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RVF Meeting DJIBOUTI April 2015

RVF Meeting DJIBOUTI April 2015. DEVELOPMENT OF RIFT VALLEY FEVER VACCINE IN MCI. Dr. Mehdi EL HARRAK. INVESTMENTS & Human ressources. 136. 14 : Vets, 1 : pharmacist, 6 : Engineers 41 : Biologists 50% : bachelors and over. MCI VACCINE PRODUCTION FACILITIES.

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RVF Meeting DJIBOUTI April 2015

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  1. RVF Meeting DJIBOUTI April 2015 DEVELOPMENT OF RIFT VALLEY FEVER VACCINE IN MCI Dr. Mehdi EL HARRAK

  2. INVESTMENTS & Human ressources 136 14 : Vets, 1 : pharmacist, 6 : Engineers 41 : Biologists 50% : bachelors and over

  3. MCIVACCINE PRODUCTION FACILITIES

  4. PARTNERSHIP:MERIAL, GalvMed & GATES FOUNDATION Training for delegations of African countries

  5. RVF control mainly by vaccination • West Africa recent outbreaks represent serious threat • Endemicitywith indications of almost yearly virus circulation • Period (1950–2011) one or more RVF outbreaks were reported in 27 seasons of which 3 major epidemics 1950–1951, 1974–1976 and 2010–2011 • Reported every 2 years in WA • Response: Yearly vaccination Pienaar et al., 2013

  6. safety & efficacy challenges with existing vaccines

  7. LIVE‐ATTENUATED VIRUS VACCINES 1. The Smithburn RVF vaccine • Reported to induce high antibody titers in sheep, but weaker antibody responses in cattle (Barnard B. J, 1979) • Used in African countries including Egypt, South Africa and Kenya. • Entailed side effects: - adverse effects in newborn kids and lambs and fetal malformation and abortion in gestating does, ewes and cows (Kamal S. A, 2009), (Smithburn K. C, 1949), (Coetzer J. A. and Barnard B. J, 1977), (Botros B, 2006). - its residual virulence renders its use unsuitable when the pregnancy status of the animals is unknown (Swanepoel R et all, 2004) - it has a potential for reversion, and, hence, are not recommended for use in countries where RVFV has not been introduced (Swanepoel R et all, 2004)

  8. New vaccines & Candidates evaluated in Target animals

  9. RVF MP12-del project • University of Texas at El Paso (UTEP) • Douglas M. Watts • George Bettinger (ancient de University of Texas, Center for Biodefense & Emerging Infectious Diseases) • Funding: USAID, Feed the Future Innovation Lab for Rift Valley Fever Control in Agriculture • US$ 6m, 5 years • Project to be started in June 2015 (strain reception) • Partners • SUA, Tanzania • SAFC Commercial • Bioject Inc., Tigard, Oregon

  10. 2. THE CLONE 13 RVF VACCINE RVF C13 during 2009-2011 outbreak in sa • Period April 2010 – March 2011: 28 million RVF doses sold, of which more than half RVF Clone 13 28 million Average 300 000 OBP RVF vaccine doses sold in South Africa between 2002 and 2010.

  11. LIVE‐ATTENUATED VIRUS VACCINES 2. THE CLONE 13 RVF VACCINE • Advantages • Large Deletion in the non-structural protein coded by the S segment (NSs) (Muller et al., 1995). • Good protective immunity in sheep & cattle • Safe in pregnant animals • Possible DIVA (NSs ELISA).The risk of reversion is considered unlikely (Dungu et al., 2010). • Registered & used extensively in South Africa • Challenges • Possibly no DIVA • No wide registration to date Temperature responsive vaccine and poor resistance to storage conditions (Daouam et all, 2013)

  12. THE CLONE 13 RVF VACCINE • Risks associated with using the CL13 vaccine in tropical (hot) countries without strict maintenance of the cold chain during vaccine storage and delivery (9 months shelf live of commercial vaccine). • The efforts to improve the thermostability of this vaccine strain are needed in order to optimize its efficacy when used in the tropical climates in which RVFV is currently circulating (Daouam et al; 2014)

  13. Development of a live attenuated thermostable vaccine against Rift Valley fever El HARRAK, M.; DAOUAM, S.; TADLAOUI, K. (MCI Santé animale, B.P. 278 MOHAMMEDIA, MOROCCO)

  14. THE New candidate RVF VACCINE Material and Methods • C13 virus has been produced on Vero cells, heated at 56°C and resistant viral particles were selected. • Three cycles of heating and cloning were performed and the most resistant clones were purified using the high dilution method. • The C61 showed a characteristic and precocious CPE, high titer and better stability if compared to other clones or the original C13 strain. • A pilot batch of RVF C61 vaccine has been produced and tested for efficacy in cattle, sheep, goats and camels using ELISA and virus neutralization test

  15. Kinetic of viral multiplication of C61 and C13 in verocells Clone 61 reached titer of 8.5 in 2 days with characteristic CPE and cell lysis

  16. Comparative Stability of C13 and C61 • Clone 61 resist more than 90 min at 56°C • The original virus loses 3 log • Clone 61 resist more than 3 hours at 45°C • The original virus loses 1 log • Clone 61 resist more than 4 days at 37°C • Inactivation of the origin virus after 3 days

  17. Stability of C61 RVF vaccine The lyophilizedC61vaccine storedat +4°Cc

  18. comparative stability of C13 & C61 vaccines after reconstitution in the diluent AT ROOM TEMPERATURE AT 4°C Drop of 0.2 (C61)/1.5 (C13) in 6h Both stable 6h

  19. C61 TESTING ON ANIMALS • Safety test on target species (sheep, goats, cattle & camels) by observation of local inflammation and body temperature. • Activity appreciated by serological response tested by virus neutralization and Elisa

  20. Body temperatureafter vaccination No local reaction at the injection site or consecutive thermal rise after vaccination of sheep, goats, cattle and camels

  21. SEROLOGICAL RESPONSE AFTER VACCINATION (Cattle) Seroneutralisation test • A dose effectclearlyobservedinvaccinatedcattle, • Neutralizing antibodies detected in vaccinated animals from day 7 post-vaccination, • Antibody response persists beyond 4 months in cattle, • The protective dose for cattle could be 105 TCID50 per dose

  22. VN SEROLOGICAL RESPONSE AFTER VACCINATION (Sheep and Goat) • The response is similar in Goats and Sheep, • Good neutralizing antibody response recorded in vaccinated animals from day 7 post-vaccination with a peak at 21-28 days. • Antibody response form a plateau that persists beyond 12 months in sheep & goats • the vaccine virus does not spread to cohabitant unvaccinated controls.

  23. ELISA SEROLOGICAL RESPONSE AFTER VACCINATION (Sheep and Goat) Similarresponseobtainedwhenused ELISA test

  24. SEROLOGICAL RESPONSE AFTER VACCINATION of CAMELS • Very good neutralizing antibody response observed in all vaccinated animals from day 12 post-vaccination, • A percentage of protection of 50% at day 14 and 92% at day 19 after vaccination • The kinetic of antibody evolve from J14 to reach a value close to 2.5 log (1:700), which represents a high titer. • Antibody response maintained more than 6 months in camels • Available commercial Elisa kit is not validated in camels

  25. VIRAEMIA AFTER VACCINATION • Blood was collected in 10 ml EDTA tubes to determine viraemia in the blood from day 1 to day 19 after vaccination. • No evidence of RVF virus presence in the blood as tested by quantitative RT-PCR; only few animals showed high Ct (>37) not compatible for virus transmission • Samples were tested for virus isolation on cell culture and no signs of cytopathic effect observed. • Blood samples determined to be negative for the presence of RVF virus when no CPE observed on the second blind cell culture passage.

  26. SEROLOGICAL RESPONSE AND VIRAEMIA AFTER VACCINATION • At the minimal dose of 103 TCID50, sheep and goat showed a good serological response while 105 TCID50should be the protective dose for cattle. • Tested for the first time in camels (bovine dose), the live vaccine RVF C61 confer a good immune response. • A single vaccination resulted in good neutralizing antibody in all vaccinated species that last for one year. • None of the vaccinated animals showed temperature or effect in the injection site. No evidence of viraemia post vaccination as tested by PCR and virus isolation. • An evaluation of efficacy and safety of the C61 vaccine in ewes at different stages of pregnancy indicated that the vaccine did not induce clinical manifestations of RVF such as abortion.

  27. CONCLUSION • The RVF control is mainly based on vaccination and new deleted vaccines are replacing the classic Smithburn strain (C13, C61, MP12). • The Clone 61 has been selected for its stability, high titre and resistance to temperature. • The C61 vaccine is safe and conserve the same immunogenic properties as the original C13 vaccine. • Deleted strains are also a possible DIVA vaccine because of NSs deletion. • C61 vaccine to be tested for mass vaccination in the field.

  28. THANK YOUMERCI شكرا

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