New Challenges for Pertussis Vaccines

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Historical perspective

The effort to control pertussis through vaccination has been ongoing for more than 100 years, since the first description of the causative bacterium, Bordetella pertussis . The whole-cell pertussis vaccine, produced by heat killing and chemical detoxification came into use in the 1930s and became a routinely used vaccination in the 1940s. With its widespread use, reported cases of pertussis declined dramatically to less than 10% of prevaccination levels. Efficacy of the whole-cell pertussis vaccine was demonstrated in a series of clinical trials sponsored by the Medical Research Council in the United Kingdom; efficacy of the vaccine correlated with protection in the mouse intracerebral test, which is now used to measure the potency of whole-cell vaccines. In the intracerebral protection assay, immunized mice are injected intracerebrally and monitored for death. Current regulatory standards for whole-cell vaccines require that each lot of vaccine demonstrate no less than mouse protective units in the intracerebral challenge test in order to be released. While increased potency of whole-cell vaccines in the intracerebral assay correlate with increased efficacy, there is a similar correlation with increased rates of adverse events.

Beginning in the 1970s, there was increasing public concern about the safety of whole-cell vaccines. High profile allegations of damage related to whole-cell vaccine led to decreased rates of pertussis vaccination in some countries and removal of the vaccine from the routine immunization schedule others. In Japan, following two infant deaths following immunization in 1975, pertussis vaccination was halted and the vaccine was reintroduced at 2 years of age rather than 3 months. Vaccine coverage dropped from 85% in 1972 to 13.6% in 1976. This resulted in a resurgence of disease, with more than 13,105 cases and 41 deaths by 1979. In the United Kingdom, rates of pertussis vaccination dropped dramatically from 77% in 1974 to 30% by 1978 after allegations that the whole-cell vaccine was the cause of encephalopathy and permanent brain damage. Despite a large study that was unable to demonstrate a link between permanent brain damage and pertussis vaccine (National Collaborative Encephalopathy Study), it was years until pertussis vaccine coverage rates increased to their previous levels and, in the interim, high rates of pertussis and infant deaths occurred. In the United States, pertussis immunization rates also declined following television “documentaries” like “A Shot in the Dark” and advocacy by antivaccination groups such as “Dissatisfied Parents Together (DPT).”

Spurred by the allegations and concerns with whole-cell pertussis vaccine, there was a concerted effort in the 1980s and 1990s to develop new and improved pertussis vaccines. Led by Japanese investigators, new pertussis vaccines were developed comprising purified components of B. pertussis . These so-called acellular pertussis vaccines included between one and five pertussis components. All of the acellular pertussis vaccines contained pertussis toxoid, the inactivated toxin that is a major virulence factor of the organism and causes many of its biological effects. Clinical trials with the first acellular vaccines were undertaken in Sweden in the 1980s but resulted in a lower than desired efficacy. Second-generation acellular vaccines were studied in a series of Phase 2 studies and leading candidates were selected for Phase 3, randomized, controlled trials which were undertaken in Sweden, Germany, Italy, and Senegal. All of these studies demonstrated that the acellular vaccines were less reactogenic than the whole-cell vaccine comparators and elicited antibody responses to their component antigens equivalent to or greater than that of the whole-cell vaccines. Efficacy of the acellular vaccines was in the range of 85%; efficacy of the whole-cell vaccines was far lower, equivalent, or higher.

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Changing epidemiology

With the licensure of acellular pertussis vaccines, a rapid shift from whole-cell to acellular vaccine use occurred in high-income countries including the United States, Canada, Europe, the United Kingdom, Australia, and New Zealand. The incidence of pertussis continued to fall, likely related to improved uptake (eg, in the United States) or replacement of a poorly performing whole-cell vaccine (eg, in Canada). With improved control of pertussis in preschool- and school-aged children, increased outbreaks of pertussis were reported among adolescents. In order to control pertussis in adolescents, adult formulations of acellular pertussis vaccine were developed, which had decreased content of diphtheria toxoid and decreased quantities of pertussis antigens (Tdap vaccines). Implementation of universal adolescent vaccination programs with Tdap led to control of pertussis in these age groups. Recommendations for Tdap immunization of adults were made in several countries to control pertussis throughout the life span and to decrease transmission of pertussis from adults to children. Most recently, Tdap has been recommended during pregnancy to induce high levels of maternal antibodies which are transferred transplacentally to the fetus and provide protection during the first months of life, prior to initiation of the infant immunization series. These recommendations were implemented in the United States and United Kingdom in response to large outbreaks that caused increased infant deaths; the effectiveness of this intervention was demonstrated recently in observational and case control studies.

In the last 5 years, there have been large outbreaks of pertussis in some but not all areas that have exclusively used acellular pertussis vaccine. Beginning in 2010, California reported more than 9000 cases, including 10 deaths. Within several years, most states in the United States reported an increased incidence of pertussis; in 2012, outbreaks in Oregon, Washington, Wisconsin, and Minnesota reported rates not seen since the early days of pertussis vaccination in the 1940s. Of concern, a cohort effect was observed whereby those children who had received all of their doses with acellular vaccines had a higher incidence than slightly older children who had received one or more doses of whole-cell vaccine prior to the switch from whole-cell to acellular vaccines. Also of concern was that protection after the preschool acellular pertussis vaccine dose began to decrease within 4–5 years, much shorter than had previously been predicted. Duration of protection after the Tdap vaccine in adolescents was even shorter, decreasing after only 2 years. Despite these reports, increased incidence of pertussis was not seen in all countries using acellular pertussis vaccines.

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