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Infectious Diseases

Vaccines Against a Vanishing Virus?

Vaccines can be one of the most powerful and effective public health interventions, as experiences with smallpox and polio make clear. But vaccine development itself is quite difficult, which is why there are (relatively) few vaccines out there. Look at dengue, for example: it’s a longstanding viral problem in tropical areas, and would seem to be just the sort of thing that could be beaten down by a vaccination program. But there are four major serotypes, and immunity to one doesn’t translate to immunity to the others, which means that you’re going to have be be vaccinated all four ways. To make things worse, the second round of infection is often much worse than the first (if you get the third and fourth varieties later on, they’re usually milder by that point, anyway). Sanofi-Pasteur has been working in the area for years in full knowledge of these and other problems) and was able to launch a vaccine (Dengvaxia) in 2016.

But last fall, the company issued a warning update, since clinical evidence had accumulated showing that the second-worse-infection problem could actually be caused after treatment with the vaccine as well. The company recommended that the vaccine only be administered to people who had previously been infected, where it would indeed prevent subsequent round of dengue. The problem is, there’s no widely available test to check if you’ve been infected that first time or not – and if you haven’t, it seems that you really shouldn’t get Dengvaxia. As far as I know, this standoff remains unresolved.

Consider next the case of the Zika virus. In 2016 there was a flat-out epidemic of Zika infection in South and Central America, an especially serious problem given its apparent effects on the developing fetus. A number of companies started work on a Zika vaccine, because this looked like joining the (already too lengthy) list of endemic mosquito-borne diseases that come back around every year.

Something unexpected has happened, though: Zika cases in South America have done nothing but fall steeply from their 2016 peak. That was going to happen to some extent anyway as the southern hemisphere changed seasons, but although the virus did come back in 2017, it was at far lower levels. 2018 has been even lower. For example, in 2016, Puerto Rico, the US Virgin Islands, and American Samoa had 36,000 cases of Zika, but in 2017 there were 665, and the last numbers I saw for 2018 were about tenfold lower than that. Where did it go? It’s hard to answer a question like that one, but you have to wonder if the virus started causing some sort of competitive disadvantage in its mosquito vector (to pick one explanation).

That leaves the people developing a Zika vaccine in an unexpected situation: how do you test for efficacy in preventing a disease that no one is coming down with any more? And in populations where a large number of people already have immunity thanks to the 2015-2016 epidemic? Now, there’s definitely a chance that the virus could come back again – that sort of thing certainly happens. But there’s also no guarantee that the next round of it, if there is a next round, will have the same profile versus the vaccine. Whatever factor made the virus disappear as a human threat will have to change again for it to re-emerge, and we really don’t know what that would involve.

So that’s led to a proposal to deliberately infect people with Zika in order to have enough patients to test the vaccine in. That sounds a bit crazy at first, like contracting for some occasional random arson to keep the fire department in practice, but the “human challenge model” is a longstanding route of vaccine development (here are some reviews on its use in cholera, respiratory viruses, dengue, and in other areas). It’s not without its ethical challenges, though, of course, which have come up again with the Zika proposal. What are the long-term effects of Zika infection? What are the chances that trial subjects could spread the disease to others? What sort of safeguards are in place to prevent women in the study from becoming pregnant? A 2017 trial proposal at the NIH was put on hold after an ethics panel recommendation, but another one is in the works now.

If you’re going to prove that a Zika vaccine works, a human challenge may be the only way. Doing that with rhinovirus is considered completely acceptable, while doing that with (say) Ebola is completely not. Where on that spectrum does Zika fit? (Interestingly, some current dengue vaccine work is including Zika vaccination as a component, which makes one wonder how that part will eventually be tested as well). If Zika itself really has vanished, this will all be a moot point – but how can anyone be sure that it has?

29 comments on “Vaccines Against a Vanishing Virus?”

  1. Silly. And yet we have a “real” ID problem here in the US; Lyme disease! Where is my Lyme vaccine? I spend a lot of time outdoors and had a full-blown case back in 2015. Luckily they caught it right at the acute-to-chronic transition (yes, I had a screaming western blot, the rash was atypical and the bite site was never found!). A 30 day course of doxy cleared it up but due to shortages at the time the pharmacy would only dispense a week’s worth at a time.

    1. John Wayne says:

      There used to be a vaccine for Lyme disease, but it was litigated out of existence. There is a French company working on what will hopefully be a better version.

      https://www.historyofvaccines.org/content/articles/history-lyme-disease-vaccine

      1. Dwayne Lunsford says:

        Correct, I was at GSK when they rolled out Lymerix and got the first dose as it was free to employees. But they pulled it before I could continue the series. In hind-sight, OspA is a lousy antigen. My bets now are on a human version of the canine vaccine.

        See:
        https://www.news.vcu.edu/article/VCU_researcher_develops_Lyme_disease_diagnostic_and_comes_closer

        1. Chrispy says:

          Why is OspA bad? I thought it was pretty clever to target an antigen that was invariant, even if it was expressed only/mostly in the ticks.

          1. Jan says:

            Crossreactive OspA antibodies are implied in the pathogenesis of Lyme-associated arthritis, that’s also why the vaccine was taken from the market.

            Your can read more about that here:
            https://www.historyofvaccines.org/content/articles/history-lyme-disease-vaccine

  2. cynical1 says:

    Interesting post but don’t be surprised if the anti-vaccine crowd tries to use your post to their advantage. They’ll say, see, we don’t need to vaccinate our kids because all the viruses are going away anyway.

  3. myma says:

    I worked in vaccines for a while. At the time of the crest of the Zika outbreak, the company I was employed at was working on Zika vaccine, publicly announced. However, all the modelling showed that Zika was either going to blow all the way around the world by the time the vaccine was licensed, or would stay local and burn out. In either case the vaccine development would not work out timing-wise or financially, so within the company it was a low priority / low resource allocation. I have since moved on from vaccines, so I don’t know if that company is still in fact working on Zika vaccine but I would not surprised if it was even lower priority / lower resourced (and not publicly announced).

  4. exMEDCHEMER says:

    My favorite human challenge model is for norovirus – they give you a cup of purified norovirus and you swig it down. How desperate for money do you have to be to enroll in that one?

    1. Ted says:

      They should really just make it an option in the cruise itinerary…

      -t

      1. BernYeeBritches says:

        They could advertise “Weight Loss Clinics At Sea- Just show up”

        Ow, My Bowels!

        1. Thoryke says:

          They could certainly save a lot on the catering costs under those conditions — after the first meal or two, no one is eating much….

  5. Isidore says:

    A number of companies, including one where I was working at the time, submitted applications to US government funded agencies and departments, including the DoD, for contracts to develop Zika vaccine. Evidently there was quite a lot of money allocated for this purpose. I have no idea what happened with those vaccine development efforts and I have been unable to find any public information on this. You government at work!

    1. Isidumb says:

      “You (sic) government at work!”

      Yes, because the government should just ignore potential outbreaks until they become full-blown outbreaks, just in case they peter out like Zika.

      The government is at work, I just doubt that your brain is.

      1. Isidore says:

        Ah, grasping onto a typo to feel superior, well I am happy to have helped shore up your self esteem! The fact is that there was no oversight on the Zika vaccine program, the government just threw money at companies with sufficiently sleek PowerPoint presentations, I saw this first hand and heard the internal discussions, when everyone was salivating at the prospect of easy money, ostensibly to be used for vaccine development but in fact expected to be directed to a great extend towards funding existing programs, which is quite easy. I mean, if you buy, with the newfound money, a cell culture hood or an HPLC or hire a tech to support the vaccine program nobody will stop you from using it for your existing programs as well, even primarily so. Granted, this was one company but I bet it was not the only one. The government has a responsibility to ensure that when taxpayer money is spent in the private sector for some worthwhile effort, such as fighting a disease outbreak, there is strict accountability on how this money is spent. I would have thought that as a taxpayer (but perhaps you are not) you’d care where your tax money goes, I certainly do.

  6. bacillus says:

    Testing Zika vaccine by challenging human volunteers has problems in addition to those related to pregnancy. For instance, zika can continue to be ejaculated in semen for up to 6 months after initial infection. CDC recommends either abstinence or physical prophlaxis for at least this time after travelling to a Zika-endemic area. One way to avoid these issues woud be to use pre-pubescent children, though I doubt that would fly! Also, like Dengue, Zika is a flavivirus and could theoretically cause the same kinds of adverse reaction in individuals previously vaccinated against the former.

    1. DanielT says:

      Would not the simpler solution be to test in post-menopausal women?

    2. Zika vaccination is a challenge. The virus persists in whole blood for several months even in the presence of naturally acquired antibodies, making it likely that effective protection will require an immunisation regime capable of eliciting a long-lasting, high titre neutralising antibody response, even if deployed as an emergency measure to reduce outbreak associated microcephaly.

      Moreover, unlike other flavivirus infections, it remains to be established if Zika infection is actually susceptible to neutralising antibodies. The other significant unknown is whether vaccination will prevent infection of reproductive tissue (Zika virus is trophic for several cell types that assist it to cross the placenta to infect neural progenitor cells). Perversely, the latter property has been exploited in an investigational live attentuated virus vaccine that preferentially destroys glioblastoma stem cells.

  7. Glen Weaver says:

    While useful, it would not be a good use of resources. Getting rid of carrier mosquitoes eliminates many diseases once. Malaria, yellow fever and dengue were all endemic in Texas in my grandparents days. Decades long projects to improve drainage, screen houses, and (later) to poison mosquitoes wiped out all three of those. Money well spent, though some of the lessons seem to have been forgotten.

    1. Scott says:

      Yeah, DDT worked wonders to make malaria a thing of the past in the US and other rich nations.

      Then it got banned due to an incorrectly-assigned impact on bird eggshell thickness (test site had heavy metal contamination, other test sites did not how thin eggshells!), and now millions of people in the developing world are dead, with more dying every year.

      Straight up criminal behavior!

      1. JB says:

        You imply that DDT has no effects on bird survival. This is objectively and demonstrably wrong.

        There is a coordinated effort to discredit Rachel Carson and the research done on the harmful effects of DDT. Please read the Angewandte essay (DOI 10.1002/anie.201704077 ) linked in my name to find out more about it.

      2. Hap says:

        And resistance to it was already being seen in 1951, years before we banned it. So how was it going to kill malaria, again?

      3. aairfccha says:

        Malaria and yellow fever were eradicated from the Panama Canal Zone before DDT was even invented.

        https://en.wikipedia.org/wiki/Health_measures_during_the_construction_of_the_Panama_Canal

    2. Falanx says:

      You missed the bit where mosquitoes are a primary pollinator of some plant species, eh?

      1. C. Paul says:

        You missed the part where there are only a few human-preying mosquito species and dozens of non-human-preying who actually do that pollinating, eh?
        And there’s no need for DDT, the release of transgenic and bacteria-sterilized male mosquitoes, who do not bite humans, have been tested successfully in the wild and could be used to eliminate harmful mosquito populations while leaving helpful pollinators and the food chain intact.

  8. aairfccha says:

    Related if semi-OT: There could be an up-and-coming virus as monkeypox might be in the process of jumping the species barrier. Although since the source is the Daily Wail, YMMV.

    https://www.dailymail.co.uk/news/article-6216301/Nearly-40-years-defeated-smallpox-scientists-fear-new-deadly-plague-strike.html

    1. johnnyboy says:

      There are indeed 3 recent documented monkeypox cases in the UK. Humans are known to be sensitive to monkeypox infection though, and human-to-human transmission has been known to occur, so it’s not a case of it recently jumping the species barrier. So it’s not just the Daily Mail, though you’d wish the apes who work there would all come down with it.

  9. Calvin says:

    Derek, the situation is even worse. Vaccines for Dengue and Zika are now unlikely to ever be approved. Let me explain as you missed a few things about Dengue which are equally relevant to Zika.
    There are four serotype for Dengue, but the second infection is much worse (hence the break bone fever description) it is believed to be because of antibody dependent enhancement (ADE). ADE is the best explanation we’ve got; it’s pretty clear that after the first infection to immune system develops enhancing antibodies (you can isolate them) that prime the immune system for a negative reaction to the second infection (as long as it is a different serotype).

    Many people in the field always thought the Sanofi vaccine would act as Dengue serotype 5 and prime the immune system. It would make things worse. Sanofi knew this as has follow up to look for this, but only for 2 years (which they thought was reasonable), and they checked the infection status at immunization. In early 2015 it was an open secret that the Sanofi vaccine “had a problem” assumed to be ADE. Sure enough they published a paper in the NEJM (https://www.nejm.org/doi/full/10.1056/NEJMoa1506223) that clearly shows negative vaccine efficacy in those who are seronegative at immunization, Page 1202 (this was exactly why Sanofi were checking). At that point many in the field thought the whole thing was a dead duck, but to many people’s surprise, Sanofi went ahead. Note that they never sought regulatory approval from the FDA or EMEA. This was all done through the local regulators. It was the WHO who suggested the narrowed indication of using only in endemic areas and in older kids/adults as an attempt to make sure that kids were more likely to be sero positive at immunization. We all know what happened. I leave it to others to comment on Sanofi’s actions here.

    So what about Zika. Well we also know (Gavin Screaton at Imperial) that Zika and Dengue antibodies interact and may be enhancing each other. Given that Dengue, Zika and CHK are in the same mosquitoes, that is a problem. Some theories suggest the 2016 Zika outbreak had a dengue component. W

    But I think what this means is that dengue vaccines and Zika vaccines are all likely to have the same ADE issue and even if you could engineer that out, the regulators might want to see 5 years or more of follow up to prove that there was ADE. That sounds a bit….expensive.

    I absolutely would not want my immune system primed by a challenge model esp as these virus are moving north all the time ( and remember that Aedes Alb can survive happily in NE US climates even if it is not as an aggressive a biter as Aedes Egyp). This is going to be a place where anti-virals come to the fore.

    And don’t be fooled by Zika’s apparent disappearance. It’s still there. The issue is that the mosquitoes can only fly a few hundred yards and so it needs pretty specific conditions to allow them to move rapidly. Once they are in cities it’s easy for them, but getting into cities takes a bit of mix of factors. But it will be back.

  10. oliver says:

    Hi Derek,

    funny that you mention Puerto Rico. I have a theory about those low cases in 2017, funny thing happened, a hurrican devastated the island!!! Could this be a factor in the low cases of ZIKA in 2017 and maybe in 2018. People tend to die from other causes after a devastating hurricane that nearly annihilated the medical system and overwhelmed the morgues with dead people?
    Just a thought.
    Cheers Oliver

    1. Derek Lowe says:

      The exact same pattern was seen in Brazil and other countries.

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