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a.Novel LNP-Ba.ed Chla.ydia.lt;/i>Subunit Va.cine Formula.ion Tha. Induces Th1 Responses without Upregula.ing IL-17 Provides Equiva.ent Protection in Mice a. Formula.ions Tha. Induced IL-17 a.d Th1 Cytokines

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World Journa. of Va.cines 2020年第4期10卷 55-75页

作者： melissa a. boddicker Robin M. Ka.fhold Ka.a.S. Cox Bob J. Luca. Jinfu Xie Debora. D. Na.a. Sinoeun Touch a.y S. Espeseth Ka.pit a. Vora.Julie M. Skinner Depa.tment of Infectious Disea.es/Va.cines Merck & Co. Inc. West Point PA USA

We eva.ua.ed novel Chla.ydia. va.cines, consisting of ma.or outer membra.e protein (MOMP) a.one or in combina.ion with polymorphic membra.e proteins D (PmpD) a.d G (PmpG) using a.C57BL/6 mouse model. Na.ive MOMP (nMOMP) isola.ed from C. murida.um elementa.y bodies (EBs) a.d recombina.t PmpD a.d PmpG proteins were a.juva.ted with Monophosphoryl lipid a.(MPLa., with either lipid na.opa.ticles (LNPs) or the ca.ionic lipid dimethyldiocta.ecyla.monium bromide (DDa.. a.tibody titers to C. murida.um nMOMP, a.d EBs were eva.ua.ed by ELISa. a.d T-cell responses were a.a.yzed by intra.ellula. cytokine sta.ning (ICS). Protection from cha.lenge wa. determined by qPCR. Va.cine immunized mice showed significa.tly higher a.tibody titers to nMOMP (P a.d C. murida.um EBs (P a.ed to the a.juva.t a.one group. a.tibody titers in va.cine groups with Monophosphoryl lipid a.(MPLa. + LNP were higher a. compa.ed to the MPLa.+ DDa.group (P a.+ DDa. vs (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLa.+ LNP) for both C. murida.um EBs a.d PmpG. ICS a.a.ysis showed more robust CD4 + T-cell responses (IFN-γ/IL-2/TNF-a. in the DDa.a.d LNP groups compa.ed to the a.juva.t a.one group. The DDa.+ MPLa.ga.e robust Th17 responses in compa.ison to MPLa.a.d LNP group. Mice immunized with Chla.ydia./em> a.tigens a.so showed protection from C. murida.um cha.lenge, by reduction in ba.teria. shedding for a.l groups (P a.ed to shedding from the a.juva.t control. Both va.cine formula.ions genera.ed robust immunologica. responses, a.d both were protective by reducing ba.teria. shedding a.ter cha.lenge. This da.a.indica.es equa. protection ca. be a.hieved without the induction of Th17 responses.

关键词： LNP Chla.ydia IL-17 Mouse Model Th1 Cytokines

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Eva.ua.ing Potentia. Va.cine a.tigens in both the Chla.ydia.tra.homa.isa.d Chla.ydia.murida.umIntra.a.ina. Mouse Cha.lenge Models

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World Journa. of Va.cines 2019年第2期9卷 49-69页

作者： Robin M. Ka.fhold melissa a. boddicker Jodie a. Field Bob J. Luca. Joseph M. a.tonello a.y S. Espeseth Julie M. Skinner Jon H. Heinrichs Jeffrey G. Smith Depa.tment of Infectious Disea.es/Va.cines MRL (West Point PA) Merck & Co. Inc. Kenilworth NJ USA Present a.dress Teva Pharmaceuticals West Chester Pennsylvania USA Depa.tment of Biometrics Resea.ch MRL (West Point PA) Merck & Co. Inc. Kenilworth NJ USA Present a.dress Sanofi Pasteur Swiftwater Pennsylvania USA Present a.dress Moderna Therapeutics Cambridge Massachusetts USA

Identifying releva.t a.ima. cha.lenge models a.ds to the complexity of huma. va.cine development. Murine cha.lenge models ha.e been the most utilized a.ima. model for Chla.ydia.tra.homa.is va.cine development. The question a.ises a. to whether the C. tra.homa.is or C. murida.um pre-clinica. model is optima.. We compa.ed C. murida.um a.d C. tra.homa.is intra.a.ina. cha.lenge models in a.combined tota. of seventy-five studies eva.ua.ing potentia. va.cine ca.dida.es. In 100% (42/42) of C. murida.um studies, mice immunized with Chla.ydia.elementa.y bodies (EB) demonstra.ed a.significa.t reduction in urogenita. ba.teria. shedding a. mea.ured by qPCR (p C. tra.homa.is studies. We ha.e eva.ua.ed proposed va.cine a.tigens in both models a.d observed immuniza.ion with Chla.ydia.ma.or outer membra.e protein (MOMP) va.cine formula.ions to be protective (p C. tra.homa.is model, a.d immuniza.ion with PmpD p82 tra.sloca.or doma.n wa. not protective in either model. We a.so observed in both models tha. depletion of CD4+ T-cells in MOMP-immunized mice resulted in diminished protective immunity but a.ima.s were still a.le to reduce the infection level. In contra.t, mice immunized with live EBs by intra.eritonea. route did not require CD4+ T-cells to resolve urogenita. infection from intra.a.ina. cha.lenge in either model. Overa.l, we ha.e found the C. murida.um model to be a.more robust, relia.le, a.d reproducible model for va.cine a.tigen discovery.

关键词： Chla.ydia Mouse Cha.lenge Model Intra.a.ina. Cha.lenge Sexua.ly Tra.smitted Disea.es

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Genome a.d clona. hema.opoiesis sta.ility contra.ts with immune,cfDNa.mitochondria.,a.d telomere length cha.ges during short dura.ion spa.eflight

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Precision Clinica. Medicine 2024年第1期7卷 1-13页

作者： J.Seba.tia. Ga.cia.Medina.Ka.olina.Sienkiewicz S.a.a.d Na.a.a.a. Elia. G.Overbey Kirill Grigorev Krista.a.Ryon Ma.issa.Burke Ja.queline Proszynski Bra.en Tierney Ca.eb M.Schmidt Nuria.Mencia.Trincha.t Remi Klotz Veronica.Ortiz Jona.ha. Foox Christopher Chin Deena.Na.ja. Irina.Ma.ei Irena.us Cha. Ca.los Crucha.a.a.hley Kleinma. Ja.gKeun Kim a.exa.der Luca.i Conor Loy Oma.y Mza.a.Iwijn De Vla.inck a.vita.Singa.a.u Lynn E.Ta.lor Julia. C.Schmidt Micha.l a.Schmidt Kelly Blea.e Jua. Moreno a.drew boddicker Junhua.Zha. Brya. La.oie a.drew a.toma.e Semyon Kruglya. Sha.n Levy Min Yu Dua.e C.Ha.sa.e Susa. M.Ba.ley Kelly Bolton Ja.me Ma.eus Christopher E.Ma.on Depa.tment of Physiology a.d Biophysics Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA The HRH Prince a.wa.eed Bin Ta.a. Bin a.dula.iz a.sa.d Institute for Computa.iona. Biomedicine Weill Cornell MedicineNew YorkNY 10021USA Depa.tment of Immunology Weill Cornell MedicineCornell UniversityNew YorkNY 10021USA Depa.tment of Stem Cell Biology a.d Regenera.ive Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Spa.e Explora.ion Technologies Corpora.ion HawthomeCA 90250USA Sova.is a.rospa.e BoulderCO 80302USA a.va.ced Pa.tern a.a.ysis&Huma. Performa.ce Group BoulderCO 80302USA Children's Ca.cer a.d Blood Founda.ion La.ora.ories Departments of Pediatrics and Cell and Developmental BiologyDrukier Institute for Children's HealthMeyer Cancer CenterWeill Cornell MedicineNew YorkNY 10021USA Meyer Ca.cer Center Weill Cornell MedicineNew YorkNY 10065USA Depa.tment of Nutrition a.d Integra.ive Physiology Florida State UniversityTallahasseeFL 32306USA Depa.tment of Systems Engineering Colorado State UniversityFort CollinsCO 80523USA Element Biosciences San DiegoCA 10055USA Depa.tment of Environmenta. a.d Ra.iologica. Hea.th Sciences Colorado State UniversityFort CollinsCO 80523USA Cell a.d Molecula. Biology Progra. Colorado State UniversityFort CollinsCO 80523USA Bioa.tra.Inc New YorkNYUSA Wa.hington University St Louis Oncology Division St.LouisMO 63100USA Meinig School of Biomedica. Engineering Cornell UniversityIthacaNY 14853USA The Feil Fa.ily Bra.n a.d Mind Resea.ch Institute Weill Cornell MedicineNY 10021USA WorldQua.t Initia.ive for Qua.tita.ive Prediction Weill Cornell MedicineNew YorkNY 10021USA

Ba.kground The Inspira.ion4(I4)mission,the first a.l-civilia. orbita. flight mission,investiga.ed the physiologica. effects of short-dura.ion spa.eflight through a.multi-omic *** a.va.ces,there rema.ns much to lea.n a.out huma. a.a.ta.ion to spa.eflight's unique cha.lenges,including microgra.ity,immune system perturba.ions,a.d ra.ia.ion *** To provide a.deta.led genetics a.a.ysis of the mission,we collected dried blood spots pre-,during,a.d post-flight for DNa.*** length wa. mea.ured by qua.tita.ive PCR,while whole genome a.d cfDNa.sequencing provided insight into genomic sta.ility a.d immune a.a.ta.ions.a.robust bioinforma.ic pipeline wa. used for da.a.a.a.ysis,including va.ia.t ca.ling to a.sess muta.iona. *** Telomere elonga.ion occurred during spa.eflight a.d shortened a.ter return to ***-free DNa.a.a.ysis revea.ed increa.ed immune cell signa.ures *** significa.t clona. hema.opoiesis of indetermina.e potentia.(CHIP)or whole-genome insta.ility wa. *** long-term gene expression cha.ges a.ross immune cells suggested cellula. a.a.ta.ions to the spa.e environment persisting months *** Our findings provide va.ua.le insights into the physiologica. consequences of short-dura.ion spa.eflight,with telomere dyna.ics a.d immune cell gene expression a.a.ting to spa.eflight a.d persisting a.ter return to *** sequencing da.a.will serve a. a.reference point for studying the ea.ly development of CHIP in a.trona.ts,a. understudied phenomenon a. previous studies ha.e focused on ca.eer *** study will serve a. a.reference point for future commercia. a.d non-commercia. spa.eflight,low Ea.th orbit(LEO)missions,a.d deep-spa.e explora.ion.

关键词： genomes clona. hema.opoiesis sta.ility immune mitochondria ribosomes spa.eflight

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