Health and Science News for Parents
May
5

Making sense out of the baboon pertussis study

written by Tara Haelle

So it’s time for me to get a monkey off my back 😉 At long last, I’m going to write about the baboon pertussis study.

I’ve been meaning to write about this study pretty much since it came out last November, and I’ve had many requests to write about it. I did actually write a short piece on the study for Scientific American’s February issue, which you can read here. But at the time it came out, I had so much going on that it was tough to find time to write a blog post that covered everything I want to cover. I’ll try to do that here, and I’ll update the post with questions I may receive.

One of the most important things to know about this study is that it does NOT mean the vaccine gives people pertussis. That's not possible. Photo by Tara Haelle

One of the most important things to know about this study is that it does NOT mean the vaccine gives people pertussis. That’s not possible. Photo by Tara Haelle

First, a bit of background. The current vaccine for pertussis, or whooping cough, is the DTaP in children up to age 7 and Tdap for those aged 7 through adulthood. It also includes the diphtheria (D) and tetanus (T) vaccines. The little “a” stands for acellular because the vaccine only contains pieces of the pertussis bacterium, in contrast to this vaccine’s predecessor, the DTP (or DPT). The DTP, administered up through the late 1990s, included the whole cell of the pertussis bacterium that causes the disease. The DTP was pretty effective considering the rapid drop in pertussis cases that followed its introduction in the 1940s. But one of its possible side effects was a fever leading to a febrile seizure that occurred in about 6 to 9 out of every 100,000 children. Febrile seizures do not cause long-term problems, but they’re scary and parents wanted a less reactive vaccine. So the DTaP was introduced, followed shortly thereafter by the Tdap as a teen and adult booster.

For a while, everything was hunky dory: the vaccine did not cause the reactions seen with the DTP and for a short while pertussis rates remained low. But by the early 2000s, pertussis infection rates had begun to grow – fast. Part of the reason the rates increased was better detection: better diagnostic tests were developed and doctors learned to better recognize the illness. But those changes accounted for only a small proportion of the increase. It soon became apparent that the acellular pertussis vaccine just wasn’t as good as the old one. Evidence began mounting that the acellular vaccine’s immunity waned sooner, and whole-cell-vaccinated individuals were better protected in outbreaks than acellular-vaccinated ones. (Edit: It’s important to note, however, that not even the immunity from the whole-cell vaccine, or even infection-derived immunity, lasts a lifetime. According to a study from 2005, the vaccine immunity lasts 4-12 years and immunity from natural infection lasts 4-20 years.)

Since then, researchers have been trying to figure out why the acellular vaccine is less effective, what confers immunity with the pertussis vaccine and how to make a better vaccine. And that’s where the baboon study comes in: it was an attempt to better understand the acellular pertussis vaccine’s weaknesses.

Here’s what the researchers, led by the FDA’s Tod Merkel, did in the FDA-funded study: baby baboons were vaccinated at 2, 4 and 6 months old with either the acellular pertussis vaccine or the whole-cell pertussis vaccine. Then, both groups, as well as a group who had previously had a natural pertussis infection and a group that was neither previously infected nor vaccinated, were “challenged,” or intentionally infected, with pertussis at 7 months old. The researchers observed any symptoms the baboons developed and took cultures of their throats.

This graph from the paper shows the levels of colonization over the days following the pertussis challenge (intentional infection) for all four baboon groups.

This graph from the paper shows the levels of colonization over the days following the pertussis challenge (intentional infection) for all four baboon groups.

As expected, the previously infected baboons and all the vaccinated baboons showed no coughing or other disease symptoms whereas the unvaccinated baboons did suffer symptoms. But disease is different from infection, in which bacteria colonize in the animals’ throats. When the researchers tested colonization, they found that the acellular-vaccinated baboons took 35 days to clear the infection, slightly longer than the 30 days it took the unvaccinated baboons to clear it. Meanwhile none of the previously infected baboons were colonized, and the whole-cell vaccinated baboons cleared the infection in 18 days.

Next, the researchers tested whether an acellular-vaccinated baboon could develop the infection naturally. Two acellular-vaccinated baboons and one unvaccinated baboon were housed with an intentionally infected, unvaccinated baboon. Within a week to a week and a half, all three of the introduced baboons became infected with similar levels of throat colonization.

So, the researchers now knew the acellular-vaccinated baboons could be infected both intentionally and via natural transmission from another infected animal. But could they pass along that infection?

The final part of the experiment involved placing two acellular-vaccinated, intentionally infected baboons in individual cages and then adding an unvaccinated baboon to each cage. Sure enough, the two unvaccinated baboons each became ill from their acellular-vaccinted cage mates.

So here’s what they learned:

  • Whole-cell vaccinated animals cleared their infections twice as fast as acellular-vaccinated animals.
  • Acellular-vaccinated animals could catch the infection from another infected animal.
  • Acellular-vaccinated animals could transmit an infection to other unvaccinated animals.

Here is what we don’t know:

Because cocooning and herd immunity may not as helpful as we'd like, it's important to get the Tdap during pregnancy to protect your newborn. The antibodies your body creates will cross the placenta and last until your baby gets the first DTaP at two months.

Because cocooning and herd immunity may not as helpful as we’d like, it’s important to get the Tdap during pregnancy to protect your newborn. The antibodies your body creates will cross the placenta and last until your baby gets the first DTaP at two months. Photo by Tara Haelle

Does this happen in humans too? Baboons’ immune systems are very similar to humans, according to Tod Merkel, but “a direct translation of the data from baboons to humans is impossible,” he told me in a phone interview. If, however, these results are true in people, “it would suggest pertussis is going to circulate more in the population.” And that’s what the epidemiological evidence is showing. In fact, another pertussis expert, Eric Harville, said this study supports the suspicions that scientists already had: “The important thing that this paper shows is that what we believed can happen is happening. Now we have experimental evidence that pertussis can transmit in the absence of severe symptoms between vaccinated individuals.”

Update: Is there evidence besides this study that asymptomatic carriage of the disease can occur in humans? Yes, actually – with the whole cell vaccine. A study in 2000 that investigated a fatal case of pertussis at an Israeli daycare found that, of 46 children who had been fully vaccinated with DTP and had been exposed to the child with pertussis, five of them tested positive for pertussis – but only two of them showed disease symptoms. The authors wrote in their conclusion, “The whole-cell vaccine for pertussis is protective only against clinical disease, not against infection.” This study did not take throat cultures nor track the infection over time – it was epidemiological, not experimental – but it adds to the evidence for the idea that what was observed in baboons is potentially true for humans as well.

Can an acellular-vaccinated animal infect another acellular-vaccinated animal? The study did not test this question directly, and this is an important question because enough individuals vaccinated, even with a subpar vaccine, may still help reduce overall infection rates. Chances are unfortunately likely, however, that transmission can occur from one acellular-vaccinated animal to another.

Here is what it means:

So, as far as we know right now, there is a reasonably high likelihood that an acellular-pertussis-vaccinated human could contract pertussis, not know it, show no clinical symptoms, and pass it along to another person. Again, it’s based on an animal model, so it’s not a certainty. But baboons share more than 96% of our DNA and their immune systems operate almost indistinguishably from ours, so it’s highly likely that what occurred in the baboons occurs in humans as well.

The extent to which it occurs, and whether the R0 value is different, is unknown right now. (The R0 value refers to the number of people a person is likely to infect during the time period when they are carrying the infection and are contagious. The R0 for pertussis is 12-17 people.) I would expect it’s reasonable to ask whether the R0 for an infected, vaccinated individual is lower than the R0 for an infected, unvaccinated individual – especially considering the evidence that unvaccinated individuals contributed to the 2010 California whooping cough epidemic. One reason the R0 would plausibly be higher for an unvaccinated person is that they would show disease symptoms, namely coughing, and the severe, chronic coughing could increase the likelihood that the infected droplets are spread around them.

These findings also mean herd immunity may not be helping us much with the acellular pertussis vaccine. That doesn’t mean it’s nonexistent — we don’t know — but it’s certainly not going to be as strong as it would be with another vaccine.

Similarly, cocooning may not be as effective as we hoped either. Cocooning means those who will be around an unvaccinated person all get vaccinated to create a protective “cocoon” around the unvaccinated individual. I searched and searched, but there is not currently any published clinical evidence regarding the effectiveness of cocooning for pertussis. There are mathematical models estimating it, and there are a couple ongoing studies, one of which has preliminary results appearing to show some cocooning benefit. Regardless, I can tell you that with my son just 7 weeks old, I asked my parents and my in-laws to be sure they had gotten their Tdap boosters.

Above all, those I interviewed emphasized that this study means that it’s more important than ever that each person gets the vaccine to protect themselves since they cannot rely on herd immunity to help much.

Finally, other questions I have been asked:

The biggest question I’ve been asked – and the biggest misunderstanding about this study – is whether the vaccine itself causes asymptomatic infection. The answer is no. The pertussis components are not only inactivated (dead), but they aren’t even complete – it’s just pieces of the bacterium. The vaccine absolutely cannot give a person pertussis.

Does the vaccine shed? No. Only live vaccines have the potential to shed (which is very rare), and DTaP and Tdap are not live vaccines.

Can this vaccine reduce the risk of transmission of pertussis? That’s unknown right now. (See my R0 discussion above.)

Why bother getting the vaccine? To protect yourself. Whooping cough is awful.

How can you protect your newborn, who is too young to be vaccinated yet, from pertussis? Get the Tdap during pregnancy, as recommended by the CDC. It’s safe and effective (confirmed again in a study just a few days ago).

Can vaccinated people find out if they’re a carrier in case of exposure? A person could get tested if they KNOW they have been exposed. Otherwise, without symptoms, there is no reason a person would get tested.

What precautions should vaccinated individuals take to reduce risk of unknowingly spreading the disease? Usual hygiene: wash your hands regularly and always cover your mouth when you cough, preferably into your sleeve or shoulder.

Are there any other pertussis vaccines being developed? Yes, multiple teams, including Harville’s, are working on them, and there is a nasal vaccine being tested that shows some promise.

There you have it, folks. What other questions do you have?

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21 Responses to “Making sense out of the baboon pertussis study”

  1. Anna O'Connell

    I loved this article. I’ve read a few of your pieces and just want to say they are a breath of fresh air. Responsible, thorough, accessible b science journalism. We need more like you. Thanks!

  2. b

    If you have received the Tdap booster within the last year or two, do you still need the vaccine during pregnancy?

    • Tara Haelle

      Yes, it is still recommended because it ensures your developing child gets the highest concentration possible of your maternal antibodies. When you get it again in the third trimester, which is when the CDC officially recommends it for every pregnancy (even if you were pregnant the previous year and got it), your body makes new antibodies which cross the placenta to the fetus. After birth, newborns whose mothers got the Tdap during pregnancy have higher antibody concentrations for pertussis, which provide a bit of extra protection during those first few months before the child can get his/her first DTaP shot at 2 months.

      Here are two studies showing those results:
      http://www.ncbi.nlm.nih.gov/m/pubmed/23799518/
      http://jama.jamanetwork.com/Mobile/article.aspx?articleid=1866102

  3. Joanna

    I guess my question is: why not go back to the whole cell vaccine? I was told when getting vaccines for my son that any of them could cause a fever, some more than others, and that high fevers could cause febrile seizures. I have a friend whose daughter gets them and yes, it means some extra ER visits. But they’re not really dangerous, just scary, and wouldn’t a more effective vaccine be worth it?

    • Tara Haelle

      Joanna, if all parents thought about this issue the way you do, then we could return to the whole cell vaccine. In fact, that’s what Dr. James Cherry (in one of the links above) advocates. However, it’s difficult enough right now to persuade many parents that the tiny risks posed by vaccines outweigh their significant benefits. Fear is a powerful emotion, and the specter of serious reactions from vaccines in many parents’ minds has already been reducing vaccination rates across the country, even if their fears are not grounded in scientific fact.

      Several researchers I’ve spoken to, including some who are very outspoken promoters of vaccines in the general public, have told me they think there’s no going back to the whole cell vaccine. Even if the seizures are not harmful long-term, too many parents will not accept that risk, which was greater with the whole cell than with any of the other vaccines (though MMR comes close).

      The only way we could return to a whole-cell vaccine is to create one that’s less reactive than the old one, and there are research teams working on that. There’s also the nasal vaccine that shows promise, and there are teams working on other acellular vaccines and non-combination vaccines. Part of the challenge is that we don’t know what confers immunity with the pertussis vaccines, so researchers can’t try to exploit whatever that mechanism is without better understanding it. This study actually did illuminate some of that mechanism (I didn’t get into the weeds in this post with the immune cells that were and were not activated because it’s pretty technical), but there are teams working on it. Let’s hope they’re successful!

  4. Dorit Reiss

    I think Joanna’s question is an excellent one. We certainly need a better pertussis vaccine.
    I think politically, going back to whole cell would be hard if not impossible, though it could be a very, very good solution.

  5. MerinSun

    I fully vaccinate my kids and I fully appreciate the fact that the outcomes of vaccines outweigh the health risks of not vaccinating. However, I am also not comfortable writing off febrile seizures as being trivial or without long-term health consequences. The odds are pretty low, but febrile seizures can morph into epilepsy. It’s a percent of a percent, I believe, but the more kids who experience a febrile seizure (who otherwise wouldn’t) the more who may develop epilepsy because of it. If the choice came down to “get the full cell” or run a much higher risk of getting pertussis (being much more likely than epilepsy) I would choose the whole cell vaccine, but I’m just not comfortable with dismissing this side effect and am glad that they’re looking more seriously at other vaccine adaptations.

    • Tara Haelle

      This is something I’ve researched pretty extensively, and I haven’t found evidence that febrile seizures can lead to epilepsy. Do you have a source for that? I have seen a study finding that long-term outcomes in children who have epilepsy and experience a febrile seizure can be poorer (reduced cognitive functioning in a small but not insignificant percentage of epileptic kids who have a febrile seizure), but that is only true for children who already have epilepsy as an underlying condition, even though the febrile seizure may be their first seizure. I have not seen any evidence that febrile seizures can cause or induce epilepsy, and several studies that have looked specifically at that question have not found evidence for it. However, if I’ve missed some of the research, I would like to see it.

      Update/edit: I went digging and did find two studies finding a much higher risk for epilepsy among those who have experienced febrile seizures:
      http://www.ncbi.nlm.nih.gov/pubmed/22459683
      http://www.ncbi.nlm.nih.gov/pubmed/17267419

      However, it’s not clear whether the febrile seizures are thought to cause/contribute to epilepsy, or whether a person with an underlying propensity to have epilepsy has the condition triggered by a febrile seizure, or whether a person who was already going to develop epilepsy is more likely to have a febrile seizure. In other words, it’s an association, but causation doesn’t seem to be established — it’s a chicken/egg thing. I’m going to read those papers when I get a chance to see if they discuss the biological mechanisms more in depth. Being at increased risk for X if you experience Y doesn’t mean Y causes X. It means that if you have Y, you should also be on the lookout for X. It’s always possible that the fact that X is in your future is the reason you experienced Y. (Or, it’s possible that Y *does* cause X.) I’m curious if they know which direction the causation (if any) flows here.

  6. Carina

    I had the same question as Joanna. Taking it a step further, why don’t adults, instead of getting a TDaP booster, get the whole cell version? And, further to the notion of adult boosters, for those of us who received our childhood vaccination regimen before the DTaP, wouldn’t we have the whole cell version and thus have the stronger immunity? What is the history on the immunization schedule for those of us who know we followed it but don’t have our original records?

    • Tara Haelle

      I’m not sure if the whole cell vaccine was ever tested with adults or administered to adults. I would need to look into that. However, the answer to your second question is that yes, adults who received the whole cell vaccine would have stronger (or, more precisely, longer lasting) immunity, but even the immunity to the whole cell vaccine eventually wanes; it just takes a lot longer. In fact, even immunity from natural infection wanes with pertussis. It’s one of those diseases whose immunity, after you’ve had the disease, doesn’t remain for the rest of your life, unlike measles or chickenpox (for most people, since some rare individuals can catch measles or chickenpox twice). Previously, it wasn’t that big a deal if immunity waned for adults who had had the whole cell vaccine because overall cases were so long each year and vaccination coverage w the whole cell was high enough that herd immunity was effective in protecting adults. (For several decades, annual cases ranged from only 1,000-4,000 or so, with few or no deaths.) Poor immunity in adults has only become an issue as the disease has resurged. The main carriers of pertussis are kids aged 8-13, right when the DTaP has waned the most.

    • Tara Haelle

      In fact, this study shows that infection-acquired immunity to pertussis wanes at anywhere from 4-20 years: http://www.ncbi.nlm.nih.gov/m/pubmed/15876927/

      I may add that to my post.

  7. […] published in November 2013 in the Proceedings of the National Academy of Sciences (USA), and reviewed in much more detail by Tara Haelle, used a baboon model (a primate that is relatively genetically close to humans, though not a great […]

  8. Alison

    “As expected, the previously infected baboons and all the vaccinated baboons showed no coughing or other disease symptoms whereas the unvaccinated baboons did suffer symptoms. But disease is different from infection, in which bacteria colonize in the animals’ throats. When the researchers tested colonization, they found that the acellular-vaccinated baboons took 35 days to clear the infection, slightly longer than the 30 days it took the unvaccinated baboons to clear it. Meanwhile none of the previously infected baboons were colonized, and the whole-cell vaccinated baboons cleared the infection in 18 days.”

    So old vaccine means 18 days of infection, no vaccine 30 days, new vaccine 35 days? Is this right? Can you help me interpret to explain to an AV who posted. Thanks

    • Tara Haelle

      That’s correct — those who had the whole-cell (old) vaccine remains infected for an average of 18 days, those who were unvaccinated remained infected for an average of 30 days and those who had the new acellular vaccine were infected for an average of 35 days. The vaccine *DID NOT* give them the illness. The pathogen was intentionally exposed to them to do the experiment after the vaccinations.

      The question, then, is why did the infection last longer in the acellular-vaccinated baboons? First, I would need to go back to the study (can’t at this moment) to see if the difference was statistically significant. It may not have been (ie, it could have been chance that there was any difference at all between the length of infection in unvaxed vs. acell-vaxed). Second, I’m not an immunologist, so I cannot speak with authority on this, but I have wondered if one possibility might be that an unvaxed baboon’s immune system mounted a stronger defense to the infection because it was a worse pathogen (it wasn’t the attenuated vaccine version of the pathogen). If something keeps hitting you hard, then you hit as hard as you can back. If it’s only a mild concern, your body may not work as hard to clear the infection. That is *my* supposition, and I would need to ask an immunologist if that’s reasonable.

      The most likely question at this point is, why bother with the vaccine then? Two reasons: first, the disease is nasty and lasts for months. Why put yourself through that, especially when “natural” immunity from the disease ALSO does not last a lifetime? (And if it’s a baby, why risk death?) Second, there is still epidemiological evidence that vaccinated individuals contract the disease and pass it on far less than those who are unvaxed. It’s possible that one reason for this is the simple fact that the main symptom is coughing. If you’re coughing all over the place, you’re more likely to transmit it to others. If you are infected but not coughing at all, even though you may be contagious, you’re less likely to pass it on to others. And of course, if you have babies in the home, then there is evidence (not yet published – study is ongoing) out of Australia that cocooning does over some protection (though not as much as if the mother gets the Tdap while pregnant).

  9. […] though the evidence for cocooning is growing, there are some flaws to the idea that are still being investigated in various parts of the world. One of the concerns is that asymptomatic carriers of pertussis (who have been vaccinated) might […]

  10. […] A recent study hints at a possible explanation for the resurgence of pertussis that we are seeing. The study examined the transmission of pertussis in baboons who were immunized with the TDaP vaccine. They found that while vaccinated baboons did not exhibit any of the symptoms of pertussis, they were still able to contract the disease and pass it on to others. (For an in depth discussion of the study, check out Tara Haelle’s summary here.) […]

  11. vero

    I’ve been getting into it recently with some anti-vaxxers. I’ve noticed a propensity to say, “Vaccines cause X,” when in fact a specific vaccine causes X and the rest do not. But there seems to be a tendency in their minds to just lump all vaccines together.

    One thing that baffled me in my first skirmish was that they did not believe in herd immunity. Just flat out did not believe it existed. And now I have an inkling of where they got their kernel of truth to then misinterpret and misrepresent. Instead of saying “The pertussis vaccine doesn’t result in herd immunity,” they’ll say, “vaccines don’t result in herd immunity.”

    • Tara Haelle

      Yes, I’ve unfortunately heard those arguments many times before also. Even before this study, however, anti-vaccine advocates have attempted to argue that “herd immunity is a myth,” though their logic was always faulty, and they had no evidence. And yes, they do frequently conflate one risk with another. That’s how “MMR causes autism” jumped to “vaccines cause autism” and “flu vaccines increases risk of Guillain Barre syndrome” jumped to “vaccines cause neurological and autoimmune disorders.” It’s frustrating and maddening.

  12. Amy

    Hi Tara,
    Do you think that an un-vaccinated person infected with pertussis would likely have a much higher bacterial load than a vaccinated infected person and therefore is much more likely to infect others? Do you know of any epidemiological studies which show that un-vaccinated pertussis carriers infect more people?

    • Tara Haelle

      I’m not aware of epidemiological studies looking at the bacterial load in vaccinated and unvaccinated persons with pertussis or looking at transmission rates, but this baboon study actually did measure the bacterial load in the vaccinated and unvaccinated baboons and found the load higher in those who had been unvaccinated than in those who received the acellular vaccine. If we presume that the baboon model is the most closely representative one for humans, then it would follow that the bacterial load in vaccinated individuals with pertussis would be lower than the load in unvaccinated individuals with pertussis. In addition, since the vaccinated ones are not showing symptoms of the disease, they would not be coughing, which is the the most common way pertussis is transmitted. That doesn’t mean they can’t transmit it, but they’re going to infect far, far fewer people if they’re not coughing all over the place. So, both because of the bacterial load difference and because of the coughing, yes, the evidence strongly suggests that an unvaccinated person would be more likely to infect others than a vaccinated one even if both had bacterial colonization of pertussis.

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