First History of Evola break
out in the world
1976
Sudan outbreak
=================
The first known outbreak of EVD
was identified only after the fact, occurring between June and November 1976 inNzara, South Sudan,[20][108] (then part of Sudan) and was caused by Sudan
virus (SUDV).
The Sudan outbreak infected 284 people and killed 151. The first identifiable
case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara, who was hospitalized on 30 June and died on 6 July.[109][18] While the WHO medical staff involved in the
Sudan outbreak were aware that they were dealing with a heretofore unknown
disease, the actual "positive identification" process and the naming
of the virus did not occur until some months later in the Democratic Republic of the
Congo.[109]
Zaire outbreak
=================
On 26 August 1976, a second
outbreak of EVD began in Yambuku, a
small rural village in Mongala
District in
northern Zaire (now known as the Democratic Republic of the
Congo).[110][111] This outbreak was caused by EBOV, formerly
designated Zaire ebolavirus, which is a different member of the genus Ebolavirus than in the first Sudan outbreak. The first
person infected with the disease was
village school headmaster Mabalo
Lokela, who began displaying symptoms on 26 August 1976.[112] Lokela had returned from a trip to Northern
Zaire near the Central African Republic border, having visited the Ebola
River between
12 and 22 August. He was originally believed to havemalaria and was given quinine.
However, his symptoms continued to worsen, and he was admitted to Yambuku
Mission Hospital on 5 September. Lokela died on 8 September, 14 days after he
began displaying symptoms.[113][114][115]
Soon after Lokela's death,
others who had been in contact with him also died, and people in the village of
Yambuku began to panic. This led the country's Minister of Health along with
Zaire President Mobutu
Sese Seko to
declare the entire region, including Yambuku and the country's capital, Kinshasa, a
quarantine zone. No one was permitted to enter or leave the area, with roads,
waterways, and airfields placed under martial
law. Schools, businesses and social organizations were closed.[116] Researchers from the CDC, including Peter
Piot, co-discoverer of Ebola, later arrived to assess the effects of
the outbreak, observing that "the whole region was in panic."[117][118][119] Piot concluded that the Belgian nuns had
inadvertently started the epidemic by giving unnecessary vitamin injections to
pregnant women, without sterilizing the syringes and needles. The outbreak
lasted 26 days, with the quarantine lasting 2 weeks. Among the reasons that
researchers speculated caused the disease to disappear, were the precautions
taken by locals, the quarantine of the area, and discontinuing the injections.[116]
During this outbreak, Dr. Ngoy
Mushola recorded the first clinical description of EVD in Yambuku, where
he wrote the following in his daily log: "The illness is characterized
with a high temperature of about 39 °C (102 °F), hematemesis,
diarrhea with blood, retrosternal abdominal pain, prostration with
"heavy" articulations, and rapid evolution death after a mean of 3
days."[120]
The virus responsible for the
initial outbreak, first thought to be Marburg
virus, was later identified as a new type of virus related to
marburgviruses. Virus strain samples isolated from both outbreaks were named as
the "Ebola virus" after the Ebola
River, located near the originally identified viral outbreak site in
Zaire.[18] Reports conflict about who initially coined
the name: either Karl Johnson of the American CDC team[121] or Belgian researchers.[122] Subsequently a number of other cases were
reported, almost all centered on the Yambuku mission hospital or having close
contact with another case.[112] 318 cases and 280 deaths (a 88 percent
fatality rate) occurred in Zaire.[123] Although it was assumed that the two
outbreaks were connected, scientists later realized that they were caused by
two distinct ebolaviruses, SUDV and EBOV.[111] The Zaire outbreak was contained with the
help of the World Health Organization and transport from the Congolese air force,
by quarantining villagers, sterilizing medical equipment, and providing
protective clothing.
1995 to 2012
==============
The second major outbreak
occurred in Zaire (now the Democratic Republic of the
Congo) in 1995, affecting 315 and killing 254.[124][125] The next major outbreak occurred inUganda in 2000, affecting 425 and killing 224; in
this case the Sudan virus was found to be the ebolavirus species responsible
for the outbreak. In 2003 there was an outbreak in the Republic of the Congo that affected 143 and killed 128, a death
rate of 90 percent, the highest to date.[126]
Between April and August 2007,
a fever epidemic[124] in a four-village region[125] of the Democratic Republic of the Congo was
confirmed in September to have cases of Ebolavirus.[128] Many people who attended the recent funeral
of a local village chief died.[125] The 2007 outbreak eventually affected 264
individuals and resulted in the deaths of 187.[1]
On 30 November 2007, the Uganda
Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in
Western Uganda. After confirmation of samples tested by the United States
National Reference Laboratories and the Centers for Disease Control, the World
Health Organization confirmed the presence of a new species of Ebolavirus, which
was tentatively named Bundibugyo.[129] The WHO reported 149 cases of this new
strain and 37 of those led to deaths.[1]
The WHO confirmed two small
outbreaks in Uganda in 2012. The first outbreak affected 7 people and resulted
in the death of 4 and the second affected 24, resulting in the death of 17. The
Sudan variant was responsible for both outbreaks.[1]
On 17 August 2012, the Ministry
of Health of the Democratic Republic of the Congo reported an outbreak of the
Ebola-Bundibugyo variant[130] in the eastern region.[131][132] Other than its discovery in 2007, this was
the only time that this variant has been identified as the ebolavirus
responsible for an outbreak. The WHO revealed that the virus had sickened 57
people and claimed 29 lives. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns
of Isiro and Viadana.[1][133]
2013 to 2014 West African outbreak
=================================================================
In March 2014, the World Health
Organization (WHO) reported a major Ebola outbreak in Guinea, a western African nation.[134]Researchers
traced the outbreak to a two-year old child who died December 2013.[135][136] The disease then rapidly spread to the
neighboring countries of Liberia and Sierra
Leone. It is the largest Ebola outbreak ever documented, and the
first recorded in the region.[134]
On 8 August 2014, the WHO
declared the epidemic to be an international public health emergency. Urging
the world to offer aid to the affected regions, the Director-General said,
"Countries affected to date simply do not have the capacity to manage an
outbreak of this size and complexity on their own. I urge the international
community to provide this support on the most urgent basis possible."[137] By mid-August 2014, Doctors Without Borders
reported the situation in Liberia's capital Monrovia as "catastrophic" and
"deteriorating daily". They reported that fears of Ebola among staff
members and patients had shut down much of the city’s health system, leaving
many people without treatment for other conditions.[138] By late August 2014, the disease had spread
to Nigeria, and one case was reported in Senegal.[139][140] [141][142] On 30 September 2014, the first confirmed
case of Ebola in the United States was diagnosed.[143] The patient died 8 days later.[144]
Aside from the human cost, the
outbreak has severely eroded the economies of the affected countries. A Financial
Times report
suggested the economic impact of the outbreak could kill more people than the
virus itself. As of 23 September, in the three hardest hit countries, Liberia,
Sierra Leone and Guinea, only 893 treatment beds were available even though the
current need was 2122 beds. In a 26 September statement, the WHO said,
"The Ebola epidemic ravaging parts of West Africa is the most severe acute
public health emergency seen in modern times. Never before in recorded history
has a biosafety
level four
pathogen infected so many people so quickly, over such a broad geographical
area, for so long."[145] The WHO reported that by 25 August more
than 216 health-care workers were among the dead, partly due to the lack of
equipment and long hours.[146] On 23 October, the Malian government
confirmed its first case.[147] In response, UNMEER, in cooperation with
the Logistics Cluster, air-lifted 1,050 kg of personal protective equipment
(PPE) and body bags from Monrovia to Mali.[148] As of 4 November 2014, 13,268 suspected
cases and 4,960 deaths had been reported;[10][107] however, the WHO has said that these
numbers may be vastly underestimated.[148][149][150]
2014 DRC Congo outbreak
==========================
An outbreak in Boende District
in Equatorial Province was stopped effectively with flexible organization and
funding,[151] as well as social mobilization led by
UNICEF advising action people could use.[152][153] The DRC outbreak was from a local Ebola
strain and not the one from West Africa (WHO).[154]
2014 spread outside of Africa
=========================
As of 15 October 2014, there
have been 17 cases of Ebola treated outside of Africa, four of whom have died.[155] In early October, Teresa Romero, a
44-year-old Spanish nurse, contracted Ebola after caring for a priest who had
been repatriated from West Africa. This was the first transmission of the virus
to occur outside of Africa.[156] On 20 October, it was announced that Teresa
Romero had tested negative for the Ebola virus, suggesting that she may have
recovered from Ebola infection.[157]
On 19 September, Eric Duncan
flew from his native Liberia to Texas; 5 days later he began showing symptoms
and visited a hospital, but was sent home. His condition worsened and he
returned to the hospital on 28 September, where he died on 8 October.[158] Health officials confirmed a diagnosis of
Ebola on 30 September—the first case in the United States.[40] On 12 October, the CDC confirmed that a nurse in Texas who had
treated Duncan was found to be positive for the Ebola virus, the first known
case of the disease to be contracted in the United States.[159] On 15 October, a second Texas health-care
worker who had treated Duncan was confirmed to have the virus.[160] They have both recovered.
On 23 October, a doctor in New
York City, who returned to the United States from Guinea after working with
Doctors Without Borders, tested positive for Ebola. His case is unrelated to
the Texas cases.[161]
Society
and culture
Weaponization
==================
Ebolavirus is classified as a biosafety level 4 agent,
as well as a Category
A bioterrorism agent
by the Centers for Disease Control and Prevention. It has the potential to be
weaponized for use in biological warfare,[162][163] and was investigated by Biopreparat for such use, but might be difficult to
prepare as a weapon of mass destruction because the virus becomes ineffective
quickly in open air.[164] Fake emails pretending to be Ebola
information from the WHO or the Mexican Government have in 2014 been misused to
spread computer malware.[165]
Literature
============
Richard
Preston's 1995 best-selling book, The Hot
Zone, dramatized the Ebola outbreak in Reston, Virginia.[166]
William
Close's 1995 Ebola:
A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the
1976 Ebola outbreak in Zaire.[167]
Tom
Clancy's 1996 novel, Executive
Orders, involves a Middle
Eastern terrorist
attack on the United States using an airborne form of a deadly Ebola virus
strain named "Ebola Mayinga" (see Mayinga
N'Seka).[168]
As the Ebola virus epidemic in
West Africa developed in 2014, a number of popular self-published and well-reviewed
books containing sensational and misleading information about the disease
appeared in electronic and printed formats. The authors of some such books
admitted that they lacked medical credentials and were not technically
qualified to give medical advice. The World Health Organization and the United
Nations stated that such misinformation had contributed to the spread of the
disease.[169]
Other
animals
Wild animals
===========
Ebola has a high mortality
among primates.[97] Frequent outbreaks of Ebola may have
resulted in the deaths of 5,000 gorillas.[170] Outbreaks of Ebola may have been
responsible for an 88 percent decline in tracking indices of observed
chimpanzee populations in 420 square kilometer Lossi Sanctuary between 2002 and
2003.[171] Transmission among chimpanzees through meat
consumption constitutes a significant risk factor, whereas contact between the
animals, such as touching dead bodies and grooming, is not.[172]
Recovered carcasses from
gorillas contain multiple Ebola virus strains, which suggest multiple
introductions of the virus. Bodies decompose quickly and carcasses are not
infectious after 3 to 4 days. Contact between gorilla groups is rare,
suggesting transmission among gorilla groups is unlikely, and that outbreaks
result from transmission between viral reservoir and animal populations.[171]
Domestic animals
================
In 2012 it was demonstrated
that the virus can travel without contact from pigs to nonhuman primates,
although the same study failed to achieve transmission in that manner between
primates.[47][173]
Dogs may become infected with
EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat
EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs
during an EBOV outbreak found that although they remain asymptomatic, about 32
percent of dogs closest to an outbreak showed aseroprevalence for EBOV versus 9 percent of those farther
away.[174] The authors concluded that there were
"potential implications for preventing and controlling human
outbreaks."
Reston virus
===============
In late 1989, Hazelton Research
Products' Reston Quarantine Unit in Reston,
Virginia, suffered an outbreak of fatal illness amongst certain lab
monkeys. This lab outbreak was initially diagnosed as simian hemorrhagic fever
virus (SHFV),
and occurred amongst a shipment of crab-eating macaque monkeys
imported from the Philippines. Hazelton's veterinary pathologist sent tissue
samples from dead animals to the United
States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland, where an ELISA test
indicated the antibodies present in the tissue were a response to Ebola virus
and not SHFV.[175] An electron microscopist from USAMRIID
discoveredfiloviruses similar
in appearance to Ebola in the tissue samples sent from Hazelton Research
Products' Reston Quarantine Unit.[176]
A US Army team headquartered at USAMRIID euthanized the surviving monkeys, and brought all the
monkeys to Ft.
Detrick for
study by the Army's veterinary pathologists and virologists, and eventual disposal
under safe conditions.[175] Blood samples were taken from 178 animal
handlers during the incident.[177] Of those, six animal handlers eventuallyseroconverted,
including one who had cut himself with a bloody scalpel.[60][178] Despite its status as a Level‑4 organism
and its apparent pathogenicity in monkeys, when the handlers did not
become ill, the CDC concluded that the virus had a very low pathogenicity to
humans.[178][179]
The Philippines and the United
States had no previous cases of Ebola infection, and upon further isolation,
researchers concluded it was another strain of Ebola, or a new filovirus of Asian
origin, which they named Reston
ebolavirus (RESTV)
after the location of the incident.[175] Reston virus (RESTV) can be transmitted to
pigs.[47] Since the initial outbreak it has since
been found in nonhuman primates in Pennsylvania, Texas, and Italy,[180] where the virus had infected pigs.[181] According to the WHO, routine cleaning and
disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the
Reston ebolavirus. Pigs that have been infected with RESTV tend to show symptoms of the disease.
Research
=========================
A number of experimental
treatments are being studied.[182] In the United States, the Food and Drug Administration (FDA)'s animal efficacy rule is being used to demonstrate reasonable
safety to obtain permission to treat people who are infected with Ebola. It is
being used because the normal path for testing drugs is not possible for
diseases caused by dangerous pathogens or toxins. Experimental drugs are made
available for use with the approval of regulatory agencies under named patient programs, known in the US as"expanded
access".[183] On 12 August 2014 the WHO released a
statement that the use of not yet proven treatments is ethical in certain
situations in an effort to treat or prevent the disease.[184]
Medications
===============
Researchers
looking at slides of cultures of cells that make monoclonal antibodies. These
are grown in a lab and the researchers are analyzing the products to select the
most promising.
Antivirals
·
Favipiravir,
approved in Japan for stockpiling against influenza pandemics, appears to be
useful in a mouse model of Ebola.[12][185] On 4 October 2014, it was reported that a
French nun who contracted Ebola while volunteering in Liberia was cured with
Favipiravir treatment.[186]
·
BCX4430 is a
broad-spectrum small
molecule antiviral
drug developed by BioCryst Pharmaceuticals and undergoing animal
testing as a
potential human treatment for Ebola by USAMRIID.[187] The drug has been approved to progress to Phase 1 trials, expected late in 2014.[188]
·
Brincidofovir is a broad-spectrum antiviral drug. Its
maker has been granted FDA approval to proceed with a trial to test its safety
and efficacy in Ebola patients.[189] It has been used to treat the first patient
diagnosed with Ebola in the USA, after he had recently returned from Liberia.[190][191]
·
Lamivudine, usually used to treat HIV/AIDS, was
reported in September 2014 to have been used successfully to treat 13 out of 15
Ebola-infected patients by a doctor in Liberia, as part of a combination
therapy also involving intravenous fluids and antibiotics to combat opportunistic bacterial infection
of Ebola-compromised internal organs.[192] Western virologists have however expressed
caution about the results, due to the small number of patients treated and
confounding factors present. Researchers at the NIH stated that lamivudine had so far failed to
demonstrate anti-Ebola activity in preliminary in vitro tests, but that they would continue to
test it under different conditions and would progress it to trials if even
slight evidence for efficacy is found.[193]
·
JK-05 is
developed by the Chinese company Sihuan Pharmaceutical along with the Chinese
Academy of Military Medical Sciences. It is reportedly being fast tracked
through human trials for Ebola treatment after successful tests in mice.[194][195]
·
Lack of available treatment options has spurred research into a
number of other possible antivirals targeted against Ebola,[196][197] including natural products such asscytovirin and griffithsin,[198][199] as well as synthetic drugs including DZNep,[200] FGI-103, FGI-104, FGI-106, dUY11
and LJ-001,[201] and other newer agents.[202][203][204][205][206][207][208]
Antisense technology
Other promising treatments rely
on antisense
technology. Both small interfering RNAs (siRNAs) and phosphorodiamidate
morpholino oligomers (PMOs)
targeting EBOV RNA
polymerase L
protein may prevent disease in nonhuman primates.[209][210] TKM-Ebola is a small interfering RNA compound,
currently being tested in a Phase I clinical trial in humans.[211][212] Sarepta Therapeutics has completed a Phase I clinical trial with
its PMO protecting up to 80-100 percent of the nonhuman primates tested.[213]
Antibodies
ZMapp is a monoclonal antibody vaccine.
The limited supply of the drug has been used to treat a small number of
individuals infected with the Ebola virus. Although some individuals have
recovered, the outcome is not considered statistically significant.[214] ZMapp has proved effective in a trial
involving rhesus macaque monkeys.[211][215][216] TheBill & Melinda Gates
Foundation has
donated $150,000 to help Amgen increase its production, and the U.S. Department of Health and
Human Services has
asked a number of centers to also increase production.[217] There was no confirmation or proof that the
ZMapp drug was a factor in the recovery of two American Ebola patients,
however;[218] a Spanish priest with Ebola had taken ZMapp
but died afterward.[219]
Researchers in Thailand claim to have developed an antibody-based
treatment for Ebola using synthesized fragments of the virus. It has not been
tested against Ebola itself. Scientists from the WHO and NIH have offered to
test the treatment against live Ebola virus, but there is still a great deal of
development needed before human trials.[220]
Other
Two selective estrogen receptor
modulators usually
used to treat infertility and breast cancer (clomiphene and toremifene) have
been found to inhibit the progress of Ebola virusin vitro as well as in infected mice. Ninety percent
of the mice treated with clomiphene and 50 percent of those treated with
toremifene survived the tests.[221] The study authors conclude that given their
oral availability and history of human use, these drugs would be candidates for
treating Ebola virus infection in remote geographical locations, either on
their own or together with other antiviral drugs.
A 2014 study found that three ion
channel blockers used in
the treatment of heart arrhythmias, amiodarone, dronedarone and verapamil, block
the entry of Ebola virus into cellsin vitro.[222]
Blood products
===============
The WHO has stated that transfusion
of whole blood or purified serum from
Ebola survivors is the therapy with the greatest potential to be implemented
immediately, although there is little information as to its efficacy.[223] In September 2014, WHO issued an interim
guideline for this therapy.[224] The blood
serum from
those who have survived an infection is currently being studied to see if it is
an effective treatment.[225] During a meeting arranged by WHO, this
research was deemed to be a top priority.[225] Seven of eight people with Ebola survived
after receiving a transfusion of blood donated by individuals who had
previously survived the infection in an 1999 outbreak in the Democratic
Republic of the Congo.[98][226] This treatment, however, was started late
in the disease meaning they may have already been recovering on their own and
the rest of their care was better than usual.[98] Thus this potential treatment remains
controversial.[18] Intravenous antibodies appear to be protective in nonhuman
primates who have been exposed to large doses of Ebola.[227] The WHO has approved the use of
convalescent serum and whole blood products to treat people with Ebola.[228]
Vaccine
=========
Many Ebola vaccine candidates had been developed in the decade
prior to 2014,[229] but as of October 2014, none had yet been
approved by the United States Food and Drug Administration (FDA) for clinical use in humans.[225][230][231] Several promising vaccine candidates have
been shown to protect nonhuman primates (usually macaques) against lethal
infection.[20][232] These include replication-deficient adenovirus vectors, replication-competent vesicular stomatitis (VSV) and human parainfluenza (HPIV-3) vectors, and virus-like particle
preparations. Conventional trials to study efficacy by exposure of humans to
the pathogen after immunization are obviously not feasible in this case. For
such situations, the FDA has established the “animal rule” allowing licensure
to be approved on the basis of animal model studies that replicate human
disease, combined with evidence of safety and a potentially potent immune
response (antibodies in the blood) from humans given the vaccine. Phase I
clinical trials involve the administration of the vaccine to healthy human
subjects to evaluate the immune response, identify any side effects and
determine the appropriate dosage.
In September 2014, two Phase I
clinical trials began for the vaccine cAd3-EBO
Z, which is based on an attenuated version of a chimpanzee adenovirus (cAd3) that has been genetically altered so
that it is unable to replicate in humans.[233] It was developed by NIAID in
collaboration with Okairos, now a division of GlaxoSmithKline. For
the trial designated VRC 20, 20 volunteers were recruited by the NIAID in Bethesda,
Maryland, while three dose-specific groups of 20 volunteers each were recruited
for trial EBL01 by University of Oxford, U.K.
A replication-competent vaccine
based on the vesicular stomatitis virus, called VSV-EBOV, was
developed by the Canadian National Microbiology
Laboratory and
licensed to the small company NewLink Genetics. With the strong support of the
U.S. Defense Threat Reduction
Agency, it started Phase I clinical trials on healthy human subjects
on 13 October 2014 at the Walter Reed Army Institute of Research in Silver
Spring, Md.[234][235][236] Also in October 2014, the U.S. National
Institute of Allergy and Infectious Diseases(NIAID) was recruiting
healthy human volunteers for a "Phase 1 Randomized, Double-Blind, Placebo
Controlled, Dose-Escalation Study to Evaluate the Safety and Immunogenicity of
Prime-Boost VSV Ebola Vaccine in Healthy Adults".[237] On 20 October, the Public Health Agency of
Canada began air shipment of 800 doses of the VSV-EBOV vaccine to the WHO in Geneva.[238] This vaccine is intended to be used in
Phase I clinical trials, to start in late October or early November. The WHO
has recruited 250 volunteers ready to begin Phase I clinical trials in four
locations: Switzerland, Germany, Gabon and Kenya. If the results of this and
following trials show that the earlier results in nonhuman primates are
replicable in humans, this vaccine could be deployed in areas such as West
Africa and would be expected to require only a single dose. Also, its efficacy
in protecting nonhuman primates when administered even after viral exposure has
occurred may help protect health-care workers after a suspected exposure.
The Health Ministry of Russia also
claims to have developed a vaccine called Triazoverin, which is said to be
effective against both Ebola and Marburg filoviruses, and
might be available for clinical trials in West Africa as soon as the start of
2015.[239][240][241]
At the 8th Vaccine and ISV Conference in Philadelphia on 27−28 October
2014, Novavax Inc. reported the
development in a "few weeks" of a glycoprotein (GP) nanoparticleEbola virus (EBOV GP)
vaccine using their proprietary recombinant technology.[242] A recombinant protein is a
protein whose code is carried by recombinant DNA. The vaccine is based on
the newly published genetic sequence[243] of the 2014 Guinea Ebola strain that is responsible for the current Ebola disease epidemic in
West Africa. In "preclinical models", a useful immune response was
induced, and was found to be enhanced ten to a hundred-fold by the company's
"Matrix-M" immunologic adjuvant. A study of the response of non-human primate to the vaccine had been
initiated. Attractive features of such a vaccine could be no need for frozen
storage, and the possibility of rapid scaling to manufacture of large dose
quantities.
