Discussion of possibility of immunization history & Ebola susceptibility

[Emily]

I've got a theory on why CDC has such lax standards for working with Ebola compared to military labs. I think their risk assessment is based on the experiences of their virus hunting scientists who dealt with the early Ebola outbreaks.

I saw one of them interviewed a couple of days ago, and he thought the problem in Texas was due to too much technology, rather than inadequate PPE or the use of a particular type of high-tech, high-risk technology. (He had personally intubated a Lassa patient and did not get sick himself.)

He said that in Zaire, only one member of the team got sick.

I was curious about that and the document below has a lot of details.

World Health Organization. Ebola haemorrhagic fever in Zaire, 1976

In spite of the doctor/scientists remaining healthy, (and some treated patients intensively), most of the nuns at the hospital got sick and died, including those who used the same PPE as the scientists. The one science team member who got ill was a Peace Corps volunteer and they weren't quite sure if he had rabies, ebola, or both so they treated him for both and he recovered in six days. At that time rabies was a mandatory vaccine for Peace Corps workers, but they gave him another dose of rabies vaccine produced with a different technology than the first. The question was left open as to whether the volunteer actually had a novel disease rather than Ebola or rabies.

My theory on why the nuns died and the scientists did not get sick at all is that virus hunters get exposed to an unusual number of pathogens in the course of their work. They also probably get a lot of exotic vaccines. So this could give them cross-protective immunity.

I predicted that a MERS antibody test was the result of cross-immunity from this kind of background and that his PCR test would likely come back negative and that did turn out to be the case:

http://www.flutrackers.com/forum/showpost.php?p=535563&postcount=18

I'm not recommending exotic vaccines to protect from Ebola, but the unusual immune profile of research scientists and lab workers should be considered when setting PPE standards.

Just my current theory on why things are going so haywire..

 

[kiwibird]

Re: Why BSL-4 standards for researchers but not health care workers?

Re: Why BSL-4 standards for researchers but not health care workers?

?.....
I saw one of them interviewed a couple of days ago, and he thought the problem in Texas was due to too much technology, rather than inadequate PPE or the use of a particular type of high-tech, high-risk technology. (He had personally intubated a Lassa patient and did not get sick himself.)

He said that in Zaire, only one member of the team got sick.

I was curious about that and the document below has a lot of details.

World Health Organization. Ebola haemorrhagic fever in Zaire, 1976

In spite of the doctor/scientists remaining healthy, (and some treated patients intensively), most of the nuns at the hospital got sick and died, including those who used the same PPE as the scientists. The one science team member who got ill was a Peace Corps volunteer and they weren't quite sure if he had rabies, ebola, or both so they treated him for both and he recovered in six days. At that time rabies was a mandatory vaccine for Peace Corps workers, but they gave him another dose of rabies vaccine produced with a different technology than the first. The question was left open as to whether the volunteer actually had a novel disease rather than Ebola or rabies.

My theory on why the nuns died and the scientists did not get sick at all is that virus hunters get exposed to an unusual number of pathogens in the course of their work. They also probably get a lot of exotic vaccines. So this could give them cross-protective immunity.
.......
Just my current theory on why things are going so haywire..

I wonder if most of the team had been vaccinated against rabies. Is is standard for MSF volunteers?

Actually - peace corps survived and Nuns didn't! Perhaps the question we. Should ask is did the Nuns get vaccinated against rabies as standard - like the Peace Corp did?

 

[Emily]

Re: Why BSL-4 standards for researchers but not health care workers?

Re: Why BSL-4 standards for researchers but not health care workers?

I wonder if most of the team had been vaccinated against rabies. Is is standard for MSF volunteers?

Actually - peace corps survived and Nuns didn't! Perhaps the question we. Should ask is did the Nuns get vaccinated against rabies as standard - like the Peace Corp did?

That's the same question I have, kiwibird. The details on the volunteer's case are here:

http://www.itg.be/internet/ebola/ebola-67.htm

The mild oozing of blood on day 5 and the appear ance of the characteristic morbilliform rash on day 6 left no doubt in our minds at this stage that this was a case of Ebola virus infection. Subsequent negative laboratory findings were unexpected. Exhaustive investigations in the USA and in South Africa have so far failed to identify the etiological agent in this case. The possibility that the disease was caused by an as yet unknown agent cannot be excluded. A confusing factor was presented by a history of a bite by a half-wild pet civet cat just prior to the patient having joined the IMC, i.e. about 2 weeks before onset of illness. Exposure to rabies could therefore not be excluded but as the patient had been given a full course of duck embryo vaccine (a routine vaccination for Peace Corps volunteers) rabies was not considered a likely diagnosis. It is possible however that the civet cat was the source of another pathogenic agent which may have been the cause of the patient's illness. It is rather curious that a civet cat also featured in the history of the index case of the 1975 South African Marburg virus disease outbreak, although no aetiological association could be established. Treatment was continued with human diploid cell vaccine.

So the additional rabies vaccine might have helped. He also got convalescent serum from Ebola patients:

The first unit of convalescent plasma was infused in the landrover, very slowly at first and with syringes containing adrenalin and solucortef at hand. This was followed by slow infusion of 5% dextrose saline. The second unit of plasma was administered that evening after accommodation was obtained in the Bumba guest house with another IMC member.

But they ended up ruling out Ebola. Was it an early case of this?

2012: New virus in Africa looks like rabies, acts like Ebola
A Novel Rhabdovirus Associated with Acute Hemorrhagic Fever in Central Africa

Here's how they all relate:
Rhabdoviridae is a virus family within the Mononegavirales order, which also contains the Bornaviridae, Filoviridae, and Paramyxoviridae families...

NIH: Rabies Vaccine Protects Nonhuman Primates Against Deadly Ebola Virus

It all makes me wonder if we need a new vaccine, or if current rabies vaccines or some other tropical vaccines might offer protection. There could be a clue in studying the histories of human survivors vs those who die.

 

[kiwibird]

Re: Why BSL-4 standards for researchers but not health care workers?

Re: Why BSL-4 standards for researchers but not health care workers?

I wonder if they used the same rabies vaccination in Lemera Emily? http://www.msf.org.uk/article/drc-family-infected-after-child-bite-rabies-horror

And how the district has fared with Ebola. Perhaps there were enough individuals with immunity to ring fence the local population..?

On the duck embryo vaccination - http://www.ncbi.nlm.nih.gov/pubmed/6887320
There is another rabies vaccination freely available - it would be interesting to see who has been using the different variants

 

[Vibrant62]

Re: Why BSL-4 standards for researchers but not health care workers?

Re: Why BSL-4 standards for researchers but not health care workers?

We need a lot of data from an area where all efforts are bent on delivering isolation and care in the short term.

Emily, Kiwibird - its a really interesting idea that is worth looking at, and I hope it happens ... but we may not get such data until after this outbreak is over.

Research and epidemiology teams need to go in to gather information on the epidemic and patient histories. Anyone seen any reports on this sort of activity?

 

[kiwibird]

Re: Why BSL-4 standards for researchers but not health care workers?

Re: Why BSL-4 standards for researchers but not health care workers?

We have strayed from the title of this thread. Perhaps we could open another specific to a discussion of - patient exposure and vaccine history and outcomes - or something more succinct. Found this from 2011 http://pubs.acs.org/doi/abs/10.1021/mp200392g

 

[Emily]

Re: Discussion of possibility of immunization history & Ebola susceptibility

I wondered if yellow fever vaccination might be protective, but this indicates it might not be:

http://www.enivd.de/EBOLA/ebola-24.htm

THE EPIDEMIOLOGY OF EBOLA HAEMORRHAGIC FEVER IN ZAIRE, 1976

J.G. BREMAN (1), P. PIOT (2), K.M. JOHNSON (1), M.K. WHITE (1), M. MBUYI (3), P. SUREAU (4), D..L. HEYMANN (1), S. VAN NIEUWENHOVE (5), J.B. MCCORMICK (1), J.P. RUPPOL (5), V. KINTOKI (3), M. ISAACSON (6), G. VAN DER GROEN (2), P.A. WEBB (1), K. NGVETE (3)
...
All five of the expatriates who died had been vaccinated against yellow fever....

 

[kiwibird]

Re: Discussion of possibility of immunization history & Ebola susceptibility

I wondered if yellow fever vaccination might be protective, but this indicates it might not be:

http://www.enivd.de/EBOLA/ebola-24.htm

Interesting that they used the 21 day incubation period too!

 

[kiwibird]

Re: Discussion of possibility of immunization history & Ebola susceptibility

Two peace corps volunteers had exposure to Ebola in West Africa and were isolated - I have not found any information on their becoming ill. Perhaps they didn't ! Current vaccination requirements for Peace Corps http://files.peacecorps.gov/learn/medical/vaccines_by_country.pdf

340 volunteers evacuated http://www.usatoday.com/story/news/...vows-to-return-to-africa-post-ebola/13624387/ July 2014

 

[Emily]

Re: Discussion of possibility of immunization history & Ebola susceptibility

Thanks for finding that doc with the current requirements for Peace Corps workers, Kiwi. I had no idea that rabies vaccine was so heavily used in humans until I saw that 1976 story. I think of rabies as a strong vaccine, but maybe its safety profile is better than I imagined.

Here is a 280 page long collection of full text article that date back to before Marburg and Ebola were even known as 'filoviruses.'

MARBURG VIRUS DISEASE
M. DIETRICH
Bernhard-Nocht Institute for Nautical and Tropical Diseases, Clinical Department, Bernhard-Nocht-
Strasse 74, 2000 Hamburg 4, Germany.
...
MORPHOLOGY AND TAXONOMIC STATUS
The virus particle size was measured 75 nm x 650 nm approximately It is a virus with high complex structure related to viruses of vesicular stomatitis and rabies. The taxonomic status is not clearly defined. It was proposed to include it to the rhabdo-virus group by morphological criteria. At the present time it is still unclassified (4).

Even if preventative rabies vaccines aren't effective protection from ebola, there could be generalized protection from post exposure use, like the Peace Corps worker was given in 1976.

THE EFFECT OF INTERFERON ON EXPERIMENTAL EBOLA
VIRUS INFECTION IN RHESUS MONKEYS
E.T.W. BOWEN (1), A. BASKERVILLE (1), K. CANTELL (2), G.F. MANN (3), D.I.H. SIMPSON
(3), A.J. ZUCKERMAN (3)
1. Microbiological Research Establishment, Porton Down, Salisbury SP4 OJG, Wiltshire, England.
2. Central Public Health Laboratory, Helsinki.
3. London School of Hygiene and Tropical Medicine, London.
...
J. De Smyter : I don't think it will make much sense to administer interferon to an animal or to a person with circulating interferon. Thus it will be very important to know this spontaneous titer of interferon in this disease in monkeys. This still does not mean that exogenous interferon would be useless. Perhaps the disease could be avoided by giving interferon or an inducer after exposure i.e. after an accident like that which occurred in Porton Down. As far as there is a possible comparison with rabies, in this infection it is possible in monkeys to stop the infection if interferon or an inducer are given immediately after exposure, the production of interferon may even be the mechanism of action of post-exposure vaccine in rabies. So there could be a useful post-exposure immediate administration of interferon.

They weren't recommending using rabies vaccine there, and the Peace Corps worker didn't get his dose of human diploid cell rabies vaccine as a treatment for Ebola, but maybe it helped him to recover from whatever it was he had.

 

[foxp3]

Re: Discussion of possibility of immunization history & Ebola susceptibility

I have to disagree I am still not convinced vaccination against rabies gives any protection against Ebola....hear me out.


The aim of the 2013 paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667758/ )
was to make a rabies vaccine engineered to express an Ebola virus glycoprotein, so to make a 2 in one vaccine with greater market appeal, before this outbreak they was little market for Ebola vaccine.

Importantly you can see the negative experimental control group were vaccinated with the routine unmodified rabies virus (RABV) vaccine alongside their test groups which got the joined RABV/EBV vaccines. As expected this rabies vaccine on its own conferred absolutley no protection against Ebola in primates. It generated anti rabies antibodies as expected, but no Ebola antibodies, or Ebola driven cell mediated responses, and when animals were infected with EBV, they died. So in summary there was no protection against Ebola in primates immunised only against rabies, there was no cross protection, the anti rabies antibodies did not neutralise Ebola. The authors didn't expected it to, that's why the rabies vaccination on its own was the negative control ( vaccine composed of whole virus).

Here is some quotes from the study.

Quote :
all three vaccines and the control vaccine induced seroconversion against RABV. ( so they all produced antibodies against rabies virus).

Quote: The result presented in Figure 2C indicates that all four vaccines induced virus-neutralizing antibodies as early as 7 days after immunization. Notably, the VNA titers were well above the critical level of 0.5 international units (I.U.), which is considered protective from RABV infection in humans result presented in Figure 2C indicates that all four vaccines induced virus-neutralizing antibodies as early as 7 days after immunization.

So this is saying they not only was anti rabies antibodies produced, but they were functional and protective.

However when we look at what effect the control ( rabies vaccination alone) has on Ebola it has this to say.

Quote : animals of the control group did not mount any cellular responses when stimulated with EBOV GP-specific peptides.

Quote control group :In contrast we were unable to detect significant levels of virus-neutralizing antibodies directed against EBOV.

Lastly when challenging the vaccinated primates with live Ebola virus here is what happened to the control group, (i.e. the ones getting the rabies vaccination without the engineered ebola glycoprotein).

Quote : As expected, all animals in the control group had to be humanely euthanized according to approved protocol mainly based on high viremia at day 6 (Figure 3C) and rash. The animals of the control group failed to mount any EBOV GP-specific responses during the course of the Ebola virus disease.

So a common rabies vaccination ( and this is a vaccine using the whole of the rabies virus, meaning animals make immune resposes to all the rabies viral epitopes, not just part like some vaccines), still under these conditions offered no protection against Ebola, no antibodies, no CMI, and fatal on challenge, so not even partial protection.


Another explanation for the nuns and not the doctors getting infected may simply be in behavioural attitudes towards their patients. Some people feel that missionary aid workers do not always put their own safety first. Extreme compassion, need to comfort, coupled to a deep belief of a fate in gods hands, and even a belief of religious protection, can lead to nuns etc giving that bit more hands on care. Dr Brantly himself said he put his arms around relatives when he perhaps shouldn't have.

Another possibility is that the nuns probably lived together in quarters, sharing each others lives, toilet facilities etc, more than the doctors who were often seen as the captains of the ship and given more space and privacy.

I am just looking for other explanations because I can not think on a molecular or immunological mechanism of why a rabies vaccine would protect against Ebola. What epitope do they share etc ?.

Just my thoughts and I could be wrong.

 

[Emily]

Re: Discussion of possibility of immunization history & Ebola susceptibility

foxp3, thanks very much for taking the time to go through that paper. I have to admit I had gotten the impression from a quick read of something that a plain old rabies vaccine had given at some pre-exposure protection. But you have convinced me otherwise.

On the other hand, I don't think post exposure use has been tested, has it? I still wonder about the Peace Corps worker's case. (Not that that was Ebola, it does sound more like Bas-Congo. I bet there is a blood sample of his stored somewhere that could be tested now.)

There are certainly other reasons the international team scientists could have done well besides cross-over antibodies of some sort. The cultural differences are something I wondered about, too. But also I read that the team brought all their own medicines in oral formats - so no need for injections.

The nuns used mainly injections to deliver thousands of treatments per month at the hospital's clinic. There were only 5 syringes usually rinsed between patients and sometimes boiled at the end of the day. This was the way the initial case was amplified. The hospital had its own syringe and instrument supply. It was when the clinic, not the hospital, shut down that the epidemic was greatly curtailed.

So possibly nicks from the needles or actually needing to be treated for some illness themselves and getting an injection is what did in the nuns. Another possibility is nutritional status. The nuns had been eating a diet that was probably close to what their patients were eating.

There is a USDA article here on selenium status and RNA virus virulence:

http://www.flutrackers.com/forum/showthread.php?p=554137#post554137

 

[kiwibird]

Re: Discussion of possibility of immunization history & Ebola susceptibility

I have to disagree I am still not convinced vaccination against rabies gives any protection against Ebola....hear me out.


The aim of the 2013 paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667758/ )
was to make a rabies vaccine engineered to express an Ebola virus glycoprotein, so to make a 2 in one vaccine with greater market appeal, before this outbreak they was little market for Ebola vaccine.

Importantly you can see the negative experimental control group were vaccinated with the routine unmodified rabies virus (RABV) vaccine alongside their test groups which got the joined RABV/EBV vaccines. As expected this rabies vaccine on its own conferred absolutley no protection against Ebola in primates. It generated anti rabies antibodies as expected, but no Ebola antibodies, or Ebola driven cell mediated responses, and when animals were infected with EBV, they died. So in summary there was no protection against Ebola in primates immunised only against rabies, there was no cross protection, the anti rabies antibodies did not neutralise Ebola. The authors didn't expected it to, that's why the rabies vaccination on its own was the negative control ( vaccine composed of whole virus).

Here is some quotes from the study.

Quote :
all three vaccines and the control vaccine induced seroconversion against RABV. ( so they all produced antibodies against rabies virus).

Quote: The result presented in Figure 2C indicates that all four vaccines induced virus-neutralizing antibodies as early as 7 days after immunization. Notably, the VNA titers were well above the critical level of 0.5 international units (I.U.), which is considered protective from RABV infection in humans result presented in Figure 2C indicates that all four vaccines induced virus-neutralizing antibodies as early as 7 days after immunization.

So this is saying they not only was anti rabies antibodies produced, but they were functional and protective.

However when we look at what effect the control ( rabies vaccination alone) has on Ebola it has this to say.

Quote : animals of the control group did not mount any cellular responses when stimulated with EBOV GP-specific peptides.

Quote control group :In contrast we were unable to detect significant levels of virus-neutralizing antibodies directed against EBOV.

Lastly when challenging the vaccinated primates with live Ebola virus here is what happened to the control group, (i.e. the ones getting the rabies vaccination without the engineered ebola glycoprotein).

Quote : As expected, all animals in the control group had to be humanely euthanized according to approved protocol mainly based on high viremia at day 6 (Figure 3C) and rash. The animals of the control group failed to mount any EBOV GP-specific responses during the course of the Ebola virus disease.

So a common rabies vaccination ( and this is a vaccine using the whole of the rabies virus, meaning animals make immune resposes to all the rabies viral epitopes, not just part like some vaccines), still under these conditions offered no protection against Ebola, no antibodies, no CMI, and fatal on challenge, so not even partial protection.


Another explanation for the nuns and not the doctors getting infected may simply be in behavioural attitudes towards their patients. Some people feel that missionary aid workers do not always put their own safety first. Extreme compassion, need to comfort, coupled to a deep belief of a fate in gods hands, and even a belief of religious protection, can lead to nuns etc giving that bit more hands on care. Dr Brantly himself said he put his arms around relatives when he perhaps shouldn't have.

Another possibility is that the nuns probably lived together in quarters, sharing each others lives, toilet facilities etc, more than the doctors who were often seen as the captains of the ship and given more space and privacy.

I am just looking for other explanations because I can not think on a molecular or immunological mechanism of why a rabies vaccine would protect against Ebola. What epitope do they share etc ?.

Just my thoughts and I could be wrong.

Thank you very much foxp3 and Emily. I can't help but think what a pity they didn't give those poor wee monkeys an extra shot, as they did the Doctor in the original article. At the very least it would have answered a few questions. I am wondering if the RABV is different to the PDEV? You will probably know straight away. I know that there are two types of rabies vaccination available in the UK. I don't even know which one is given to the military here. Perhaps if I fiond the manufacturer they will have info available about who uses it currently. Will write again when I find out. It certainly bears investigating thoroughly - could make a huge difference to a lot of people. I know that New Zealand is selenium deficient because of the soil. I wonder if different continental African countries have deficiencies too... Thank you again both. Very interesting.

 

[gsgs]

Re: Discussion of possibility of immunization history & Ebola susceptibility

or genetical differences ?