I have received many questions about whether immunizing with Reston virus could protect against infection with Ebola virus. Usually the question comes together with the statement ‘because Reston virus does not cause disease in humans’. I can think of two reasons why a Reston virus vaccine is not a good idea.
There have been very few confirmed human infections with Reston virus (4 according to Fields Virology 6th Edition), and although these individuals did not show signs of disease, the number is too small to make any conclusions. For example, if the case fatality ratio of Reston virus in humans were 1%, we might not have yet seen any deaths due to the small number of confirmed infections. However if we were to immunize a million people with a Reston virus vaccine, and the case fatality ratio were 1%, there would be 10,000 deaths, obviously an unacceptable rate for a vaccine. As the virus causes disease in nonhuman primates, and there are so few human infections, it is not possible to know the case fatality ratio.
The other problem is that in general, infection with one of the Ebolaviruses does not confer protection against the others*. For example, animals that survive challenge with Ebola virus (Zaire) are not protected from infection with Sudan virus. For this reason, vaccines need to be prepared against representatives of all the species. I am not aware of any animal studies that have assessed whether Reston virus infection protects from infection with the other Ebolaviruses, but there is no reason to believe that such cross-protection would be achieved.
Vaccines are currently being tested against Ebola virus (species Zaire ebolavirus), cause of the outbreak in west Africa.
*Thanks to Andrea Marzi for information on cross-protection.
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“However if we were to immunize a million people with a Reston virus
vaccine, and the case fatality ratio were 1%, there would be 10,000
deaths, obviously an unacceptable rate for a vaccine”
There is no effective immunization which is 100% safe. The only effective vaccines are ones that cause disease in a small % of the patients.
somewhat off topic q about antigens my background is not biology: is it possible to detect antibodies maybe through immunostaning, for instance as a test to see if plasma transfussion was responsible for someones recovery to ebola..
These answers are not based on scientific studies. These are opinions. There are no death or illnesses attributed to Ebola Reston in humans; that’s a fact. I like to see if those who were positive to Ebola Reston antibody would be immune to Ebola Zaire using scientific testing, not opinions. The use of cowpox virus as a vaccine proved to be quite effective in eliminating smallpox and there were lots of doubters that it would work during Dr. Edward Jenner’s time. Because Ebola Reston is lethal to apes but harmless to humans is a well-known fact, humans should be used for effectiveness trial.
Addendum: The extremely effective use of cowpox virus as smallpox vaccine didn’t involve millions of $$$ research grants, modern virology, modern immunology. It was purely observation and let’s not forget pure will to fight against public opinion. Look at some comic caricature of people getting the vaccine developing cow appendages, done purely to mock Dr. Edward Jenner.
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The trick to your proposed experiment is that it involves infecting humans with one of the Ebola strains to test whether they are immune to Ebola – hugely unethical. As Dr. Racaniello says, the evidence shows that surviving infection with one strain (species) of Ebola doesn’t protect you from infection with another strain. I’m not sure where opinion comes in to it…
Cowpox (actually, if you listen to the TWiV podcast, more likely horsepox) and smallpox is a great example where infection (or vaccination) with one virus family member protects from infection by another species within the same family (Poxivridae). However, Measles and Mumps are viruses in the same family (Paramyxoviridae), and we must vaccinate against both of the with the MMR, since they do not cross-protect. Likewise, the MMR vaccine does not protect people from infection with Hendra and Nipah viruses, despite them also being Paramyxoviridae members. The lesson here is that while we can try to hypothesize about Ebola based on examples from other virus families, it’s important to look for counter-examples elsewhere in the biological world (or even just in the virological world) and examine the available evidence before making sweeping claims about the use of one infection to combat another.
Sorry to pick on you, but in response to this – we’ve established good vaccines against the low-hanging fruit, the stuff that is easy to vaccinate against, where we know that infection leads to immunity, and we have significant portions of the population that may encounter the pathogen so we can see whether the vaccine actually worked.
The vaccines that involve millions of $$$ in research grants, and modern virological and immunological approaches, are against pathogens where infection doesn’t necessarily lead to immunity (you can get re-infected; Norovirus, Hepatitis C), where an antibody response is ineffecive or down-right dangerous (RSV), where the virus is excellent at avoiding and subverting the immune response for long periods of time (HIV), or where we have little opportunity to test whether the vaccine actually protects humans from infection due to rarity of outbreaks or serious ethical concerns (Ebolaviruses). Believe it or not, we (researchers) are actually dedicated to the cause of protecting humans and animals from harmful infection – we’re certainly not in it for the lifestyle or the money.
It’s true, there are no vaccines that are 100% safe, but that’s not a good reason to stop trying to make them safer! In particular, when vaccinating people you need the risk of harm from the vaccination to be lower than the risk of harm from infection with the disease, and for the vaccination to work. None of these things have been established with the use of Ebola Reston in humans.
Good question, but it’s more complicated than what you are proposing. We currently can’t differentiate between antibodies from one person versus antibodies from another – so while we could find out if the survivor has antibodies to Ebola (the antigen) in his/her serum, we would not be able to tell whether they were his/her own antibodies, or whether they were from the plasma transfusion from the other person. Additionally, we wouldn’t actually know whether the antibodies were responsible for the person surviving – just because they’re there doesn’t mean they were doing anything. This is where clinical trials come in, but the ethics are extremely difficult to navigate, especially since animal data is inconclusive (passive immunization – serum from previously infected animals – doesn’t seem to have much of an effect, if I recall correctly).
1. Find out if those already exposed to Ebola Reston might be immune to the deadly Ebola Zaire, Look for those researchers, monkey handlers, and pig farmers who seroconverted to E. Rest on.
2. See if their sera can neutralize Ebola Zaire.
I’m not questioning the motive that you have. I’m merely pointing out that the effectiveness of cowpox on those English milkmaids against smallpox is beyond question. Horse pox ? English milkmaids don’t milk horse. That’s in Mongolia where mares milk is fermented to make ‘milk beer’ or komiz.
I don’t see as to who it can be “unethical” when a proven to be harmless virus such as the Ebola Reston can be unethical if inoculated to humans. Nobody has died or even gotten sick from Ebola Reston. How about testing if the sera of those who seroconverted upon exposure to Ebola Reston, can it neutralize the deadly Ebola Zaire ? If you know already that it’s not going to work, that’s not scientific research, that’s an opinion that has to be tested with experimentation. This is the time when I wish I had a few million dollars purely to study Ebola Reston as a virus and those who were exposed to it. LOL but really I mean it seriously.
Ah the unethical part of it (as I understood your original question) would have been “challenging” people with the Ebola Zaire etc. However, we actually don’t know that Ebola Reston is harmless in humans, only that we haven’t seen humans get sick from it yet – but there aren’t a lot of humans that we know actually got exposed to the virus.
There was a group who did test serum from people who demonstrated antibodies against Ebola Reston for their cross-reactivity against the other species of Ebola (http://www.ncbi.nlm.nih.gov/pubmed/21666792), and there was some weak cross-reactivity (the Reston serum did bind some proteins from the other Ebolavirus species), but they never tested whether that interfered with infection at all (whether the serum could actually neutralize the virus), so you’re right, your question does remain unanswered. It would not be surprising if someone is looking at that though – not to use wild-type Reston infection as a vaccine, but maybe an attenuated, or killed/inactivated Reston? Or maybe just glycoproteins from Reston?
I guess I replied to your points above, but re: the smallpox, I was commenting that the virus we ended up using to vaccinate the world against smallpox was actually probably an extinct horsepox virus; the one Jenner observed/used was most likely cowpox as you say. There’s a good TWiV episode from earlier this year where Rich Condit talks about that, and it’s come up in earlier TWiVs as well.
Nobody has died or gotten sick from Ebola Reston. I’m referring to the monkey handlers and pig farmers in the Philippines as well as the researchers in Reston, Virginia.
They were handling those animals before they died. The Hazmat suit were donned after viruses that are identical to Ebola were noted in the Electron Microscope ! Yes, some became seroconverted to Ebola Reston, infected but not sick, nor did they die. I want those folks. I want their sera, I want to see if their blood will tell us if they’re already immune to this spreading deadly Ebola (without inflicting harm on them of course). Where are those folks who worked with Ebola Reston before ? The world needs you !
What inspired Dr. Edward Jenner on smallpox vaccination is that when he was growing up he heard this milkmaid uttered that she would never get smallpox because she had already cowpox ! Fast forward to the present, I like to see those exposed to Ebola say that they can’t get sick of Ebola because they had Ebola, the harmless kind already.
I truly respect you for the dialogue that we have. I did a lot of reading and attented lots of conference as part of Homeland Preparedness about these microbes that can be weaponized. What interested me a lot is smallpox.
While we haven’t seen anyone get sick from Ebola Reston yet, there still haven’t been a lot of people exposed to it. There were workers in the Philippines, and in the labs in the US, that were exposed to infected pigs, and some of them seroconverted, while others didn’t. This suggests that the virus might not be that infectious in humans (the people who didn’t seroconvert), and that it might not always be pathogenic (seroconverted but didn’t get sick). However, there are a lot of viruses out there that don’t hurt /most/ people, but do kill others – viruses such as Epstein Barr virus, where some people never show signs of infection, others get vague flu-like symptoms, and then others get “Mono,” or develop Lymphoma. BK and JC viruses are excellent examples of viruses that silently infect most people with absolutely no symptoms – until someone who is immunocompromised becomes infected, or the virus “reactivates” because the immune system isn’t keeping it under control. and the virus wreaks havoc in various organ systems, becoming highly pathogenic. Things like this are why simply infecting people with wild-type Ebola Reston will never be a good vaccine: we don’t know what it will do to different parts of the population, like if there are genetic mutations that render people highly susceptible to fulminant (hemorrhagic, even) infection, and the risk for most people in the world of getting Ebola is still extremely low, so the potential cost of the “vaccination” (infection) would outweigh any potential benefit. An attentuated, or killed version of Reston is not unfeasible, though, (if we found evidence of cross-protection) as that would significantly reduce or eliminate much of the risk.
(The idea of smallpox weaponization nauseates me – I am thankful that it would be extremely difficult, and far more likely to kill the weaponizer than the intended targets.)
Let’s get those folks who seroconverted and see if they’ve developed humoral and cellular cross-immunity. Where are you. THE WORLD NEEDS YOU. We don’t really have to duplicate the bold approach of Dr. Edward Jenner which will never be FDA approved nor passed by the Ethics Committee. Of course mutation can bring a lot of endless possibilities however that should not stop the pursuit of studying this idea ! In Dr. Edward Jenner time, comic caricatures showed vaccinee developing cow appendages. Even “experts” disagreed with him.
Again, where are those who seroconverted ? Are they dead already ? If they died from Ebola Reston let this idea be put to rest !
Would it be possible to tag the antibodies transfused? but nevertheless…how meaningful would it be… as you said! With no proper experimentation and controls survival is just under too many variables… I “imagine” that experimentation would be thought as unethical thou LOL!
What you mean by a non alive and live virus
I once wondered the same. But researching differences between DNA viruses like smallpox VA RNA viruses like Ebola answered a lot of questions .
Mutation rates, etc
Reston did not have many human hosts. Certainly not enough for us to say it is harmless. Lassa fever is asymptomatic in 80-90% of people who have it, but becomes hemoragic in the other 10-15%.
No need to chance