Ebola virus final

BIOTECHNOLOGY

1. EBOLA: EMERGING THREAT TO HUMANITY Presented by Deepti Singh Ph.D. (Biotechnology) Enrol.No . B-1384/14 COLLEGE OF BIOTECHNOLOGY DUVASU, MATHURA Doctoral seminar on

2. OUTLINE INTRODUCTION HISTORY OUTBREAKS TYPES TRANSMISSION LIFE CYCLE SYMPTOMS PREVENTION DIAGNOSIS TREATMENT VACCINES CONCLUSION BIBLIOGRAPHY

3. INTRODUCTION Ebola viruses cause a severe illness known as Ebola hemorrhagic fever that can be lethal to humans. Although hemorrhagic fever can be brought on by several types of viruses, Ebola produces one of the most deadly forms of viral hemorrhagic fevers. Mortality rates for Ebola hemorrhagic fever are high, ranging from 50 percent to 90 percent, with death usually occurring from shock rather than blood loss.

4. HISTORY The virus takes its name from the Ebola River in the northern Congo basin of central Africa, where it first emerged in 1976. Prevention is through isolation of the infected person/s so it does not spread. In Hot Zone in Africa a cave called Kitum cave is found which links two separate single-incidence occurrences of Ebola. Scientists went to the cave and took blood samples from everything they can find. They found nothing at all and the results were never formally published. Kitum cave was stuffed with bats; so the fruit bat find could explain how two people died of Ebola in separate incidents after visiting Kitum cave.

5. Past outbreaks EVD first appeared in in 1976 in 2 simultaneous outbreaks – Zaire, Sudan and Yambuku , DRC. The latter occurred in a village near Ebola(origin of name). Year Country Ebolavirs species Cases Deaths Case fatality 2012 Democratic Republic of Congo Bundibugyo 57 29 51% 2012 Uganda Sudan 7 4 57% 2012 Uganda Sudan 24 17 71% 2011 Uganda Sudan 1 1 100% 2008 Democratic Republic of Congo Zaire 32 14 44% 2007 Uganda Bundibugyo 149 37 25% 2007 Democratic Republic of Congo Zaire 264 187 71%

6. Year Country Ebolavirus Species Cases Deaths Case fatality 2005 Congo Zaire 12 10 83% 2004 Sudan Sudan 17 7 41% 2003 (Nov-Dec) Congo Zaire 35 29 83% 2003 (Jan-Apr) Congo Zaire 143 128 90% 2001-2002 Congo Zaire 59 44 75% 2001-2002 Gabon Zaire 65 53 82% 2000 Uganda Sudan 425 224 53% 1996 South Africa (ex-Gabon) Zaire 1 1 100% 1996 (Jul-Dec) Gabon Zaire 60 45 75%

7. Year Country Ebola species Cases Deaths Case fatality 1995 Democratic Republic of Congo Zaire 315 254 81% 1994 Cote d'Ivoire Taï Forest 1 0% 1994 Gabon Zaire 52 31 60% 1979 Sudan Sudan 34 22 65% 1977 Democratic Republic of Congo Zaire 1 1 100% 1976 Sudan Sudan 284 151 53% 1976 Democratic Republic of Congo Zaire 318 280 88%

8. PRESENT OUTBREAK The recent outbreak (2014) in West Africa is the largest and complex outbreak since the Ebola virus was first discovered in 1976. It has spread between countries starting in Guinea then spreading across land borders to Sierra leone and Liberia, by air(1 traveller only) and by land(1 traveller) to Senegal. These are the most severly affected countries due to weak health systems. The index case was a pregnant woman who prepared bushmeat from an animal. On Aug 8, 2014 WHO declared it as “Public Health Emergency of international Concern”. Zaire species is involved in the present outbreak of Ebola.

9. IMPORTANT TIMELINE OF EBOLA OUTBREAK March 22: Guinea confirms a previously unidentified hemorrhagic fever, which killed over 50 people in its south eastern Forest Region, is Ebola. One study traces the suspected original source to a 2-year-old boy in the town of Gueckedou . Cases are also reported in the capital, Conakry. March 30: Liberia reports two Ebola cases; suspected cases reported in Sierra Leone. May 26: WHO confirms first Ebola deaths in Sierra Leone . June 23: With deaths above 350, making the West African outbreak the worst Ebola epidemic on record, MSF says it is "out of control" and calls for massive resources. July 25: Nigeria, Africa's biggest economy, confirms its first Ebola case, a man who died in Lagos after traveling from Monrovia. Aug. 2: A U.S. missionary physician infected with Ebola in Liberia is flown to Atlanta in the United States for treatment. Aug. 5: A second U.S. missionary infected with Ebola is flown from Liberia to Atlanta for treatment. Aug. 8: WHO declares Ebola "international public health emergency," stops short of urging ban on trade and travel. Aug. 12: WHO says death toll has topped 1,000, approves use of unproven drugs or vaccines. A Spanish priest with Ebola dies in a Madrid hospital.

10. Aug. 24: Democratic Republic of Congo declares Ebola outbreak in a northern province, apparently separate from larger outbreak. An infected British medical worker is flown home from Sierra Leone for treatment. Aug. 29: Senegal reports first confirmed Ebola case Sept. 3: Epidemic's pace accelerates; deaths top 1,900. Officials say there were close to 400 deaths in the past week. A third U.S. missionary doctor infected with Ebola is flown out of Liberia for treatment in Omaha, Nebraska. Sept. 26 - New WHO tally: 3,091 dead out of 6,574 probable, suspected and confirmed cases Sept. 30 - CDC confirms the first diagnosis in the United States of a patient infected with Ebola. The patient, being treated at a hospital in Dallas, had travelled to West Africa Oct. 17 –WHO declares Senegal free of Ebola. Oct. 20-WHO declares Nigeria free of Ebola.

11. EPIDEMIOLOGICAL STATUS Ebola first emerged in Sudan and Zaire in the year 1976. The first outbreak of Ebola (Ebola-Sudan) infected over 284 people, with a mortality rate of 53%. A few months later, the second Ebola virus emerged from Yambuku , Zaire, (Ebola-Zaire); it had the highest mortality rate of any of the Ebola viruses (88%), infected 318 people. On the basis of available evidence and the nature of similar viruses, researchers believe that the virus is animal-borne and is normally maintained in an animal host that is native to the African continent. The virus is not known to be native to any other continents, though.

12. TYPES OF EBOLA There are five subtypes of Ebola viruses: Bundibugyo virus (BDBV). Sudan virus (SUDV). Taï Forest virus (TAFV). Zaire Ebola virus (EBOV). Reston virus. Each of these viruses were named after the location in which the disease had its first out break.

13. WHERE CAN THE VIRUS BE FOUND? Originates in primates including gorillas, chimpanzees, and humans and some domestic pigs, also elephants in central Africa Host cell: Ebola interacts specifically with liver cells and cells of the reticulo -endothelial system. The lining of blood capillaries are attacked. The capillaries start to leak fluids and plasma proteins. Some patients experience intravascular coagulation, and loss of normal clotting capability.

14. The virus kills gorillas and chimpanzees and other monkeys. Because it kills apes in such high percentage – they are not likely to be its natural host.

15. TOWARDS DETECTING THE NATURAL HOST OF THE VIRUS

16. HOW IS IT TRANSMITTED? Ebola is transmitted by blood, bodily fluids, and tissue of infected people. Ebola can be transmitted in the simplest of ways. If you are walking in the bush and an elephant has the virus and the elephant sneezes, the virus can be transmitted by entering your mouth or even touching an open cut.

17. LIFE CYCLE First in the non-human animal. Gets transmitted to the human by direct contact with their faeces and bodily fluids. Animal can sneeze and the virus can make direct contact with a human mouth or even a cut. Gets into the host cell (liver cell). The virus multiplies in the cell. Then is transferred by the human to another animal or human through the same way the virus was transferred him/her.

18. THE WEAK LINK The transmission and spread can be cut off near the end of stage 4 by isolating the human thus he/she can’t contaminate anyone or anything else. As the man’s body fluids and tissue is not in contact with any other possible hosts the virus continues to multiply within the person till death.

19. WHERE DOES EBOLA HIDE? Fruit Bats Ebola in liver and spleen cells. Fruit bats do not show any symptoms. More research needs to be done.

20. SYMPTOMS OF DISEASE Time Frame Symptoms that occur in most Ebola patients: Symptoms that occur in some Ebola patients: Within a few days of becoming infected with the virus: high fever, head ache, muscle aches, stomach pain, fatigue, diarrhea Sore throat, hiccups, rash, red and itchy eyes, vomiting blood, bloody diarrhea Within one week of becoming infected with the virus: Chest pain, shock, and death Blindness and bleeding

21. CONTROLLING EBOLA To control Ebola and make sure it does not spread, one needs to isolate the person in and enclosed area until he/she dies. This affects some communities cultural aspects as this means none of the persons family or friends can give the person a good bye hug, hold, etc. since the virus is contagious. This also means a funeral can’t be held and even if it is the best for people on a global basis, their culture has been invaded and they weren’t allowed to do what they might have been doing for generations.

22. CONT….. A successful virus does not kill its host and also does not seriously harm it. When the traditional host of a virus is wiped out, the virus will try to jump to other species, and it will mutate. A virus that is benign to a moth may be a killer of humans. Conserving the environment can keep these killers in harmless hosts inside the rain forests and jungles of the world. Wipe out their environments and the hosts will die, the viruses will mutate and jump species, and we could be in serious trouble.

23. EBOLA IS NOT SPREAD BY:

24. DIAGNOSIS OF EBOLA Diagnosing Ebola can be difficult at first since early symptoms, such as fever, are nonspecific to Ebola infection. However, if a person has the early symptoms and has had contact with Ebola they should be isolated and public health professionals notified. Samples from the patient can then be collected and tested to confirm infection.

25. The diagnosis is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture, detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by ELISA is effective early and in those who have died from the disease. Virions can be seen and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot tell the difference between the various filoviruses despite there being some length differences. Detecting antibodies against the virus is effective late in the disease and in those who recover. SPECIFIC METHODS

26. Timeline of Infection Diagnostic tests available Within a few days after symptoms begin Antigen-capture enzyme-linked immunosorbent assay (ELISA) testing IgM ELISA Polymerase chain reaction (PCR) Virus isolation Later in disease course or after recovery IgM and IgG antibodies Retrospectively in deceased patients Immunohistochemistry testing PCR Virus isolation Source : Centers for Disease Control and Prevention http://www.cdc.gov/vhf/ebola/diagnosis/index.html Accessed Oct. 14, 2014 EBOLA DIAGNOSTIC TECHNIQUES

27. Immunochromatographic method

28. EBOLA VIRUS DIAGNOSIS Real Time PCR (RT-PCR): Used to diagnose acute infection. More sensitive than antigen detection ELISA. Identification of specific viral genetic fragments. Performed in selected certified laboratories. RT-PCR sample collection: Volume: minimum volume of 4mL whole blood. Plastic collection tubes. Whole blood preserved with EDTA is preferred . Whole blood preserved with sodium polyanethol sulfonate (SPS), citrate, or with clot activator is acceptable.

29. CONT….. Virus isolation Requires Biosafety Level 4 laboratory . Can take several days. Immunohistochemical staining and histopathology On collected tissue or dead wild animals; localizes viral antigen. Serologic testing for IgM and IgG antibodies (ELISA): Detection of viral antibodies in specimens, such as blood, serum, or tissue suspensions. Monitor the immune response in confirmed EVD patients.

30. POTENTIAL EBOLA TREATMENTS Antibody therapy Convalescent whole blood and plasma Monoclonal antibodies ( ZMapp ) Antiviral therapy RNA-based drugs Brincidofovir (CMX-001) Immunomodulators 4. Coagulation modulators

31. MONOCLONAL ANTIBODIES - ZMapp Cocktail of 3 monoclonal antibodies: c13C6 and c2G4 and c4G7 Manufactured in tobacco plants. Targets Ebola virus glycoprotein. Attaches to the virus and block its infective potential. Not yet tested in human trials. Small number of cases from current outbreak given drug on compassionate basis with variable results. Current supplies of drug exhausted. Efforts being made to scale up production, task difficult due to its complex production processes.

32. RNA-BASED DRUGS Interfere with translation of Ebola virus mRNA to protein. Prevent virus from replicating. Favipiravir (T-705) Orally Approved for influenza treatment in Japan. Efficacy against Ebola in mice ( Oestereich et al 2014). AVI-7537 Intravenously In early stage development for treatment of Ebola virus. It is an antisense phosphorodiamidate morpholino oligimers (PMO) that inhibits VP24 protein of Ebola virus.

33. CONT….. TKM-Ebola Intravenously. It is a small interfering RNA ( siRNA ), affecting 3 of Ebola’s 7 proteins. Limited safety and efficacy data are available. Clinical hold on phase 1 trials in early 2014, because of increased cytokine levels in healthy individuals. FDA has approved the emergency use of TKM-Ebola during the current outbreak. Risk versus benefit should be estimated when deciding whether to use this agent.

34. BRINCIDOFOVIR (CMX-001) Orally Brincidofovir is a prodrug of cidofovir but fewer renal side-effects than cidofovir . In vitro tests have shown its potential for treatment of EVD. IMMUNOMODULATORS Interferons Commercially available. Efficacy in rodents. Delayed time to death (Smith et al 2013).

35. COAGULATION MODULATORS Severe coagulation disorder occurs in EVD. Recombinant Activated Protein C Inhibits clotting factors. Levels of protein C low in EVD. Recombinant Nematode Anticoagulant Protein Inhibits clotting factors. Limited success with both in NHP studies. (Hensley et al 2007; Geisbert et al 2003)

36. LINE OF TREATMENT There are no approved treatments available for EVD. Clinical management focus - supportive care of complications: hypovolemia, electrolyte abnormalities, haematologic abnormalities, refractory shock, hypoxia, haemorrhage , septic shock, multi-organ failure. Recommended care includes: volume repletion. maintenance of blood pressure (with vasopressors if needed) maintenance of oxygenation. pain control. nutritional support. treating secondary bacterial infections. Source: Centers for Disease Control and Prevention. http://www.cdc.gov/vhf/ebola/hcp/clinician-information-us-healthcare-settings.html Accessed Oct. 14, 2014

37. CONT…. Among patients from West Africa, large volumes of intravenous fluids have often been required to correct dehydration due to diarrhea and vomiting. Several investigational therapeutics for Ebola virus disease are in development. There are no approved vaccines available for EVD. Several investigational Ebola vaccines are in development, and Phase I trials are underway for some vaccine candidates. Source: Centers for Disease Control and Prevention. http://www.cdc.gov/vhf/ebola/hcp/clinician-information-us-healthcare-settings.html Accessed Oct. 14, 2014

38. DNA vaccines, adenovirus-based vaccines, and VSIV-based vaccines have entered clinical trials. No licensed vaccine for EVD is available. Several vaccines are being tested, but none are available for clinical use. POSSIBILITY OF VACCINES?

39. EBOLA VACCINES - HISTORICALLY Debate about requirement for vaccine previously- Rarity of disease. Lack of interest from pharmaceutical industry Potential cost. View has changed in recent years- Increasing frequency of outbreaks with high case fatality rates. Number of imported cases of viral haemorrhagic fever and laboratory exposures. Potential misuse of EVD as bioterrorism agent.

40. WHO TO VACCINATE? Valuable for: Medical personnel First responder Military personnel Researchers Ring vaccination in outbreak

41. WHAT’S IN THE PIPELINE? Several candidate vaccines being developed. Two identified as being at the most advanced stage of development. Both are recombinant vector vaccines: Chimpanzee adenovirus serotype 3 (cAd3-EBO) Recombinant vesicular stomatitis virus ( rVSV -EBO) Both are being fast-tracked but data on safety and efficacy are limited.

42. 1. CHIMPANZEE ADENOVIRUS SEROTYPE 3 (cAd3-EBO) Based on recombinant adenovirus 3 (cAd3) technology- a surface protein gene of Ebola virus is inserted into a modified chimpanzee adenovirus resulting virus cannot replicate in humans, but is intended to induce an immune response Pre-existing immunity in humans may be a problem, impairing vaccine efficacy. However, cAd3 is a rare adenovirus serotype, with most humans not having pre-existing immunity.

43. CONT….. cAd3-EBO tested in 16 NHPs and found to be 100% protective (Stanley et al 2014). Phase 1 human trials began in September in US and Oxford. Being developed by GlaxoSmithKline and US National Institute of Health.

44. 2. RECOMBINANT VESICULAR STOMATITIS VIRUS VACCINE ( rVSV -EBO) VSV causes mild flu-like illness in humans. Gene for surface glycoprotein of Ebola inserted into VSV - this recombinant virus is then intended to induce an immune response in humans to Ebola virus. Jones et al (2005) 100% protective against Zaire Ebola virus (ZEBOV) in NHPs after a single vaccination. Feldmann et al (2007) demonstrated varying degrees of protection post-exposure in NHPs if vaccine given up to 24 hours after exposure to a lethal dose of Ebola virus.

45. CONT…. Given to lab worker exposed to ZEBOV following needle stick injury in Hamburg, 2009 VSV viraemia but did not develop EVD. It’s not possible to know if treatment was effective or if patient was never infected. Phase 1 human trials has began. Being developed by Public Health Agency of Canada, NewLink Genetics and others.

46. To obtain samples and study the disease in remote areas where outbreaks occur. A high degree of biohazard containment is required for laboratory studies and clinical analysis. CD4+ T cells are important master‐regulators of the immune response and other cellular compartments to produce more robust and long lasting immunity. Lack of CD4+ T cells in Ebola infection that is thought to underlie the suboptimal antibody responses in infected subjects and the ultimate inability to mount sufficient antibody responses to suppress the infection. Potent vaccination strategy against Ebola must include a robust CD4+ T cell‐mediated response, likely critical in providing T cell help to the B cell compartment. DIFFICULTY IN MAKING VACCINES

47. CONCLUSION Ebola is a threat not only to humans but also to our closest living relatives - the great apes. The western lowland gorilla populations have been reduced by Ebola to such an extent that they are now considered "critically endangered". About a third of the gorillas in protected areas have died from Ebola in the past 15 years. Scientists are concerned that their numbers may not be able to recover and fear that they could become extinct in decade.

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52. Stay Safe!!