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Chikungunya virus vaccines? Prof Andreas Suhrbier, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Group Leader; Inflammation Biology QIMR B -PRF NHMRC Australia -Prof Griffith University & James Cook University -Adj Ass Prof University of Queensland. -Member; Australian Infectious Disease Res. Centre. TEL +61 7 3362 0415 email [email protected] www.qimrberghofer.edu.au/page/Lab/Inflammation_Biology/ QIMR-B, >600 scientists students & staff “chikungunya” derived from the Makonde language (Tanzania) means "that which bends up" referring to the severe joint-pain-induced posture of afflicted individuals - CHIKV is a biosafety level 3 pathogen (PC2 in Singapore). - Category C Priority Pathogen by the National Institute of Allergy and Infectious Disease (USA). - US Army, CHIKV recognized as a potential bioweapon. - Information export controlled under Defense Trade Controls Act, 2012 (Australia) Vadilal Sarabhai Hospital, Ahmadabad, India ALPHAVIRUSES THAT CAUSE ARTHRITIC DISEASE IN HUMANS - Transmitted by mosquito (arboviruses) - Single stranded positive sense RNA virus, ≈12 kb genomes. - Symptomatic infections nearly always associated with weeks to months polyarthritis/polyarthralgia. Suhrbier, A. et al. 2012. Nature Rev. Rheumatol. 8, 420–429. Virus Chikungunya virus Ross River virus Barmah Forest virus Sindbis virus family Karelian fever Ockelbo virus Pogosta virus O'nyong-nyong Igbo Ora Mayaro Occurrence Large sporadic epidemics every 2-50 years Mean of ≈4,000 cases per annum in Australia. Also an epidemic (1979/80) >60,000 cases Mean of ≈ 1000 cases per annum in Australia Rare (Karelia, West Russia) Mean ≈30 cases per annum (Sweden) Mean ≈140 (range 1-1282) cases p.a. (Finland) Rare epidemics, >2 million cases in 1959-61 Small outbreaks (30-100 cases) Largest ever CHIKV epidemic started 2004; Estimated 1.4-6.5 million cases. (Imported cases in ≈ 40 countries – not shown) First ever CHIKV transmission in Europe Reached PNG 2013 CHIKV has been in the USA, 1827/8 Approximate geographical locations of diseases associated with arthritogenic alphaviruses. For CHIKV disease, locations of documented large outbreaks are shown; epidemics prior to 1952 are shown in dashed lines and were initially classified as outbreaks of dengue, but were likely to have been due to CHIKV. *Geographical locations of RRV and BFV diseases overlap, with BFV restricted to the Australian mainland. ‡Main location of diseases caused by the Sindbis virus family. § O’nyongnyong virus disease outbreaks in 1959–1961 (East Africa), 1996–1997 (Uganda), 2003 (West Africa). Abbreviations: BFV, Barmah Forest virus; CHIKV, chikungunya virus; RRV, Ross River virus Suhrbier, A. et al. 2012. Nature Rev. Rheumatol. >1 million CHIKV cases in the Americas 2014 First chikungunya case locally acquired in the United States reported in Florida July 2014 Reunion Island, French holiday destination CHIKV EPIDEMIC 2005/6, REUNION ISLAND (FRANCE) >250 deaths – often elderly with comorbidities and very young High attack rate -266,000 cases of CHIKV disease were reported (38% of the population). (50% Grande Comore Island in 2005) Rapid rise in case numbers -increased to 130,000/month in 4 months -45,000 cases during the week of 29 Jan, 2006. Eurosurveillance, Volume 11, Issue 34, 24 August 2006 Reunion cases Imported cases 100’s of imported case in France East-,Central-, and South-African (ECSA) phylogroup The Indian Ocean/ Reunion Island epidemic was associated with a new clade of CHIK viruses Mutation allowed efficient CHIK virus transmission by A. albopictus Normal vector A. aegypti Schuffenecker et al Plos Med July 2006 3 ( 7 ) e263 © Landcare Research Introduced Native Intercepted Aedes albopictus; a global invader Tiger mosquito An aggressive biter – the BBQ stopper CHRONIC DISEASE ELISA based serology Virus % asymptomatic Fever Rash Myalgia Arthralgia arthritis CHIKV 5-18% 90% 40-50% 90% >95% RRV 55-75% 20-60% BFV ? 50% Very 15-40% 90% common 80-100% 70-90% SINV ONNV MAYV 8% 100% 80-100% 3-6 months 50-100% 50-80% 70-95% 40-60% 30-50% 40-80% 50% 95% 70% 60-100% 75% 50-90% Disease characterised by acute and chronic symmetrical polyarthritispolyarthralgia. A Suhrbier, MC Jaffar-Bandjee, P Gasque. 2012. Arthritogenic alphaviruses - an overview. Nat Rev Rheumatol. 8(7):420-9. Prior to the recent epidemic, chikungunya was not generally considered to be a fatal illness Reunion Island 260,000 CHIK cases 260 deaths (0.1%) Mostly >75 years old Ahmedabad (2006) 60,777 suspected CHIK cases 2944 more deaths than in same period of previous year (4.8%) Mavalankar et al 2008 For 610 atypical cases of CHIK: 222 were severe, 65 died. Economopoulou et al 2009 Developed country mortality 0.01% – 0.1% similar to influenza CHIKV SEVERE MANIFESTATIONS (RARE) Severe disease manifestation more prominent in the elderly, the very young & in patients with comorbidities e.g. hypertension, lupus or cardiac disorders. Haemorrhage & shock (occasional) Rudd et al J Virol. 2012. 86(18):9888-98. Mother to child transmission. Reunion experience: 19 children born to viraemic mothers in 7,504 pregnancies • About half the children borne to viraemic mothers became infected. • About half the infected neonates developed serious disease; haemorrhage, DIC and/or cardiac and neurological manifestations (often leading to permanent disabilities) Chronic disease The main burden of CHIKV disease is chronic polyarthritis/polyarthralgia Often several months occasionally > 1 year (Hoarau et al. 2010. J Immunol 184:5914-27) Viral arthritis is likely due to presence or persistence in joints of virus or viral products that stimulate innate & cognate immune responses Virus, viral antigens and/or viral RNA/DNA found in arthritides caused by Chikungunya virus (Hoarau et al. 2010) Ross River virus Rubella Echovirus Parvovirus B19 Caprine arthritis encephalitis virus Avian reovirus Adenovirus CMV EBV Varicella Virus infections can cause auto-immune responses but no good evidence these are responsible for arthritic disease or result in autoimmune disease Molecular mimicry – an attractive hypothesis, but little/no evidence. A. Suhrbier, S. Mahalingham. The immunobiology of viral arthritides. 2009. Pharmacol Ther. 124(3):301-8. Treatments Rash – anti-histamine, calamine lotions (pruritis) Indian J Dermatol. 2010 55(1): 64–67 Rheumatic symptoms/fever NSAIDS/paracetomol - can provide relief, but often inadequate. Rectal NSIADs (suppository) Injectable NSAIDs in emergency settings? Drug Saf. 1993 Nov;9(5):380-93. NSAIDS plus steroids - some benefit - J. Rheumatol. 4, 94–101. (2009). but must consider side effects of steriods J Clin Rheumatol.10:326-30 (2004) Chloroquine - ineffective - J. Med. Virol. 83, 1058–1059 (2011). - Arthritis Rheumatol. 2014 Feb;66(2):319-26. Methotrexate - benefit in some chronic patients (RA-like disease) Expert Rev. Anti Infect. Ther. 8(9), 987–996 (2010). J Assoc Physicians India. 59:83-6 (2011) No benefit in acute RRV mouse model PLoS One. 2013. 8(8):e71146 VACCINES Entity Candidate CHIKV vaccines in development Vaccine type Pre- Phase Phase Phase Clinical I II III (1998) (2000) USAMRIID Live, attenuated (TSI-GSD-218, MRC-5 attunated strain of 15561) Valnova/Karolinska Inst. Live, attenuated (CHIKV-Δ5nsP3) Takeda/UTMB Live, attenuated (CHIKV/IRES) Arbovax/NC State Uni Live, attenuated (transmembrane deletion) UTMB Live, attenuated chimeric (various alphavirus backbones) Themis Bioscience/Inst Pasteur Live, vectored (measles virus) (2015) Profectus/Yale/UTMB Live, vectored (VSVΔG-CHIKV) 2016? Karolinska Inst/CSIC Madrid Live, vectored (MVA-CHIKV E1E226KE3) Uni Wisconsin/Takeda Live, vectored (MVA-CHIKV E2E3) NIAID/Leidos Biomed Virus-like particles (HEK293 production process) TI Pharma/Wageningen Uni Virus-like particles (Baculovirus/insect cell production process) Merck Virus-like particles (Baculovirus/insect cell production process) Bharat Biotech Inactivated (various strains, various methods) Indian Immunological Inactivated (formalin-treated 181/25 from US Army) DRDE India Inactivated (formalin-treated India 2006 isolate) Nanotherapeutic Inc (from Baxter) Inactivated (proprietrary adjuvant formulation) Medigen DNA (plasmid-launched 181/25 live attenuated) DRDE India Recombinant subunit (E coli expressed E1/E2) National Inst. Virology, India Recombinant subunit (E coli expressed E2) Sementis (Australia) Recombinant SCV (live recombinant attenuated vaccina) (2014) 2016? Early CHIKV vaccines • Formalin-inactivate vaccine; human study (Harrison et al 1971 J Immunol 107; 643-647). • Live-attenuated vaccine. Phase II human trial (Edelman et al., 2000). Side effects included arthralgia Lancet 2014; 384: 2046–52 • 25 participants were enrolled 10 μg (n=5), 20 μg (n=10), and 40 μg (n=10). • Neutralising antibodies were detected in all dose groups after the second vaccination • All injections were well tolerated, with no serious adverse events reported. Manufacturing costs? Memory? Adjuvant not used but could provide benefits. Lancet Infect Dis 2015; 15: 519–27 • 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) • Second vaccination resulted in a 100% seroconversion for all participants • No vaccination-related serious adverse events were recorded. Overcoming measles immunity especially in recently vaccinated children requires dose increases increasing risk of adverse events CHIKV vaccines – some considerations Sporadic epidemics (2-50 years), usually self limiting disease, mortality low and usually restricted to elderly and patients with comorbidities. Protective correlate • Antibodies are protective (T cells have a minor role) • T cells also associated with arthritis (induction of CD4 T cells in the absence of good antibodies in mouse models promotes arthritis upon challenge – Poo et al Plos NTD 2014) Market for CHIKV vaccines? Tourists? Army? General population? Desirable for an epidemic setting • A single shot, rapid onset of protective immunity. • Capacity for rapid manufacture and deployment • Low cost, highly stable (afflicted countries often resource poor) QIMR Berghofer 7 suite Biosafety level 3 floor with equipment animal houses & insectaries. Large PC2 mouse breeding facility 14,000 cage capacity >140 genetically modified mouse strains Research Innovation 2012; Battling viral rheumatism Viraemia 6 5 4 3 2 1 0 0 1 2 3 4 5 6 Days post CHIKV inoculation Control Reunion 10 Foot width x breadth, mm2 ± SE Viraemia, log10CCID50/ml ± SE Adult wild-type mouse model of chikungunya virus infection (viraemia) and disease (foot swelling/arthritis) Arthritis Control 9 8 7 0 2 4 6 8 10 12 Days post CHIKV inoculation Reunion Island isolate Female C57BL/6 mice > 6 weeks old 14 Dominance of monocytes/macrophages and NK cells in the swollen feet of CHIKV infected mice FACS Cells FACS markers % of cells 7 days post infection ± SE Monocytes CD11b+, F4/80lo/- 45 ± 9.9 Macrophages NK cells CD4 T cells CD8 T cells B cells F4/80+, CD11b+ NK1.1+ CD3+, CD4+ CD3+, CD8+ CD19+ CD11c+, F480-, NK1.1B220-, PDCA1CD11c+, B220+, PDCA1+ 21 ± 4 16.3 ± 6 5.2 ± 1.3 1.2 ± 0.2 4.6 ± 2 Conventional DC Plasmacytoid DC 6.4 ± 1.1 3.8 ± 2.1 Virus strain LR2006-OPY1 injected s.c. into the foot Air hole J. Virol. Meth. 1995. 52:51-54 Many virus isolates contaminated with mycoplasmas MycoAlert™ Mycoplasma Detection Kit MYCOPLASMA NO MYCOPLASMA Hela and Hoechst staining Results in < 20 min Grow virus prep on LCLs (non permissive for alphavirus infection for a week) prior to testing ENDOTOXIN CONTAMINATION (often in FCS, glassware, trypsin, sucrose etc) “High sensitivity” endotoxin assay detection limit Clear inhibition of alphavirus infection in macrophage cell lines Johnson.et al 2005. J Biol Chem. 280(6):4037-47 65C 30 mins to inactivate virus RAW264-HIV-LTR-LUC cell line Detection sensitivity 5-10 pg/ml E. coli LPS Examples of the evaluation of vaccines in the adult wild-type CHIKV mouse model 1. Simple inactivated whole virus vaccine Gardner et al. J Virol. 2010 84(16):8021-32 2. rBaculovirus VLP vaccine Metz et al PLoS NTD 2013;7:e2124 A collaboration with Wageningen University, The Netherlands. 3. rAdenovirus vaccine Wang et al 2011 Vaccine 29;2803–2809 A commercial collaboration with GenPhar Inc., USA. 4. rSementis Copenhagen Vector (SCV) A commercial collaboration with Sementis, Australia 4. Foroderm transcutaneous immunisation A collaboration with University Queensland, Australia Model adopted by EU Integrated CHIKV Research Program, e.g. • rMVA vaccine (García-Arriaza et al. J Virol. 2014. 88(6):3527-47) • Attenuated vaccine (Hallengärd et al. J Virol. 2014 88(5):2858-66) Metz et al, 2013 CHIKV VLP production in Sf21 insect cells VIRAEMIA Gorben Pijlman, Wageningen University ARTHRITIS Single shot: Complete protection against viraemia Complete protection against arthritic disease Rapid high volume production 9 8 SCV -CHIK Control vector PBS 7 6 5 4 3 2 1 0 0 1 2 3 4 Day post challenge 5 % increase in foot swelling (arthritis) + SE Log10 CCID50/ml ± SE The Sementis Copenhagen Vector (SCV) is a genetically attenuated, live virus vaccine vector, based on the Copenhagen strain of the Vaccinia Virus 80 SCV -CHIK Control vector PBS 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 Day post challenge Complete protection from viraemia and arthritis by single vaccination with rSCV-CHIKV vaccine SCV can be produced from a biotechnology “friendly” custom cell line under serum and protein free conditions in bioreactors COI: A Suhrbier is on the SAB of Sementis ForodermTM : Novel Drug Delivery Technology Dr Tarl Prow et al University Queensland, Australia Potential for self administration Foroderm + inactivated CHIKV 120 NEGATIVE CONTROLS Topical inactivated CHIKV Topical inactivated CHIKV+QuilA Foroderm plus QuilA POSITIVE CONTROL Sub. cut. inactivated CHIKV 110 100 90 80 70 60 50 40 Arthritis 30 20 10 0 0 Viraemia, log10 CCID50 ml + SE % increase in foot swelling (arthritis) + SE Single application of inactivated CHIKV vaccine with Foroderm provides complete protect against Arthritis and Viraemia 5 10 15 20 30 25 35 Days post challenge 6 5 Viraemia 4 3 2 1 0 0 1 2 3 4 Days post challenge 5 6 Phase II/III testing? Sporadic epidemics (2-50 years) Epidemics Year No. of cases Tanzania 1952 ? Central East Africa 1959-62 ≈2 m (O'nyong'nyong) Thailand 1962 ≈40,000 India 1963/4 >100,000 Outbreak size Vietnam Myanmar 1975 ? and location Indonesia 1982 ? unpredictable Reunion Island 2005-2006 >250,000 India/Asia/Caribbean/S America 2006-2015 1.4-6.5 m By the time ethics approval given, trial infrastructure set up and volunteers vaccinated. Epidemic has passed or does not arrive. USA FDA unlikely to give approval on animal data alone CAN EMERGING ECONOMIES DO THEIR OWN APPROVAL ? E.g. Brazil ? India ? Mosquito control • Use real insect repellent (eg DEET) • Wear long sleeved clothes • Uses mats, coils, screens indoors • Use impregnated bed nets • Spraying •Remove peri-domestic breeding sites •Add fish to ponds and water tubs Make mosquitos less able to transmit CHIKV with Wolbachia Wolbachia is a genus of bacteria which infects insects Release of Wolbachia infected mosquitos into the wild population results in spread of the Wolbachia infection into the population Wolbachia infected A . aegypti mosquitos replicate dengue virus, chikungunya virus & yellow fever virus less efficiently RT PCR + Wol - Wol Hurk et al 2012 PLoS Negl Trop Dis 6(11): e1892. Walker et al., 2011. Nature 476, 450–453. Scot ONeil Hoffmann et al 2011. Nature. 2011;476:454-7. RA and UP regulated in RA patients 282 genes UP regulated in CHIKV arthritis Healthy -2 0 SD from mean Improving treatment options Surprising overlap in inflammatory signature between CHIKV and rheumatoid arthritis. Drugs being used/developed for RA may find application for treatment of CHIKV. (Nakaya et al, 2012. Arth Rheum 64 (11):3553-63) Heat map showing the relative expression levels of the 282 2 4.5 5 8 7 7.5 RA inflammation score up-regulated genes in CHIKV infected mouse feet et that were enriched in RA patients. Columns represent the 5 control, and 5 RA samples in the study and their respective inflammation scores. QIMR-B Joy Gardner Penny Rudd Itaru Anraku Thuy T Le Lee Major Wayne A. Schroder Ecole Nationale Vétérinaire, Nantes, France Thibaut Larcher et al Commissariat à l'Énergie Atomique (CEA), Paris Karine Labadie, Pierre Roques et al University of Texas Medical Branch Stephen Higgs et al University of Queensland Tarl Prow University of Wageningen Roy Hall Gorben Piljman et al Alex Khromykh Griffith University Suresh Mahalingham Nestor Rulli Funding National Health & Medical Research Council, Australia Australian Infectious Disease Research Center Queensland Tropical Health Alliance Université de la Réunion Hôpital Félix Guyon La Réunion, France Marie-Christine Jaffar-Bandjee Philippe Gasque Emory Vaccine Center Helder Nakaya, Bali Pulendran Thanks to • Luis Mateo and Rebecca Pawliw (Alere, Brisbane, Australia) for supply of purified inactivated CHIKV. • Clay Winterford (QIMR) for histology/immunohistochemistry Information resources French guidelines for the management of chikungunya (acute and persistent presentations). November 2014. Simon et al. Med Mal Infect. 2015 Jul;45(7):243-63. Queensland chikungunya management plan 2014–2019. https://www.health.qld.gov.au/cdcg/documents/chikungunyamanagement-plan.pdf (accessed 14/7/15). Chikungunya virus. Centers for Disease Control and Prevention. http://www.cdc.gov/chikungunya/fact/index.html (accessed 17/6/15).