The Experts below are selected from a list of 1377 Experts worldwide ranked by ideXlab platform
Bruce S. Klein - One of the best experts on this subject based on the ideXlab platform.
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requisite elements in vaccine Immunity to blastomyces dermatitidis plasticity uncovers vaccine potential in immune deficient hosts
Journal of Immunology, 2002Co-Authors: Marcel Wuthrich, Hanna I. Filutowicz, Thomas F Warner, Bruce S. KleinAbstract:Understanding fundamental mechanisms of vaccine Immunity will allow proper use and optimization of vaccines. Vaccination with a genetically engineered, live, attenuated strain of Blastomyces dermatitidis carrying a targeted deletion at the BAD1 locus confers Sterilizing Immunity against experimental lethal pulmonary infection. We found in this study that αβ T cells are requisite for durable vaccine Immunity, whereas other T and B cells are dispensable. In immune-competent animals, CD4 + T-cell derived cytokines TNF-α and IFN-γ mediate vaccine Immunity. Surprisingly, these factors are dispensable in immune-deficient animals, which rely on alternate mechanisms for robust vaccine Immunity, yet still require O 2 − production rather than generation of NO. Our results clarify the cellular and molecular bases behind the first genetically engineered fungal vaccine. They also illustrate a sharp difference in vaccine mechanisms between immune-competent and immune-deficient hosts, which underscores the plasticity of residual immune elements in compromised hosts, and points to the feasibility of developing vaccines against invasive fungal infection in this fast growing patient population.
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requisite elements in vaccine Immunity to blastomyces dermatitidis plasticity uncovers vaccine potential in immune deficient hosts
Journal of Immunology, 2002Co-Authors: Marcel Wuthrich, Hanna I. Filutowicz, Thomas F Warner, Bruce S. KleinAbstract:Understanding fundamental mechanisms of vaccine Immunity will allow proper use and optimization of vaccines. Vaccination with a genetically engineered, live, attenuated strain of Blastomyces dermatitidis carrying a targeted deletion at the BAD1 locus confers Sterilizing Immunity against experimental lethal pulmonary infection. We found in this study that alphabeta T cells are requisite for durable vaccine Immunity, whereas other T and B cells are dispensable. In immune-competent animals, CD4(+) T-cell derived cytokines TNF-alpha and IFN-gamma mediate vaccine Immunity. Surprisingly, these factors are dispensable in immune-deficient animals, which rely on alternate mechanisms for robust vaccine Immunity, yet still require O(2)(-) production rather than generation of NO. Our results clarify the cellular and molecular bases behind the first genetically engineered fungal vaccine. They also illustrate a sharp difference in vaccine mechanisms between immune-competent and immune-deficient hosts, which underscores the plasticity of residual immune elements in compromised hosts, and points to the feasibility of developing vaccines against invasive fungal infection in this fast growing patient population.
Zhenhua Zheng - One of the best experts on this subject based on the ideXlab platform.
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zika virus attenuation by codon pair deoptimization induces Sterilizing Immunity in mouse models
Journal of Virology, 2018Co-Authors: Ting Wang, Zhongyuan Tan, Dan Luo, Yuanjiu Miao, Jianhong Sun, Yuan Zhang, Yan Liu, Hanzhong Wang, Zhenhua ZhengAbstract:Zika virus (ZIKV) infection during the large epidemics in the Americas is related to congenital abnormities or fetal demise. To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. Here we designed novel live attenuated ZIKV vaccine candidates using a codon pair deoptimization strategy. Three codon pair-deoptimized ZIKVs (Min E, Min NS1, and Min E+NS1) were de novo synthesized and recovered by reverse genetics and contained large amounts of underrepresented codon pairs in the E gene and/or NS1 gene. The amino acid sequence was 100% unchanged. The codon pair-deoptimized variants had decreased replication fitness in Vero cells (Min NS1 ≫ Min E > Min E+NS1), replicated more efficiently in insect cells than in mammalian cells, and demonstrated diminished virulence in a mouse model. In particular, Min E+NS1, the most restrictive variant, induced Sterilizing Immunity with a robust neutralizing antibody titer, and a single immunization achieved complete protection against lethal challenge and vertical ZIKV transmission during pregnancy. More importantly, due to the numerous synonymous substitutions in the codon pair-deoptimized strains, reversion to wild-type virulence through gradual nucleotide sequence mutations is unlikely. Our results collectively demonstrate that ZIKV can be effectively attenuated by codon pair deoptimization, highlighting the potential of Min E+NS1 as a safe vaccine candidate to prevent ZIKV infections.IMPORTANCE Due to unprecedented epidemics of Zika virus (ZIKV) across the Americas and the unexpected clinical symptoms, including Guillain-Barre syndrome, microcephaly, and other birth defects in humans, there is an urgent need for ZIKV vaccine development. Here we provided the first attenuated versions of ZIKV with two important genes (E and/or NS1) that were subjected to codon pair deoptimization. Compared to parental ZIKV, the codon pair-deoptimized ZIKVs were mammal attenuated and preferred insect to mammalian cells. Min E+NS1, the most restrictive variant, induced Sterilizing Immunity with a robust neutralizing antibody titer and achieved complete protection against lethal challenge and vertical virus transmission during pregnancy. More importantly, the massive synonymous mutational approach made it impossible for the variant to revert to wild-type virulence. Our results have proven the feasibility of codon pair deoptimization as a strategy to develop live attenuated vaccine candidates against flaviviruses such as ZIKV, Japanese encephalitis virus, and West Nile virus.
Rebecca C Christofferson - One of the best experts on this subject based on the ideXlab platform.
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route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques
PLOS Neglected Tropical Diseases, 2020Co-Authors: Michael K Mccracken, Gregory D Gromowski, Lindsey S Garver, Brad A Goupil, Kathryne D Walker, Heather Friberg, Jeffrey R Currier, Wiriya Rutvisuttinunt, Kevin L Hinton, Rebecca C ChristoffersonAbstract:Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of Sterilizing Immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans.
Marcel Wuthrich - One of the best experts on this subject based on the ideXlab platform.
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requisite elements in vaccine Immunity to blastomyces dermatitidis plasticity uncovers vaccine potential in immune deficient hosts
Journal of Immunology, 2002Co-Authors: Marcel Wuthrich, Hanna I. Filutowicz, Thomas F Warner, Bruce S. KleinAbstract:Understanding fundamental mechanisms of vaccine Immunity will allow proper use and optimization of vaccines. Vaccination with a genetically engineered, live, attenuated strain of Blastomyces dermatitidis carrying a targeted deletion at the BAD1 locus confers Sterilizing Immunity against experimental lethal pulmonary infection. We found in this study that αβ T cells are requisite for durable vaccine Immunity, whereas other T and B cells are dispensable. In immune-competent animals, CD4 + T-cell derived cytokines TNF-α and IFN-γ mediate vaccine Immunity. Surprisingly, these factors are dispensable in immune-deficient animals, which rely on alternate mechanisms for robust vaccine Immunity, yet still require O 2 − production rather than generation of NO. Our results clarify the cellular and molecular bases behind the first genetically engineered fungal vaccine. They also illustrate a sharp difference in vaccine mechanisms between immune-competent and immune-deficient hosts, which underscores the plasticity of residual immune elements in compromised hosts, and points to the feasibility of developing vaccines against invasive fungal infection in this fast growing patient population.
-
requisite elements in vaccine Immunity to blastomyces dermatitidis plasticity uncovers vaccine potential in immune deficient hosts
Journal of Immunology, 2002Co-Authors: Marcel Wuthrich, Hanna I. Filutowicz, Thomas F Warner, Bruce S. KleinAbstract:Understanding fundamental mechanisms of vaccine Immunity will allow proper use and optimization of vaccines. Vaccination with a genetically engineered, live, attenuated strain of Blastomyces dermatitidis carrying a targeted deletion at the BAD1 locus confers Sterilizing Immunity against experimental lethal pulmonary infection. We found in this study that alphabeta T cells are requisite for durable vaccine Immunity, whereas other T and B cells are dispensable. In immune-competent animals, CD4(+) T-cell derived cytokines TNF-alpha and IFN-gamma mediate vaccine Immunity. Surprisingly, these factors are dispensable in immune-deficient animals, which rely on alternate mechanisms for robust vaccine Immunity, yet still require O(2)(-) production rather than generation of NO. Our results clarify the cellular and molecular bases behind the first genetically engineered fungal vaccine. They also illustrate a sharp difference in vaccine mechanisms between immune-competent and immune-deficient hosts, which underscores the plasticity of residual immune elements in compromised hosts, and points to the feasibility of developing vaccines against invasive fungal infection in this fast growing patient population.
Ting Wang - One of the best experts on this subject based on the ideXlab platform.
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zika virus attenuation by codon pair deoptimization induces Sterilizing Immunity in mouse models
Journal of Virology, 2018Co-Authors: Ting Wang, Zhongyuan Tan, Dan Luo, Yuanjiu Miao, Jianhong Sun, Yuan Zhang, Yan Liu, Hanzhong Wang, Zhenhua ZhengAbstract:Zika virus (ZIKV) infection during the large epidemics in the Americas is related to congenital abnormities or fetal demise. To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. Here we designed novel live attenuated ZIKV vaccine candidates using a codon pair deoptimization strategy. Three codon pair-deoptimized ZIKVs (Min E, Min NS1, and Min E+NS1) were de novo synthesized and recovered by reverse genetics and contained large amounts of underrepresented codon pairs in the E gene and/or NS1 gene. The amino acid sequence was 100% unchanged. The codon pair-deoptimized variants had decreased replication fitness in Vero cells (Min NS1 ≫ Min E > Min E+NS1), replicated more efficiently in insect cells than in mammalian cells, and demonstrated diminished virulence in a mouse model. In particular, Min E+NS1, the most restrictive variant, induced Sterilizing Immunity with a robust neutralizing antibody titer, and a single immunization achieved complete protection against lethal challenge and vertical ZIKV transmission during pregnancy. More importantly, due to the numerous synonymous substitutions in the codon pair-deoptimized strains, reversion to wild-type virulence through gradual nucleotide sequence mutations is unlikely. Our results collectively demonstrate that ZIKV can be effectively attenuated by codon pair deoptimization, highlighting the potential of Min E+NS1 as a safe vaccine candidate to prevent ZIKV infections.IMPORTANCE Due to unprecedented epidemics of Zika virus (ZIKV) across the Americas and the unexpected clinical symptoms, including Guillain-Barre syndrome, microcephaly, and other birth defects in humans, there is an urgent need for ZIKV vaccine development. Here we provided the first attenuated versions of ZIKV with two important genes (E and/or NS1) that were subjected to codon pair deoptimization. Compared to parental ZIKV, the codon pair-deoptimized ZIKVs were mammal attenuated and preferred insect to mammalian cells. Min E+NS1, the most restrictive variant, induced Sterilizing Immunity with a robust neutralizing antibody titer and achieved complete protection against lethal challenge and vertical virus transmission during pregnancy. More importantly, the massive synonymous mutational approach made it impossible for the variant to revert to wild-type virulence. Our results have proven the feasibility of codon pair deoptimization as a strategy to develop live attenuated vaccine candidates against flaviviruses such as ZIKV, Japanese encephalitis virus, and West Nile virus.
