Yellow ow feve ver immun uniza ization ion dur uring ing preg egnan nancy cy A mo mous use model del: : gestat station onal al perf rform ormance ance and d viral ral antigen igen distri stribu bution ion in placen acenta ta and d fetuse ses Estela Bevilacqua Lab for Research in Maternal-Fetal Interaction & Placenta Dept of Cell and Developmental Biology, Institute of Biomedical Sciences University of São Paulo, SP – SP Brazil bevilacq@usp.br ILLUSTRATION BY CINYEE CHIU
a) For people living in areas where there is a high potential for YF virus exposure b) For travelers visiting these areas The yellow fever vaccine should be avoided in pregnant women as far as possible. However, if travel is unavoidable, the vaccine should be given! The benefits of vaccination usually outweigh its potential risks!
Vac acci cination tion during ring pregnanc gnancy The potential risk of viral transmission (through the placenta) to the fetus No vaccination during associated with the pregnancy in endemic possibility of neuroinvasion areas increases the of the 17 DD yellow fever risk for the disease virus led to the general compromising mother recommendation to do not and baby survival administer the vaccine during pregnancy except when epidemiologically It is imperative to spread justified. knowledge and awareness about the gestational vaccination Popular strategies that disincentive immunization in general!
Vac acci cination tion during ring pregn gnanc ancy Disease risk to a developing fetus from maternal vaccination during pregnancy is primary theoretical! Relative risk for spontaneous abortions Abortion, stillbirth and Congenital YF malformation rates after Malformation vaccination similar to that found in the general after vaccination in population pregnant women Nishioka et al. 1998 Suzano et al., 2006 Tsai et al., 1933 D’Acremont et al., 2008 Bentlin et al., 2011 Cavalcanti et al., 2007 It is imperative to spread knowledge and awareness about the gestational vaccination!
Aim of of th this stu tudy To evaluate the effect of vaccination against yellow fever in mice gestational performance correlating these data with the placental structure, immunolocalization of the virus antigen and the viral activity at the maternal- fetal interface, maternal liver, and fetal organism. Knowledge to help to demystify vaccination against yellow fever during pregnancy
Phase se I: To identi ntify fy potenti ential al pregn gnanc ancy phase ses duri ring ng placenta entati tion on and organo anogene enesis sis in in whic ich vaccina natio tion might ght indu duce ce relevant nt changes Animals Pregnant adult, 3-months old, CD-1 mice on 0.5, 5.5, 11.5 and 13.5 gestation days (gd) (n= 10-13/gestational age) Yellow fever 17DD vaccine (parts 00PVFA028Z; 066VFA061Z and 082VFB006Z) Oswaldo Cruz Foundation (Bio-Manguinhos, RJ, Br) Administration - subcutaneous Doses - 2.0 log 10 PFU Control group - sterile saline (n=10-11/gestational age) Analysis gd18.5 – euthanasia in CO2 chamber Measurements: number of placentas, early and late resorptions, dead and alive fetuses, implantation sites, fetal and placental weight All animal care and experimental procedures were followed according to Brazilian College of Animal Experiments (COBEA) and were approved by the Ethics Committee for Animal Research (CEEA) of Biomedical Sciences Institute of the University of São Paulo, SP.
Phase I Gd 0.5 : post-fertilization stage 0.5 gd 1.5 gd GD 5.5 : post-implantation stage
Phase I Gd 11.5 and 13.5 : Placenta maturation and fetal organogenesis stage http://animalia-life.club/other/mouse-embryo- development-timeline.html / 11 Apr 2019 Placental barrier
Phase I Effec ect t of anti-yellow ellow fever vaccina natio tion admi minis nister tered d on gestati tion on days 0.5, 5.5, 11.5 and 13.5 on the gestationa tional l parame ameter ters Implantation No. of No. of (%) Alive (%) Fetal n sites (no.) fetuses stillborn fetuses Losses Control gd 0.5 71 10.0 ± 1.52 9.79 ± 1.15 O.47 ± 0.58 93.8 6.2 Vaccinated gd 0.5 53 10.60 ± 3.71 9.60 ± 4.9 O.38 ± 0.89 94.9 5.1 Control gd 5.5 183 12.29 ± 2.14 12.06 ± 2.27 0.07 ± 0.26 97.8 2.2 74.0 26.0 2.32 a ± 1.76 Vaccinated gd 5.5 160 12.25 ± 1.92 9.71 ± 2.62 Control gd 11.5 79 10.37 ± 2.38 9.88 ± 2.23 0.25 ± 0.46 93.9 7.02 Vaccinated gd11.5 61 11.0 ± 2.45 10.25 ± 2.99 0.32 ± 0.46 90.9 9.0 Control gd 13.5 82 11.54 ± 1.05 10.28 ± 1.31 0.78 ± 0.53 91.14 8.86 Vaccinated gd13.5 74 10.03 ± 1.94 9.86 ± 2.05 0.54 ± 0.36 89.91 10.09 Values correspond to mean SD; * highlight statistical differences in comparison to the respective age-control. Significant increase in stillbirth and fetal loss rate when the vaccine is a p = 0.000 ( Student t -test ). administered on gd5.5
Phase I Effec ect t of anti-yellow ellow fever vaccina natio tion admi minis nister tered d on gestatio tion n days 0.5, 5.5, 11.5 or 13.5 on placental ental and fetal l weight ghts n Fetal weight (g) Placental weight (g) Control gd 0.5 28 0.92 ± 0.20 0.12 ± 0.05 Vaccinated gd 0.5 47 0.88 ± 0.16 0.13 ± 0.02 Control gd 5.5 180 0.89 ± 0.19 0.13 ± 0.03 0.75 a ± 0.21 0.15 b ± 0.06 Vaccinated gd 5.5 151 Control gd 11.5 72 0.84 ± 0.15 0.13 ± 0.09 Vaccinated gd 11.5 41 0.87 ± 0.08 0.13 ± 0.03 Control gd 13.5 72 0.84 ± 0.15 0.13 ± 0.09 Vaccinated gd 13.5 41 0.87 ± 0.08 0.12 ± 0.08 Values correspond to mean SD; Values indicated by asterisks highlight statistical differences in comparison to the respective age-control. Student t -test ( a p = 0.000; b p =0.0000). gd5.5 - period of susceptibility to vaccinal yellow fever virus during pregnancy?
Phase I Dead fetuses were macroscopically Morphologica phological l analy alysis sis subdivided into: A - stillbirth (absence of heartbeat, but no visible degeneration – late fetal death ) B - early fetal death (with apparent development delay & degenerative signals) C - post-implantation resorptions (implantation sites with no recognizable Dead fetuses: macroscopical analysis on gestation fetal structures) day 18.5.
Phase se II: II: Mother hers immuniz unization tion on on gd gd 5.5. . Identif ntifica cation tion of of viral al antig igen en distri tribution ution in maternal ernal liver er, , placenta centas s and fetal tal organism anism Post-implantation resorptions (implantation sites with no recognizable fetal structures) Gd 18.5 Early fetal death (with apparent YFV Analyses development delay and degenerative signals) Gd 5.5 Stillborn puppies (absence of heartbeat, no visible degeneration – late fetal death ) n=18 n=25 Live and apparently healthy fetuses Immunolocalization and PCR for yellow fever vaccine virus on the maternal liver and fetal organism
Immunolocalization of the yellow fever antigen after vaccination on gd 5.5 Phase II A-C: Maternal and fetal liver – rare areas of reactivity Liver D-F : Immunolocalization Mother Live fetus Stillborn of YF antigen in stillborn G-I: Negative Stillbirth controls Ganglion cells Nerve cells Brain cells J : Liver of a patient with YF Controls (-) (-) (-) (+)
Phase II % YFV immunoreactivity/histological section (n=5) 0.8 0,8 0.6 0,6 0.4 0,4 0.2 0,2 0.0 0 Liver Liver Abdominal Brain Liver Abdominal Brain (x10) region region (x10) Mother Live fetuses Stillborns Vaccine virus reactivity is scarcely detectable in the organs of alive fetuses but, it is frequent in the tissues of stillbirths (mainly nervous cells) Invasion and colonization of vaccinal YF in tissues of stillbirths
Phase II Immunolocalization of the YF antigen after vaccination on gd5.5 Placentas of live fetuses and stillbirth A-D: Placentas from live fetuses Junctional zone Few cells show immunoreactivity to the YF viral Live antigen (arrowheads) in Fetuses junctional ( A,C ) and labyrinth (-) zones ( D ). Labyrinth E-J: Placentas from stillbirth The reaction is intense in Junctional zone junctional zone ( E-F : spongiotrophoblast, G : glycogen Stillbirth cells) and in the labyrinth ( H-I ) B and J: negative controls Labyrinth Vaccine virus reactivity is largely distributed in zone (-) numerous placental cells in the stillbirth samples
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