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Challenges of a Zika virus vaccine development

Challenges of a Zika virus vaccine development. Kaoutar AKOUH , Séverine BERARD, Chaïma MRIZAK M2 AREIPS - 27/ 02/2017. Introduction. Many rare but potentially very dangerous diseases or emerging infections regularly breaking out

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Challenges of a Zika virus vaccine development

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  1. Challenges of a Zika virus vaccine development Kaoutar AKOUH, Séverine BERARD, Chaïma MRIZAKM2 AREIPS - 27/02/2017

  2. Introduction • Many rare but potentially very dangerous diseases or emerging infections regularly breaking out • Endemic disease, from the Greek “endêmon nosêma”: disease rooted in a particular ecosystem • Endemic diseases are still a public health problem: Malaria, HIV / AIDS, Yellow fever, Dengue and Zika • Obstacle = Absence of effective antiviral drugs and vaccines against emerging viral diseases

  3. Zika virus > Description and pathology Zikavirus vaccine> Preclinicaldevelopment> Clinicaldevelopment> Regulatoryevaluation and strategy

  4. VIRUS DESCRIPTION & PATHOLOGY

  5. Zika virus - Structure ZIKV: member of the Flavivirusgenus in the familyFlaviviridae➔ RNA virus, icosahedral and enveloped Campos GS, Bandeira AC, Sardi SI. (2015) Zika virus outbreak, Bahia, Brazil. CDC Emerging Infectious Diseases

  6. Zika virus - Genomestructure • non-segmented, single-stranded, positive sense RNA genome • ZIKV genome encodes for a polyproteinwith :> 3 structural proteins> 7 nonstructuralproteins Faye et al. 2014 : ZIKV: recombination in nature ⇒ loss of the N-linked glycosylation site (protein E) ⇒ adaptationresponse to the Aedesdalzielivector ⇒ enzootic ⇒ Many hosts Blazquez et al.,2016; Faye et al. 2014)

  7. Zika virus - Transmission cycle Aedes aegypti et albopictus Arbovirus (Blazquez et al.,2016)

  8. ZIKV : 1st discovered in a monkey in the Zika Forest of Uganda HistoricalbackgroundofZika 1947 • At least 14 human cases (Southeast Asia and Africa) • Other cases : likely to have occurred but not reported? Before 2007 • ZIKV: 1st detected outside of Asia and Africa ==> causing the 1st large outbreak ever reported (Yap) 2007 • Emerged as a new public health threat that caused a large outbreak in French Polynesia 2013 2014 • Explosive outbreak in Brazil 2015 2015 Calvet, Santos et al. 2016; http://www.who.int/mediacentre/factsheets/zika/fr/

  9. Where has Zika been found? • Before 2015, Zikaoutbreaksoccurred in Africa, SoutheastAsia, and the Pacific Islands. • Currentlyoutbreaks are occurring in many countries and territories.

  10. Clinical features

  11. Clinical features If there are clinical manifestation : mild and self-limiting

  12. Clinicalfeatures

  13. Zikaand pregnancy • Brazil has confirmed far more malformations of the brain in babies born to mothers who were infected with Zika than any other country. ⇒ ZIKV can pass from a pregnant woman to her fetus during pregnancy or around the time of birth • Brazil: > 50% are avoiding getting pregnant because of ZIKV Now: no trimesterknown to be absent of risk for congenital ZIKV syndrome Eppes et al. Fev 2017; https://www.theguardian.com/world/2016/dec/22/half-adult-women-brazil-pregnancy-zika-virus-survey

  14. Neurologicaland Congenital Zika Syndrome • Increased incidence of microcephaly> in neonatesfrominfectedmothers > Detection ofspecific IgG AB in maternalserumsamples:important approach for diagnosis • 2 cases offoetalmicrocephaly> in womenreporting ZIKV-likesymptomsduringpregnancy> Further ZIKV detection by RT-PCR in amnioticfluid ⇒ Growingevidenceslinking ZIKV infection innewborns to> Guillain-Barré syndrome(Impairment of peripheral nerves characterized by a weakness or even a progressive paralysis)> Microcephaly Sumita, Rodrigues et al. 2016; Calvet, Santos et al. 2016, Oliveira Melo, Malinger et al. 2016

  15. ZIKV infection : Diagnostic Screening for microcephaly is insufficient: >> Multiple malformations: may not entail microcephaly>> Neuronal death may occur over time and microcephaly will be observed with age ⇒ we should test and not just screen for microcephaly with ultrasound • Necessity of developing and implementingrapid, sensitive, and specific screening and diagnostic testing for bothviral detection and estimation of timing of exposure Eppes et al. Fev 2017

  16. ZIKV infection : Diagnostic Surge in attempts to rapidlyadvanceperinatalclinicaltesting⇒ butongoinghindrances to molecular and sonographic-based screening and diagnosis of congenital ZIKV infection

  17. ZIKV: a public threat Collaboration for the rapiddevelopmentof a safe and effective vaccine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973112/

  18. Target Product Profile - TPP • Preferred and minimal product characteristics for a vaccine targeted to the proposed priority population during outbreaks situations. • Specifically intended for ZIKV vaccines in the context of an ongoing epidemic or an imminent outbreak of ZIKV.

  19. Target Product Profile

  20. Actors involved in ZVV development

  21. ZIKA VIRUS VACCINE DEVELOPMENT

  22. Context of an Ongoing Outbreak • Preclinical & Clinicalstudiesconductedin parallel ⇨Accelerate the development • Numerousearlydevelopmentactivitiesin parallelwith the clinicalevaluation ⇨ Accelerate the production process Many vaccine candidates fail to transition frompreclinical to clinicaltestingbecause of a lack of soundmanufacturingcapabilities. Source : « Meeting Report : WHO consultation on considerations for regulatory expectations of ZVV for use during an emergency »

  23. Pre-clinical Development

  24. Vaccinal Agent • Effective vaccines developedagainstotherFlaviviruses ⇨ probability of technical & regulatorysuccess • 2 geneticlineages (african & asian) but only1 serotype ⇨ monovalent vaccine wouldbesufficient

  25. Vaccine platforms Source : Zika Virus: Immunity and Vaccine Development- Cell 167, October 20, 2016 Published by Elsevier Inc.

  26. Vaccine platforms

  27. Vaccine platforms TPP

  28. Animal Studies • Preclinical development investigates vaccine safety, immunogenicity and potential efficacyin animal models. • Mouse and nonhuman primate ZIKV disease models • Mechanisms of immune enhancement and the potential association with severe Zika outcomes are being explored • in vitro and in animal models Source :Fast Track ZV development – Is it possible? NEJM 375;13 September 29,2016

  29. Zika animal models Balb/c mice • robust ZIKV replication : viremia observed ⇒ measurable infection • magnitude and duration of the viremia similar to that observed in human infection ⇒ promisingmodels for vaccine testing ⇒ assessment of immunogenicity Zika virus animal models, Suitability for vaccine testing, National institute of health

  30. Zika animal models Rhesus macaques • Susceptible to infection by an Asian-lineage ZIKV. >> detectable virus in the blood, saliva, urine and CSF • Infection in non-pregnant macaques >> mild/asymptomatic (plasma viremialasts ⋍10 days) • infection of pregnantmacaques : >> mothersremainhealthythroughout the pregnancy >> fetusesfrom 1st trimester infections are smallerthan the average ⇒promisingmodels for vaccine testing ⇒ assessment of immunogenicity ⇒ severeoutcomes Zika virus animal models, Suitability for vaccine testing, National institute of health

  31. Plasmid DNA vaccine

  32. Plasmid DNA vaccine : construction • prM-Envalreadyused for YF, dengue • DNA vaccine expressing ZIKV pre-membrane and envelope (prM-Env) https://france.promega.com/resources/pubhub/inspiration/zika-perspectives-responses/

  33. Plasmid DNA vaccine : preclinical development in mice

  34. Plasmid DNA vaccine : immunogenicity in Balb/c mice • ZIKV prM-Env immunogens • Deletion mutants : lacking prM and/or lacking the transmembrane region or the full system of Env • To assess the immunogenicity : • Groups of Balb/c mice (n=5-10/group) : single dose of 50 µg of each DNA vaccine by the IM route at week 0. • Env-specific antibody responses evaluated at week 3 by ELISA. a, Schema of ZIKV prM-Env immunogens and deletion mutants. RA Larocca et al. Vaccine Protection against Zika Virus from Brazil. Nature DOI: 10.1038/nature18952 (2016).

  35. Plasmid DNA vaccine :immunogenicity in Balb/c mice • prM-Env vaccine induces ZIKV-specificneutralizingantibodies ⇒ cells infection inhibited RA Larocca et al. Vaccine Protection against Zika Virus from Brazil. Nature DOI: 10.1038/nature18952 (2016).

  36. Plasmid DNA vaccine :protective efficacy in Balb/c mice Infection of vaccinated and sham control Balb/c mice, week 4, IV route, 10^5 viral particles Shamcontrolmice : 6 days of detectableviremia , meanpeak viral load on day 3 DNA prM-Envvaccinatedmice : no detectableviraemiaatany time point http://www.medicalbiochemist.com/2016/08/zikavaccine.html

  37. Plasmid DNA vaccine : CD4 and CD8 depletion in prM-Env vaccinated mice Depletion of CD4 and CD8 T Lymphocytes in vaccinatedmice : protection maintained ⇒ humoral immune response RA Larocca et al. Vaccine Protection against Zika Virus from Brazil. Nature DOI: 10.1038/nature18952 (2016).

  38. Plasmid DNA vaccine : preclinical development in rhesus macaque

  39. Plasmid DNA vaccine : immunogenicity in rhesus macaques Immunization of 12 monkeyswith 5 mg of DNA vaccine (expressingprM-E) atweeks 0 and 4. DNA prM-ENv vaccine inducedZIKV-specificneutralizingantibodiestiters in all animalsafter the week 4 boostimmunization (only minimal MN50 titersdetectedafter the initial priming immunization).

  40. Plasmid DNA vaccine : protective efficacy in rhesus macaques Rhesusmonkeysvaccinatedwith the DNA prM-Env vaccine or sham vaccinechallenged by SC route with10^6 viral particles. Complete protection (no viral load) for rhesusmonkeysvaccinated DNA vaccine.

  41. Inactivated virus vaccine : preclinical development in mice

  42. Purified inactivated virus vaccine : immunogenicity in mice Balb/c mice : single immunizationof 1µg of the PIV vaccine, withalum or alumalone (IM and SC routes). => Antibodytitershigher in the group PIV vaccine by IM route PIV vaccine by both routes alsoinduce ZIKV-specificneutralizingantibodies RA Larocca et al. Vaccine Protection against Zika Virus from Brazil. Nature DOI: 10.1038/nature18952 (2016).

  43. Purified inactivated virus vaccine : protective efficacy in mice Atweek 4 : all micewere IV challengedwith ZIKV-BR. ⇒Complete protection in the PIV vaccine group by IM route. RA Larocca et al. Vaccine Protection against Zika Virus from Brazil. Nature DOI: 10.1038/nature18952 (2016).

  44. Inactivated virus vaccine : preclinical development in rhesus monkeys

  45. Purified inactivated vaccine : immunogenicity in rhesus monkeys Development of ZIKV Env-specificbindingantibodies and ZIKV neutralizingantibodies Immunization by SC route atweeks 0 and 4 ZIKV PIV vaccine + alum (n=8) Alumonly (sham vaccine; n=8) Sham control monkeys no specificantibody response

  46. Purified inactivated vaccine :protective efficacy in rhesus monkeys Infection of PIV vaccinatedmonkeys and sham control monkeys SC route, 10^6 particles of ZIKV-BR or ZIKV-PR Viral loadsmeasured : PIV-vaccinatedmonkeys : no detectable virus in the samplescomparingwithshamcontrolsmonkeys.

  47. Preclinical development : to conclude • Immunogenicity and protectedefficacyof the PIV vaccine and the DNA prM-Env vaccine in mice and monkeys. • Transfer of purified IgG fromvaccinatedmice or monkeys : passive protection. • No specificclinicalsafety adverse eventsrelated to the vaccine. • Robust protectionagainst ZIKV challenge using doses, routes, schedulesthat are typicallyevaluated in clinical trials.

  48. Clinical Development Source : Vaccine Development for Zika Virus – Timelines and Strategies – Anna P.Durbin, MD

  49. Primary Goal of vaccination • Prevention of Infection • Prevention of CongenitalZika Syndrome • Microcephaly+ seriousbrain anomalies in infants ⇨ Public Health Objective

  50. Target Population Outbreaksetting ⇨ thoseathigherrisk in priority • Women of childbearingage • Perhapspregnantwomen in endemicareas. But : > Killedor subunitprotein vaccine only > Vaccination veryearly in pregnancy > Quick protective response > Minimum of doses (one) Source : Vaccine Development for Zika Virus – Timelines and Strategies – Anna P.Durbin, MD

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