New developments in rabies vaccines - Noël TORDO - working together to stop the ongoing tragedy of rabies! - OIE
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New developments
in rabies vaccines
Noël TORDO
working together to stop the ongoing tragedy of rabies!
Tools for prevention/therapy
Pasteur’s vaccine in 2011
rabid rabbit spinal cord human vaccines (prevention + therapy)
-> dessiccated
nervous tissue (->encephalitis)
Not recommended
• sheep brain (Semple)
• suckling by WHO
mouse brain (Fuenzalida)
cell culture: safe + efficient (expensive ?)
animal vaccines (prevention)
nervous tissue (injection)
cell culture (injection)
attenuated/recombinant (oral, wildlife)
No efficient antiviral
WHO Recommendations: Post-Exposure Prophylaxis
Category I no treatment
• touch, feed an animal
• licks on intact skin
Category II clean wound (soap)
• minor scratches vaccine (cell culture)
• abrasions without blood
• nibbling of uncovered skin
clean wound (soap)
Category III vaccine (cell culture)
• transdermal bite(s) HRIG (20IU/kg)
• scratches
• exposures to bats
ERIG (40IU/kg)
• licks on broken skin /mucous membranes
Rabies vaccines evolution: improved efficacy & safety
• WHO pre-qualified vaccines for IntraMuscular (IM) 1 dose = 2.5IU, 1-0.5 mL
• WHO recommended vaccines for IntraDermal (ID) 1 dose = 0.1 mL
Nerve Tissue Semple Sheep, Goat or Rabbit brain Local Producers (LP)
Vaccines
Fuenzalida Suckling mouse brain LP
Embryo- PDEV: Vaxirab™
Vaxirab™
Duck Embryo
nated Eggs Purified Duck Embryo vaccine (Zydus
(Zydus Cadila, India)
Cadila, India)
PHKC:
Primary Hamster Kidney Cell LP China
Primary
Animal Cells PCEC: Rabipur™
Rabipur ™ // RabAvert
RabAvert ™™
Purified Chicken Embryo Cell (Novartis,
(Novartis,India
India / Germany)
Germany)
Human Diploïd HDCV: Imovax
ImovaxRabies,
Rabies, Sanofi Pasteur
Sanofi Pasteur
Cell Line Human Diploïd Cell Vaccine
Cell Culture Rabivax ™ (SII, India)
Vaccines
Verorab
Verorab ™,
™,
Verorab™,Sanofi
Sanofi
SanofiPasteur
Pasteur
Pasteur
PVRV: Purified Vero Cell Rabies
Vaccine Abhayrab™ (HBI, India)
Continuous Other Chinese et Indian LP
Cell Line
CPRV: Chromato- PVRV Speeda™ (Liaoning
graphically Purified serum Chengda, China), Butantan,
PVRV free Rabirix™/Indirab™, Brazil
(Bharat Biotech, India)
WHO Schedules : Post-Exposure Prophylaxis
WHO position paper, Wkly Epidemiol Rec 2010;85:309-20
5 visits
IM 5 IM doses
Essen
Cat III: RIG J0 J3 J7 J14 J21 J28 J90 1y
IM 3 visits
Zaghreb 4 IM doses
ID 4 visits
Thai Red 4 ID doses
Cross
J0 J3 J7 J14 J21 J28 J90
Improving Post-Exposure Prophylaxis (PEP)
US Advisory Committee on Immunization Practices
4 visits
IM Acip
Cat III: RIG
X 4 IM doses
J0 J3 J7 J14 J21 J28 J90 1y
Rupprecht CE, et al. Vaccine 2009;27:7141-8
• Reduce cost, limit shortage
• Increase compliance for complete PEP
• Decrease wastage of vaccine
Thai Red « One week » schedule
ID Cross
Cat III: RIG J0 J3 J7 J14 J21 J28 J90 1y 3 visits
Shantavasinkul P, Tantawichien T, Wilde H, et al. Clin Infec Dis 2010;50:56-60. 12 ID doses
WHO Schedules : Pre-Exposure vaccination (PrEP)
• people at risk: veterinarians, farmers, laboratory workers…
• travellers/residents in dog rabies endemic countries
or
D0 D D7 D14 D21 D28 1 year
3
upon exposure 5 years
or
WHO encourages studies for immunization programmes
of children/infants in dog rabies endemic countries
Animal vaccines (more brents) Parenteral administration Target : domestic animals Inactivated (+ adjuvants), modified life (attenuated), recombinants Potency >1 IU / dose; annual boosters Oral administration Target : stray / wild animals Administred as baits (oral immunization needs replicative antigen) Efficacy and safety (target & non-target species) Monitoring the impact of oral vaccination campaigns in the field
Animal vaccines for oral use
Modified life vaccines
SAD lineage: ERA, SAD-Bern, SAD-B19, Vnukovo-32
Residual pathogenicity for adult rodents, skunks
SAG1-SAG2 : R333D mutant obtained by selection with MAb
Residual pathogenicity for suckling mice
Recombinant vaccines
Poxviruses : Vaccinia (VV), canarypox (ALVAC), MVA, Lumpy skin
VV efficient in fox, coyote, dog, raccoon; non efficient for skunks
ALVAC efficient for cats parenterally
Adenovirus : CaV2, HuAd5
CaV2 efficient parenterally in mouse, dog, cat, swine, sheep
CaV2 efficient orally in mouse, dog, raccoon, skunk
Herpes virus: pseudo-rabies : efficient orally in dogs
Diversity of the Lyssavirus genus
Much more to expect
phylogenyCurrent vaccines (genotype 1) protect against phylogroup 1
Human sera
ABLV
0.5 IU/ml
EBLV 1
EBLV 2
PCECV
Lyssavirus
0.5 IU/ml
CVS CVS CVS
Malerczyk et al., Vaccine, 2009, 27 : 5320-5
Humans
Dogs, Cats
Rabbits
Lyssa G-protein
lentivirus
Wright et al., J. Gen.Virol, 2008, 89: 2204-13
pseudotypeCurrent vaccine (genotype 1) do not protect against
phylogroup II lyssaviruses + West Caucasian Bat (WCBV)
pGPV pGMok
Virus challenge RFFIT
RABV LBV MOKV WCBV
RABV 250Options to enlarge the vaccine spectrum
anti-rabies -> anti-lyssavirus
• Characterize « conserved » antigenic sites / epitopes
requires more research
• Combine antigens / antigenic sites / epitopes on a same « carrier »
• Associate antigens / antigenic sites / epitopes in a same dose
combined vaccine already exist :
RABV + canine adenovirus / distemper / parvovirusIncreasing the vaccine spectrum: DNA vaccine
mouse
chimerical lyssavirus Glycoprotein G i.m.
dog
pGPV
pGMokPV
pGMok
(Bahloul et al. 1998 Vaccine 16: 417-25)pGPV pGMok
pGMokPV
Bahloul et al. 1998 Vaccine 16: 417-25
Jallet et al. 1999, J. Virol 73: 225-33
Desmezières et al, 1999 JGV: 2343-51Increasing the vaccine spectrum:
Vaccinia virus expressing 2 lyssavirus G proteins
VNAbs Challenge
RABV VV recombinants
expressing G genes
from 2 ≠ lyssavirus
protect mice against
both homologous
MOKV lyssavirus
Weyer et al, Epidemiol.
Infect. 2008, 136 : 670-8
WCBVRabies virus as a vector:
Shuffling / duplicating / adding genes along the genome
• HIV Gag inserted at the N/P junction
HIV1Gag IFNß
• IFNß inserted at the G/L junction
divalent vaccine RABV / HIV
adjuvent effect / less pathogenic
Virology, 2008, 382: 226-38
RABVG RABVG
• Two G proteins
more immunogenic, larger spectrum
• Deletion of the P protein
RABVG RABVG
reoriented immune response
Vaccine, 2008, 26: 6405-14
• RABV G replaced by HIV Gag
HIV1Gag
single cycle RABV vector (more safe)
J. Virol, 2010, 84: 2820-31
• Ebola GP inserted at the N/P junction
divalent vaccine RABV / EBOLA
J. Virol, 2011, in press
EBO GPG All papers from the M. Schnell ’ labRabies virus as a vector:
Shuffling / duplicating / adding genes along the genome
Faber et al. Zoon Public Health, 2009, 56: 262-9
• GAS constructs Faber et al. PNAS, 2009, 106: 11300-5
• G double mutants : R333D + N194S
N P M GAS L • Highly immunogenic by oral route
1xGAS
• good candidate for PrEP + PEP
N P M GAS GAS L
2xGAS • Non pathogenic for:
N P M GAS GAS L dog, skunk, raccoon, mongoose
2xGAS
N P M GAS GAS GAS L • 3xGAS non pathogenic by IC
3xGAS to immunocompromised mice
to suckling mice
• Rupprecht’s constructs Wu et al. Vaccine, 2010, 29: 4195-201
• G simple mutant : R333D
• Exchanging M G positions
• IM injection then lethal challenge
protects 100% mice / hamsters
• Co - infection with a lethal challenge
better than inactivated vaccineConclusions and future challenges
Human vaccines
Reduce the number of shots / visits (developing countries)
using highly attenuated (3xGAS-adenovirus)
priming children in regions at risk
Homogeneize ID procedures (based on potency rather than volume)
Increase vaccine spectrum RABV -> Lyssavirus (conserved epitopes,
Animal vaccines combined antigens)
Long lasting immunity in a single shot (cattle in the Amazonas)
Shift on attenuated rabies vaccines (3 GAS ?)
understand the basis of their immunity
P is « controling » the INF induction / signalisation -> deletion is not neutral
Gene transcription is regulated in cascade - > switching gene position is not neutral
Combine rabies with other antigens -> targetting species
Dog: rabies, distemper, parvovirus, leshmaniosis, … dog contraception…Acknowledgments
Adrian VOS, IDT - biologica
Michaël ATTLAN, Sanofi - Pasteur
Unit Antiviral Strategies :
C. Jallet, M. Chteoui
G. Castel, H. Badrane, C. BalhoulMultivalent vaccinology: chimerical G protein
carrying foreign epitopes/antigen
pGPV
NH2 COOH
pGEBL1-PV
pGMok-PV
pGIII
Bahloul et al. 1998 Vaccine 16: 417-25
Jallet et al. 1999, J. Virol 73: 225-33
Desmezières et al, 1999 JGV: 2343-51You can also read
