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.

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.

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:

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 R 0 value is different, is unknown right now. (The R 0 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 R 0 for pertussis is 12-17 people.) I would expect it’s reasonable to ask whether the R 0 for an infected, vaccinated individual is lower than the R 0 for an infected, unvaccinated individual – especially considering the evidence that unvaccinated individuals contributed to the 2010 California whooping cough epidemic. One reason the R 0 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 R 0 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?