News headlines highlighting an outbreak of a vaccine-preventable disease often leave readers shaking their heads. These diseases – measles, chickenpox, whooping cough – could have been prevented if only the infected children had been vaccinated. Right? Well, in the case of whooping cough, the situation is a bit more complicated.
“That is the case for most other infectious diseases where we’re seeing increases, but not pertussis,” says Dr. Tod Merkel, Principal Investigator, Laboratory of Respiratory and Special Pathogens, Office of Vaccines Research and Review, of the Center for Biologics Evaluation and Research at the FDA. “In populations that are not vaccinated, both the number of reported cases and the severity of disease is higher, but it’s not unvaccinated individuals that are driving the infection.” So if the disease isn’t spreading due to an unwillingness to vaccinate, what is the reason?
The increase in whooping cough, also known as pertussis, has been remarkably high in the past decades. This is a disease that had a mere 1000 cases reported in the U.S. in 1976, but in the past ten years, the rate of increase has been especially high, peaking in 2012 with nearly 50,000 reported cases. Even though the rate of disease is increasing, the rate of vaccination has remained the same: a near-universal vaccination rate of 95% for children entering school, and over 80% of adolescents receiving booster shots.
The first vaccine became widely used in the 1940s, and pertussis, caused by Bordetella pertussis, has been preventable since then. The first vaccine was a whole-cell vaccine, meaning that the bacteria were grown and killed, giving vaccinated individuals protection against a wide range of bacterial antigens. However, it had a few mild side effects, such as muscle soreness and low-grade fever (and, infrequently, high-grade fever), that could irritate the newly-vaccinated infants (and their parents). To counteract a declining acceptance of the whole-cell vaccine, an acellular pertussis vaccine was developed, which contain just a few pertussis proteins, rather than the entire bacterium. The acellular vaccine produced less side effects and prevented disease as well as the whole-cell vaccine, so it seemed like a good alternative.
As pertussis cases increased in the years following the change in vaccine, scientists began to wonder why. Tod Merkel, alongside postdoctoral fellow Jason Warfel and technician Lindsey Zimmerman, hypothesized that although the acellular vaccine may prevent disease, it may not prevent infection. Although infected individuals would not suffer disease symptoms, they would be able to pass the bacteria to other uninfected people. Their initial study, comparing the acellular vaccine to a single whole-cell vaccine in a baboon model of infection, revealed two important findings: first, that “the vaccinated animals, regardless of which vaccine they were given, were protected from disease,” says Merkel. However, the second important finding was that animals differed in the amount of Bordetella bacteria colonizing their trachea and lungs.
“We looked at three groups,” explains Merkel, “animals that had had pertussis and had recovered, which had a natural immunity from experiencing the disease. They could not be reinfected; we did not isolate any bacteria out of those animals. Animals that were vaccinated with the whole-cell vaccine were initially infected and colonized but they very rapidly cleared the infection. Animals that were vaccinated with the acellular vaccine, they were heavily colonized, and it took them up to 3-4 weeks to clear the infection.” Merkel’s group further showed that these asymptomatically colonized animals were able to transmit their infection to other animals.
Now a new study published in Clinical and Vaccine Immunology expands these results to additional whole-cell vaccines. “From manufacturer-to-manufacturer, there’s variability, and some even suspect there’s variability from lot-to-lot made by the same manufacturer. We wanted to show that we could get the same result with more than one whole-cell vaccine,” says Merkel. By selecting three WHO-qualified whole-cell vaccines that are currently manufactured and widely used throughout the world, Merkel’s team showed that all the whole-cell vaccines tested prevented infection better than the acellular vaccine (also known as DTaP). Animals immunized with one of three whole-cell vaccines were colonized for shorter periods of time, and with a lower bacterial burden, than animals immunized with the acellular vaccine (see figure, left).
Merkel thinks the asymptomatic carriage seen in acellular-vaccinated populations explains the increased disease incidence in the U.S. “We think the vaccine, although it’s preventing disease in the individuals who are vaccinated, is not preventing them from becoming infected, carrying and transmitting the bacteria,” says Merkel. “An acellularly vaccinated population has more carriage, more transmission of pertussis through the population. As a result, individuals who are unvaccinated, undervaccinated, or whose immunity is waning are at risk for disease.”
Different vaccine types elicit different immune responses
Why is there a difference in infection between differently vaccinated populations? Could the vaccines, both based on Bordetella pertussis, stimulate different immune responses? Previously, the comparison of whole-cell and acellular vaccination had shown both a natural infection and the whole-cell vaccination induced a strong Th1 immune response, which is important to activate mucosal immune defenses, as well as a Th2 immune response, which is important to produce antibodies. The acellular vaccine induced only a strong antibody response.
The current study confirmed that immunization with the whole-cell vaccines initiated high levels of IL-17A, a cytokine important for mucosal immunity (see figure, right). “We think the antibodies are sufficient to prevent the disease symptoms, and that’s why we think the acellular animals are protected from disease. But we think you need that cellular response to actually clear bacteria out of the airway,” explaining why the animals immunized with the whole-cell vaccine were able to quickly clear the bacteria. But no matter the vaccine type, Merkel emphasized, those that receive the vaccine are protected against disease: “Individuals who are vaccinated are protected from disease.”
The disease is accompanied by the characteristic “whoop” sound while the patient tries to catch his or her breath. Despite nearly 90% vaccine coverage worldwide, the WHO estimates approximately 89,000 pertussis-related deaths occurred in 2008. Whooping cough is particularly dangerous in very young babies; most deaths occur in those younger than 3 months old. These very young can’t receive the vaccination themselves, but can be protected if their mothers receive the vaccine during pregnancy.
Bordetella pertussis is a finicky microbe. It doesn’t survive in the environment, and although it’s transmitted by aerosol droplets between people, it doesn’t survive in the air very well. There is no known animal reservoir, so the bacterium relies on human transmission to survive.
Because the bacterium doesn’t survive well in air, transmission occurs mostly where people are interacting in close quarters. “You see transmission within classrooms,” says Merkel, “you see a lot of transmission in households. It requires a continuous chain of transmission in order to be maintained in a population.” Merkel explains that if scientists could develop a vaccine that actually breaks that chain of transmission, we could dramatically reduce or even eliminate pertussis from the population. “I think that concept is an exciting one and one that drives our work.”
-- Julie Wolf