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Current Status of Zika Virus Vaccine Development

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Current Status of Zika Virus Vaccine Development Current status of Zika virus vaccine development Michael Nissen FRACP FRCPA Director, Scientific Affairs & Public Health GSK Vaccines Asia-Pacific, Singapore Travel Vaccine Update-MVEC 31 July 2017 Specific opinions expressed are in my academic & personal capacity as an invited Disclosure speaker for this meeting, and do not necessarily reflect the position of GSK Employee of GlaxoSmithKline Vaccines & hold stock on LSTE Adjunct Professor at Children’s Health Research Centre, University of QLD, Australia GSK Asia HQ- Singapore: Artistic impression Zika Virus (ZIKV) ▪ RNA virus 1 ▪ Flavivirus genus1 Asian 2,3 lineage ▪ 2 lineages: African & Asian ZIKV ▪ Reservoirs: humans, non human 1 African primates lineage flaviviruses ▪ ZIKV enzootic cycle probably borne - maintained primarily in DENV monkey/mosquito cycle in Africa Mosquito but a human-mosquito-human WNV cycle obviously exists (Yap, JEV 1 French Polynesia, etc.) YFV ▪ Antibodies detected in borne numerous animal species (bats, - Tick 1 flaviviruses rodents, sheep, goats, ...) Phylogenetic tree of flaviviruses 4 ZIKV: Zika virus; DENV: dengue virus; WNV: West Nile virus; JEV: Japanese encephalitis virus; YKV: Yellow fever virus 1. Musso & Gubler. Clin Microbiol Rev 2016; 29: 487-524. 2. Enfissi et al. Lancet 2016; 387:227-8. 3. Haddow et al. PLoS Negl Trop Dis 2012; 6:e1477. 4. Duong & Buchy. Int J Infect Dis (in revision) ZIKV Transmission ▪ Bite of an infected female mosquito of the Aedes species (Culex unlikely) 1,2 ▪ Blood transfusions & laboratory- acquired infections 1,3 ▪ Sexual intercourse (semen up to 80 days, vaginal secretions ~2 weeks) 3,4 ▪ Maternal-fetal transmission: during all trimesters of pregnancy and during the perinatal period 3,5 ▪ Breast milk found positive for ZIKV: Copyright free picture obtained from: 1 https://commons.wikimedia.org/wiki/File:Aedes_aegypti_during_bloo risk of transmission? d_meal.jpg 1 Barzon et al. FEMS Microbiol Lett 2016; 363(18).pii: fnw202 2. Huang YS et al. Vector Born Zoonotic Dis 2016. DOI: 10.1089/vbz.2016.2058 3. Abushouk AI et al. J Clin Virol 2016; 84:53-58. 4. Prisant N et al. Clin Infect Dis 2016; pii: ciw699. 5. Besnard M et al. Euro Surveill 2014; 19(13). pii: 20751 ZIKV Clinical diagnosis ▪ Incubation period: ~3-12 days 1 ▪ Usually very mild disease; ~ 3/4 infections are unnoticed 2 ▪ Fever <38.5°C 3 ▪ Fatigue 3 ▪ Maculopapular rash 3 ▪ Myalgias, arthralgias, joint swelling (hands & feet ++), headache, malaise 2,3 ▪ Nonpurulent conjunctivitis, conjunctival hyperemia 2 ▪ Spectrum of disease overlaps that caused by DENV and Copyright free image from: http://phil.cdc.gov/phil/details.asp CHIKV 1,3 1. Ioos S et al. Med Mal Infect 2014; 44:302-7. 2 Musso & Gubler. Clin Microbiol Rev 2016; 29:487-524. 3. Kelser EA. Microbes Ingect 2015; 18: 163-6. ZIKV Neurological complications ▪ Guillain-Barré syndrome (GBS): – 18 countries with increased incidence of GBS and/or confirmation of ZIKV infection among GBS cases 1 Normal head size – French Polynesia: 20 fold increased 2 incidence during Zika outbreak Microcephaly ▪ Microcephaly: – >20 countries reported microcephaly and other CNS malformations potentially associated with Zika infections 1 – Close to 2000 cases reported (1st Sept Copyright free images from http://www.wikidoc.org/index.php/File:Microcephaly_2.jpg 2016) 1 – Mainly decreased cortical development and atrophy 3 – ZIKV Ag or RNA found in brain and placenta of fetus with microcephaly 4 1. WHO. Zika virus, Microcephaly and Guillain-Barré syndrome. 2016. Available at: http://www.who.int/emergencies/zika-virus/situation-report/1-september-2016/en/ (accessed September 1 2016). 2. Oehler E et al, Euro Surveill 2014; 19(9). pii: 20720 3. de Oliveira Melo et al. JAMA Neurol 2016; doi:10.1001/jamaneurol.2016.3720 4. Barzon et al. FEMS Microbiol Lett 2016; 363(18).pii: fnw202 Zika vaccination Where? → Multiple sites Who is at priority? Placebo group? • Epidemics may • Women of wane & recur 1 childbearing age • Controversial with no previous during Ebola 1 •Flavivirus-naïve ZIKV infection & vaccine trials & non-naïve not pregnant 1 • Probably populations 1 • Risk for fetus acceptable for during incident Zika in healthy pregnancies? 1 adults (usually 1 •sexual partners? 2 non-severe) 1. Lipsitch & Cowling. Science 2016; 353: 1094-5. 2. Marston et al. N Engl J Med 2016; 375:1209-12. 7 8 9 Vaccine development strategies (1) “Traditional” approach: phase 1 & 2 assess safety and immunogenicity (including in flavivirus-naïve and non-naïve groups) 1 End point = Animal challenge for symptomatic efficacy, additional 1 infection human safety studies 1 1 End point = symptomatic & asymptomatic infections 1 Human challenge for Active surveillance with regular efficacy and additional samples collection 1 human safety studies 1 2 1. Marston et al. N Engl J Med 2016; 375:1209-12. 10 > 60 research institutes and companies are working on the development of Zika vaccines 2 1 1 11 1. Available at: http://fortune.com/2016/10/04/drugmakers-zika-vaccine/ 2. Dawes BE et al. npj Vaccines 2016; 1: 16007; doi: 10.1038/npjvaccines.2016.7 12 Examples of Zika vaccine development strategies Recombinant Recombinant chimeric live Purified subunit YF 17D, DENV, JEV, measles,.. inactivated virus virusVirus-vectored- Single- vaccinesvectored round DNA & replicating VLP Adenovirus oral RNA viruses Dawes BE et al. npj Vaccines 2016; 1: 16007; doi: 10.1038/npjvaccines.2016.7 13 Live-attenuated virus vs. inactivated-virus vaccines? Inactivated, subunit,... Live- attenuated are periods of PROS: Mayimmune be protective system after PROS: Better adapted for a singlechange dose 1 pregnant women 1 and, consequently, increased CONS: May need several doses vulnerability to CONS: Not adapted for with delay for protective infection1 pregnant women 1 immunity beyond peak of vulnerability of fetus 1 1. Marston et al. N Engl J Med 2016; 375:1209-12. 14 Gene-based vaccines are feasible Direct gene transfer into mouse muscle in vivo Wolff JA et al. 1990 Science : Vol. 247 pp. 1465-1468 RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase, luciferase, and beta-galactosidase were separately injected into mouse skeletal muscle in vivo. Protein expression was readily detected in all cases, and no special delivery system was required for these effects. Gene vaccination with naked plasmid DNA: mechanism of CTL priming Corr M et al. J Exp Med. 1996 Oct 1; 184(4): 1555–1560. In summary, intramuscular injection of plasmid DNA encoding the influenza virus nucleoprotein results in the induction of NP-specific CTL restricted to the MHC class I molecules expressed by bone marrow-derived APC 16 17 Fig. 1 Immunogenicity of the ZIKV PIV vaccine. Peter Abbink et al. Science 2016;353:1129-1132 Published by AAAS Fig. 2 Protective efficacy of the ZIKV PIV vaccine. Peter Abbink et al. Science 2016;353:1129-1132 Published by AAAS Fig. 4 Adoptive transfer studies in rhesus monkeys. Peter Abbink et al. Science 2016;353:1129-1132 Published by AAAS Gene-based vaccines: DNA1,2 1 2 mRNA 3 Nucleus 4 pDNA Protein Electroporation Viral vectors Jet injector MHC 1 MHC 2 (e.g. Adenovirus, Gene gun Poxvirus…) CD8+ CTLs CD4+ HTLs Options for DNA delivery Illustrative figure based on concepts from: 1. Selby M et al. Expert Opinion on Investigational Drugs 1998 7:12 2. Weiner DB and Nabel GJ 2013; The development of gene-based vectors for immunization; in Vaccines (6th edition) p1232-1242 22 Rapid development of a DNA vaccine for Zika virus by Kimberly A. Dowd, Sung-Youl Ko, Kaitlyn M. Morabito, Eun Sung Yang, Rebecca S. Pelc, Christina R. DeMaso, Leda R. Castilho, Peter Abbink, Michael Boyd, Ramya Nityanandam, David N. Gordon, John Robert Gallagher, Xuejun Chen, John-Paul Todd, Yaroslav Tsybovsky, Audray Harris, Yan-Jang S. Huang, Stephen Higgs, Dana L. Vanlandingham, Hanne Andersen, Mark G. Lewis, Rafael De La Barrera, Kenneth H. Eckels, Richard G. Jarman, Martha C. Nason, Dan H. Barouch, Mario Roederer, Wing-Pui Kong, John R. Mascola, Theodore C. Pierson, and Barney S. Graham Science Volume ():aai9137 September 22, 2016 Published by AAAS Fig. 4 Protection from ZIKV challenge correlates with NAb titers present at challenge. Kimberly A. Dowd et al. Science 2016;science.aai9137 Published by AAAS Gene-based vaccines: mRNA1 „naked“ mRNA Self amplifying mRNA (SAM) 1 (+) SAM Nucleus Nucleus mRNA RNA-Polymerase (RP) mRNA (-) SAM 2 RP ++ Protein (+) SAM Protein MHC 1 MHC 2 MHC 1 ▪ No genomic integration ▪ No anti-vector immunity ▪ Manufacturing simplicity (rapid response to emerging pathogens) Figure adapted from: 1. Brito LA. et al. Adv Genet. 2015;89:179-233 Gene-based vaccines: mRNA1 Options for delivery mRNA polar/hydrophilic instable complexed to cationic enclosed carrier (e.g. liposomes) (e.g. cationic emulsions; protamin) Options for mRNA delivery Figure adapted from: 1. Brito LA et al. Adv Genet. 2015;89:179-233 Gene-based vaccines: mRNA Liposome-carrier strongly enhance immunogenicity Lipid NanoParticle (LNP) / HIV gp140 mRNA (SAM®) IgG CD4+ CD8+ Controls: 1µg RNA15 µg pDNA Geall et al. 2012, Proc. Natl. Acad. Sci., 109 (36):14604-9 Potential for Zika Vaccine: Preclinical research of a synthetic mRNA vaccine in public-private partnership (start in 2016) Self-amplifying mRNA (SAM®) vaccine ▪ Self-amplifying mRNA to express Zika Inject self- Antigen expression virus structural proteins in vaccinee amplifying In the vaccinee mRNA ▪ Transformative technology to simplify vaccine R&D and manufacturing Amplification ▪ SAM® vaccine does not require cell culture-based manufacturing ▪ Is scalable and flexible Immune response Goals: ▪ Prevent vertical transmission Manufacture self- amplifying mRNA ▪ Prevent Zika virus complications in a cell-free system Version 1, January 5h 2017 29 30 Identification of the most promising candidates can be challenging .... Trials evaluating multiple candidates over time against a common group? 1 2 1. Marston et al. N Engl J Med 2016; 375:1209-12. 2. Beck J. The need to include pregnant women in Zika vaccine trials.
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