Vaccines for Venezuelan equine encephalitis
Section snippets
Venezuelan equine encephalitis virus and its replication
Venezuelan equine encephalitis virus (VEEV, Alphavirus in the Togaviridae family) is an enveloped virus with a non-segmented, positive-sense RNA genome of approximately 11.4 kb (Fig. 1). The 5′ two-thirds of the genome encodes four nonstructural proteins (nsP1 to nsP4) that form an enzyme complex required for viral replication [1], [2], [3]. The full-length RNA then serves as a template for the synthesis of positive-sense genomic RNA and for transcription of a subgenomic 26S RNA [1]. The
Epidemiology of encephalitic alphaviruses
Most of the encephalitic viruses in the Family Togaviridae, genus Alphavirus are zoonotic pathogens that are transmitted via hematophagous arthropods. These pathogens have a widespread distribution in North, Central and South America (reviewed in [5]). Some of them are highly infectious via the aerosol route, thus have been responsible for numerous laboratory accidents (>150 documented cases without an associated perforating injury) and/or have been developed as a biological weapon in the U.S.
Disease in humans
VEEV infection has an incubation period of 2–10 days, which results typically in non-specific flu-like symptoms. Severe encephalitis is a less common outcome of VEEV infection in comparison to EEEV and WEEV infection, although VEEV-associated encephalitis is a more common outcome in children. Neurological disease, including disorientation, ataxia, mental depression, and convulsions can be detected in up to 14% of infected individuals, especially children, although the human case-fatality rate
Mouse model for VEEV infection
The murine model for VEEV-induced disease is established and typically utilizes subcutaneous inoculation [6], [7], [8], [9]. Previous studies have demonstrated that the murine model is characterized by biphasic disease, which starts with the productive infection of lymphoid tissue and culminates in the destruction of the CNS by viral replication and a “toxic” neuroinflammatory response that is uniformly lethal [10], [11], [12], [13], [14], [15], [16]. By the time the acute encephalitis has
Humoral immunity
Protection from peripheral inoculation or natural alphavirus infection depends mostly on the production of neutralizing antibodies [17], [18]. While virus neutralizing antibody is important for the protection against natural (peripheral) challenge mediated by mosquito-borne transmission, more recent studies demonstrate that even relatively high serum titers of polyclonal neutralizing antibody achieved via passive transfer (not achievable with any vaccination known to authors) do not protect
Alpha Beta (αβ) T cell response
The αβ T cells represent the major proportion of T cells that respond to various pathogens and are subdivided into CD4+ helper and CD8+ cytotoxic cells. These “conventional” T cells have been well characterized functionally. Prior studies in mice vaccinated with TC-83 suggest that Th1-type responses predominate [22]. However, in mice vaccinated parenterally with TC-83, cytotoxic T cell activity could not be detected in the spleen or draining lymph node [23]. It was previously demonstrated that
Gamma delta (γδ) T cell response
Recent studies suggest an important role for another well studied T cell subpopulation, γδ T cells, in disease development and lethal outcomes of VEEV infection [19]. Specifically, qualitative and quantitative changes in the inflammatory cellular infiltrates in vaccinated and challenged mice suggest a regulatory role in the secondary response to virus. However, direct evaluation of their role in pathology vs. protection is limited by the lack of feasible methods for isolating sufficient
Live-attenuated VEE vaccines
Following upon the success of the 17D yellow fever vaccine by Theiler [43], VEEV was attenuated by 83 serial passages in guinea pig heart cells to produce the TC-83 strain [44]. TC-83 was first tested extensively in equids during the 1971 Texas VEE epizootic/epidemic, where it may have contributed to limiting the spread northward. Although the vaccine produces viremia, fever and leucopenia in horses, robust neutralizing antibodies are generated as well as protection from VEEV challenge [45].
Inactivated VEE vaccines
Due to the economic devastation caused by VEE epizootics in regions of Latin American that relied on equids for agriculture and transportation, vaccines were first produced soon after VEEV was isolated in 1938 [59], [60]. Formalin-inactivated preparations were initially made from mouse brain and other animal tissues following infection with wild-type, subtype IAB strains isolated during epizootics [61]. These vaccines were probably efficacious in most animals, but the equid-amplification
Sindbis virus-based chimeric vaccine approach
Recombinant live-attenuated vaccines and, in particular, an alphavirus-based approach, represent a viable approach to the production of safe, immunogenic and efficacious vaccines against the encephalitis alphaviruses [19], [21], [65], [66], [67]. By utilizing as a vector the genome of Sindbis virus (SINV), a relatively nonpathogenic alphavirus in humans, chimeric SIN/VEE virus(es) can be designed to express all of the structural proteins of the virulent alphavirus. These constructs contain the
Alphavirus replicons
Because only the nonstructural proteins and cis-acting RNA sequences are required for alphavirus genome replication, the structural protein genes can be replaced and foreign antigens expressed at high levels [68], [69]. These replicon genomes can be packaged into virus-like particles by capsid and envelope proteins provided in trans from a second genetic construct (Fig. 4). To reduce the probability of recombination between replicon and “helper” RNAs, two separate helpers can be used to encode
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