# The Zimmermann Affair: a worthless victory

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Sometimes, I tend to say that every time a quack loses their license, a hungry kitten gets a bowl of milk. So I could say I’m doing it all for the kittens, but in reality, I like seeing quacks struck off for far more prosaic reasons. Deep down, I do believe that there is a public law duty incumbent on professional bodies – even where the ‘profession’ they regulate is of  a professionality as dubious as naturopathic ‘medicine’ – to maintain certain key standards within their regulated practitioners. But this is also a story about the insufficiency of self-regulation, and what can go wrong with it – the pitfalls inherent in the idea that the profession will regulate itself, and keep dangerous actors out of the sphere of public practice. It is the story of a case where the system worked well, and yet remains insufficient to protect the public, raising serious questions as to whether regulation of health professions should indeed be delegated to secondary bodies, whose ultima ratio is to expel a member, but who are powerless once the quack in question perpetrates their quackery outside their aegis. I present you… the Zimmermann affair.

A few months ago, you might have heard of a Canadian naturopath, Ms Anke Zimmermann,1 published a rather interesting little article on her blog, recounting a story of a 4-year-old with behavioural problems whom she claimed to have cured with… behavioural therapy? Paroxetine? Psychotherapy? DBT? Benzos? Nope. Those are all bad, evil Big Pharma products. Nope, she went for a state-of-art treatment (about 250 years old) called lyssinum. Which is exactly what you think it is: the saliva of a rabid dog.

When the inimitable 6E23, everyone’s best resource on just how delusional homeopaths are, has reposted it, I was genuinely convinced that this must be a troll.

At this point, I saw two scenarios. Either Ms Zimmermann was administering a placebo that did not contain what it claimed to have contained (that is, she was bullshitting her marks2), or, worse, she was administering an extremely harmful pathogen to a child, before even giving the proper medical subspeciality (child behavioural psychology) a chance.3 If it was the latter, something very bad was going on.

You see, rabies is one of the worst diseases in existence. Personally, I’d rather have Ebola haemorrhagic fever than symptomatic rabies, having seen both. There are all of six known cases of survival of symptomatic rabies, using the controversial and largely hit-and-miss Milwaukee Protocol. It’s not to be trifled with. It’s also a controlled biological agent. I do suppose I don’t need to point out that administering it to anyone, least of all a child, is not so much bad medicine as pure, blank insanity.

Giving her the benefit of the doubt, I asked Ms Zimmermann some straightforward questions – namely, is she lying or is she insane? Obviously, something better than the ‘memory of water’ was expected here. Alas, it was not forthcoming – insults, on the other hand, were.

## The law

In British Columbia, the locus delicti (where the act has taken place), ‘naturopathic physicians’ (“naturopaths“, because I’m loath to dignify them with the title ‘physician’), practice under the statutory instrument B.C. Reg. 282/2008 (the “Regulation“), made under the authority delegated by the Health Professions Act 1996, R.S.B.C. 1996 c. 183 (the “Act”). Part II of the Act defines regulated health practitioners, including ‘naturopaths’, their discipline and registration being subject to the Regulation. The Regulation further appoints the College of Naturopathic Physicians of B.C. (the “College“) as the responsible regulatory authority for naturopaths, although you might be forgiven for finding ‘responsible’, ‘regulatory’, ‘authority’ and ‘naturopaths’ in the same sentence more than a little oxymoronic. Even without the oxy-.

## The facts

On 17 April 2018, I lodged a formal complaint with the Registrar of the College. In it, I recited the pertinent facts. These bear repeating here.

Facts: Chronology of events
3. The Practitioner owns, among others, the domain drzimmerman.org (the “Website”) and the Twitter account @drzimmermann as well as the Facebook profile at @doctorzimmermann.
4. On 08 February 2018, the Practitioner posted on the Website, under the section “Successful Cases”, a case report titled “A Child with Aggression and Behavioural Problems” (the “Case Report”). The Case Report was available, at the time of this Statement, under the URL https://www.drzimmermann.org/successful-clinical-cases/a-child-with-aggression-and-behavioural-problems. It is also exhibited as Exhibit 1 to this e-mail.
5. In the Case Report, the Practitioner describes, in her words,
“A 4-year-old boy with sleep and behavioural problems, including aggression and violence towards school mates, hiding under tables and growling, improves nicely with a homeopathic remedy made from the saliva of a rabid dog, Lyssinum.”
6. The Case Report concerns a “nearly 5-year-old” boy named Jonah (the “Patient”). Jonah was, according to the Case Report, brought into the Practitioner’s care on 06 October 2018 with complaints of “sleep and behavioural problems”. Patient exhibited, according to the Case Report, “an inability to fall asleep at night, a fear of the dark, of wolves, werewolves, ghosts and zombies … [t]here is a history of a dog bit [sic] which drew blood.”
7. The Practitioner states that she “decided to give a homeopathic remedy made from rabies”. This is based on the theory that the “The dog who bit him may have recently been vaccinated with the rabies vaccine or the dog bite in and of itself may have affected the boy with the rabies miasm”.
8. The Practitioner describes the administration of Lyssinum 200CH, 2 pellets, and at a follow-up meeting, a “dose” (unspecified quantity) of Lyssinum 10M. The Case Report does not discuss a referral to an appropriate secondary referral service, such as a child psychotherapist, developmental psychotherapist or a psychiatrist experienced in early life affective and social integration disorders.
Facts: Rabies, “rabies miasm” and Lyssinum
9. Rabies is an infection of the central nervous system caused by the rabies virus (RABV) and, in rare cases, the Australian Bat Lyssavirus (ABLV). Rabies is a typical zoonotic virus that can exist in some animals without symptom, but is characteristically symptomatic – and almost always fatal – in canids and primates, including humans. RABV and ABLV are genetically related, and constitute part of the genus Lyssavirus, a genus of the family Rhabdoviridae, of which RABV is the type species. They belong to Group V (negative-sense single-strand RNA) of the Baltimore classification of viruses.
10. Rabies in the human is transmitted typically by bite, specifically by transfer of the virus through the saliva of an infected animal, with dogs being frequent carriers throughout the world, except in the Americas, where widespread vaccination of pets and strays has led to a vastly reduced prevalence of RABV in canines, with most cases caused by chiropteran (bat) bites. Rabies causes over 17,000 deaths per annum.
11. In humans, rabies has a widely varying incubation period, ranging from several days to up to six years, but typically around two to three months. During this period, rabies cannot be detected, as the virus is safely ensconced in nerve tissue. Post-exposure prophylaxis (rabies immunoglobulin and/or the rabies vaccine) is usually highly successful and not connected to severe side effects.
12. Symptomatic rabies initially manifests as non-specific viral symptoms, including headaches and fever. It eventually evolves rapidly to a meningoencephalitis or encephalitis, with the clinical course mirroring this as focal neurological deficits, anxiety, agitation, altered mental state and hallucinations as well as the characteristic aversion to water (hydrophobia). This is inevitably followed by delirium, coma and demise of the infected person, within 2-10 days after symptoms have first presented. A low number of patients (six, to be specific) have survived owing to a treatment developed by Rodney Willoughby, Jr. M.D. (the Wisconsin Protocol), in which a coma is induced using midazolam and ketamine and high-dose antivirals – ribavirin and amantadine – are administered. The overall survival rate of this treatment is, according to an ITT analysis, approximately 8%, and many patients survive with moderate to severe neurological sequelae. The above ought to recapitulate the seriousness of what is a fortunately only rarely seen infectious disease in the Western Hemisphere.
13. Rabies is not particularly infectious, but it is categorized as a BSL-2 agent. It is not a Select Agent but subject to export restrictions. Most health authorities recommend BSL-3 treatment.
14. The concept of rabies miasm is not known to any branch of science. It is not an acknowledged medical phenomenon. It is not an acknowledged biological phenomenon. It has no acceptable biological explanation that is in line with the current state of science.
15. The rabies prophylactic vaccine is an inactivated (killed) viral vaccine. Upon injection subcutaneously, it disperses in the subject’s bloodstream, stimulating the creation of antibodies. Neither antibodies nor the inactivated RABV antigen are present in any appreciable number in an animal’s saliva after vaccination. Nor are either RABV antigen or anti-RABV immunoglobulin associated with behavioural-cognitive symptoms that are in line with those reported in the Case Report for the Patient. The Practitioner’s theory that the history of dog bite may have caused his behavioural issues is unsupported by any clinical evidence or feasible scientific mechanism. It is also not an acknowledged medical phenomenon. It is not an acknowledged biological phenomenon.
16. Lyssinum, from the Greek lyssa ‘rage’ referring to rabies, also known as Hydrophobinum, referring to the characteristic symptom of hydrophobia in rabies, is described as a ‘nosode of rabies’ and is described as a trituration (solution of a water-insoluble substance in lactose in homeopathy) of the saliva of a rabid dog, according to the National Center for Homeopathy.
17. It is unclear whether Lyssinum contains any active viral particles. The dilutions described are 200CH and 10M. CH refers to centennial dilutions, in which the original substance, known as the “mother tincture” in homeopathy, is diluted to 1:100, and vigorously shaken. 200CH therefore amounts to 1:100^200, a vast number: there are approximately 10^80 atoms in the entire observable universe, therefore, a mere 40C dilution of a single small molecule would occupy the entire observable universe. In other words, it is unlikely that Lyssinum contains anything other than its excipients, and no active viral particles were present.
18. At the same time, the Practitioner claims that the vaccine was made “from the saliva of a rabid dog”. The probability may be infinitesimally small that any of the RABV in the original substance or “mother tincture”, if it ever existed, would remain in the substance, if we assume a uniform distribution of particles. But it cannot be conclusively excluded that this would not, in fact, be the case. For instance, it is improbable but not impossible for all the viral particles from the “mother tincture” to end up in a single, extremely infectious, granule. In that sense, the Practitioner is administering a high chance of an inert placebo or an extremely low but nonzero chance of a potentially fatal illness, to a 4-year-old with behavioural problems.
19. Practitioner’s responses to questions about her practice and her use of a substance that may potentially infect a patient with an incurable and virtually always fatal illness consisted of insults, the threat to use the scientific position – that her practice of using Lyssinum is either falsely stating that it is anything but lactose or otherwise it may carry a small but nonzero risk of an incurable and virtually always fatal illness – as proof of “ignorance” of homeopathy at a conference, as well as threats to report the Complainant to “the authorities” for “harrassment [sic]”.
20. It remains open what the Practitioner’s beliefs were as to the contents of the granules. If the practitioner believed that they were indeed made by sequential dilutions of a highly infectious substance, then she could not exclude with 100% certainty that she was not administering a pathogen causing an incurable and virtually always fatal illness. On the other hand, if she did not believe that the granules were created by sequential dilutions of a highly infectious substance, then she had no reason to make therapeutic or other claims, including the very claim that they were in fact made “from the saliva of a rabid dog”. These possibilities are mutually exclusive but jointly complementary.

On the same day, the College accepted jurisdiction in all five questions posed in my submission, namely:

21. Complainant hereby requests your consideration of the above outlined facts in order to determine whether
a. the use of Lyssinum was in compliance with the Practitioner’s duty towards the Patient,
b. the Practitioner has discharged her duty of care towards the Patient by treating him with a questionable remedy that has no scientific validity or evidence-based track record in treating aggression or childhood affective or social disorders instead of referring him to a more appropriate professional assessment,
c. the Practitioner has discharged her duty of care towards the Patient by the use of a homeopathic medicine ahead of excluding a possible psychiatric, psychological or neurological aetiology,
d. the Practitioner has endangered the Patient’s health by using a treatment that may potentially cause a lethal and untreatable infectious disease, or
e. the Practitioner has made claims about the origin of the treatment that are intended to present Lyssinum as having a therapeutic potential that is not warranted by suitable, clinically validated scientific evidence.

## Truth and consequences

On 27 November, I received a communication from the College, notifying me of a consent order between Ms Zimmermann and the College:

The Committee determined pursuant to section 33(6)(c) of the Act that this would be an appropriate case in which to seek a consent order in view of the Committee’s concerns of the Registrant’s professional conduct.The Registrant consented to the immediate cancellation of her registration with the College. She agreed not to apply for reinstatement or otherwise seek registration with the College for a minimum period of five (5) years from the date of the Consent Order. As such, the Registrant is not permitted to practice naturopathic medicine. The Registrant is further not permitted to use the reserved titles: “naturopath”, “naturopathic physician”, “naturopathic doctor”, “physician” or “doctor’.

As the Registrant’s Consent Order pertains to a “serious matter” as defined in the Act, it requires public notification. Accordingly, a notice regarding the cancellation of the Registrant’s registration has been placed on the College’s website, at www.cnpbc.bc.ca. Please note that the public notification does not contain any identifiable information about you. The Registrant’s Consent Order will be disclosed to the Inquiry Committee, the Discipline Committee and/or the Registration Committee in the event of any future proceedings following consideration by those committees of the merits of any future complaint or application.

The public notice is available here and the College’s Notice of Disposition is available to press and interested parties upon request. And ideally, the story were to be over here. But it’s not.

## Self-regulation and its insufficiency

What, then, is the outcome of l’affaire Zimmermann? It’s not merely a potentially dangerous and/or deluded homeopath who stood at trial, and was judged by a jury of her peers. Rather, the whole case is a sad and disappointing verdict on the Regulation and the self-regulatory regime of SCAM (supplements, complementary and alternative medicine) industry. In this case, self-regulation ultimately failed due to its own set boundaries: they may strip Ms Zimmermann of her fancy postnominals and the right to call herself a naturopathic physician, but can continue without a shred of a license as a homeopath, selling the same snake oil to the same clientele of the desperate, the crunchy and the credulous. What could have been a chance to get an immensely harmful practitioner of pseudoscience and make-believe medicine off the street who herself cannot honestly answer whether she is deluding her customers or gambling with a child’s life has been traded for a cheap consent order, under which she might not practice under the College’s aegis, and with that, that’s all done. Clearly, this proves that the naturopathic ‘profession’ cannot be trusted with self-regulation.

In the end, this is another sad story about the regulation of alternative “medicine”, and the state it is in. It is another story of missed opportunities, of could-have-beens and should-have-beens, and of a government that disclaimed all responsibility for the lives of the citizens who put it into power, delegating it to colleges of make-believe medicine who are fine with all sorts of pseudomedicine as long as it does not happen under their purview and with their name on the leaflet – and to hell with patient welfare, right?

Watch this space. I doubt this is the last we’ve heard of Ms Zimmermann. We can only hope that her next foray will not end up with consequences that are harder to repair than a child whose anger issues never got the adequate treatment but instead where inefficiently soothed by some balls of lactose.

References   [ + ]

 1 ↑ Naturopathic doctorates are not doctorates in any sense of the word, and I am not going to degrade my doctorate, or yours, by treating them as such 2 ↑ Homeopaths and naturopaths do not have patients. Doctors and nurses have patients. Homeopaths and naturopaths, like all fraudsters, have marks. 3 ↑ Funny that. Isn’t it the same crowd who complain about ‘allopathic medicine’ or ‘Schulmedizin’ trying to treat everything with drugs? Or is that not the case if globuli are involved?

# Automagic epi curve plotting: part I

As of 24 May 2018, the underlying data schema of the Github repo from which the epi curve plotter draws its data has changed. Therefore, a lot of the code had to be adjusted. The current code can be found here on Github. This also plots a classical epi curve.

One of the best resources during the 2013-16 West African Ebola outbreak was Caitlin RiversGithub repo, which was probably one of the best ways to stay up to date on the numbers. For the current outbreak, she has also set up a Github repo, with really frequent updates straight from the WHO’s DON data and the information from DRC Ministry of Public Health (MdlS) mailing list.1 Using R, I have set up a simple script that I only have to run every time I want a pre-defined visualisation of the current situation. I am usually doing this on a remote RStudio server, which makes matters quite easy for me to quickly generate data on the fly from RStudio.

### Obtaining the most recent data

Using the following little script, I grab the latest from the ebola-drc Github repo:

# Fetch most recent DRC data.
library(magrittr)
library(curl)
library(dplyr)

current_drc_data <- Sys.time() %>%
format("%d%H%M%S%b%Y") %>%
paste("raw_data/drc/", "drc-", ., ".csv", sep = "") %T>%
curl_fetch_disk("https://raw.githubusercontent.com/cmrivers/ebola_drc/master/drc/data.csv", .) %>%
read_csv()

This uses curl (the R implementation) to fetch the most recent data and save it as a timestamped2 file in the data folder I set up just for that purpose.3 Simply sourcing this script (source("fetch_drc_data.R")) should then load the current DRC dataset into the environment.4

### Data munging

We need to do a little data munging. First, we melt down the data frame using reshape2‘s melt function. Melting takes ‘wide’ data and converumnts it into ‘long’ data – for example, in our case, the original data had a row for each daily report for each health zone, and a column for the various combinations of confirmed/probable/suspected over cases/deaths. Melting the data frame down creates a variable type column (say, confirmed_deaths and a value column (giving the value, e.g. 3). Using lubridate,5 the dates are parsed, and the values are stored in a numeric format.

library(magrittr)
library(reshape2)
library(lubridate)

current_drc_data %<>% melt(value_name = "value", measure.vars = c("confirmed_cases", "confirmed_deaths", "probable_cases", "probable_deaths", "suspect_cases", "suspect_deaths", "ruled_out"))
current_drc_data$event_date <- lubridate::ymd(current_drc_data$event_date)
current_drc_data$report_date <- lubridate::ymd(current_drc_data$report_date)
current_drc_data$value <- as.numeric(current_drc_data$value)

Next, we drop ruled_out cases, as they play no significant role for the current visualisation.

current_drc_data <- current_drc_data[current_drc_data$variable != "ruled_out",] We also need to split the type labels into two different columns, so as to allow plotting them as a matrix. Currently, data type labels (the variable column) has both the certainty status (confirmed, suspected or probable) and the type of indicator (cases vs deaths) in a single variable, separated by an underscore. We’ll use stringr‘s str_split_fixed to split the variable names by underscore, and join them into two separate columns, suspicion and mm, the latter denoting mortality/morbidity status. current_drc_data %<>% cbind(., str_split_fixed(use_series(., variable), "_", 2)) %>% subset(select = -c(variable)) %>% set_colnames(c("event_date", "report_date", "health_zone", "value", "suspicion", "mm")) Let’s filter out the health zones that are being observed but have no relevant data for us yet: relevant_health_zones <- current_drc_data %>% subset(select = c("health_zone", "value")) %>% group_by(health_zone) %>% summarise(totals = sum(value, na.rm=TRUE)) %>% dplyr::filter(totals > 0) %>% use_series(health_zone) This gives us a vector of all health zones that are currently reporting cases. We can filter our DRC data for that: current_drc_data %<>% dplyr::filter(health_zone %in% relevant_health_zones) This whittles down our table by a few rows. Finally, we might want to create a fake health zone that summarises all other health zones’ respective data: totals <- current_drc_data %>% group_by(event_date, report_date, suspicion, mm) %>% summarise(value = sum(value), health_zone=as.factor("DRC total")) # Reorder totals to match the core dataset totals <- totals[,c(1,2,6,5,3,4)] Finally, we bind these together to a single data frame: current_drc_data %<>% rbind.data.frame(totals) ### Visualising it! Of course, all this was in pursuance of cranking out a nice visualisation. For this, we need to do a couple of things, including first ensuring that “DRC total” is treated separately and comes last: regions <- current_drc_data %>% use_series(health_zone) %>% unique() regions[!regions == "DRC total"] regions %<>% c("DRC total") current_drc_data$health_zone_f <- factor(current_drc_data\$health_zone, levels = regions)


I normally start out by declaring the colour scheme I will be using. In general, I tend to use the same few colour schemes, which I keep in a few gists. For simple plots, I prefer to use no more than five colours:

colour_scheme <- c(white = rgb(238, 238, 238, maxColorValue = 255),
light_primary = rgb(236, 231, 216, maxColorValue = 255),
dark_primary = rgb(127, 112, 114, maxColorValue = 255),
accent_red = rgb(240, 97, 114, maxColorValue = 255),
accent_blue = rgb(69, 82, 98, maxColorValue = 255))

With that sorted, I can invoke the ggplot method, storing the plot in an object, p. This is so as to facilitate later retrieval by the ggsave method.

p <- ggplot(current_drc_data, aes(x=event_date, y=value)) +

# Title and subtitle
ggtitle(paste("Daily EBOV status", "DRC", Sys.Date(), sep=" - ")) +
labs(subtitle = "(c) Chris von Csefalvay/CBRD (cbrd.co) - @chrisvcsefalvay") +

# This facets the plot based on the factor vector we created ear
facet_grid(health_zone_f ~ suspicion) +
geom_path(aes(group = mm, colour = mm, alpha = mm), na.rm = TRUE) +
geom_point(aes(colour = mm, alpha = mm)) +

# Axis labels
ylab("Cases") +
xlab("Date") +

# The x-axis is between the first notified case and the last
xlim(c("2018-05-08", Sys.Date())) +
scale_x_date(date_breaks = "7 days", date_labels = "%m/%d") +

# Because often there's an overlap and cases that die on the day of registration
# tend to count here as well, some opacity is useful.
scale_alpha_manual(values = c("cases" = 0.5, "deaths" = 0.8)) +
scale_colour_manual(values = c("cases" = colour_scheme[["accent_blue"]], "deaths" = colour_scheme[["accent_red"]])) +

# Ordinarily, I have these derive from a theme package, but they're very good
# defaults and starting poinnnnnntsssssts
theme(panel.spacing.y = unit(0.6, "lines"),
panel.spacing.x = unit(1, "lines"),
plot.title = element_text(colour = colour_scheme[["accent_blue"]]),
plot.subtitle = element_text(colour = colour_scheme[["accent_blue"]]),
axis.line = element_line(colour = colour_scheme[["dark_primary"]]),
panel.background = element_rect(fill = colour_scheme[["white"]]),
panel.grid.major = element_line(colour = colour_scheme[["light_primary"]]),
panel.grid.minor = element_line(colour = colour_scheme[["light_primary"]]),
strip.background = element_rect(fill = colour_scheme[["accent_blue"]]),
strip.text = element_text(colour = colour_scheme[["light_primary"]])
)


The end result is a fairly appealing plot, although if the epidemic goes on, one might want to consider getting rid of the point markers. All that remains is to insert an automatic call to the ggsave function to save the image:

Sys.time() %>%
format("%d%H%M%S%b%Y") %>%
paste("DRC-EBOV-", ., ".png", sep="") %>%
ggsave(plot = p, device="png", path="visualisations/drc/", width = 8, height = 6)

### Automation

Of course, being a lazy epidemiologist, this is the kind of stuff that just has to be automated! Since I run my entire RStudio instance on a remote machine, it would make perfect sense to regularly run this script. cronR package comes with a nice widget, which will allow you to simply schedule any task. Old-school command line users can, of course, always resort to ye olde command line based scheduling and execution. One important caveat: the context of cron execution will not necessarily be the same as of your R project or indeed of the R user. Therefore, when you source a file or refer to paths, you may want to refer to fully qualified paths, i.e. /home/my_user/my_R_stuff/script.R rather than merely script.R. cronR is very good at logging when things go awry, so if the plots do not start to magically accumulate at the requisite rate, do give the log a check.

The next step is, of course, to automate uploads to Twitter. But that’s for another day.

References   [ + ]

 1 ↑ Disclaimer: Dr Rivers is a friend, former collaborator and someone I hold in very high esteem. I’m also from time to time trying to contribute to these repos. 2 ↑ My convention for timestamps is the military DTG convention of DDHHMMSSMONYEAR, so e.g. 7.15AM on 21 May 2018 would be 21071500MAY2018. 3 ↑ It is, technically, bad form to put the path in the file name for the curl::curl_fetch_disk() function, given that curl::curl_fetch_disk() offers the path parameter just for that. However, due to the intricacies of piping data forward, this is arguably the best way to do it so as to allow the filename to be reused for the read_csv() function, too. 4 ↑ If for whatever reason you would prefer to keep only one copy of the data around and overwrite it every time, quite simply provide a fixed filename into curl_fetch_disk(). 5 ↑ As an informal convention of mine, when using the simple conversion functions of lubridate such as ymd, I tend to note the source package, hence lubridate::ymd over simply ymd.

# Ebola: a primer.

[su_note]After this post was published, a lot of people have asked me to do a Reddit AMA, where I could answer some questions from a wide audience. The AMA has concluded by now, but you can read the questions and answers here.[/su_note]

As I’m writing this, the beginnings of what could well be a major outbreak are raging in Bikoro territory, Equateur province, in the northeast of the Democratic Republic of the Congo (DRC). Recent news indicate that Mbandaka, the capital of Equateur and home to a busy port and a million people, has now reported cases as of 17 May. The death toll has reached 25 as of the time of writing, and it’s anyone’s guess how bad it’ll get – having learned from the unexpectedly extensive devastation of the West African Zaire ebolavirus outbreak (2013-16), everybody is preparing for the worst case scenario. Me and ebolaviruses have a long relationship, going back over a decade – I sometimes tend to wistfully remark that I know more about virion protein (VP) 24 of the Zaire ebolavirus (EBOV) than I know about some of my own family members. The reverse of the medal is that reading some of the nonsense in the press is borderline physically painful. I’ve assembled these resources for interested laypeople – especially journalists intending to comment on the Bikoro outbreak, in hopes that it will somewhat reduce misunderstandings.

### Some taxonomy pedantry for starters

To start with, a point of pedantry: there are multiple ebolaviruses, so technically, ‘Ebola virus’ is a misnomer. Viral taxonomy is a complex thing, governed largely by the International Committee on the Taxonomy of Viruses (ICTV). The latter has preliminarily determined the taxonomy of filoviruses to look as follows:1

• Family Filoviridae
• Genus Ebolavirus
• Species Bundibugyo ebolavirus (BDBV)
• Species Reston ebolavirus (RESV or RESTV)
• Species Sudan ebolavirus (SUDV)
• Species Taï Forest ebolavirus, formerly Côte d’Ivoire ebolavirus (TAFV)
• Species Zaire ebolavirus (EBOV or ZEBOV)
• Genus Marburgvirus
• Species Marburg marburgvirus (MARV)

By far the most important of these are EBOV and SUDV. These have been responsible for almost all major outbreaks – TAFV had only one single human case (CFR:2 1/0, 0%), RESV killed a lot of monkeys3 but a number of humans, despite seroconverting,4 did not fall ill. SUDV is generally regarded as somewhat more benign than EBOV, with a CFR around 50% (range 41-65%, discounting the 2011 Luweero case, where the single patient died). EBOV is the type species of ebolavirus, and it commonly has mortalities up to 93%. It is almost definite that the current outbreak in the DRC is an EBOV outbreak.

Viral species are further subdivided into strains. This is important for ebolaviruses, EBOV in particular, because there seems to be an emerging divergence. Typically, ebolavirus outbreaks claim up to 3-400 lives at most, tend to be over in 3-4 months and are fairly localised. Because non-RESV ebolaviruses, at least in humans, need contact with bodily fluids, long chains of transmission are rare. The 2013-16 West African outbreak, however, seems to have upended this hypothesis. That outbreak lasted almost twelve times the average for all known outbreaks until then, and claimed more lives than all known ebolavirus outbreaks (since the index outbreak in Yambuku, DRC, in 1976) put together. Why this was the case is a bit of a mystery, but there is now an understanding that EBOV strains that are more similar to the Mayinga (EBOV/May) strain isolated in 1976 are different from strains more similar to the Makona strain (EBOV/Mak), which was the prevalent strain in the West African outbreak.

### Background and history

Ebolaviruses belong to the family of filoviridae, so named for their threadlike appearance – they are among some of the longest viruses, reaching a length of up to 14,000nm and a width of approximately 80nm. The genome of ebolaviruses is relatively simple, approximately 19,000 base pairs long, and stored as a single-strand negative sense RNA, making ebolaviruses, and all other filoviridae, (–)ssRNA or Baltimore V viruses. This is significant as negative-sense single-strand RNA viruses need to be translated into positive-sense RNA by RNA polymerase, and therefore aren’t directly infectious.

Ebolaviruses, and other filoviruses, are probably pretty old – in fact, the study by Taylor et al. (2014) has found genetic fossils5 of EBOV-like VP35 in the same location of several cricetid rodents’ (voles and hamsters) genomes, suggesting that ebolaviruses have diverged from marburgviruses around the time the common ancestor of hamsters and voles lived, sometime around the miocene (16-23 million years ago).6

We also know that EBOV only relatively recently diverged from other ebolaviruses (sometime in the last century), but the first acknowledged outbreak of an ebolavirus took place in 1976 in Yambuku, in what was then Zaïre and is today the DR Congo. The story of this outbreak is extensively told in a retrospective article by Joel Breman and a number of others who have been present at the initial outbreak, written four decades later. Arguably, we saw the emergence of a physiologically and epidemiologically different strain of EBOV during the West African EBOV epidemic, too – at least in the wild, EBOV/Mak behaved very differently from EBOV/May: characterised by long chains of transmission, a somewhat lower CFR7 and a much longer epidemic duration with a significantly larger number of cases – indeed, the 2013-16 outbreak claimed more lives than every single known filoviral outbreak since the first recorded filoviral epidemic, the 1967 Marburg outbreak, put together. Recent evidence seems to suggest that infection with EBOV/Mak does seem to exhibit some significant differences from the previously known strains that are clinically different to the point that they might explain the difference between the 2013-2016 West African outbreak and previous epidemics, which typically were regionally limited, originated in central Africa (Sudan and Zaire) rather than the coastal states of the Gulf of Guinea and lasted a few months with no more than 3-400 cases.8

• Two of the protagonists of the 1976 Yambuku outbreaks have written amazing autobiographies that are worth reading. No Time to Lose, by Peter Piot, is a fascinating book, although most of it – like Peter Piot’s career – is devoted to STDs, especially the fight against AIDS. His colleague and countryman, Guido van der Groen, has also written an engaging and well-written memoir, On the Trail of Ebola.
• Murphy, F.A. (2016): Historical perspective: what constitutes discovery (of a new virus)? In: Kielian, M. et al. (eds)., Advances in Virus Research95:197-220. – What’s it like to discover a virus? Fred Murphy, whose transfer electron micrograph graces the header of this blog  post and has become inextricably associated with ebolaviruses, was working as CDC’s chief viropathologist in 1976, and if not a father of EBOV’s discovery, he is at the very least its godfather. His experiences with Ebola specifically are summarised in section 5.8 of the chapter.
• Tropical medicine professor and ID physician David Brett-Major‘s book, A Year of Ebola, is an up-close-and-personal account of a year of the 2013-2016 West African outbreak, and the challenges that rendering assistance in the chaos of such an outbreak. For those unfamiliar with what a major, multi-party public health intervention involves, this book is a must-read.
• A good and somewhat lighthearted starter is my interview with Devon from the Bugs, Blood and Bones podcast: part 1 | part 2. This discusses many of the principal points you should know about ebolaviruses, especially the reason we can’t simply eliminate ebolaviruses as easily as, say, smallpox.

### The (proteomic) nature of the beast

Ebolaviruses are remarkably simple for all the destruction they’re capable of. To understand the issues that curing ebolavirus infections raises, it’s important to understand how the virus itself is constructed and how it operates on a molecular level. The ebolavirus genome encodes seven proteins: a nucleoprotein (NP), a RNA polymerase (L), the glycoprotein GP, and four viral proteins (VPs): VP24, VP30, VP35 and VP40 (sometimes referred to as the matrix protein). For this reason, some of Ebola’s viral proteins ‘moonlight’ – that is, they fulfill multiple functions, depending on their polymerisation state.

• The overall structure of the virion is given by the ebola matrix protein or VP40. As a hexamer looking a bit like the S-shaped Tetris piece,9 it’s responsible for the structure of the virion, while as a crown-shaped octamer wrapped around the RNA, it regulates RNA transcription. The matrix protein’s main purpose, other than serving as a physical outer shell, is to connect the nucleocapsid with the target cell’s membrane, allowing penetration. VP40 also gives ebolaviruses the characteristic structure. For this reason, and the fact that it also coordinates some aspects of the viral lifecycle – in particular virion assembly and ‘budding’, that is, egress from infected cells –, it’s being considered as a therapeutic target.10

• The RNA is surrounded by a dynamic nucleocapsid, made up of VP35, VP30 and VP24. The purpose of this is to store and, at the necessary time, deliver, the genetic payload. The nucleoprotein NP is wrapped around the RNA genome.
• VP24 is also used to disrupt the innate immune system, specifically the STAT1 signalling pathway. Normally, in response to viral infections, interferons phosphorylate the STAT1 protein, which then binds to karyopherin alpha (KPNA). Karyopherin alpha is an ‘importin’, a shuttle protein. Once STAT1 is bound to KPNA, it is ferried to the nucleus, and stimulates gene transcription. VP24 selectively tricks this: it binds competitively to KPNA, so that STAT1 cannot bind to it. In a sense, VP24 is hijacking the cell’s internal shuttle system, preventing an adequate immune response but maintaining the ability to use the system for its own purposes.
• L, or RNA-dependent RNA polymerase, is required because ebolaviruses are negative-sense single strand RNA viruses, and thus a complementary, positive sense strand needs to be generated for transcription.
• GP, the ebolavirus glycoprotein, is perhaps the most essential part of the internal machinery of an ebolavirus. GP is responsible for infecting new cells, and for a cytopathogenic effect on endothelial cells – in other words, GP damages the cells that line blood vessels in particular and has been observed to cause endothelial cell loss. This in turn results in the haemorrhagic symptoms that characterise EVD’s haemorrhagic stage.11

### Ebola virus disease (EVD) and pathophysiology

Human and primate ebolavirus infection (regardless of species or strain) causes Ebola Virus Disease (EVD), sometimes referred to as Ebola haemorrhagic fever (EHF). EVD is more accurate as the well-known haemorrhagic manifestations are far from ubiquitous (about half the cases at best).12

EVD begins with nonspecific signs – like a bad flu: after an incubation time of about 4 days to two weeks, fatigue, fever, loss of appetite and muscle aches set in, along with vomiting, diarrhoea and more vomiting. Despite its apparent simplicity, ebolaviruses carry out a complex and multifactorial propgramme of destruction:

1. Prodromic stage: In the early, prodromic stage, the viral protein VP24 inhibits interferon type I and II signalling, effectively cutting the communication lines of the immune system and allowing the virus to proliferate in peace. During this time, the patient may be asymptomatic or have nonspecific symptoms like headaches, fatigue and a mild
2. Early disseminating stage: Ebolaviruses preferentially attack certain white blood cells that allow it to spread through the lymphatic system, in particular dendritic cells, macrophages and monocytes, and later on spread prolifically through liver cells and the adrenal gland, causing liver damage (leading to clotting issues and the diagnostically significant elevated transaminase levels). The death of the infected monocytes (called a cytopathic or cytopathogenic effect) causes immunosuppression through low lymphocyte counts and releases pro-inflammatory molecules, in particular TFN-alpha, and the interleukins IL-6 and IL-8, creating a state somewhat reminiscent of sepsis. GP also assists in inhibiting neutrophils, white blood cells crucial for immune reactions, from activating.
3. Vascular endothelial damage: Glycoprotein (GP) in vascular endothelial cells (the cells lining the walls of blood vessels) destroys the integrity of blood vessels around three to four days after infection, leading to bleeding.
4. Liver injury and DIC: GP, when expressed in the liver, causes liver damage, and also suppresses the production of integrins. Integrins are transmembrane proteins that allow cells to attach to the various molecules outside the cell, which is crucial for clotting. Together, these lead to a paradoxical state called disseminated intravascular coagulation (DIC): small blood clots form in the capillaries all over the body, leading to ischemia (lack of blood supply) and organ failure, while at the same time using up all the clotting factors and platelets. This is responsible for the later haemorrhagic manifestations.
5. At this stage, patients that do not recover succumb to the combined effects of multi-organ failure, volume loss from diarrhoea and massive haemorrhage.

Together, these have a damaging effect on vascular endothelial cells, the cells lining the walls of blood vessels, leading to internal bleeding and the haemorrhagic manifestations.

Eventually, the haemorrhagic (bleeding) symptoms – bleeding under the skin, uncontrollable bleeding from blood draws, bleeding into the sclerae (the whites of the eyes), blood in vomit and faeces – may begin, largely because damage to the liver and depletion of clotting factors.

Death usually occurs 8-14 days from onset of symptoms. Contrary to popular perception, death is actually not caused by bleeding out – the blood loss is quite simply not enough to be fatal, even in the haemorrhagic cases. Rather, ebolaviruses turn the body’s own inflammatory cascades on overdrive, causing a state that’s somewhat similar to septic shock. Survivors begin to feel better around 10-14 days after first symptoms, but recovery is slow and can take months.

• Geisbert, T.W. and Feldmann, H. (2011): Ebola haemorrhagic fever. Lancet 377:849-62. – a great summary, while intended for professional audiences, it is probably the most comprehensive article on what we know about ebolaviruses. Nb. that it was written before the 2013-16 West African outbreak.
• Munoz-Fontela, C. and McElroy, A.K. (2017): Ebola virus disease in humans: pathophysiology and immunity. In: Mühlberger E. et al. (eds.), Marburg- and Ebolaviruses. Springer, 2017. – This is a rather pricey book, and aimed at public health experts, but is probably the best summary of post-West African outbreak scholarship on all things ebola- and marburgviruses. For those writing for a professional audience or desiring a more comprehensive understanding of the underlying biology, it’s a must-have. Disclaimer: many of the chapter authors and editors are friends and/or valued colleagues.

### Ecology and reservoir hosts

Finding the reservoir host of ebolaviruses and Marburg marburgvirus has consumed an incredible amount of scientific effort during the 1980s and 1990s, with relatively little to show for it. It was clear from the very beginning that ebolaviruses are zoonotic – that is, there’s a reservoir host, an animal in which the virus can persist and multiply without causing disease. This explains why it sometimes appears as if ebolaviruses (and Marburg) came out of nothing, wreaked havoc, then disappeared as fast as they appeared. Using RT-PCR and qRT-PCR, it’s now clear that that the reservoir hosts are bats, and a number of species, in particular certain fruit bats. Bats have a complex interferon (IFN) system, much more complex than the human or NHP13 IFN system. This seems to give them an ability to manage the infection in their bodies (see the Kühl and Pöhlmann paper below).There’s a global increase of bat-borne pathogens causing outbreak – these are almost all viral (the related henipaviruses Hendra virus in Australia and Nipah virus in Malaysia/Bangladesh, the coronaviruses MERS-CoV and SARS-CoV, rabies, etc.). As humanity, in need of arable land across the world to feed the exploding population and mineral resources like diamonds and coltan, encroaches upon traditional habitats of Chiropteran species, especially the caves and jungles where they roost, interactions between bats and humans will become more and more frequent, raising the risk of infections. Clearly a strategy to manage ebolaviruses must also be able to manage the ecological problem of habitat loss.

• Kühl, A. and Pöhlmann, S. (2012): How Ebola Virus Counters the Interferon System. Zoon Pub Health 59:116-131. – great paper, but tough to digest for non-technical audiences. For those who prefer a slightly more relaxed version, see the next link.
• Fagre, A. (2016): Why don’t bats get Ebola? Scientific American Guest Blog, July 18, 2016. – same topic as above, just for more popular audiences.
• On ecology, the chapter Ecology of Filoviruses in Mühlberger et al. (eds.), op cit, is worth reading.
• For understanding zoonotic diseases, Spillover by David Quammen (2013) is an excellent read. Ebola: The Natural and Human History of a Deadly Virus, written in 2014, updates his chapter on ebolaviruses – largely EBOV – for an audience hungry for information after the 2013 West African outbreak. – Quammen has a great style and writes well, without Preston’s sensationalism. If this is your first foray into writing about, or trying to understand, filoviral zoonoses, both books are very much worth reading. The added value of whatever was added to the Ebola chapter in Spillover in Ebola: The Natural and Human History is, to me at least, dubious. It is, however, a much shorter read for those pressed for time.

### Treatment and prophylaxis

So far, no particular agent has proved to be conclusively effective against EBOV infection after symptoms have emerged, and treatment is mainly symptomatic. It is haunting that the state of the art in treating filoviral haemorrhagic fever 2018 is not much different from the approach Margaretha Isaäcson and her team used on the three Marburg cases – Cases 1 and 2, Australian hitchhikers, and Case 3, a nurse who took care of both Cases 1 and 2 – in 1975:

At this stage, it became clear that there would be no specific treatment that could be relied upon to attack and kill the virus responsible for this infection. The girls’ only chance of survival would, therefore, depend on meticulous, ongoing monitoring of various organ functions and managing clinical problems in anticipation or as they presented themselves. This approach required a large team in support of the core formed by the clinicians responsible for the daily evaluation, treatment and general management of the patients.
– from the notes of Margaretha Isaäcson, 26 February 1975

Treatment is focused on volume and electrolyte replacement (intravenously or using oral rehydration salts aka ORSs), pain management and blood transfusions to combat blood loss. To manage disseminated intravascular coagulation and the ensuing coagulopathy, heparin and clotting factors have both been used, with mixed success. Intensive care can greatly increase survival chances, but in low resource settings this remains a challenge. The West African outbreak has demonstrated the utility and sustainability of three-segment (four, if you count the morgue) Ebola Treatment Centres (ETCs, see image) as an easy and inexpensive way to reduce nosocomial spread (spread within a healthcare facility). The model ETC design, which separates confirmed, low-probability and high-probability cases, reduces the risk to lower probability cases by separating them from higher-probability or confirmed cases. One of the painful lessons of the 1976 Yambuku outbreak was that reuse of medical equipment, in particular of hypodermic needles and syringes, can greatly contribute to the spread of ebolaviruses, and this makes overcoming the logistic challenges of dealing with an ebolavirus outbreak in an isolated and ill-accessible location all the more acute.

There are no specific treatment options for EVD that have stood the test of time and rigorous trials. A few of the most often discussed specific treatment options are outlined below:

• Convalescent plasma has for a long time been the best hope against filoviral infections, but is not always accessible and has its own risks, such as residual viral loads. It also doesn’t keep too well (like liquid plasma, it must be kept between +2ºC and +6ºC). It is taken from survivors of the infection using plasmapheresis, a process quite similar to haemodialysis except in this case, the dialysate is retained. This contains antibodies that the patient developed following his infection. Convalescent plasma also contains a range of other antibodies, and these can cause various immune reactions – importantly, convalescent plasma must come from healthy individuals (‘donor qualified’, i.e. adequate haemoglobin levels and free from bloodborne pathogens) that are compatible with the recipient’s blood type. In regions where ebolaviruses are endemic, this is one of the easiest treatment options to implement, but the efficacy of convalescent plasma may be hampered by epitopic dissimilarity (that is, if the strain the donor recovered from and the strain the recipient is suffering from are too dissimilar, the antibodies won’t work). The WHO has worked out a detailed guideline on using convalescent plasma, which also highlights one of its greatest drawbacks: it works best for patients with early stage disease.
• ZMapp is a biological drug, specifically a monoclonal antibody. Monoclonal antibodies are artificially created equivalents of the antibodies in convalescent plasma. The great benefit of ZMapp over convalescent plasma is that it only contains antibodies specifically against EBOV, and as such the risk of immune reactions is negligible. ZMapp’s efficacy is quite controversial, as due to the scarcity and cost of the drug, the number of patients treated was too low to really be able to draw conclusions from.
• Brincidofovir is a broad spectrum antiviral against DNA viruses, such as cytomegalovirus, smallpox and herpes simplex. For some reason, its lipid moiety appears to have shown some efficacy against EBOV, even though EBOV is not a DNA virus but a (-)ssRNA (negative single sense RNA, Baltimore Group V) virus. However, a very small (n=4) Phase II trial in Liberia was prematurely cancelled, and all enrolled subjects died of EVD, after the manufacturer decided to stop pursuing EVD as a target for brincidofovir.
• Favipiravir is also a broad spectrum antiviral, with specific activity against RNA viruses, initially developed against influenzaviruses. The JIKI trial was conducted in Gueckedou, the ground zero of the 2013-2016 outbreak, in September 2014, and has indicated some efficacy for patients with less severe disease (low to medium viral loads). Controversially, because the criteria weren’t met for a proper randomised clinical trial in late 2014, the JIKI trial was historically controlled, and this has drawn extensive professional criticism.

There are a range of ebolavirus vaccines, most specifically targeting EBOV. The two currently available vaccines are rVSV-ZEBOV and the cAd3-ZEBOV vaccine (colloquially referred to as the NIAID vaccine).

• rVSV-ZEBOV is a somewhat quirky viral vaccine. It is intended to create antibodies to GP, the virion glycoprotein of EBOV. Normally, vaccines contain an adjuvant and an antigen, such as a viral protein (e.g. the HPV vaccine contains the protein shell, called the L1 major capsid protein, of various HPV strains). The immune system then recognises this as foreign and generates antibodies against them. rVSV-ZEBOV works a little different – it actually contains a live virus, VSV (vesicular stomatitis virus or Indiana vesiculovirus, a distant relative of rabies), which is harmless in humans but causes a disease very similar to foot and mouth disease in cattle and horses. This recombinant (hence r) VSV expresses small amounts of GP, to which the body then generates antibodies. In a ring vaccination trial called Ebola ça Suffit-GRV Trial, 7,284 participants were recruited in Guinea and a parallel trial with the rVSV-ZEBOV vaccine was carried out in Sierra Leone by the CDC (the STRIVE VSV-EBOV trial). The trial faced complex ethical dilemmas. Placebo control would clearly not be ethically (or politically) acceptable, so instead the trial participants were randomised into two cohorts, some of whom received the vaccine after a three week delay. However, due to encouraging early results, the control arm was effectively dispensed with and everybody was vaccinated. The National Academies of Sciences, Engineering and Medicine published an report in which they assessed the trials, and found that much like in the case of favipiravir, it’s hard to do assess a life-saving treatment in the middle of a lethal epidemic. The WHO has announced that it will use the rVSV-ZEBOV vaccine to ring vaccinate contacts of known, laboratory confirmed cases, from 21 May onwards, and has a stock of 7,000 doses of the vaccine in cold storage in Kinshasa. Ring vaccination has been used successfully in the eradication of smallpox, and there is ample evidence to its efficacy and the ability to control further spread, provided contact tracing is successful.
• cAd3-ZEBOV aka the NIAID/GSK vaccine is a similarly structured vaccine, but derived from a chimpanzee adenovirus, ChAd3. Like the rVSV-ZEBOV vaccine, the cAd3-ZEBOV vaccine expresses glycoproteins from EBOV and, depending on configuration, SUDV.14 This vaccine is considered less ‘ready for use’, and while it’s been found safe, it is not clear what efficacy it will ultimately have.

• On Ebola treatment centres, Chowell, G. and Viboud, C. (2015): Controlling Ebola: key role of Ebola treatment centres. Lancet Inf Dis 15(2):139-141. – a good outline of the cheap yet surprisingly effective three-stage treatment centre model.
• Medecins Sans Frontieres, who have pioneered the three-stage treatment centre structure, have a great interactive guide to a treatment centre that reflects the idea of segregation by infection probability quite well.
• David Kroll’s article in Forbes asks the question on everyone’s mind: how will we know if the Ebola drugs used during the West African outbreak have indeed worked?Most patients received multiple different treatments, and the sample size was quite small – most of the patients in Africa have only received the usual symptomatic treatment. Clearly, there’s a huge ethical issue, and one of health equity, involved here: many drugs, high costs, many patients, and a willingness to give patients every possible chance at survival. The moral imperatives and the practicalities of the situation make it hard for researchers to gauge efficacy of individual treatments.
• Adebamowo, C. et al. (2014). Randomised controlled trials for Ebola: practical and ethical issues. Lancet 384:1423-1424. – when it comes to clinical trials for diseases with high mortality, complex ethical issues arise. This makes research and the traditional methods of evaluating treatments difficult. Randomised controlled trials, the gold standard when it comes to assessing the efficacy of medical interventions, are difficult to conduct in the middle of a devastating epidemic, and raises complex ethical issues.
• National Academies of Sciences, Engineering and Medicine (2017). Integrating Clinical Research into Epidemic Response: The Ebola Experience. The National Academies Press, Washington, DC. – this is probably the best overview of the current state of the art when it comes to vaccines for EBOV after the West African outbreak. Chapter 4 is a must-read for vaccines, and chapter 3 for clinical treatments. Furthermore, Chapter 2 is a great in-depth exploration of the Scylla and Charybdis of doing high-quality, evidence-based clinical research in the middle of an epidemic with a high-mortality viral disease.

### Keeping up to date & other stuff to read

The situation is currently quite rapidly evolving, and information flow is often quite restricted due to unreliable communication links. Perhaps the best source of information about what’s going on at the time is ProMED-mail, run by ISID. I also tweet pretty prolifically about the emerging crisis and other public health issues (you can find me at @chrisvcsefalvay), and of course you can find all my blog posts and public appearances that involve filoviruses on this page. I’m also always happy to answer questions, here in the comments thread or using the contact form (if you’re writing for a publication, please use the contact form).

I hope this primer to ebolaviruses was helpful, and if you intend to write about the subject, you now feel better informed. Please feel free to raise any questions that you think remain open in the comment thread below!

References   [ + ]

 1 ↑ See ICTV page on filoviral taxonomy. 2 ↑ Case-fatality rate, i.e. the number of cases versus the number of deaths. Typically given as case/fatality, percentage – e.g. 10/3 (30%) means 10 cases, 3 died, 30% CFR. 3 ↑ This is the outbreak dramatised in Preston’s Hot Zone. 4 ↑ Seroconversion refers to developing antibodies against a pathogen. It does not mean actually becoming sick as well, just that the body has encountered the pathogen and has responded to it. 5 ↑ A fossil gene is what happens when a virus does not infect or kill the host, but rather incorporates bits and pieces of the viral genome into its own. 6 ↑ Taylor, D.J. et al. (2014). Evidence that ebolaviruses and cuevaviruses have been diverging from marburgviruses since the Miocene. PeerJ 2 Sep 2014, 2:e556. 7 ↑ Case-fatality ratio or case-fatality rate, which is a misnomer, since it’s neither a rate nor a ratio in the epidemiological sense. Normally given as a percentage, it is defined as $\frac{C_d}{\Sigma C}$$\frac{C_d}{\Sigma C}$, where $C_d$$C_d$ describes all deceased cases and $\Sigma C$$\Sigma C$ is defined as the total of all cases that meet the inclusion criteria. 8 ↑ Versteeg, K. and Geisbert, T.W. (2017). Infection with the Makona variant results in a delayed and distinct host immune response compared to previous Ebola virus variants. Scientific Reports 7:9730. 9 ↑ Officially, a ‘mirrored Z free tetromino‘. Except, of course, it’s a hexomino. 10 ↑ Madara, J.J., Harty, R.N. et al. (2015). The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target. Future Virol (10)5: 537-546. 11 ↑ Yang, Z.Y., Nabel, G.J. et al. (2000). Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nature Med 6(8):886-9. 12 ↑ The descriptions of ebolaviruses or even Marburg turning patients into bags of goo or exploding with blood, largely inspired by Preston’s Hot Zone, are wildly inaccurate. Still, it’s one nasty disease. 13 ↑ Non-human primate. 14 ↑ The vaccine is intended to express glycoproteins from both when in production use. The current Phase II UK trials, conducted by Oxford University’s Jenner Institute, are done with a variant expressing only EBOV GP.