I spoke with virologist Ian Goodfellow, whose laboratory works on noroviruses, about why he went to Sierra Leone to establish an Ebolavirus diagnostic and sequencing laboratory. The obstacles he encountered were considerable, but the results were very useful. Recorded at the Emerging Infectious Diseases A to Z (EIDA2Z) conference hosted by the National Emerging Infectious Diseases Laboratories (NEIDL).
On episode #370 of the science show This Week in Virology, the TWiVomics review ten captivating virology stories from 2015.
You can find TWiV #370 at www.microbe.tv/twiv.
An Ebolavirus vaccine has shown promising results in a clinical trial in Guinea. This vaccine has been in development since 2004 and was made possible by advances in basic virology of the past 40 years.
The ability to produce the Ebolavirus vaccine, called rVSV-EBOV, originates in the 1970s with the discovery of the enzyme reverse transcriptase, the development of recombinant DNA technology, and the ability to rapidly and accurately determine the sequence of nucleic acids. These advances came together in 1981 when it was shown that cloned DNA copies of RNA viral genomes (a bacteriophage, a retrovirus, and poliovirus), carried in a bacterial plasmid, were infectious when introduced into mammalian cells. Production of an infectious DNA copy of the genome of vesicular stomatitis virus (VSV) was reported in 1995. In their paper the authors noted:
Because VSV can be grown to very high titers and in large quantities with relative ease, it may be possible to genetically engineer recombinant VSVs displaying foreign antigens. Such modified viruses could be useful as vaccines conferring protection against other viruses.
This technology was subsequently used in 2004 to produce replication competent VSV carrying the genes encoding the glycoproteins of filoviruses, which others had shown are the targets of neutralizing antibodies. When injected into mice, these recombinant viruses induced neutralizing antibodies that were protective against lethal disease after challenge with Ebolavirus.
In a series of experiments done over the next 10 years, rVSV-EBOV was shown to protect nonhuman primates from lethal disease. In these experiments, animals were injected intramuscularly with the vaccine and challenged with Ebolavirus. The vaccine induced protection against lethal disease and prevented viremia. Extensive studies of the VSV vector in ~80 nonhuman primates showed no serious side effects, and only transient vector viremia.
The rVSV-EBOV was originally developed by Public Health Agency of Canada, and subsequently licensed to NewLink Genetics. Financial support has been provided from Canadian and US governments and others. From 2005 to the present, the NIH Rocky Mountain Laboratory in Hamilton, Montana has also been involved in this work, particularly with nohuman primate challenge studies. In November 2014 Merck entered an agreement with NewLink to manufacture and distribute the vaccine.
In August 2014, well into West Africa Ebolavirus outbreak, Canada donated 800 vials of vaccine to WHO, which then established the VSV Ebola Consortium (VEBCON) to conduct human trials.
The results of Phase I trials of rVSV-EBOV in Africa (Gabon, Kenya) and Europe (Hamburg, Geneva) were published on 1 April 2015. These trials comprised three open-label, dose-escalation trials, and one randomized, double blind controlled trial in 158 adults. Each volunteer was given one injection of 300,000 to 50 million plaque-forming units of rVSV-EBOV or placebo. No serious vaccine related events were reported, but immunization was accompanied by fever, joint pain, and some vesicular dermatitis. A transient systemic infection was observed, followed by development of Ebolavirus-specific antibody responses in all participants, and neutralizing antibodies in most.
The interim results of a phase III trial of rVSV-EBOV, begun on 23 March 2015 in Guinea, have just been published. It is a cluster-randomized trial with a novel design that is modeled on the ring vaccination approach used for smallpox eradication in the 1970s. In ring vaccination, individuals in the area of an outbreak are immunized, in contrast to treating a larger segment of the population. During this trial, when a case of Ebolavirus infection was identified, all contacts and contacts-of-contacts were identified. Some of these individuals were immediately immunized intramuscularly with 2 x 107 PFU, and others (randomly chosen) were immunized three weeks later. The primary outcome was Ebolavirus disease confirmed by PCR. As new cases arose in other areas (clusters), these were treated in the same way, hence the name of cluster-randomized trial.
The press has widely reported that the vaccine was ‘100% protective’. This outcome sounds much better than is represented by the data, so let’s look at the numbers.
Zero cases of Ebolavirus disease were observed in 2,014 immediately vaccinated people, while 16 cases were identified in those given delayed vaccine (n=2,380). These numbers were used to calculate the vaccine efficacy of 100%. While statistically significant, the numbers are small.
More telling are the results obtained when we consider all individuals eligible for immunization, not just those who were immunized (some were excluded for a variety of reasons). Of 4,123 eligible individuals, 2,014 were immunized as noted above, but 2,109 did not receive vaccine. Eight cases of Ebola virus disease were noted in the non-immunized population. This number is small, a consequence of the fact that the outbreak is waning.
On the basis of these interim results, the data and safety monitoring board decided that the trial should continue. However because the board felt that the vaccine is a success, they decided to curtail randomization of subjects into immediately vaccinated and delayed vaccinated groups. Now all contacts and contacts-of-contacts will immediately receive vaccine. As a consequence of this change, it will not be possible to improve the accuracy of vaccine efficacy. For example, when many more individuals are immunized in the future, many fewer that 100% might be protected from disease.
There are two lessons I would like you to remember from this brief history of an Ebolavirus vaccine. Developing a vaccine takes a long time (minimum 11 years for rVSV-EBOV) and depends on advances made with both basic and clinical research. Don’t believe anyone who says that this vaccine was made in a year. And always look at the numbers when you hear that a vaccine has 100% efficacy.
The thousands of survivors of the Ebolavirus outbreak in western Africa – more than at any other time – are fortunate to have survived the disease. However, their health problems are not behind them. A new study shows that the survivors of Ebolavirus have long-term sequelae more than 2 years after infection.
Acute infections caused by viruses such as Ebolavirus are characterized by rapid production of infectious virus particles, followed by resolution and elimination of infection by the host. However, chronic symptoms may persist for a long time after the infection is cleared. There have been long-term health consequences identified in survivors of previous Ebolavirus outbreaks. These include joint and muscle pain, vision and hearing loss, abdominal pain, bleeding, malaise, and psychological problems. Some patients were unable to perform their previous jobs for up to one year.
The long term health consequences of infection was studied in detail for the 2007 outbreak of Bundibugyo ebolavirus in Uganda. Survivors (49) were contacted 29 months after the outbreak and provided information about health status and their ability to function, and blood samples were obtained for further study. Controls for the study were seronegative contacts.
The results show that survivors of Bundibugyo ebolavirus infection are at significantly greater risk than controls for long term health problems. These include ocular problems (pain, blurred vision), loss of hearing, sleep difficulty, and joint pain. Other issues are abdominal and back pain, fatigue, impotence, severe headaches, memory problems and confusion. No differences in results of blood analyses were observed between the two groups. This study only included adults; children who have recovered should also be examined as their health care needs may be different.
These results confirm that there are long-term sequelae of Ebolavirus infection. The basis for the complications is not known, but is likely a consequence of tissue damage due to viral replication and the immune response. Whether or not virus was present in the patients was not determined. However it is known that Ebolavirus can persist in the testicles and eye long after it is absent from serum.
Other serious viral infections are also accompanied by long term health effects. For example, 29% of Lassa virus survivors have hearing loss, while joint pain persists for 3-5 years in about 10% of those infected with chikungunya virus.
Ebolavirus is a highly lethal virus, and those who survive infection are fortunate. Despite recovering, their health problems are not over. The size of the recent outbreak provided impetus for clinical trials of vaccines and antivirals; now research is needed to determine how to best care for the many survivors.
Update: The NIH has announced a study in Liberia to examine the long-term consequences of Ebolavirus infection.
An otherwise balanced review of selected aspects of Ebolavirus transmission falls apart when the authors hypothesize that ‘Ebola viruses have the potential to be respiratory pathogens with primary respiratory spread.’
The idea that Ebolavirus might become transmitted by the respiratory route was suggested last year by Michael Osterholm in a Times OpEd. That idea was widely criticized by many virologists, including this writer. Now he has recruited 20 other authors, including Ebola virologists, in an attempt to lend legitimacy to his hypothesis. Unfortunately the new article adds no new evidence to support this view.
In the last section of the review article the authors admit that they have no evidence for respiratory transmission of Ebolavirus:
It is very likely that at least some degree of Ebola virus transmission currently occurs via infectious aerosols generated from the gastrointestinal tract, the respiratory tract, or medical procedures, although this has been difficult to definitively demonstrate or rule out, since those exposed to infectious aerosols also are most likely to be in close proximity to and in direct contact with an infected case.
It is possible that some short-distance transmission of Ebolavirus occurs through the air. But claiming that it is ‘very likely’ to be taking place is an overstatement considering the lack of evidence. As might be expected, ‘very likely’ is exactly the phrase picked up by the Washington Post.
I find the lack of critical thinking in the following paragraph even more disturbing:
To date, investigators have not identified respiratory spread (either via large droplets or small-particle aerosols) of Ebola viruses among humans. This could be because such transmission does not occur or because such transmission has not been recognized, since the number of studies that have carefully examined transmission patterns is small. Despite the lack of supportive epidemiological data, a key additional question to ask is whether primary pulmonary infections and respiratory transmission of Ebola viruses could be a potential scenario for the future.
Why is the possibility of respiratory transmission of Ebolaviruses a ‘key additional question’ when there has been no evidence for it to date? To make matters worse, the authors have now moved from short-range transmission of the virus by droplets, to full-blown respiratory aerosol transmission.
The authors present a list of reasons why they think Ebolavirus could go airborne, including: isolation of Ebolaviruses from saliva; presence of viral particles in pulmonary alveoli on human autopsies; and cough, which can generate aerosols, can be a symptom of Ebolavirus disease. The authors conclude that because of these properties, the virus would not have to change very much to be transmitted by aerosols.
I would conclude the opposite from this list of what Ebolavirus can do: there is clearly a substantial block to respiratory transmission that the virus cannot overcome. Perhaps the virus is not stable enough in respiratory aerosols, or there are not enough infectious viruses in aerosols to transmit infection from human to human. Overcoming these blocks might simply not be biologically possible for Ebolavirus. A thoughtful discussion of these issues is glaringly absent in the review.
The conclusion that Ebolavirus is ‘close’ to becoming a full-blown respiratory pathogen reveals how little we understand about the genetic requirements for virus transmission. In fact the authors cannot have any idea how ‘close’ Ebolavirus is to spreading long distances through the air.
It is always difficult to predict what viruses will or will not do. Instead, virologists observe what viruses have done in the past, and use that information to guide their thinking. If we ask the simple question, has any human virus ever changed its mode of transmission, the answer is no. We have been studying viruses for over 100 years, and we’ve never seen a human virus change the way it is transmitted. There is no evidence to believe that Ebolavirus is any different.
Viruses are masters of evolution, but apparently one item lacking from their repertoire is the ability to change the way that they are transmitted.
Such unfounded speculation would largely be ignored if the paper were read only by microbiologists. But Ebolavirus is always news and even speculation does not go unnoticed. The Washington Post seems to think that this review article is a big deal. Here is their headline: Limited airborne transmission of Ebola is ‘very likely’ new analysis says.
Gary Kobinger, one of the authors, told the Washington Post that ‘we hope that this review will stimulate interest and motivate more support and more scientists to join in and help address gaps in our knowledge on transmission of Ebola’. Such hope is unrealistic, because few can work on this virus, which requires the highest levels of biological containment, a BSL-4 laboratory.
I wonder if Osterholm endorses Kobinger’s hopes. After all, he opposed studies of influenza virus transmission in ferrets, claiming that they are too dangerous. And the current moratorium on research that would help us understand aerosol transmission of influenza viruses is a direct result of objections by Osterholm and his colleagues about this type of work. The genetic experiments that are clearly needed to understand the limitations of Ebolavirus transmission would never be permitted, at least not with United States research dollars.
The gaps in our understanding of virus transmission are considerable. If virologists are not able to carry out the necessary experiments to fill these gaps, all we will have is rampant and unproductive speculation.
On episode #312 of the science show This Week in Virology, the TWiVbolans discuss the finding that human noroviruses, major causes of gastroenteritis, can for the first time be propagated in B cell cultures, with the help of enteric bacteria.
You can find TWiV #312 at www.microbe.tv/twiv.
This morning I received this email from President Lee Bollinger:
Dear fellow members of the Columbia community:
As you may have seen in the media, Dr. Craig Spencer is being treated for Ebola at Bellevue Hospital in Manhattan. Dr. Spencer, an emergency department physician at NewYork-Presbyterian/Columbia University Medical Center, recently returned from a humanitarian mission with Doctors Without Borders to one of the outbreak areas in Western Africa. We admire and appreciate all of those willing to do this vital and selfless public health work around the globe.
It’s critical to bear in mind what our public health and infectious disease experts have emphasized – that the risk to people in New York City and at Columbia remains extremely low. If you or anyone has any concerns, please visit the University’s Ebola Preparedness site or the New York City Department of Health Ebola update page. You may also contact Student Health Services or Workforce Health and Safety for Faculty/Staff with Hospital Responsibilities.
We must keep Dr. Spencer in our thoughts and wish him a full and speedy recovery, as we do the vulnerable populations he serves. We will also continue to keep the Columbia community informed as we learn more from City, State, and Federal health officials.
Lee C. Bollinger
The transition between incubation period (when there are no symptoms) and the first clinical signs is a dangerous period. During this time the patient may continue to move around in public despite having fever and other indications of infection. It will be important to trace as many of this physician’s contacts as possible, a difficult task in a city of over 8 million people. Apparently the physician traveled around the city, using the subways, the night before having a fever. Whether any virus is shed during this time, in amounts sufficient to infect others, is unknown, but could be determined by studying the contacts of such infected individuals.
On episode #307 of the science show This Week in Virology, Tara Smith joins the TWiEBOVsters to discuss the Ebola virus outbreak in west Africa, spread of the disease to and within the US, transmission of the virus, and much more.
You can find TWiV #307 at www.microbe.tv/twiv.
On episode #306 of the science show This Week in Virology, the Grand Masters of the TWiV discuss Ebola virus transmission, air travel from West Africa, Ebola virus infectivity on surfaces, the Dallas Ebola virus patient, and Ebola virus in dogs.
You can find TWiV #306 at www.microbe.tv/twiv.
On episode #303 of the science show This Week in Virology, the TWiV team discusses transmission of Ebola virus, and inhibition of Borna disease virus replication by viral DNA in the ground squirrel genome.
You can find TWiV #303 at www.microbe.tv/twiv.