Ebola virus final

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Presented by Deepti Singh Ph.D. (Biotechnology) Enrol.No. B-1384/14 COLLEGE OF BIOTECHNOLOGY DUVASU, MATHURA

Transcript of Ebola virus final

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Presented by

Deepti SinghPh.D. (Biotechnology)

Enrol.No. B-1384/14

COLLEGE OF BIOTECHNOLOGY

DUVASU, MATHURA

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OUTLINE

• INTRODUCTION• HISTORY• OUTBREAKS• TYPES• TRANSMISSION• LIFE CYCLE• SYMPTOMS• PREVENTION• DIAGNOSIS• TREATMENT• VACCINES• CONCLUSION• BIBLIOGRAPHY

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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 ofviruses, Ebola produces one of the most deadly forms of viralhemorrhagic fevers.

• Mortality rates for Ebola hemorrhagic fever are high, ranging from50 percent to 90 percent, with death usually occurring from shockrather than blood loss.

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HISTORY

The virus takes its name from the Ebola River in the northern Congobasin of central Africa, where it first emerged in 1976.

Prevention is through isolation of the infected person/s so it doesnot spread.

In Hot Zone in Africa a cave called Kitum cave is found which linkstwo separate single-incidence occurrences of Ebola. Scientists went tothe cave and took blood samples from everything they can find. Theyfound nothing at all and the results were never formally published.Kitum cave was stuffed with bats; so the fruit bat find could explainhow two people died of Ebola in separate incidents after visiting Kitumcave.

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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 CountryEbolavirsspecies Cases Deaths Case fatality

2012Democratic 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%

2008Democratic Republic of Congo Zaire 32 14 44%

2007 Uganda Bundibugyo 149 37 25%

2007Democratic Republic of Congo Zaire 264 187 71%

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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%

1996South Africa (ex-Gabon) Zaire 1 1 100%

1996 (Jul-Dec) Gabon Zaire 60 45 75%

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Year Country Ebola species

Cases Deaths Case fatality

1995Democratic

Republic of Congo Zaire 315 254 81%

1994 Cote d'Ivoire Taï Forest 1 0 0%

1994 Gabon Zaire 52 31 60%

1979 Sudan Sudan 34 22 65%

1977Democratic

Republic of Congo Zaire 1 1 100%

1976 Sudan Sudan 284 151 53%

1976Democratic

Republic of Congo Zaire 318 280 88%

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PRESENT OUTBREAK

The recent outbreak (2014) in West Africa is the largest andcomplex outbreak since the Ebola virus was first discovered in 1976.

It has spread between countries starting in Guinea then spreadingacross land borders to Sierra leone and Liberia, by air(1 travelleronly) and by land(1 traveller) to Senegal.

These are the most severly affected countries due to weak healthsystems.

The index case was a pregnant woman who prepared bushmeatfrom an animal.

On Aug 8, 2014 WHO declared it as “Public Health Emergency ofinternational Concern”.

Zaire species is involved in the present outbreak of Ebola.

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IMPORTANT TIMELINE OF EBOLA OUTBREAK

• March 22: Guinea confirms a previously unidentified hemorrhagic fever, whichkilled over 50 people in its south eastern Forest Region, is Ebola. One study tracesthe suspected original source to a 2-year-old boy in the town of Gueckedou. Casesare also reported in the capital, Conakry.

• March 30: Liberia reports two Ebola cases; suspected cases reported in SierraLeone.

• May 26: WHO confirms first Ebola deaths in Sierra Leone.

• June 23: With deaths above 350, making the West African outbreak the worstEbola epidemic on record, MSF says it is "out of control" and calls for massiveresources.

• July 25: Nigeria, Africa's biggest economy, confirms its first Ebola case, a man whodied in Lagos after traveling from Monrovia.

• Aug. 2: A U.S. missionary physician infected with Ebola in Liberia is flown to Atlantain the United States for treatment.

• Aug. 5: A second U.S. missionary infected with Ebola is flown from Liberia toAtlanta for treatment.

• Aug. 8: WHO declares Ebola "international public health emergency," stops shortof urging ban on trade and travel.

• Aug. 12: WHO says death toll has topped 1,000, approves use of unproven drugsor vaccines.

• A Spanish priest with Ebola dies in a Madrid hospital.

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• Aug. 24: Democratic Republic of Congo declares Ebola outbreak in anorthern province, apparently separate from larger outbreak.

• An infected British medical worker is flown home from Sierra Leone fortreatment.

• Aug. 29: Senegal reports first confirmed Ebola case

• Sept. 3: Epidemic's pace accelerates; deaths top 1,900. Officials say therewere close to 400 deaths in the past week.

• A third U.S. missionary doctor infected with Ebola is flown out of Liberia fortreatment in Omaha, Nebraska.

• Sept. 26 - New WHO tally: 3,091 dead out of 6,574 probable, suspected andconfirmed cases

• Sept. 30 - CDC confirms the first diagnosis in the United States of a patientinfected with Ebola. The patient, being treated at a hospital in Dallas, hadtravelled to West Africa

• Oct. 17 –WHO declares Senegal free of Ebola.

• Oct. 20-WHO declares Nigeria free of Ebola.

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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 theEbola 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 normallymaintained in an animal host that is native to the African continent.

• The virus is not known to be native to any other continents,though.

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TYPES OF EBOLA

There are five subtypes of Ebola viruses:

1. Bundibugyo virus (BDBV).

2. Sudan virus (SUDV).

3. Taï Forest virus (TAFV).

4. Zaire Ebola virus (EBOV).

5. Reston virus.

Each of these viruses were named after the location in which thedisease had its first out break.

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WHERE CAN THE VIRUS BE FOUND?

• Originates in primates including gorillas, chimpanzees, and humansand some domestic pigs, also elephants in central Africa

• Host cell: Ebola interacts specifically with liver cells and cells of thereticulo-endothelial system. The lining of blood capillaries areattacked. The capillaries start to leak fluids and plasma proteins.Some patients experience intravascular coagulation, and loss ofnormal clotting capability.

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The virus kills gorillas andchimpanzees and other monkeys.Because it kills apes in such highpercentage – they are not likelyto be its natural host.

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TOWARDS DETECTING THE NATURAL HOST OF THE VIRUS

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HOW IS IT TRANSMITTED?

• Ebola is transmitted by blood, bodily fluids, and tissue of infectedpeople.

• Ebola can be transmitted in the simplest of ways. If you are walkingin the bush and an elephant has the virus and the elephant sneezes,the virus can be transmitted by entering your mouth or eventouching an open cut.

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LIFE CYCLE

• First in the non-human animal.

• Gets transmitted to the human by direct contact with their faecesand bodily fluids. Animal can sneeze and the virus can make directcontact 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 humanthrough the same way the virus was transferred him/her.

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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 oranything else.

• As the man’s body fluids and tissue is not in contact with any otherpossible hosts the virus continues to multiply within the person tilldeath.

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WHERE DOES EBOLA HIDE?

• Fruit Bats

• Ebola in liver and spleencells.

• Fruit bats do not show anysymptoms.

• More research needs to bedone.

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SYMPTOMS OF DISEASETime Frame Symptoms that

occur in most Ebola patients:

Symptoms that occur in some Ebola patients:

Within a few days of becominginfected 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

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CONTROLLING EBOLA To control Ebola and make sure it does not spread, one needs toisolate the person in and enclosed area until he/she dies.

This affects some communities cultural aspects as this means noneof 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 forpeople on a global basis, their culture has been invaded and theyweren’t allowed to do what they might have been doing forgenerations.

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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 viruswill 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 harmlesshosts inside the rain forests and jungles of the world. Wipe outtheir environments and the hosts will die, the viruses will mutateand jump species, and we could be in serious trouble.

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EBOLA IS NOT SPREAD BY:

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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.

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• The diagnosis is confirmed by isolating the virus, detecting its RNA orproteins, or detecting antibodies against the virus in a person's blood.

• Isolating the virus by cell culture, detecting the viral RNA by polymerasechain reaction (PCR) and detecting proteins by ELISA is effective earlyand in those who have died from the disease.

• Virions can be seen and identified in cell culture by electronmicroscopy due to their unique filamentous shapes, but electronmicroscopy cannot tell the difference between the various filovirusesdespite there being some length differences.

• Detecting antibodies against the virus is effective late in the disease andin those who recover.

SPECIFIC METHODS

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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.htmlAccessed Oct. 14, 2014

EBOLA DIAGNOSTIC TECHNIQUES

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Immunochromatographic method

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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.

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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.

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POTENTIAL EBOLA TREATMENTS

1. Antibody therapy

a. Convalescent whole blood and plasma

b. Monoclonal antibodies (ZMapp)

2. Antiviral therapy

a. RNA-based drugs

b. Brincidofovir (CMX-001)

3. Immunomodulators

4. Coagulation modulators

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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.

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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.

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CONT…..

TKM-Ebola

• Intravenously.

• It is a small interfering RNA (siRNA), affecting 3 of Ebola’s 7proteins.

• Limited safety and efficacy data are available.

• Clinical hold on phase 1 trials in early 2014, because of increasedcytokine levels in healthy individuals.

• FDA has approved the emergency use of TKM-Ebola during thecurrent outbreak.

• Risk versus benefit should be estimated when deciding whether touse this agent.

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BRINCIDOFOVIR (CMX-001)

• Orally

• Brincidofovir is a prodrug of cidofovir but fewer renal side-effectsthan 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).

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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)

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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, septicshock, 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

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CONT….

• Among patients from West Africa, large volumes of intravenousfluids have often been required to correct dehydration due todiarrhea and vomiting.

• Several investigational therapeutics for Ebola virus disease are indevelopment.

• There are no approved vaccines available for EVD.

• Several investigational Ebola vaccines are in development, andPhase 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

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• DNA vaccines, adenovirus-based vaccines, and VSIV-based vaccineshave entered clinical trials.

• No licensed vaccine for EVD is available. Several vaccines are beingtested, but none are available for clinical use.

POSSIBILITY OF VACCINES?

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EBOLA VACCINES - HISTORICALLY

• Debate about requirement for vaccine previously-

o Rarity of disease.

o Lack of interest from pharmaceutical industry

o Potential cost.

• View has changed in recent years-

o Increasing frequency of outbreaks with highcase fatality rates.

o Number of imported cases of viralhaemorrhagic fever and laboratory exposures.

o Potential misuse of EVD as bioterrorism agent.

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WHO TO VACCINATE?

• Valuable for:

Medical personnel

First responder

Military personnel

Researchers

Ring vaccination in outbreak

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WHAT’S IN THE PIPELINE?

• Several candidate vaccines being developed.

• Two identified as being at the most advanced stage ofdevelopment.

• Both are recombinant vector vaccines:

1. Chimpanzee adenovirus serotype 3 (cAd3-EBO)

2. Recombinant vesicular stomatitis virus (rVSV-EBO)

• Both are being fast-tracked but data on safety and efficacy arelimited.

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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 modifiedchimpanzee adenovirus

– resulting virus cannot replicate in humans, but is intended toinduce an immune response

• Pre-existing immunity in humans may be a problem, impairingvaccine efficacy.

• However, cAd3 is a rare adenovirus serotype, with most humans nothaving pre-existing immunity.

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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 ofHealth.

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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 - thisrecombinant virus is then intended to induce an immune responsein humans to Ebola virus.

• Jones et al (2005)

– 100% protective against Zaire Ebola virus (ZEBOV) in NHPs aftera single vaccination.

• Feldmann et al (2007)

– demonstrated varying degrees of protection post-exposure inNHPs if vaccine given up to 24 hours after exposure to a lethaldose of Ebola virus.

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CONT….

• Given to lab worker exposed to ZEBOV following needle stick injuryin 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, NewLinkGenetics and others.

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To obtain samples and study the disease in remote areas whereoutbreaks occur.

A high degree of biohazard containment is required for laboratorystudies and clinical analysis.

CD4+ T cells are important master‐regulators of the immune responseand other cellular compartments to produce more robust and longlasting immunity.

Lack of CD4+ T cells in Ebola infection that is thought to underlie thesuboptimal antibody responses in infected subjects and the ultimateinability to mount sufficient antibody responses to suppress theinfection.

Potent vaccination strategy against Ebola must include a robust CD4+ Tcell‐mediated response, likely critical in providing T cell help to the Bcell compartment.

DIFFICULTY IN MAKING VACCINES

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CONCLUSION

Ebola is a threat not only to humans but also to our closest livingrelatives - the great apes.

The western lowland gorilla populations have been reduced by Ebolato such an extent that they are now considered "criticallyendangered". About a third of the gorillas in protected areas have diedfrom Ebola in the past 15 years.

Scientists are concerned that their numbers may not be able torecover and fear that they could become extinct in decade.

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