Filovirus-like particles as vaccines and discovery tools

Abstract

Ebola and Marburg viruses are members of the family Filoviridae, which cause severe hemorrhagic fevers in humans. Filovirus outbreaks have been sporadic, with mortality rates currently ranging from 30 to 90%. Unfortunately, there is no efficacious human therapy or vaccine available to treat disease caused by either Ebola or Marburg virus infection. Expression of the filovirus matrix protein, VP40, is sufficient to drive spontaneous production and release of virus-like particles (VLPs) that resemble the distinctively filamentous infectious virions. The addition of other filovirus proteins, including virion proteins (VP)24, 30 and 35 and glycoprotein, increases the efficiency of VLP production and results in particles containing multiple filovirus antigens. Vaccination with Ebola or Marburg VLPs containing glycoprotein and VP40 completely protects rodents from lethal challenge with the homologous virus. These candidate vaccines are currently being tested for immunogenicity and efficacy in nonhuman primates. Furthermore, the Ebola and Marburg VLPs are being used as a surrogate model to further understand the filovirus life cycle, with the goal of developing rationally designed vaccines and therapeutics. Thus, in addition to their use as a vaccine, VLPs are currently being used as tools to learn lessons about filovirus pathogenesis, immunology, replication and assembly requirements.Expert Rev. Vaccines 4(3), 429-440 (2005) Ebola (EBOV) and Marburg (MARV) viruses are the only members of the family Filoviridae, and were named according to their filamentous shape. EBOV and MARV cause acute and rapidly progressive hemorrhagic fever with mortality rates in humans of up to 90% [1,2]. The reservoir for filoviruses is unknown, although the consumption of monkey meat is often associated with onset of disease. Animals ranging from insects to mammals have been analyzed in the hopes of identifying a carrier, but to no avail [3]. After exposure, the onset of clinical symptoms can be as short as 2 days and as long as 21, although most infected humans and nonhuman primates die within 7-10 days of exposure [4]. In addition to hemorrhage and bleeding, other symptoms of filovirus infection include fever, headache, generalized myalgia, prostration, conjunctivitis, rash, lymphadenopathy, pharyngitis and edema [5].Filoviruses are considered serious public health threats, and are classified as biosafety level (BSL)-4 agents and Category A biothreat agents by the US Centers for Disease Control and Prevention [6,101]. Features that characterize filoviruses as a significant global health risk include high morbidity and mortality rates, potential for person-to-person transmission, relative stability in the environment, and feasibility of large-scale production. Additionally, the filoviruses have a low infectious dose, an extremely rapid rate of replication and can be easily transmitted, including via aerosols [4,7,8]. Bolstering the fear of their use as bioterrorism agents, several hemorrhagic fever viruses have a history of state-sponsor...

Vacuolar Protein Sorting Pathway Contributes to the Release of Marburg Virus

“…Particles derived from cells expressing MARV VP40 are heterogeneous in terms of length and shape (30,49,59). In order to better understand the nature of the different particles, we screened particulate material released into the supernatants of cells expressing VP40.…”

“…In recent years, virus-like particles (VLPs), which are formed upon recombinant expression of the viral matrix and/or surface glycoproteins, have been recognized as representing powerful tools for developing novel vaccines and investigating certain aspects of the viral replication cycle (24,44,59,63). Matrix proteins from many enveloped RNA viruses, including retroviruses, rhabdoviruses, filoviruses, paramyxoviruses, orthomyxoviruses, and arenaviruses, are able to induce VLPs (10, 14, 18, 28-30, 48, 49, 52).…”

Monovalent virus-like particle vaccine protects guinea pigs and nonhuman primates against infection with multiple Marburg viruses

“…Each of these candidate vaccines presents with concerns, for example, acceptable vaccine doses, vaccine safety and the impact of prior immunity to the vaccine vector. While the majority of work developing filovirus vaccines has utilized virus vectors, several studies demonstrate that subunit vaccines can safely and specifically protect against MARV [11,12]. While vaccination of guinea pigs or NHPs with either a recombinant baculovirus-produced GP or DNA vaccine encoding GP alone is not entirely efficacious, a prime-boost strategy with both the DNA vaccine and baculovirus-produced recombinant GP successfully protected animals from both lethal EBOV and MARV infection [2,13,14].…”

“…While vaccination of guinea pigs or NHPs with either a recombinant baculovirus-produced GP or DNA vaccine encoding GP alone is not entirely efficacious, a prime-boost strategy with both the DNA vaccine and baculovirus-produced recombinant GP successfully protected animals from both lethal EBOV and MARV infection [2,13,14]. Our laboratory has taken advantage of the phenomenon that MARV virus-like particles (mVLPs) are produced spontaneously in MARV GP-and matrix protein VP40-transfected mammalian cells, and we are working to develop a mVLP-based vaccine [12,[15][16][17][18].…”

Targeting mucosal dendritic cells with microbial antigens from probiotic lactic acid bacteria

“…Additionally, several live bacterial and viral vectors have been designed to promote cytokines that induce a microenvironment for cellular immunity in vivo. Promising results were recently achieved in both animals and humans for mucosa-targeting pathogens such as papillomavirus, calivirus, hepatitis E virus and filoviruses [63] by using nonreplicating virus-like particles [64][65][66][67][68]. However, none of these vaccines has to date been approved by the US FDA for human use.…”