MADRID – The explanation for the ongoing resurgence in pertussis in adolescents and adults in the United States and other developed countries lies largely in the waning effectiveness of current acellular pertussis vaccines as early as 2-3 years post boosters, according to Stanley A. Plotkin, MD, chair of the steering committee for the Global Pertussis Initiative.

“The problem seems to lie in the lack of persistence of immunity after vaccination using the acellular pertussis vaccines. To say that this is not controversial would clearly be wrong, but that is my view,” he declared at the annual meeting of the European Society for Paediatric Infectious Diseases.

It’s a view supported by persuasive evidence, added Dr. Plotkin, emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia.

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There are other reasons for the resurgence of pertussis, he noted. Better diagnosis and improved surveillance are certainly factors. So is increased virulence of pertussis strains in response to vaccine immunity. There is intriguing preliminary evidence from a study in baboons conducted by scientists at the Food and Drug Administration that suggests acellular vaccine doesn’t protect against pertussis infection and transmission, even though symptoms are prevented (Proc Natl Acad Sci USA. 2014 Jan 14;111[2]:787-92). If that work is confirmed in humans, it would mean that circulation of Bordetella pertussis is intensified in the United States and other countries using acellular vaccine.

In the United States, investigators at Northern California Kaiser Permanente have shown that the effectiveness of acellular pertussis in the Tdap vaccine wanes rapidly in adolescents. Indeed, it plunged from 69% effectiveness in the first year after vaccination to less than 9% by year 4 (Pediatrics. 2016 Mar;137[3]:e20153326).

In contrast, whole-cell pertussis vaccines provide roughly 6-10 years of protection against infection, and native infection provides persistent protection against reinfection for 7-20 years, Dr. Plotkin noted.

He was senior coauthor of a recent study that addresses why acellular pertussis vaccine immunity wanes so quickly. He and his coinvestigators demonstrated that while whole-cell pertussis vaccines promote vigorous Th1 and Th17 responses, which discourage pharyngeal colonization, acellular pertussis vaccines orient the immune system toward a less salutary Th1/Th2 response (Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029454).

In addition, other investigators have shown that repeated booster doses of acellular pertussis vaccine generate higher levels of antigen-specific IgG4, which doesn’t bind complement and results in impaired phagocytosis and a suboptimal inflammatory response. In contrast, priming of the immune system via administration of a whole-cell pertussis vaccine at birth followed by acellular pertussis boosters results in improved phagocytosis and complement-mediated microbial killing via preferential induction of IgG1(Cold Spring Harb Perspect Biol. 2017 Mar 13. doi: 10.1101/cshperspect.a029553).

Possible solutions to the pertussis problem

The long-term solution is clear, Dr. Plotkin said: “I think a new vaccine for adolescents and adults is badly needed.”

Infants don’t need a new vaccine; that’s not where the vaccine failures are occurring. “Again, I stress that the problem so far has not been in infants, it has been in adolescents and adults,” he said.

A new vaccine is a daunting prospect. Given the huge investment vaccine manufacturers made in the 1990s to bring the current acellular vaccines to the market, they are hardly eager to launch development programs for new pertussis vaccines. They have other vaccine development priorities.

Moreover, the regulatory challenges are huge unless the Food and Drug Administration and other licensing authorities are willing to forgo the large, long, and expensive clinical trials that have traditionally been required. In lieu of such efficacy studies, they would need to consider studies demonstrating better immunogenicity based upon antibody titers, or animal studies.

“The possibility of a human challenge study in adults is an idea I like; I’m not sure about the FDA,” the pediatrician said.

Until a new or improved vaccine becomes available, the most important strategy to control the resurgence of pertussis is acellular vaccination of pregnant women in their third trimester to provide passive protection to the newborn via transplacental antibody. That practice is already recommended in the United States and many other countries. And while it reduces the risk of pertussis in early infancy – the most serious form of the disease – that strategy won’t have any real impact on the adult burden of disease, which Dr. Plotkin estimated at more than 600,000 cases annually.

Cocooning – a strategy of vaccinating all of a newborn’s family contacts – has been promoted in guidelines but has proved difficult to implement. “I think cocooning strategies by and large have been a failure,” he declared.

More frequent boosters of current acellular pertussis vaccines would presumably increase effectiveness, but that would be costly and tough to put in place on a public health scale.

A return to using conventional whole-cell pertussis vaccines would be a tough sell to the public and is probably flat out unacceptable. Developing a less reactogenic whole-cell vaccine might be a work-around, but it hasn’t been done yet.

The easiest way to improve acellular pertussis vaccine for adolescents and adults is to improve the pertussis toxin antigen component. Increasing the dose of pertussis toxin could generate more and longer-lasting antibodies to it. An even more exciting possibility is based upon evidence more than a decade old that genetic inactivation of pertussis toxin results in antibody levels far higher and presumably more bactericidal than the formalin-inactivated pertussis toxin included in current vaccines, according to Dr. Plotkin.

Adding stronger adjuvants to a Tdap vaccine for adolescents is another appealing strategy. There are plenty to choose from, including some that would presumably have an easier pathway to regulatory approval because they are already contained in licensed vaccines. This beefed-up adjuvant strategy, like the notion of changing the antigens in acellular pertussis vaccines to those from currently circulating strains, is feasible albeit more difficult than simply improving the pertussis toxin component of existing vaccines, he said.

The Global Pertussis Initiative is sponsored by Sanofi Pasteur. Dr. Plotkin reported serving as a consultant to that vaccine manufacturer and numerous others but declared he had no financial conflicts regarding his presentation.

bjancin@frontlinemedcom.com

Pertussis resurgence is real, but possible solutions exist