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Whooping cough bounces back

Replacement vaccine is not so great at protecting kids

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2:00pm, April 4, 2014

PERTUSSIS REDUX  Whooping cough, a disease nearly vanquished in the United States in the 1970s, has made a comeback that coincides with a change in vaccines.

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Whooping cough has turned up in North America after decades of near absence, and we have only ourselves to blame.

In the last several years, the highly contagious microbe that causes whooping cough has spawned a string of outbreaks, adeptly piercing the shield of vaccination that once afforded solid protection against it. The last time whooping cough was this pervasive in the United States, Dwight Eisenhower was president and newscasters were smoking cigarettes on TV.

Caused by the Bordetella pertussis bacterium, whooping cough is emerging from the shadows in response to a fateful switch of vaccines embraced in the 1990s, just when it seemed the disease was licked. The vaccine used today has proved less potent than its predecessor. Meanwhile, curious changes are appearing in the pertussis bacterium itself, possibly in response to the weaker vaccine, and they may further undermine its effect. To top it off, a phobia against vaccines has induced some parents to skip or delay their kids’ shots, contributing to the disease’s spread.

“The newer vaccine’s protection wanes over time, the pathogen is morphing and more patients aren’t getting vaccinated on time,” says Jason Glanz, an epidemiologist at the University of Colorado Denver and the Kaiser Permanente Institute for Health Research Colorado. “Put them together and you get greatly increased risk.”

A worrisome trend

Whooping cough, also called pertussis, is easy to catch and hard to shake. The trademark symptom is three weeks of a wrenching, can’t-catch-your-breath cough, but it can last longer. The disease is treatable with antibiotics early on. But by the time the coughing starts, the bacteria targeted by these drugs have left behind toxins that infiltrate cells lining the airways of the body. Whooping cough can be fatal in infants, often by leading to pneumonia.

In its prevaccination heyday in the 1930s, whooping cough was a major problem, sickening between 100,000 and 265,000 people a year in the United States. But after scientists developed a vaccine and put it to use (combined with vaccines for diphtheria and tetanus) in the 1940s, cases dropped steadily to a low of 1,010 in 1976. From then until the 1990s, many doctors rarely saw a case.

U.S. cases stayed well below 5,000 per year until 1993. But during the 1990s, the newer vaccine (also with diphtheria and tetanus vaccines) replaced the old one and rates began to rise. California’s 2010 outbreak reached epidemic proportions, with 9,120 people sickened and 10 infants dead. In 2012, the state of Washington reported 4,916 cases, Minnesota 4,142 and Wisconsin 6,880. The Centers for Disease Control and Prevention tallied more than 48,000 cases nationwide that year, including 20 deaths. The 2012 toll was the highest since 1955. Canada, Australia and Europe have also had recent bouts with pertussis after adopting the newer vaccine.

Yet many poor countries have dodged the problem, maintaining low infection rates by sticking with the older vaccine.

The West appears loath to go back to the older, tougher vaccine out of fear that its dramatic but harmless side effects might further put off parents already dubious about vaccinating their children. So health officials are exploring ways to improve the newer vaccine. Devising, testing and getting approval for a more potent version, however, could take up to a decade.

Side effects backlash

People in the United States who are in their late teens or older probably received one of several old pertussis vaccines. That inactivated, whole-cell vaccine offers up the full pertussis bacterium, bristling with scores of proteins that our bodies recognize as foreign and build an immune response against. The resulting all-hands-on-deck response engenders immune memory that will awaken when faced with a live pertussis bacterium, even years later.

But the whole-cell vaccine’s rampant immune reaction carries a downside. Babies commonly run fevers, get agitated and feel pain at the injection site. “Those babies are really unhappy,” says James Cherry, a semiretired infectious disease physician at the UCLA School of Medicine.

Harsher reactions can occur, too. Among more than 15,000 babies included in a 1981 analysis by Cherry and his colleagues, nine developed seizures shortly after an injection and nine others had an episode of listlessness. None of the babies showed long-term effects from these episodes, but such events are alarming for parents, Cherry says.

On top of that, the whole-cell pertussis vaccine was dogged by allegations that it might cause encephalopathy, which carries the risk of brain damage. Starting in 1946, anecdotal cases dribbled in that seemed to link encephalopathy in babies with the whole-cell vaccine. But a 1983 analysis of 33 cases found no connection.

Nevertheless, by then the specter of side effects had attached to the whole-cell vaccine like a burr. It didn’t help that the shots made many babies miserable, so a search began for an alternative vaccine that didn’t use a whole cell. Public health officials endorsed the goal, and pharmaceutical companies developed acellular — meaning no cell — vaccines that contain up to five of the antigens found on the pertussis bacterium. Fewer antigens would still trigger immunity, scientists figured, with fewer side effects.

“What drove acellular vaccine development was misinformation about encephalopathy,” Cherry says. Although five studies in the 1990s showed the whole-cell vaccines still worked better, the push for acellular shots gained momentum.

The acellular vaccines tested well enough. Some even outperformed a whole-cell pertussis vaccine in Italian and Swedish trials published in 1996 in the New England Journal of Medicine.

But Stanley Plotkin, a pediatrician formerly at the University of Pennsylvania and inventor of the widely used rubella vaccine, recalls that the whole-cell vaccine used for these comparisons was an oddly ineffective version made by Connaught Laboratories that protected only about one-third of recipients. Another whole-cell pertussis shot, CDC reported a year later, protected recipients at rates of 83 to 94 percent. Comparing the new acellular versions with a weak whole-cell vaccine “made the acellular vaccines look good,” says Plotkin, who currently advises vaccine maker Sanofi Pasteur.

Those two European trials were also brief, following children less than three years on average. Other trials were shorter. In each, the acellular vaccine seemed to impart protection and had few side effects. “People wanted this to work,” Cherry recalls.

Whooping cough was on the ropes at the time. Whole-cell vaccines had established a semblance of “herd immunity,” says Stacey Martin, a CDC epidemiologist. With so many people protected, the pathogen had trouble getting a foothold in the population. This respite allowed people to focus on other matters, such as vaccine side effects.

Just as the first acellular pertussis shots were getting approved during the 1990s, vaccines of all stripes came under fire. A paper linking the measles-mumps-rubella vaccine to autism appeared in Lancet. Although retracted years later, it damaged vaccines in the public eye. Other false claims arose on front pages only to be refuted later with less fanfare. Vaccine safety had become an issue, and the whole-cell pertussis vaccine — with its history of squalling babies — was an easy target.

Public health agencies in many developed countries began to recommend the acellular vaccine in the late 1990s. “The switch was made because of parental concern about these side effects,” says Douglas Opel, a pediatrician and researcher at the University of Washington in Seattle. “Unfortunately, what we got was something that doesn’t work as well. And because of that, we’ve got more pertussis.”

Protection fades

Soon after whooping cough outbreaks in 2010 to 2012 sent tens of thousands of people to doctors, the hammer of science dropped squarely on the acellular vaccine. Physicians Nicola Klein and Roger Baxter and their team at the Kaiser Permanente Vaccine Study Center in Oakland, Calif., tapped into the massive Kaiser patient database to identify people who had gotten a course of acellular shots in early life. During 2006 and 2011, they found, the acellular vaccine protected only 53 to 64 percent of kids who got it.

It occurred to the researchers that U.S. teenagers — who were babies in the 1990s — represented a mixed group of vaccine recipients. Some had gotten the old whole-cell pertussis shots as infants and others received acellular shots. When the Kaiser researchers assessed more than 1,000 teens for signs of the pertussis microbe, they found it in only 3.4 percent of children who had received whole-cell shots but in 18.3 percent of the acellular vaccine recipients. Kids who got the newer vaccine had failed to fully fight off the bacteria when exposed to it.

The researchers also looked at how children ages 4 to 12 fared during the outbreak. These kids typically got five doses of the acellular vaccine spread out from age 2 months to 7 years. Their protection seemed short-lived, even after five doses. Their odds of getting pertussis rose by 42 percent per year after the final shot. That report appeared in 2012 in the New England Journal of Medicine.

Plotkin says these long-term problems didn’t show up in the earlier trials that led to approval and adoption of acellular vaccines. In retrospect, he says, researchers “did not understand that the immunology of acellular would lead to faster waning of immunity.” Exactly why protection fades is still being sorted out.

The same incomplete protection showed up in a 2013 study that involved baboons (SN Online: 11/25/13). Researchers vaccinated infant baboons with three shots of either an acellular vaccine, a whole-cell vaccine or gave no vaccine. When scientists exposed them to live pertussis at age 7 months, the unvaccinated baboons predictably got sick. Neither of the other groups showed any severe symptoms, but those that received the acellular vaccine retained live pertussis microbes in their nasal cavities, meaning they could still transmit the disease, and they did in fact give it to other healthy baboons. The animals that got the whole-cell vaccine demolished the invading microbes, a U.S. Food and Drug Administration team reported in the Proceedings of the National Academy of Sciences.

The FDA study offered “the first hard data” in support of lingering transmissibility even after acellular vaccination, Martin says. “One of the things we rely on is herd immunity. If you’re not effectively eliminating transmission, herd immunity may not be achievable.” That could spell trouble for children who don’t get vaccinated, since their only protection comes from being part of the “herd.”

A moving target

B. pertussisdoes its dirty work with a slew of key compounds. Some are toxins that irritate cells lining the windpipe and airways of the lungs and send people into severe coughing jags. Others are dubbed adhesins because they help the microbe stick to these tissues. The microbe’s genetic instructions for building these adhesins has changed, according to recent evidence. That’s bad news for an already weak vaccine.

Since 2000, tests of pertussis samples in Japan have shown a loss of one of its key adhesins — pertactin — which is often a component of the acellular vaccine.

CDC biologist Lucia Pawloski and her colleagues screened 1,300 pertussis microbe samples collected from patients from 1935 to 2012 and found that 306 seemed unable to make pertactin. All but one of those dated to 2010 or later, suggesting that the pathogen morphed recently. The researchers described their findings in Clinical and Vaccine Immunology in 2013. They’ve also identified at least 10 mutations in the gene that encodes pertactin.

European researchers, writing in the October 2012 Clinical and Vaccine Immunology, called pertactin loss “alarming.” If the immune system is primed by the vaccine to recognize pertactin, but the bacteria has evolved to no longer carry it, the immune system may be less likely to “see” and go after the invader. While this hasn’t been established, Plotkin says, “it’s disturbing because it means the pertactin portion of the vaccine may no longer have an effect.”

B. pertussisapparently is also undergoing genetic changes that increase production of the pertussis toxin, researchers in the Netherlands reported in 2009 in Emerging Infectious Diseases. They suggested that use of the relatively weak acellular vaccine encouraged these changes in the microbe.

No going back

Some of the resurgence in pertussis may result from better detection of the disease in clinics, says Cherry. But he and others agree that the acellular vaccine is underperforming and that a better shot is needed. “If you put in 10 new antigens, that might be good,” Cherry says, “but you need to get the balance right.”

Maybe dosing can be tweaked to add boosters. The current vaccine regimen stops at five shots for most people; some scientists believe that’s not enough. Booster shots given later might rekindle some immunity, and acellular vaccine boosters have proved safe to give to the elderly.

But the thinking on boosters is in flux. The Advisory Committee on Immunization Practices, which advises CDC on vaccination schedules, decided against calling for boosters in 2013. Even though acellular vaccine protection fades over time, the panel reasoned that boosters would add only modest protection and would be expensive. Cherry, a former member of ACIP, says money never used to be part of the equation. “We never discussed the cost of anything when I was on it. It’s just scientifically sound” to vaccinate, he says. “This to me is very appalling.”

ACIP Chair Jonathan Temte, a family physician at the University of Wisconsin–Madison, says the panel is instead making a priority of vaccinating pregnant women in the third trimester.

“Current policy is aimed at trying to protect individuals who are the most vulnerable, infants in their first six months of life,” Temte says. Late-pregnancy vaccination triggers immunity that carries over to the newborn, and is part of a larger strategy endorsed by ACIP that scientists call “cocooning,” in which a newborn in the house is surrounded by family members and caregivers who have been freshly immunized.

But none of the suggestions — improving the acellular vaccine, pregnancy vaccination or boosters — seize upon an obvious alternative: Switch back to a whole-cell pertussis vaccine.

The whole-cell vaccine is still used in more than half the world, including India, Indonesia, South America, most of Africa and Pakistan, with good results. In Thailand, for example, where about 90 percent of pertussis shots given are whole-cell, whooping cough has steadily declined and there is “a substantial rise in herd immunity,” scientists reported in the June 4, 2013 Proceedings of the National Academy of Sciences.

But no one interviewed for this story expects the United States to embrace whole-cell again.

“I certainly would be happy to go back to the whole-cell vaccine,” Kaiser Permanente’s Klein says. “It seemed to provide longer-lasting immunity. But I think the climate on refusal and hesitancy is such that it’s a completely different world. I don’t know that most parents would accept [it] at this point.”


Refusals and delays

U.S. schools typically require vaccination for pertussis and other infectious diseases before kindergarten. States allow exemptions, however, for medical, religious or philosophical beliefs. States with easy-to-get exemptions had roughly 50 percent more pertussis cases than states that made it harder to skip shots, according to a 2006 report in JAMA by Saad Omer of Emory University and his colleagues.

After the 2010 pertussis outbreak in California, Omer and colleagues identified 39 population clusters with high rates of nonmedical exemptions from vaccination and found pertussis cases were 20 percent more likely to pop up in those areas than elsewhere in the state.

Even with recent outbreaks, whooping cough remains a vague and distant threat to many people. “It’s not like polio in the 1950s,” says Jason Glanz of the Kaiser Permanente Institute for Health Research Colorado. Up to 15 percent of children nowadays don’t get shots on time, he says.

The current vaccine is weaker than hoped, but it’s better than nothing, and missing shots means less protection, says CDC epidemiologist Stacey Martin. She and colleagues checked the histories of 682 children who had whooping cough and 2,016 others who didn’t get sick during the California epidemic. The sick kids were one-ninth as likely to have completed a five-dose regimen of shots as were kids who never got sick, the scientists reported in JAMA in 2012.

Pediatricians can counter vaccination resistance with the right approach, says Douglas Opel, a pediatrician at the University of Washington in Seattle. Opel’s team videotaped 111 doctor-parent conversations on vaccines, with permission. In Pediatrics in 2013, the scientists reported that most doctors started the vaccine chat with a declaration such as, “We have to do some shots today.” Three-fourths of parents addressed that way promptly agreed to vaccination.

When the doctor was equivocal — “What do you want to do about shots today?” — only one of 24 parents promptly accepted. Three offered their own plan for their child, such as one shot per visit. The other 20 resisted, and fewer of their children ultimately got vaccinations on time.

“We live in a more consumerist society than we did 30 years ago,” Opel says. “The doctor-parent relationship has become less authoritarian. I think that’s a good thing. The flip side of that is everything becomes a discussion,” he says, which can delay vaccination. 

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