RESPIRATORY SYNCYTIAL VIRUS VACCINE DESIGN USING STRUCTURE BASED MACHINE LEARNING MODELS
Date
2021
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Abstract
Human Respiratory Syncytial Virus (RSV) disease remains a global concern for both young and old [1] and to date no approved vaccine capable of reducing or preventing RSV disease exists. Numerous vaccine candidates currently being tested [2,3] are legacies of classic vaccine design approaches. Current vaccine design underutilizes modern computational strategies to help identify or optimized new vaccine candidates. A combination of computational and traditional methodologies should be expected to optimize target selection and candidate prioritization. The fields of computational protein folding/function prediction and systems biology [4] allow researchers to develop virtual protein designs and then create them physically for functional testing. Systematically prioritized vaccine target/candidates can then be produced using more traditional virus generation strategies [5] and evaluated for efficacy. Focusing on a specific RSV protein, nonstructural protein 1 (NS1), this work demonstrates a process for design, development, and testing of novel virus vaccines. NS1 of RSV is unique in that it is the initial virus encoded gene [6] and is the most abundant viral protein produced by RSV during viral infection [7], yet incompletely characterized [8]. Although there exist related viruses in other species (Cow, goat, mice, sheep) [9], there remain no known human virus relatives to either the NS1 gene sequence itself or the RSV viral genome organization. It has been reported that patients possess serum antibodies against NS1 [10], however these antibodies are likely not part of a protective host response to eliminate or reduce virus/disease. Therefore, NS1 is an appropriate target protein for computational analysis due to its significance as an evolutionary unique protein retained in the most proximal position in the human RSV virus genome.
NS1 of RSV has been associated with various processes including host cell apoptosis [11], interferon and interferon simulated gene regulation (and related processes) [12,13], and viral genome replication [14], but no confirmed mechanism detailing NS1 physical association with various interacting partners. The fact that NS1 is 1) a nonstructural cytosolic protein (i.e. not part of any known virus structure) and 2) only recently described in a crystal structure [15], contribute to its difficult study. NS1 has also been shown to be disposable such that an RSV virus in which the NS1 gene sequence has been deleted is viable [16] and a leading live attenuated RSV vaccine virus candidate (ClinicalTrials.gov Identifier: NCT03596801; RSV 6120/∆NS1 and RSV 6120/F1/G2/∆NS1) [17].
Balancing the level of virus growth (not too high, but high enough to invoke the appropriate immune response) and the level of antigenicity required for appropriate immune system induction [3] is complicated further when deletion vaccines are compared to full length wild-type virus since the initial growth conditions are not equivalent, one virus is shorter than the other. NS1 protein seems to participate in multiple measurable biologic phenomena that could be used as measurable functional readouts. Therefore, an analysis of mutation changes to the NS1 protein will provide a selection of vaccine candidates capable of reaching a variety of growth/antigenicity optima.