Ebola virus vaccine vs. HIV vaccine like comparing apples to oranges

I am getting frustrated with everyone saying that since we’ve not found a vaccine for HIV, we’ll never find one for Ebola virus. Being involved in vaccine research, and having previous experience with studying HIV recombination and mutation rates, here’s my take on why there’s little comparison between the two.

While both Ebolavirus and HIV are RNA viruses, there are key differences that make comparing vaccine development between the two akin to comparing apples and oranges. There are two general classes of RNA viruses, those that don’t have a DNA phase, and those that do. The ones that lack a DNA phases are by far the most common, and viruses of this type can be further broken down into four subgroups based upon the strandedness and polarity of their genome. These four subgroups are positive sense (+) single-stranded (ss) RNA viruses, negative (-) ssRNA viruses, double-stranded (ds) RNA viruses, and ambisense ssRNA viruses. Effective vaccines have been made to prevent infection with viruses of each of these subtypes, with the exception of the latter. Viruses that do require a DNA intermediate are known as retroviruses, and thus far no effective vaccine against any retrovirus has approved.

The Ebolavirus genus, a class of -ssRNA virus, belongs to the first group, as members of this genus replicate without a DNA phase. Upon entry into a host cell, the viral RNA is transcribed into a complementary template known as messenger (m)RNA. This newly transcribed strand serves a dual purpose, being translated to give rise to the viral proteins, and also serving as a template for the synthesis of new -ssRNA. The newly replicated -ssRNA strands are then packaged by the viral proteins and replication is complete. As with all viruses that replicate without a DNA phase, there are somewhat frequent transcriptional errors that give rise to nucleotide substitutions, resulting in either synonymous or non-synonymous mutations. In synonymous mutations, the mismatched base still codes for the same amino acid as the original one, meaning the transcribed protein is unchanged. In non-synonymous mutations a new amino acid is coded for, and the protein itself is changed. In DNA viruses, as with host cells, DNA undergoes proof-reading, with incorrect bases being excised and the correct ones inserted. RNA viruses lack proof-reading capabilities, hence their higher mutation rate. The substitution rate of Ebola virus, the genus member responsible for the current outbreak, has been found to be 8 × 10−4 per site PER YEAR, including both synonymous and non-synonymous mutations.

In contrast to viruses that don’t use a DNA intermediate, retroviruses, such as HIV, have a much more complex replication system. Each retrovirus virion contains two complete genomes, each of which is comprised of +ssRNA. Unlike other +ssRNA viruses, rather than immediately transcribing the RNA, the virus first uses an enzyme called reverse transcriptase (RT), which reverse transcribes the viral RNA into an RNA/DNA double helix, degrades the RNA, and then creates a complement of the newly created DNA, resulting in the formation of the DNA double helix. At this point, another enzyme, integrase, transports the viral helix into the nucleus of the cell and inserts it into the host cell’s genome. Once the viral DNA has been incorporated into the host cell’s DNA, that particular cell will ALWAYS be infected with HIV. The host cell’s machinery that normally transcribes human genes then transcribes the viral DNA, giving rise to mRNA that then exits the nucleus. Once in the cytoplasm, the viral mRNA is translated to form new viral proteins. Two strands of the genome are packaged by the viral proteins, and replication is complete.

Replication of retroviruses is incredibly rapid, with billions of replication cycles occurring per day. Additionally, they have incredibly high mutation rates, with HIV-1 having a mutation rate of about 2.2-5.4 × 10-5 PER CYCLE. Two aspects of the retrovirus replication cycle are responsible for this phenomenally high mutation rate. Firstly, reverse transcriptase (RT) is highly error prone. There is no proof-reading, and if the wrong base is inserted, it stays inserted. Secondly, during reverse transcription, RT hops from one genome to the other, in a process known as recombination. This is particularly problematic with HIV-1, as there are multiple subtypes of the virus. There are four identified subtypes of HIV-1, M, N, O, and P. Of these, both M and O can be broken down into sub-subtypes, with subtype M having 11 distinct clades. When an individual Is infected with multiple subtypes, or clades, recombination results in a progeny virus that may be very dissimilar to its progenitors. To date, 66 circulating recombinant forms (CRFs) (viruses with genomes with unique sequences derived from recombination between two or more subtypes that have been identified in three or more patients) of HIV-1 subtype M have been identified, though thousands more unique recombinant forms (URFs) have been found. To add to this, the vast majority of HIV patients haven’t had their viruses genotyped, and with the high mutation and recombination rates, a genome prevalent in a patient today may be undetectable tomorrow. Because of this, it is highly likely that are hundreds, if not thousands, of CRFs that have not been identified, and probably millions of URFs.

With Ebola virus, we need ONE vaccine. With the huge diversity between HIV subtypes, clades, CRFs, and URFs, there is virtually no chance that any one vaccine will ever be effective against all forms of the virus. Once a person is infected, they stay infected until every single infected cell dies, and with the high mutation and recombination rates there’s always going to be the possibility that the vaccine that worked on the virions produced yesterday won’t be effective on the ones produced today. It’s a very daunting challenge, though not insurmountable. There are regions of the genome that are highly prone to recombination and others that appear to be resistant, and it is possible that while one vaccine alone won’t be effective, a combination of multiple vaccines might do the trick. A couple of weeks ago, I went to a seminar given by someone who’s had great success with a vaccine against one particular clade and was in the midst of animal trials with a vaccine against another, and if that one worked as well, she was planning on testing both with CRFs of the two clades

And just to top it all off, here’s a listing of some RNA viruses that we’ve found vaccinations for:
Canine distemper virus (+)
Smallpox virus (+)
Rubella virus (+)
Feline calicivirus (+)
Equine arteritis virus (+)
Porcine reproductive and respiratory syndrome virus (+)
Foot and mouth disease virus (+)
Duck hepatitis virus (+)
Porcine teschovirus (+)
Japanese encephalitis virus (+)
Tick-borne encephalitis virus (+)
West Nile virus (equine only) (+)
Yellow fever virus (+)
Bovine diarrhea virus (+)
Classical swine fever virus (+)
Bovine ephemeral fever virus (-)
Measles virus (-)
Mumps (-)
Rabies virus (-)
Influenza virus (-)
Infectious bursal disease virus (ds)
Bluetongue virus (ds)
African horse sickness virus (ds)
Epizootic hemorrhagic disease virus (ds)
Rotavirus (ds)

http://www.sciencemag.org/content/345/6202/1369.full

http://www.hiv.lanl.gov/content/sequence/HelpDocs/subtypes-more.html

Wow! That was a very thorough explanation! I particularly liked the list of RNA viruses for which we have developed vaccines, it’s encouraging.

Bravo!

Ebola does target some immune cells, but does not become a permanent part of the targeted cell’s DNA. So where a cure for HIV would require somehow ferreting out those infected cells, the same is not the case for Ebola.

Interesting. Thanks for info!

Sincere thanks for the detailed post.

What was the average development time for those vaccines, from “it’s not a problem [we need to apply resources to | we have resources to apply to]” to “problem solved”?

Interesting, thanks.

I thought one of the reasons HIV was hard to fight was because it covered itself in sugars that tricked the host’s immune system into not attacking it. Looking online I can’t find that cite but I did find some things about vpu which may be what I was reading about originally. Does ebola have anything similar to this to mask itself from the immune system?

I had read that Ebola has some immunosuppressive motifs in common with Rabies, your explanation was awesome. Thank you!

It’a kind of hard to put a timeline on this. With the majority of viruses that have been found to cause significant human disease in the western world, the need for a vaccine was drastic, and funding was plentiful. For example, for over a century rubella was thought to be a mild form of measles that was more of an inconvenience that something to be feared. In 1941, following an epidemic in Australia, an ophthalmologist noted a correlation between rubella infection during pregnancy and congenital cataracts in infants, but this information didn’t really have much of an impact on the world of virology at the time. A subsequent pandemic throughout Europe and North America between 1962 and 1965 finally brought the disease to the world’s attention. Prior to this pandemic, the causative agent had never been isolated, but now that rubella was the “in” thing, the virus was isolated in 1962 and a a vaccine was licensed and available seven years later in 1969.

In contrast, a family of rotaviruses cause severe diarrhea, predominately in children five and younger. While children in developed nations are sometimes affected by these viruses, we’ve had medicines to suppress diarrhea and hydration therapy and electrolyte replacement available here for years. For us, rotaviruses truly are an inconvenience, but only very, very rarely are they a true problem. In contrast, it’s estimated that 450,000 children a year die due to rotavirus infection in developing nations. We’ve had rotaviruses isolated since 1973, but these were considered a low priority and nobody actively sought a vaccine for them for years. It wasn’t until thirty-three years after their discovery that a safe and effective vaccine was finally licensed in 2006.

The major issue really is funding. While exotic and deadly diseases like ebola and the henipaviruses (popularized in Contagion) are quick to draw media and Hollywood attention, they’re still perceived as abstract, something affecting others and somebody else’s problem. While of course there are always going to be researchers studying these, research is expensive, especially so when working with an organism that requires an enhanced biosafety level, and their funding source may not allow for vaccine development. If vaccine development is included in their funding, it’s typically only a small percentage. Therefore, researchers studying these organisms usually lack the funding necessary to do studies on vaccine efficacy beyond tissue culture and/or rodent studies. I can attest all to well that the results you get in in vitro studies are often not recapitulated in vivo, and what works in rodents may not work in primates.

And of course, once you do have a vaccine that’s been demonstrated to be effective in primates, you’ve got to go through clinical trials to ensure safety and efficacy in humans. This in itself can take as long as it took to develop the vaccine in the first place, though if the need is great, it can be greatly expedited.

As an anecdote, I’m currently in year 1 of a very well-funded vaccine development project with funding for six years. My particular organism is particularly intractable, but even so, I hope to begin mouse trials with my first candidate vaccine in year 2, guinea pig trials in year 2 or 3, at the latest, and primate trials in year 4. Of course, none of this is written in stone, and as I said above, what works in one organism may not be effective in another. Thus every stage of the process is ongoing, and we’ll have to keep identifying new vaccine candidates each step of the way.

With ebolavirus, we’ve got a head-start already, as several candidate vaccines have already been tested and shown to be effective in primates. One of these, manufactured by GlaxoKlineSmith is already undergoing human trials and another is being sent by Canada to WHO tomorrow, so that they can start trials with it.

Wesley Clark, I’ll answer your question in more detail tomorrow, but short answer yes. Sorry, but I’ve got to get to bed!

Best ebola thread on the boards.

An apple a day keeps the doctor away.

Ebola does too. :smiley:
I guess HIV is more like oranges.

Thanks for starting this thread and providing so much insight.

Do you happen to know whether or not there have been promising vaccines that worked great on other great apes, but not on humans? IOW, once the vaccines are proven to work on great apes, is there a sense of “now we’ve got it!” or are the human trials more like “well, anything can still happen now … fingers crossed”?

If I may throw out another question:

Do the quoted facts about retroviruses explain why HIV can be spread even while the virus is in its incubation phase (does HIV even have an appreciable incubation phase?)?

I was discussing Ebola transmission on another board, and I repeated that those infected with Ebola were not contagious during the incubation period. Then I said, off-the-cuff, that as far as I was aware, ALL viruses were like that. Someone answered back that HIV was a exception. We were both left wondering whether HIV was kind of/sort of unique in that aspect, or if in fact many viruses can be spread during incubation.

I don’t know jack about retroviruses in general, but I have a fair knowledge about HIV safety, and this is the first time I’ve heard this. After the initial infection, which is like an exceptionally bad flu, the viral load in the body drops and the victim stops presenting symptoms, while remaining infectious. But I don’t think this is an incubation phase - the victim isn’t going to get any sicker from the HIV itself. It’s the wide range of opportunistic infections and cancers that finish the job.

Wonderful OP and thread. Worth the price of admission. I had never had any idea why HIV was so hard to discover a vaccine for.

Imagine if we had started working on an Ebola vaccine when the disease first appeared. Prevention is always cheaper than remediation.

Yeah, I am wondering if HIV’s quick replication (citing Amberlei) essentially means it actually has no appreciable incubation period at all. Perhaps: “Sure, there’s an incubation period after HIV infection … all of 10 minutes.” Or something like that.