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Cela inclut toutes les souches circulantes annotes dans la base de donnes de Los Alamos (de 100 150 par soustype) Il faut des pools multiples de Env, Gag et Pol afin de limiter le nombre total de peptides dans chaque pool (160 peptides par pool, 9 pools) P. ex. Env1, Env2 et Env3 Considr comme une illustration des souches de VIH-1 en circulation (bonne concordance avec les souches transmises de la base de donnes) Cryoprservation des PBMC : toujours dans les 8 heures de la veinopuncture sur place PgP'PP2P&PPPPPUPP"W  """2  +$$$$x$$m((!(( ((a,,0"0448"8<<< w #BEssais cliniques des vaccins prventifs contre le VIH (1988-2005)*CC  C 0d$Activit du rseau HVTN en 2006-2007%% % 18 protocoles en cours; plus de 3 400 participants inscrits 7 essais (inscriptions en cours) ADN + MVA (HVTN 067) ADN + Ad5 ou Ad35 (HVTN 069, 072*) ADN avec IL-12, IL-15 (HVTN 070) Ad5 seul (HVTN 071*, 503* Phambili) 8 essais (inscriptions termines)) MVA + FPV (HVTN055) ADN + MVA (HVTN 065) ADN avec IL-12, IL-15 (HVTN 060, 063) ADN + Ad5 (HVTN 068, 204) ADN + polypeptide rT-help (HVTN 064) Ad5 seul (tude Step 502 du rseau HVTN) * 3 essais arrts en raison des rsultats de l tude Step_Z~Z$ZZ;Z]n $9  Wv  RuGHVTN 502 (tude STEP) : vaccin trivalent MRKAd5 contre le VIH (clade B)HH H S>HVTN 502 : Plan de l tude STEP    MRK Ad5-HIV (gag, pol et nef) 1010 UP administr IM 0, 1 et 6 mois La moiti des sujets a reu le vaccin et l autre, le placebo (eau sale) Plan d essai initial : 1500 pts srongatifs pour le VIH ayant des titres Ad5 faibles (<200) Essai modifi en juillet 2005 : ajout de 1 500 sujets ayant des titres Ad5 levs (>200) Inscription stratifie selon les titres Ad5 : <18, 18-200, 201-1000, >1000 Les volontaires de l tude ont reu un counseling rgulier afin d viter une infection au VIH et ont fait l objet d un dpistage du VIH tous les 6 mois Objectifs primaires de l tude : Au sein des participants ayant des titres Ad5 faibles, les vaccins seront moins susceptibles d tre infects par le VIH, et/ou Au sein des participants ayant des titres Ad5 faibles qui acquirent l infection, les vaccins auront une charge virale moyenne d quilibre plus basse. Au sein des participants ayant des titres Ad5 faibles, le vaccin sera scuritaire et bien tolr. @ZZIZ ZZ{Z" #"  "X!v"#  {$$@     kRisque relatif estim d une infection au VIH Vaccin : Placebo (IC 95 %)6K>  K  l,Rsum de l tude STEP   bLe test de concept a produit des rsultats dfinitifs 33 mois aprs l inscription des premiers participants Le vaccin ne prvenait pas l infection et ne diminuait pas la charge virale d quilibre Le nombre de cas d infection tait plus lev chez les pts ayant reu le vaccin que chez les pts ayant reu le placebo Cette tendance semble se concentrer dans la strate des sropositifs pour le Ad5 (randomisation au sein de la strate)zlpnYpnxpnupnlYD,  u  mRsum (suite)    Les analyses multivaries confirment la tendance la hausse globale du risque d infection par le VIH chez les vaccins comparativement aux pts ayant reu le placebo [rapport des taux d incidence (HR) estim : 1,6 2,0] Le risque accru d infection VIH est plus marqu chez les hommes non circoncis ayant une immunit pralable contre l Ad5 [HR estim des vaccins = 4,2 4,8]. Par contre, l existence d un risque accru chez les hommes circoncis sans immunit pralable contre l Ad5 n a pas t dmontre [HR estim des vaccins = 0,6 0,8]. On ignore encore si le risque accru tient la sropositivit pour le Ad5 ou au fait de ne pas tre circoncis (un seul facteur de risque et non les deux) De nouvelles donnes ont t prsentes, le mardi 5 fvrier, CROI 2008, Boston diffusion Web www.retroconference.org/2008 mise jour continue de l information www.hvtn.orgPPUPaP"bW' s$MOU  a y n"Orientations futures et hypothses##  # On attend les donnes sur le statut srologique pour le HSV-2, le typage du complexe HLA, le regroupement par rseau sexuel des ppts et on envisage une possible leve de l insu D autres analyses multivaries seront effectues Les mcanismes susceptibles d expliquer la hausse des cas d infection VIH font l objet d tudes en laboratoire tudes sur les rcipiendaires de vaccin et les primates nonhumains Les donnes seront prises en compte dans l laboration de protocoles pour d autres approches par vecteur Ad5 1rDn1 qDn &   e~f_| Conclusions    Le secteur des vaccins prventifs contre le VIH est la croise des chemins. La dmarche itrative de la recherche clinique coordonne aux travaux sur modle animal est prometteuse. Il faut dcouvrir de meilleurs immunognes (en particulier ceux capables d induire des anticorps neutralisant large spectre dirigs contre les isolats transmis) et parvenir mieux comprendre les micro-phnomnes en jeu dans la transmission du VIH. Le Sommet sur les vaccins contre le VIH des NIH se tiendra le mardi 25 mars 2008, Rockville (MD). Le rseau HVTN entend poursuivre ses recherches cliniques en faisant appel la collaboration, dans l esprit de l Entreprise mondiale pour un vaccin contre le VIH. \-" &  6 =i   Xlments prendre en compte : laboration du programme d essais cliniques de l ICVV WW W HCrer un quilibre entre la recherche prliminaire (phase I/IIA) et les capacits d essai sur l efficacit (phase IIB/III). tablir une relation entre le programme de recherche sur les primates non humains et le programme de recherche clinique. Le fait de travailler partir d chantillons de muqueuses pose un dfi. La participation et l adhsion de la collectivit sont essentielles et doivent tre privilgies. |yIb  /L/46;< =$A)F/K4M>RS_[``fghijjkolpmqnro;   0` ` ̙33` 333MMM` ff3333f` f` f` 3>?" dd@?" dd@  @` n?" dd@   @@``PT    @ ` `p>>   _W (  `  s *"~`  C *Acolorbar"=  6}  $[   T Click to edit Master title style! !  0}  Z   SClick to edit Master text styles Second level Third level Fourth level Fifth level!     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Keefer M.D. Directeur associ de l administration scientifique Rseau d essais des vaccins contre le VIH uu u H  0޽h ? ̙33___PPT10i.E:+D=' 2= @B +[ k 0 z0 (  0 ~ 0 s *+}`A  }  0 s *L'  } ,M'Mt. 0 <dj: B    H 0 0޽h ? ̙33y___PPT10Y+D=' 2= @B + / 0 Px(  P~ P s *d*  d # P N(d1?"`@  9Recherche et conception de vaccins contre le VIH (HIVRAD).:8 Z28 : ) P N81?"`pVj MDveloppement prclinique/clinique intgr de vaccins contre le sida (IPCAVD) N8 Z2N N H P N 1?"` {  V Rseau d essais des vaccins contre le VIH6,8 Z2+ , ( P NT1?Cl@ Jquipes de conception et de mise au point de vaccins contre le VIH (HVDDT)0K0 Z2J K  P Tp1?` `  6Ressources de dveloppement/ contratcadre prclinique7 7 7   P s *̘"`   bRseau d essais des traitements prventifs du VIH&2 1 2   P s * 9  x$VEU simiens et laboratoires centraux$% $ % .  P N1? H Soutien ractif, bases de donnes, typage HLA, clonage et squenage8I 2D I   P s *"` L  RProgramme d essais des vaccins du USMHRP $* ) *   P c $䰍"`   LProgramme d essais des vaccins des CDC&' & '   P N1?"`;_ 4Subventions l innovation 8 Z2   V P T 1?"`P  jCentre d immunologie pour le vaccin VIH/sida (CHAVI) *6 5 6  P 0p ] ^ Dv. avancs"     P 0Í} ?Programmes de recherche et de dveloppement de vaccins du NIAID@(2@ @ E P 0Ս4 GRecherche fondamentale Dveloppement prclinique Essais cliniques nG0 Z2 2 H H P 0޽h ? 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A TB .8  c $1 ?Y> > TB /8  c $1 ?YTB 08  c $1 ? $ $ZB 18  s *1 ? $$TB 28  c $1 ? 3 3 ZB 38  s *1 ? 3 3 TB 48  c $1 ? ZB 58  s *1 ?  TB 68  c $1 ?  ZB 78  s *1 ? ZB 88  s *1 ?FAFTB 98  c $1 ?FllZB :8  s *1 ? l ZB ;8  s *1 ?lTB <8  c $1 ?YZB =8  s *1 ?FFZB >8  s *1 ?  ZB ?8  s *1 ?  ZB @8  s *1 ? A8 0t|0 <Les hommes dont on ignorait s ils taient circoncis ou non (49, 2,7 %) ont t exclus des analyses. Toutes les analyses se fondent sur le modle de rgression risques proportionnels de Cox pour les donnes relatives au dlai avant l vnement.    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RRwanda   ~ (  NA11ȜȜ?Region_3GTB (  c $DUZM)TB (  c $DkQtTB (  c $DMTB (  c $D.TB (  c $DTB (  c $DoOTB (  c $DU,TB  (  c $DAdTB !(  c $D1 -TB "(  c $Db TB #(  c $DXTB $(  c $D;5TB %(  c $D'ybTB &(  c $D;uTB '(  c $Dy&TB ((  c $D)ZlB )( <(DjJC  *(  T`RMQ@1 VTanzania    lB +( B <HSDjJR; N  * ,(    -(  TLWM M  Z Rgion III g   GN o *Q  .(  o *Q  /(  T[Mpn   QKenya   lB 0( <(DjJ L N lB 1( <(DjJ -3  2(  T`MJ *N  VTanzania     3(  T,dMo T /  RUganda    4(  T hMo 8   RRwanda   ~ 5(  NA11ȜȜ?Region_3 Q lB 6( B <(DjJH /  o lB 7( B <(DjJU N [ 8(   9(  BMԔM |  @  :(  TM I  THTVN g   ZB ;(  s *DԔ 2Z ZB <( s *DԔ Z  =(  B̖MԔP [  @  >( < M` O J g   F a  (Q ?(   Q Q @(  < Ma l Q Y Rgion II g    A(  HM (2  f South Africa    T   u  B( #   u lB C( <DjJ4  D(  TA11ȜȜ?Region_2  [ u  E(   VBCDEFD++ "%+1=BGFKPX_fov}~xqlcZLC:1+ % # @              S" ! < f  F(  B,CDEF,@   1 U  G(  BC%DE F%@H W  H(  BCdDE F(%7KFWd@ P .  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Graham 2  H ( 0޽h ? ̙33___PPT10e.+D=' 2= @B + f 0  <(   ~  s *0^[  0 ~  s *\0Z 0 H  0޽h ? ̙33___PPT10i.D+D=' 2= @B +$ R 0 P $(  P r P S 80$[  0 r P S 0Z 0 H P 0޽h ? ̙3380___PPT10.yg>u 6 0  <(  ~  s *|0M  0 ~  s *0Z 0 H  0޽h ? ̙33___PPT10i.D+D=' 2= @B +LM 0 T\(  T T c $0, @0  0 @  p T 0 ?, P   0H T 0.k ? ̙3380___PPT10.l(S 0 `8(  d  c $,J:   0  s *0, [$  0 " H  0.k ? ̙3380___PPT10.7`@i](X 0 8(  d  c $,WK   0  s *0, L)  0 " H  0.k ? ̙3380___PPT10.@lV] 0 f(  ^  S ,`P   0  c $de, @0  0 \HIV Vaccine Trial& = Units d essai de vaccins anti-VIH (HVTU) Criteria for U.S. Sites = Critres pour les sites amricains Criteria for International& = Critres pour les sites internationaux Scientific Leadership = Leadership scientifique Access to& = Accs aux populations prioritaires Capacity for& = Capacit monter un large effectif Statistical & Data& = Centre de gestion des donnes et des statistiques Steven Self, Ph.D. Laboratory Program = Programme de laboratoire M. Juliana McElrath, M.D., Ph.D. Principal Investigator = Chercheur principal Lawrence Corey, M.D. Directeur : Dr Jim KublinH@ 2E  4@   H  0.k ? ̙3380___PPT10. ((^ 0  8(  d  c $,XK   0  s *0, )  0 " H  0.k ? 3380___PPT10.p^4_ 0 @,(  ^  S ,`P   e  c $e, @0  e " H  0.k ? ̙3380___PPT10.Zp4C 0 P (  X  C ,`P   M  S M, @0  M " H  0.k ? ̙3380___PPT10.lg NR3# 0 jb` (   X  C ,`P   eb  S e, @0  e Pox = Pox Enveloppe Proteins & Peptides = Protines et peptides de l enveloppe Adenovirus = Adnovirus Adenovirus = Adnovirus DNA = ADN Enveloppe Proteins & Peptides = Protines et peptides de l enveloppe Other = Autres Pox = Pox   H  0.k ? ̙3380___PPT10.lgzY3pc 0  (   X  C ,`P   e  S e, @0  e ZHVTN trial & = Centres d essais du rseau HVTN . H  0.k ? ̙3380___PPT10.mgkd 0 ,  (  , X , C ,`P   e , S Ȼe, @0  e " H , 0.k ? ̙3380___PPT10.pgpyi 0 T  (  T X T C ,`P   e T S e, @0  e " H T 0.k ? ̙3380___PPT10.yg`uu 0 XP0 (   d  c $,XK   eD  s *0e, M)  e 4Gag, Pol, and Nef are major targets of the T cell response in HIV-1-infected patients Highly conserved across clades at the amino acid level 80-85% gag 80-85% nef >90% pol Gag, pol, nef are major targets of T cell response in HIV+ Highly conserved across clades at aa level: gag 80-85%, nef 80-85%, pol >90%U8@D@@D@@D@@]+F H  0.k ? ̙3380___PPT10.Pv 0 rj (   d  c $,XK   e^  s *e, )  e Vaccination with MVA& = La vaccination vecteur MVA ou Ad5 induit une rponse des lymphocytes T CD4+ et CD8+ CD4+ T cells = Lymphocytes T CD4+ CD8+ T cells = Lymphocytes T CD8+ Response rate = Taux de rponse For Env. Gag& = Pour Env, Gag ou Pol Vaccination details = Dtails de la vaccination : FPV boost = Rappel FPV MVA boost = Rappel MVA group 1 = groupe 1 group 2 = groupe 2 groups combined = groupes combins *Only.. = Seuls les vaccins administrs avant les essais d immunognicit sont indiqus dI@    U H  0.k ? 3380___PPT10.@kT(| 0  8(   d  c $,WK   e  s *e, L)  e " H  0.k ? ̙3380___PPT10.@l'~ 0  w(   d  c $,XK   e  s *_,, M)  e aTimeline for the development of an effective HIV-1 vaccine highlighting the process and noting the key times for the next series of Phase III efficacy trials This work is highly leveraged through CRADAs and our relationship with the NIH The essential milestones are noted with each product noting the critical immunologic milestones required to move forward with full advanced development. Safety is also necessary as we progress forward The key Thai trial is noted in the green box and will be launched next month You could then mention the 3rd and 4th generation products underdevelopment The VRC DNA prime and adeno virus boost vaccine for which we are preparing sites in Africa 4th generation products are being designed by the program and endorsed by NIH to include MVA (modified vaccinia vectored vaccines and new strategies using the modified lethal factor of anthrax to induce cellular and humoral immunity to the HIV-1 structure proteins. 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