Last data update: Sep 23, 2024. (Total: 47723 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Resch TK [original query] |
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Microneedle patch as a new platform to effectively deliver inactivated polio vaccine and inactivated rotavirus vaccine
Moon SS , Richter-Roche M , Resch TK , Wang Y , Foytich KR , Wang H , Mainou BA , Pewin W , Lee J , Henry S , McAllister DV , Jiang B . NPJ Vaccines 2022 7 (1) 26 We recently reported a lack of interference between inactivated rotavirus vaccine (IRV) and inactivated poliovirus vaccine (IPV) and their potential dose sparing when the two vaccines were administered intramuscularly either in combination or standalone in rats and guinea pigs. In the present study, we optimized the formulations of both vaccines and investigated the feasibility of manufacturing a combined IRV-IPV dissolving microneedle patch (dMNP), assessing its compatibility and immunogenicity in rats. Our results showed that IRV delivered by dMNP alone or in combination with IPV induced similar levels of RV-specific IgG and neutralizing antibody. Likewise, IPV delivered by dMNP alone or in combination with IRV induced comparable levels of neutralizing antibody of poliovirus types 1, 2, and 3. We further demonstrated high stability of IRV-dMNP at 5, 25, and 40 °C and IPV-dMNP at 5 and 25 °C, and found that three doses of IRV or IPV when co-administered at a quarter dose was as potent as a full target dose in inducing neutralizing antibodies against corresponding rotavirus or poliovirus. We conclude that IRV-IPV dMNP did not interfere with each other in triggering an immunologic response and were highly immunogenic in rats. Our findings support the further development of this innovative approach to deliver a novel combination vaccine against rotavirus and poliovirus in children throughout the world. |
An optimized reverse genetics system suitable for efficient recovery of simian, human and murine-like rotaviruses.
Sanchez-Tacuba L , Feng N , Meade NJ , Mellits KH , Jais PH , Yasukawa LL , Resch TK , Jiang B , Lopez S , Ding S , Greenberg HB . J Virol 2020 94 (18) An entirely plasmid-based reverse genetics (RG) system was recently developed for rotavirus (RV), opening new avenues for in-depth molecular dissection of RV biology, immunology, and pathogenesis. Several improvements to further optimize the RG efficiency have now been described. However, only a small number of individual RV strains have been recovered to date. None of the current methods have supported the recovery of murine RV, impeding the study of RV replication and pathogenesis in an in vivo suckling mouse model. Here, we describe useful modifications to the RG system that significantly improve rescue efficiency of multiple RV strains. In addition to the 11 RVA segment-specific (+)ssRNAs, a chimeric plasmid was transfected, from which the capping enzyme NP868R of African swine fever virus (ASFV) and the T7 RNA polymerase were expressed. Secondly, a genetically modified MA104 cell line was used in which several compounds of the innate immune were degraded. Using this RG system, we successfully recovered the simian RV RRV strain, the human RV CDC-9 strain, a reassortant between murine RV D6/2 and simian RV SA11 strains, and several reassortants and reporter RVs. All these recombinant RVs were rescued at a high efficiency (≥80% success rate) and could not be reliably rescued using several recently published RG strategies (<20%). This improved system represents an important tool and great potential for the rescue of other hard-to-recover RV strains such as low replicating attenuated vaccine candidates or low cell culture passage clinical isolates from humans or animals.IMPORTANCE Group A rotavirus (RV) remains as the single most important cause of severe acute gastroenteritis among infants and young children worldwide. An entirely plasmid-based reverse genetics (RG) system was recently developed opening new ways for in-depth molecular study of RV. Despite several improvements to further optimize the RG efficiency, it has been reported that current strategies do not enable the rescue of all cultivatable RV strains. Here, we described helpful modification to the current strategies and established a tractable RG system for the rescue of the simian RRV strain, the human CDC-9 strain and a murine-like RV strain, which is suitable for both in vitro and in vivo studies. This improved RV reverse genetics system will facilitate study of RV biology in both in vitro and in vivo systems that will facilitate the improved design of RV vaccines, better antiviral therapies and expression vectors. |
Serial passaging of human rotavirus CDC-9 strain in cell culture leads to attenuation: characterization from in vitro and in vivo studies.
Resch TK , Wang Y , Moon S , Jiang B . J Virol 2020 94 (15) Live oral rotavirus vaccines have been developed by serial passaging in cell culture and found safe in infants. However, mechanisms for the adaptation and attenuation of rotavirus vaccines are not fully understood. We have prepared a human rotavirus vaccine strain CDC-9 (G1P[8]) which when grown in MA104 cells to passages 11 or 12 (P11/P12), had no nucleotide and amino acid sequence changes from the original virus in stool. Upon adaptation and passages in Vero cells, the strain underwent five amino acid changes at passage 28 (P28) and one additional change at P44/P45 in VP4 gene. We performed virologic, immunological and pathogenic characterization of wild-type CDC-9 virus P11/P12 and its two mutants at P28 or P44/P45 using in vitro- and in vivo-model systems. We found that mutants CDC-9 P28 and P44 induced upregulated expression of immunomodulatory cytokines. On the other hand, the two mutant viruses induced lower STAT-1 phosphorylation and grew to two logs higher titers than wild-type virus in human CaCo-2 cells and simian Vero cells. In neonatal rats, CDC-9 P45 showed reduced rotavirus shedding in fecal specimens and did not induce diarrhea compared to wild-type virus, and modulated cytokine responses comparable to Rotarix infection. These findings indicate that mutant CDC-9 is attenuated and safe. Our study is the first to provide insight into the possible mechanisms of human rotavirus adaptation and attenuation and supports ongoing efforts to develop CDC-9 as a new generation of rotavirus vaccine for live oral or parenteral administration.IMPORTANCE Mechanisms for in vitro adaptation and in vivo attenuation of human rotavirus vaccines are not known. The present study is the first to comprehensively compare the in vitro growth characteristics, virulence, and host response of a wild-type and an attenuated human rotavirus CDC-9 strain in CaCo-2 cells and neonatal rats. Our study identifies critical sequence changes in the genome that render human rotavirus adapted to high growth in Vero cells and attenuated and safe in neonatal rats thus supports clinical development of CDC-9 for oral or parenteral vaccination in children. |
Inactivated rotavirus vaccine by parenteral administration induces mucosal immunity in mice
Resch TK , Wang Y , Moon SS , Joyce J , Li S , Prausnitz M , Jiang B . Sci Rep 2018 8 (1) 561 To improve the safety and efficacy of oral rotavirus vaccines, we developed an inactivated rotavirus vaccine (IRV) for parenteral administration. Since it remains unknown whether parenteral vaccination can induce mucosal immunity, we performed a comprehensive assessment of immune responses to IRV in mice with an adjuvant-free dissolving polymer MN patch or by alum-adjuvanted IM injection. We demonstrated that IRV induced the expression of the gut homing receptor LPAM-1 on T and B cells in spleen and mLN of vaccinated mice. MN patch IRV vaccination induced a slight Th1 phenotype while IM vaccination induced a balanced Th1/Th2 phenotype. In addition, a dose-sparing effect was seen for rotavirus-specific serum IgG and neutralizing activity for both vaccination routes. Our study is the first to show that parenterally administered IRV can induce mucosal immunity in the gut, in addition to strong serum antibody response, and is a promising candidate vaccine in achieving global immunization against rotavirus. |
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