Clint A Haines1, Rafael K Campos1, Sasha R Azar2, K Lane Warmbrod2, Tiffany F Kautz1, Naomi L Forrester2, Shannan L Rossi1,2,3. 1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA. 2. Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA. 3. Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Abstract
Background: Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas. There are no approved vaccines or antivirals. TC-83 and V3526 are the best-characterized vaccine candidates for VEEV. Both are live-attenuated vaccines and have been associated with safety concerns, albeit less so for V3526. A previous attempt to improve the TC-83 vaccine focused on further attenuating the vaccine by adding mutations that altered the error incorporation rate of the RNA-dependent RNA polymerase (RdRp). Methods: The research presented here examines the impact of these RdRp mutations in V3526 by cloning the 3X and 4X strains, assessing vaccine efficacy against challenge in adult female CD-1 mice, examining neutralizing antibody titers, investigating vaccine tissue tropism, and testing the stability of the mutant strains. Results: Our results show that the V3526 RdRp mutants exhibited reduced tissue tropism in the spleen and kidney compared to wild-type V3526, while maintaining vaccine efficacy. Illumina sequencing showed that the RdRp mutations could revert to wild-type V3526. Conclusions: The observed genotypic reversion is likely of limited concern because wild-type V3526 is still an effective vaccine capable of providing protection. Our results indicate that the V3526 RdRp mutants may be a safer vaccine design than the original V3526.
Background: Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas. There are no approved vaccines or antivirals. TC-83 and V3526 are the best-characterized vaccine candidates for VEEV. Both are live-attenuated vaccines and have been associated with safety concerns, albeit less so for V3526. A previous attempt to improve the TC-83 vaccine focused on further attenuating the vaccine by adding mutations that altered the error incorporation rate of the RNA-dependent RNA polymerase (RdRp). Methods: The research presented here examines the impact of these RdRp mutations in V3526 by cloning the 3X and 4X strains, assessing vaccine efficacy against challenge in adult female CD-1 mice, examining neutralizing antibody titers, investigating vaccine tissue tropism, and testing the stability of the mutant strains. Results: Our results show that the V3526 RdRp mutants exhibited reduced tissue tropism in the spleen and kidney compared to wild-type V3526, while maintaining vaccine efficacy. Illumina sequencing showed that the RdRp mutations could revert to wild-type V3526. Conclusions: The observed genotypic reversion is likely of limited concern because wild-type V3526 is still an effective vaccine capable of providing protection. Our results indicate that the V3526 RdRp mutants may be a safer vaccine design than the original V3526.
Authors: W D Sudia; V F Newhouse; I D Beadle; D L Miller; J G Johnston; R Young; C H Calisher; K Maness Journal: Am J Epidemiol Date: 1975-01 Impact factor: 4.897
Authors: K Lane Warmbrod; Edward I Patterson; Tiffany F Kautz; Adam Stanton; Dedeke Rockx-Brouwer; Birte K Kalveram; Kamil Khanipov; Saravanan Thangamani; Yuriy Fofanov; Naomi L Forrester Journal: PLoS Pathog Date: 2019-04-04 Impact factor: 6.823
Authors: Edward I Patterson; Kamil Khanipov; Mark M Rojas; Tiffany F Kautz; Dedeke Rockx-Brouwer; Georgiy Golovko; Levent Albayrak; Yuriy Fofanov; Naomi L Forrester Journal: Virus Evol Date: 2018-02-15