Wednesday, May 23, 2018

EID Journal: Reemergence of Reston Ebolavirus in Cynomolgus Monkeys, the Philippines, 2015


Long time readers with good memories will recall in September of 2015, in Ebola Reston Discovered In Philippine Lab Monkeys, we looked at the  announcement of the discovery of Ebola Reston among laboratory monkeys being kept at an unnamed research laboratory in the Philippines.
Ebola Reston is one of five known Ebola virus species, and the only one found to be endemic outside of Africa.
Unlike its African cousins, Ebola Reston – while capable of infecting humans – is not known to produce illness or death in man.  It can, however, produce serious illness in non-human primates, and can infect pigs (generally asymptomatically).
Ebola Reston was first discovered in crab-eating macaques - imported from the Philippines - at a research laboratory in Reston, Virginia (USA) (hence the name) in 1989. This discovery was recounted somewhat sensationally in the book, The Hot Zone, by Richard Preston.
In the October 2014 CDC Review of Human-to-Human Transmission of Ebola Virus described the 1989 Reston laboratory outbreak and subsequent infection of personnel. 
Similarly, an outbreak of Reston virus (Reston ebolavirus species, which does not cause EVD in humans) infection occurred in a quarantine facility housing non-human primates in separate cages and the transmission route could not be confirmed for all infected primates.
Multiple animal handlers developed antibody responses to Reston virus suggesting asymptomatic infection was occurring in humans with direct animal contact and implicating animal handling practices in transmission between primates
Somewhat famously, in late 2008 Ebola Reston made another high profile appearance when it was reported for the first time in pigs, again from the Philippines.  This from the FAO.
First detection of Ebola-Reston virus in pigs

FAO/OIE/WHO offer assistance to the Philippines

Manila/Roma, 23 December 2008 - Following the detection of the Ebola-Reston virus in pigs in the Philippines, FAO, the World Organization for Animal Health (OIE) and the World Health Organization (WHO) announced today that the government of the Philippines has requested the three agencies send an expert mission to work with human and animal health experts in the Philippines to further investigate the situation.
An increase in pig mortality on swine farms in the provinces of Nueva Ecija and Bulacan in 2007 and 2008 prompted the Government of the Philippines to initiate laboratory investigations. Samples taken from ill pigs in May, June and September 2008 were sent to international reference laboratories which confirmed in late October that the pigs were infected with a highly virulent strain of Porcine reproductive and respiratory syndrome (PRRS) as well as the Ebola-Reston virus.

(Continue . . .)

Roughly a month later, we learned that several farm workers in contact with infected pigs tested positive for antibodies to the Ebola-Reston virus.  None displayed any signs of illness (see Ebola Reston in pigs and humans in the Philippines).

While not currently viewed as a human health threat, the World Health Organization hedges its bets slightly with Ebola Reston by stating:
Among workers in contact with monkeys or pigs infected with Reston ebolavirus, several infections have been documented in people who were clinically asymptomatic. Thus, RESTV appears less capable of causing disease in humans than other Ebola species.
However, the only available evidence available comes from healthy adult males. It would be premature to extrapolate the health effects of the virus to all population groups, such as immuno-compromised persons, persons with underlying medical conditions, pregnant women and children. More studies of RESTV are needed before definitive conclusions can be drawn about the pathogenicity and virulence of this virus in humans.
Two years ago (March 2016) we took another look at this Ebola outlier (see I'm Not Dying, I'm Just Reston) after a study was published in Nature Scientific Reports that found relatively few differences between Ebola Reston and the deadlier strains.
By focusing on a few key areas of the virus that are believed to affect its virulence in a human host, the authors concluded that only a few changes in one Ebola virus protein (VP24) might be needed to turn Ebola Reston into a virus that can cause human disease.
Although somewhat speculative, this study does remind us that viruses can change behavior over time, and that just because Ebola Reston doesn't appear to produce disease in humans today, that doesn't guarantee how it will behave tomorrow.

All of which serves as prelude to a new study, published this week in the CDC's EID Journal, which provides us with details on the 2015 Ebola Reston outbreak and subsequent investigation at the Primate lab in the Philippines.

Volume 24, Number 7—July 2018

Reemergence of Reston ebolavirus in Cynomolgus Monkeys, the Philippines, 2015
Catalino Demetria, Ina Smith, Titus Tan, Daniel Villarico, Edson Michael Simon, Rex Centeno, Mary Tachedjian, Satoshi Taniguchi, Masayuki Shimojima, Noel Lee J. Miranda, Mary Elizabeth Miranda, Melissa Marie R. Rondina, Rowena Capistrano, Amado Tandoc, Glenn Marsh, Debbie Eagles, Ramses Cruz, and Shuetsu Fukushi

In August 2015, a nonhuman primate facility south of Manila, the Philippines, noted unusual deaths of 6 cynomolgus monkeys (Macaca fascicularis), characterized by generalized rashes, inappetence, or sudden death. We identified Reston ebolavirus* (RESTV) infection in monkeys by using serologic and molecular assays.
We isolated viruses in tissues from infected monkeys and determined viral genome sequences. RESTV found in the 2015 outbreak is genetically closer to 1 of the 4 RESTVs that caused the 2008 outbreak among swine. Eight macaques, including 2 also infected with RESTV, tested positive for measles. Concurrently, the measles virus was circulating throughout the Philippines, indicating that the infection of the macaques may be a reverse zoonosis. Improved biosecurity measures will minimize the public health risk, as well as limit the introduction of disease and vectors.


In 2015, 19 years after the last known epizootic occurrence of RESTV in macaques in the Philippines, we detected and confirmed the incidence of RESTV in macaques in a primate facility south of Manila, by serologic and molecular testing. In spite of the long hiatus, RESTV was found in a controlled environment in which monkeys are systematically housed to avoid spread of diseases and to which no wild monkeys have been introduced. Personnel in the facility had no evidence of infection because no RESTV antibodies were detected.

We observed rats in cages in the primate facility that housed the primates being tested, indicating the potential for small animals to gain access to the facility. A recent study identified the microbat Miniopterus schreibersii as a possible reservoir of RESTV (6); therefore, this bat species and similar ones of this size may be the source of infection in the quarantine facility. If this is the case, improved biosecurity measures are warranted to limit the introduction of disease. However, we do not claim the bat species as the direct source of infection in 2015 outbreak. Because the facility building has its own anteroom with welded wire window screens, there is little likelihood that bats entered the facility.

Dual infections of RESTV and simian hemorrhagic fever virus (SHFV) in cynomologus monkeys has been reported in a facility in Reston, Virginia, and SHFV is the suspected causal agent for mortality in monkeys (17). Dual infections of RESTV and PRRSV in swine have been identified in the Philippines (5) and in Shanghai, China (18). In these cases, all of the RESTV-positive swine were coinfected with PRRSV. In contrast, we found in this study that 1 (ID: DrpZ1–26D-B) of the 10 macaques positive for RESTV antibody was also positive for MV antibody. Furthermore, another macaque (ID: DrpZ2–10B-G) was confirmed to have dual infection of RESTV and MV by using PCR. The results show similarities with dual infections such as SHFV and RESTV in macaques (17), or RESTV and PRRSV infections in swine (5). However, MV was not detected among most macaques positive for RESTV that died from the disease. Also, it remains unclear whether the MV infection supports an increase in RESTV replication in macaques. We found that 8 macaques had antibodies against MV, and 1 was MV PCR positive. Considering the risk for human-to-primate transmission (19,20), there is a possibility that MV infection in macaques is associated with human MV outbreak in the Philippines, although further studies are required to identify the mode of transmission of MV infection in macaques.

The RESTV sequences obtained were most similar to Reston-08-E from the Philippines 2008 outbreak in swine (5) (Figure 1). There were 3 nucleotide variations between the viral isolates that were sequenced, 2 of which in isolate DrpZ5–2B-F resulted in nonconservative changes in the NP and VP24 proteins that were unique when compared to all of the RESTV isolates sequenced. 

Because of the similarity with other Ebola viruses and the virus’ ability to infect humans, there is a concern that RESTV could mutate during passage through animals like macaques and cause an epidemic of disease in humans. Because it could mutate to pose health consequences for humans, continued surveillance is required to reduce the risk of transmitting Reston Ebola virus. 

Dr. Demetria is the head of the Rabies and Special Pathogens Laboratory at the Research Institute for Tropical Medicine in The Philippines. He has a strong interest in emerging zoonotic infectious diseases.
Ebola viruses, the Marburg Virus, Nipah, MERS, and a long list of other pathogens are carried by bats, making their study increasingly important in the world of virology and epidemiology.

A list of some recent bat-related blogs include:

Indian Government Responds To Reported Nipah Outbreak In Kerala

Back To The Bat Cave: More Influenza In Bats

EID Journal: A New Bat-HKU2–like Coronavirus in Swine, China, 2017

Emerg. Microbes & Infect.: Novel Coronaviruses In Least Horseshoe Bats In Southwestern China

SARS-like WIV1-CoV poised for human emergence

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