Emerging Infectious Diseases: Update of Ebola Virus Disease

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1 Emerging Infectious Diseases: Update of Ebola Virus Disease Assist Prof. Nasikarn Angkasekwinai, MD., MTM&H. Division of Infectious Diseases and Tropical Medicine Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol university

2 Confirmed weekly Ebola virus disease cases reported nationally from Sierra Leone and Guinea Liberia was declared free of Ebola virus transmission in the human population on 3 September 2015 Sierra Leone: last case reported: 13 Sep, declared free of Ebola virus transmission in the human population on 7 November 2015 ~1000 cases/week <10 cases/week Guinea 4 new cases in past 21 days WHO: Ebola situation Report (source:

Geographical distribution of new and total confirmed cases in Guinea, Liberia, and Sierra Leone (11 Nov, 2015) Guinea Cases 3,805 Death 2,536 Liberia Cases 10,666 Death

3 Geographical distribution of new and total confirmed cases in Guinea, Liberia, and Sierra Leone (11 Nov, 2015) Guinea Cases 3,805 Death 2,536 Liberia Cases 10,666 Death 4,806 Sierra Leone Cases 14,122 Death 3,955 Total cases 28,599 Total Death 11,299 WHO: Ebola situation Report (source:

4 Surveillance system to detect EVD among live and dead individuals End of outbreak: no new case 42 days after the last direct contact with a patient or burial WHO: EMERGENCY GUIDANCE : Surveillance strategy during Phase 3 of the Ebola response, 5 November 2015

5 Screening criteria for EVD testing in live patients WHO: EMERGENCY GUIDANCE : Surveillance strategy during Phase 3 of the Ebola response, 5 November 2015

6 Diagrams of Ebola Management Center, Monrovia, Liberia

Clinical features of Ebola Virus Disease Rapid clinical assessment required triage of patients into one of three categories: Those who were clinically hypovolemic, not in shock, and

7 Clinical features of Ebola Virus Disease Rapid clinical assessment required triage of patients into one of three categories: Those who were clinically hypovolemic, not in shock, and able to provide self-care Those who were hypovolemic, not in shock, but unable to provide self-care Those in shock with evidence of organ failure Chertow et al. N Engl J Med 2014; 371;22,

8 EVD: Clinical presentation and laboratory parameters Cohort study of 150 patients with confirmed EVD at Sierra Leone during 1 month 63%: stage 2 or 3 disease, 50% had AKI even in early disease (prerenal) Clinical features Typical patient Standard treatment Stage 1: Early or mild Non-specific features: pyrexia, weakness, lethargy, myalgia, and arthritis Ambulatory, able to compensate for fluid losses via oral intake ORS, symptomatic treatment, zinc or MTV, targeted electrolyte replacement Stage 2: gastrointestinal involvement As above plus: diarrhea, vomiting or abdominal pain, or both Unable to compensate for fluid losses via oral intake due to emesis or loss of large volumes As per stage 1, plus: IV fluid ( ml/24 h for adults, guided by fluid and electrolyte balance), IV ceftriaxone Stage 3: complicated As above plus: haemorrhage, shock, neurological involvement, or signs of organ failure Critically ill, usually hypovolaemic, often with confusion or seizures, bleeding As per stage 1 + 2, plus: As clinically indicated: sedation or antiepileptics, vitamin K and FFP Hunt L, et al. Lancet Infect Dis, August 11, 2015

9 Laboratory markers in association with outcome of patients with EVD Marked electrolyte imbalance was found in all stages of EVD. Common hematological abnormalities - mild thrombocytopenia, lymphocytosis, and raised haematocrit levels Multivariate analysis with variables associated with mortality - low Ebola virus RT-PCR cycle threshold (OR=6.72 [ ], p=0.013) - RIFLE-3 acute kidney injury (OR=5.84 [ ], p=0.033) Disease stage on admission was not associated with mortality. Hunt L, et al. Lancet Infect Dis, August 11, 2015

10 Prevention and treatment windows associated with Ebola virus infection and disease Ebola Virus Infection Ebola Disease Pre-Exposure Post-Exposure Prophylaxis Post-Exposure Treatment Disease Prevention Vaccine Post-Exposure prophylaxis Antibody therapy Antiviral? Vaccine? Disease Cure Antiviral compound Antibody therapy

11 Structure of ebolavirus and ebolavirus vaccine vectors Xiao-Xin Wu, et al. Cell Physiol Biochem 2015;37:

Current promising ebolavirus vaccine candidates Ad5, adenovirus 5; Ad26, adenovirus 26; MVA-BN, Modified Vaccinia Ankara-Bavarian Nordic; ChAd3,

12 Current promising ebolavirus vaccine candidates Ad5, adenovirus 5; Ad26, adenovirus 26; MVA-BN, Modified Vaccinia Ankara-Bavarian Nordic; ChAd3, Chimpanzee adenovirus type 3 ; VSV, vesicular stomatitis virus; GP, glycoprotein; NP, nucleoprotein Xiao-Xin Wu, et al. Cell Physiol Biochem 2015;37:

13 Timeline/key events in ebolavirus vaccine development. Xiao-Xin Wu, et al. Cell Physiol Biochem 2015;37:

14 rvsv ZEBOV vaccine N Eng J Med 2015; 10, 1056 Highly potent and safe Protection by mucosal delivery was as effective as that by systemic injection the potential to confer cross-protection between ebolavirus species rvsv-zebov vaccine was the first replication-competent ebolavirus vaccine to show protection in NHPs durable protection effective against aerosol exposure to EBOV in NHPs may serve not only in a prophylactic setting but also confer post-exposure protection.

15 rvsv ZEBOV vaccine Assess safety, side-effect profile, and immunogenicity of rvsv- ZEBOV at various doses between to158 healthy adults in Europe and Africa. rvsv ZEBOV vaccine is reactogenic but immunogenic at various doses, with higher titers of neutralizing antibodies at higher doses. Side effects such as transient vaccine viremia, fever and arthritis were observed (low dose did not prevent vaccine-induced arthritis)

open-label, cluster-randomised ring vaccination trial enrolled clusters of all contacts and contacts of contacts, randomly allocated 1:1 to immediate vaccination or delayed (21 days later)

16 open-label, cluster-randomised ring vaccination trial enrolled clusters of all contacts and contacts of contacts, randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rvsv-zebov: one dose of 2 10⁷ PFU, IM 48/90 clusters (4123 people) receive immediate vaccination no cases of Ebola virus disease with symptom onset at least 10 days 42/90 clusters (3528 people) receive delayed vaccination There were 16 cases of Ebola virus disease from seven clusters Vaccine effectiveness was 75.1% Henao-Restrepo AM,et al. Lancet 2015; 386:

17 Antibody therapy: Transfusion therapy Use blood or plasma transfusions from convalescent patients 1995 outbreak of EVD at the Democratic Republic of the Congo 8 patients infected with Ebola virus were treated with blood transfusions from 5 convalescent patients only 1 died. Animal study-conflicting result* Challenge/ limitation Selection of donor among EBV survivors Require resource/ infrastructure to properly and safely collected blood Controlling convalescent donor being virally free of pathogen HIV, HBV, HCV, syphilis, malaria Require blood types match

18 Antibody therapy: ZMapp Cocktail of 3 humanized monoclonal antibodies, targets EV envelope glycoprotein (MB-001 and ZMaAb) MB-003 monoclonal antibodies 1 ( c13c6, c6d8 and h13f6) High protection rate against EBOV infection among rhesus macaques (protected four of six animals: 67%) MB-003 were first administered at 48 h post-exposure followed by two additional doses ZMaAb (m1h3, m2g4 and m4g7) 100% efficacy in NHPs (4/4 of cynomolgus macaques survived EBOV infection ZMaAb were given 24-h after exposure followed by two additional doses 3 days apart. 2 Immune response induced in NHPs during the ZMAb treatment and EBOV challenge is sufficient to protect survivors against a subsequent exposure at 10 week 3 1. Olinger GG Jr, et al. Proc Natl Acad Sci USA. 2012;109(44): Qiu X, et al. Sci Transl Med. 2012;4(138):138ra81 2. Qiu X, et al. Sci Rep. 2013;3:3365 ZMapp (c13c6 and 2G4 and 4G7)

19 Antibody therapy: ZMapp

20 Antibody therapy: ZMapp Rhesus macaques were treated with ZMapp at 3, 4 or 5 days after challenge with EBOV at a lethal dose of 50 mg/kg per dose All animals survived and 3 weeks follow-up post EBOV-exposure demonstrated an undetectable viral load July 2014, two US-HCW were given Zmapp and showed a decline in the level of Ebola plasma viral load in correlation with clinical improvement

21 Antibody therapy: ZMapp Advantage The capacity to confer rapid and specific immunity in all populations The ability to provide higher-than-natural levels of immunity compared to vaccinations Limitation Limited supplies of the drug since the three monoclonal antibodies of ZMapp are currently extracted from the plant (Nicotiana benthamian) To overcome potential rate-limiting steps in large-scale production, ZMapp can be manufactured using Chinese hamster ovary (CHO) cells

22 Antiviral compound for treatment of EVD Drug Favipiravir 1,2 (200mg) Mechanism of action Nucleotide analog and viral RNA polymerase inhibitor French drug safety agency approved compassionate use of favipiravir in patients with EVD Brincidofovir phase III trial against CMV, adenovirus Prodrug of cidofovir Inhibit DNA polymerase Exact mechanism in EVD? In vitro Animal Human rapid viral clearance survival of all animals infected with EBOV through intranasal inoculation Phase II 225 confirmed EVD (> 1 yr) h0: 2400 mg; h8: 2400 mg; h16: 1200 mg. Day-1 to Day-9: 1200 mg bid. Fast tract FDA approval 1.Oestereich L, et al. Antiviral Res. 2014;105: Smither SJ, et al. Antivir Res. 2014;104:153 5

23 Antiviral compound for treatment of EVD Drug BCX TKM-Ebola 4 Mechanism of action -Novel adenosine analog inhibits viral RNA polymerase -It does not incorporate into human RNA or DNA Small Interfering RNA target EV-RNA polymerase L, formulated with lipid nanoparticles Preliminary data from the incomplete phase II trial indicated no therapeutic benefit was achieved from the use of TKM-Ebola In vitro Animal Human Post-exposure IM administration protects against EBV in rodent models prevents infection in animals challenged with a lethal dose of EBOV given IM 30 min after challenge with EBV no data in humans the timing of treatment? Phase I in US. Phase II in Guinea 3. Warren TK, et al. Nature.2014 Apr 17;508(7496): Tekmira Pharmaceuticals Corporation. Tekmira provides update on TKM-Ebola-Guinea

24 Post-Ebolavirus disease syndrome (PEVDS) Pathogenesis direct cytopathic effect (active replication of EBV in an immuneprivileged organ: eye, joint, gonad, CNS) persistence of the virus cross-reactive antibodies to host proteins Ophthalmic symptoms 3/20 survivors (1995 outbreak) suffered from uveitis (40-72 days after onset) viable ZEBV was isolated from the aqueous humor 14 weeks after the onset of EVD and 9 weeks after viremia clearance in patient with severe unilateral panuveitis Carod-Artal FJ. Expert Rev. Anti Infect. Ther. 13(10), (2015) Varkey JB, et al. N Engl J Med 2015;372(25):2423-7

43-y/o male physician, EVD He arrived at Emory University Hospital 4 days after the

He was treated with an experimental small interfering RNA antiviral agent

course was complicated by multiorgan system failure requiring mechanical ventilation

25 43-y/o male physician, EVD He arrived at Emory University Hospital 4 days after the onset of symptoms. He was treated with an experimental small interfering RNA antiviral agent (TKM ), convalescent plasma, and aggressive supportive care The hospital course was complicated by multiorgan system failure requiring mechanical ventilation for 12 days and hemodialysis for 24 days. Complain bilateral ocular burning,foreign-body sensation, and photophobia Varkey JB, et al. N Engl J Med 2015;372(25):2423-7

26 Post-Ebolavirus disease syndrome (PEVDS) Fatigue & musculoskeletal pain Low back/ sacroiliac pain/ bilateral enthesitis of Achilles tendon Arthralgias (80%), myalgias (55%) (can occur among convalescents at 6 and 21-month F/U) Other symptoms Sensorineural hearing loss Headache (may persist for months) Low mood, anxiety, coping problems and cognitive symptoms affecting attention, concentration, short-term memory problem Erectile dysfunction

27 Persistence of virus among convalescent patients EBOV RNA has been detected after the onset of the disease Breast milk-up to 15 days Vaginal secretions-up to 33 days Ocular aqueous humor-up to 98 days Semen-up to 101 days (infectious virus-up to 82 days)

28 Ebola RNA Persistence in Semen of EVD Survivors Previous recommendation for survivors of EVD Practice sexual abstinence or use a condom for 3 months after recovery Cross-sectional study of 100 male survivors, Sierra Leone 9/9 (100) 26/40 (65%) 11/43 (26%) The longest time after the onset of EVD symptoms that a semen specimen remained positive by RT-PCR was 284 days (9 months) 0/1(0%) The shortest time after symptom that semen was negative by RT- PCR was 128 days (4 months) Deen GF, et al. N Engl J Med 2015 October 14

29 Conclusion Need more timely and accurate EBOV detection. Multi-disciplinary team-based will be extremely important particularly given the socio-cultural factors that have fueled and sustained EVD outbreaks. Multidisciplinary healthcare services must be implemented for EVD survivors lack of specialized service in poor country Additional research to identify and reduce barriers to their access, distribution and administration of new agents for prevention, acute therapy and post-exposure prophylaxis.

Copyright Emory Healthcare 2014 All Rights Reserved.

Copyright Emory Healthcare 2014 All Rights Reserved. This document is provided as a courtesy to those interested in Emory Healthcare and does not constitute medical or any other advice and does not create any physician-patient relationship. Also, Emory Healthcare