. Full article

Ebolavirus Disease (EVD) is a severe haemorrhagic fever that occurs in epidemic outbreaks, with a high fatality rate and no specific therapies available. rVSVΔG-ZEBOV-GP (Ervebo^®), a live-attenuated recombinant vesicular stomatitis virus vector expressing the glycoprotein G of Zaire Ebolavirus, is the first vaccine approved for prevention of EVD. Both innate and adaptive responses are deemed to be involved in vaccine-induced protection, yet the mechanisms are not fully elucidated. A global transcriptomic approach was used to profile the blood host-response in 51 healthy volunteers enrolled in a phase 1/2 clinical trial. Signatures of the host responses were investigated assessing the enrichment in differentially expressed genes (DEGs) of specific “blood transcription modules” (BTM). Comparison of gene-expression levels showed that vaccination produces a peak of 5469 DEGs at day one, representing 38.6% of the expressed genes. Out of 346 BTMs, 144 were significantly affected by vaccination. Innate immunity pathways were induced from day 1 to day 14. At days 2 and 3, neutrophil modules were downregulated and complement-related modules upregulated. T-cell and cell-cycle associated modules were upregulated at days 7 and 14, while at day 28, no modules remained activated. At day 14, a direct correlation was observed between ZEBOV glycoprotein-specific antibody titres and activation of seven BTMs, including two related to B-cell activation and B cell receptor signalling. Transcriptomic analysis identified an rVSVΔG-ZEBOV-GP-induced signature and demonstrated a direct correlation of blood transcriptomic changes with ZEBOV glycoprotein-specific antibody titres. Full article

rVSVΔG-ZEBOV-GP is a live, attenuated, recombinant vesicular stomatitis virus (rVSV)-based vaccine for the prevention of Ebola virus disease caused by Zaire ebolavirus. As a replication-competent genetically modified organism, rVSVΔG-ZEBOV-GP underwent various environmental evaluations prior to approval, the most in-depth being the environmental risk assessment (ERA) required by the European Medicines Agency. This ERA, as well as the underlying methodology used to arrive at a sound conclusion about the environmental risks of rVSVΔG-ZEBOV-GP, are described in this review. Clinical data from vaccinated adults demonstrated only infrequent, low-level shedding and transient, low-level viremia, indicating a low person-to-person infection risk. Animal data suggest that it is highly unlikely that vaccinated individuals would infect animals with recombinant virus vaccine or that rVSVΔG-ZEBOV-GP would spread within animal populations. Preclinical studies in various hematophagous insect vectors showed that these species were unable to transmit rVSVΔG-ZEBOV-GP. Pathogenicity risk in humans and animals was found to be low, based on clinical and preclinical data. The overall risk for non-vaccinated individuals and the environment is thus negligible and can be minimized further through defined mitigation strategies. This ERA and the experience gained are relevant to developing other rVSV-based vaccines, including candidates under investigation for prevention of COVID-19. Full article

Filoviruses are among the deadliest infectious agents known to man, causing severe hemorrhagic fever, with up to 90% fatality rates. The 2014 Ebola outbreak in West Africa resulted in over 28,000 infections, demonstrating the large-scale human health and economic impact generated by filoviruses. Zaire ebolavirus is responsible for the greatest number of deaths to date and consequently there is now an approved vaccine, Ervebo, while other filovirus species have similar epidemic potential and remain without effective vaccines. Recent clinical success of REGN-EB3 and mAb-114 monoclonal antibody (mAb)-based therapies supports further investigation of this treatment approach for other filoviruses. While efficacious, protection from passive mAb therapies is short-lived, requiring repeat dosing to maintain therapeutic concentrations. An alternative strategy is vectored immunoprophylaxis (VIP), which utilizes an adeno-associated virus (AAV) vector to generate sustained expression of selected mAbs directly in vivo. This approach takes advantage of validated mAb development and enables vectorization of the top candidates to provide long-term immunity. In this review, we summarize the history of filovirus outbreaks, mAb-based therapeutics, and highlight promising AAV vectorized approaches to providing immunity against filoviruses where vaccines are not yet available. Full article

Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo^® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity. Full article

Ebola virus epidemics can be effectively limited by the VSV-EBOV vaccine (Ervebo) due to its rapid protection abilities; however, side effects prevent the broad use of VSV-EBOV as vaccine. Mechanisms explaining the efficient immune activation after single injection with the VSV-EBOV vaccine remain mainly unknown. Here, using the clinically available VSV-EBOV vaccine (Ervebo), we show that the cell-intrinsic expression of the interferon-inhibitor Usp18 in CD169⁺ macrophages is one important factor modulating the anti-Ebola virus immune response. The absence of Usp18 in CD169⁺ macrophages led to the reduced local replication of VSV-EBOV followed by a diminished innate as well as adaptive immune response. In line, CD169-Cre^+/ki x Usp18^fl/fl mice showed reduced innate and adaptive immune responses against the VSV wildtype strain and died quickly after infection, suggesting that a lack of Usp18 makes mice more susceptible to the side effects of the VSV vector. In conclusion, our study shows that Usp18 expression in CD169⁺ macrophages is one important surrogate marker for effective vaccination against VSV-EBOV, and probably other VSV-based vaccines also. Full article