At Issue

Pertussis vaccines and the next steps in development

Infectious Diseases in Children asked C. Buddy Creech, MD, MPH, associate professor of pediatrics, division of pediatric infectious diseases, and director of the Vanderbilt Vaccine Research Program, and Kathryn M. Edwards, MD, Sarah H. Sell and Cornelius Vanderbilt professor of pediatrics, division of pediatric infectious diseases, Vanderbilt University, whether a whole cell pertussis vaccine with better immunity or a more improved acellular vaccine with fewer side effects would be the better development path.

C. Buddy Creech
Kathryn M. Edwards

Winston Churchill famously quipped that mid-20th century Russia was “a riddle wrapped in a mystery inside an enigma.” Generating durable protection against Bordetella pertussis in a safe and effective manner has proven equally enigmatic.

To be fair, great strides have been made against this pediatric scourge since Jules Bordet and Octave Gengou first grew the organism in 1906, leading to the development of the first crude pertussis vaccines. Whole cell pertussis vaccines were licensed in the United States in the 1940s and remained the standard of care in the U.S. until the 1990s. However, because of the marked local and systemic reactions associated with the whole cell vaccines, acellular pertussis vaccines were developed in an effort to improve the overall safety profile of pertussis vaccine while still providing protection against severe pertussis disease.

Now, using the techniques of modern immunology and non-human primate models of pertussis colonization and disease, new insights about pertussis have evolved. First, there are substantial differences between the immune responses after whole cell (DTP) and acellular vaccines (DTaP). DTP polarizes towards a Th1 response, while also engaging a robust Th17 response; in contrast, DTaP tends to generate a Th2 response. Secondly, the initial encounter with pertussis antigens primes and constrains the subsequent responses to antigen boosts. The Th1 responses stimulated by whole cell vaccine remain, as do the Th2 responses stimulated by acellular vaccine, even after subsequent booster doses of vaccine.

Finally, data from non-human primate models of disease highlight the functional differences between vaccination and natural pertussis disease. Baboons recovering from a natural pertussis challenge are neither colonized nor do they develop disease upon live pertussis challenge. Animals vaccinated with DTaP are protected from disease, but not from colonization or transmission. Animals vaccinated with whole cell pertussis vaccines are also protected from disease on natural challenge and shed organisms but for a shorter time than those vaccinated with DTaP. Taken together, these data suggest that natural infection with pertussis stimulates the best immunity, with whole cell vaccine offering distinct immunologic advantages over acellular vaccine.

Where does that leave pertussis vaccine development? The first step is to dissect the correlates of protection in the non-human primate model and to compare the key immunologic differences between DTP and DTaP in order to enhance protection against both colonization and disease. The next step will then be to design new vaccines containing novel adjuvants to enhance the immune responses, to investigate the addition of novel pertussis antigens to the existing acellular vaccines, or to generate live attenuated mucosal vaccines that would stimulate the immune response to natural infection. These new approaches will need to be carefully tested. In the interim we will need to continue to use the current vaccines widely and to protect infants prior to immunization with the use of maternal vaccines.

Disclosures: Creech and Edwards report no relevant financial disclosures.

Infectious Diseases in Children asked C. Buddy Creech, MD, MPH, associate professor of pediatrics, division of pediatric infectious diseases, and director of the Vanderbilt Vaccine Research Program, and Kathryn M. Edwards, MD, Sarah H. Sell and Cornelius Vanderbilt professor of pediatrics, division of pediatric infectious diseases, Vanderbilt University, whether a whole cell pertussis vaccine with better immunity or a more improved acellular vaccine with fewer side effects would be the better development path.

C. Buddy Creech
Kathryn M. Edwards

Winston Churchill famously quipped that mid-20th century Russia was “a riddle wrapped in a mystery inside an enigma.” Generating durable protection against Bordetella pertussis in a safe and effective manner has proven equally enigmatic.

To be fair, great strides have been made against this pediatric scourge since Jules Bordet and Octave Gengou first grew the organism in 1906, leading to the development of the first crude pertussis vaccines. Whole cell pertussis vaccines were licensed in the United States in the 1940s and remained the standard of care in the U.S. until the 1990s. However, because of the marked local and systemic reactions associated with the whole cell vaccines, acellular pertussis vaccines were developed in an effort to improve the overall safety profile of pertussis vaccine while still providing protection against severe pertussis disease.

Now, using the techniques of modern immunology and non-human primate models of pertussis colonization and disease, new insights about pertussis have evolved. First, there are substantial differences between the immune responses after whole cell (DTP) and acellular vaccines (DTaP). DTP polarizes towards a Th1 response, while also engaging a robust Th17 response; in contrast, DTaP tends to generate a Th2 response. Secondly, the initial encounter with pertussis antigens primes and constrains the subsequent responses to antigen boosts. The Th1 responses stimulated by whole cell vaccine remain, as do the Th2 responses stimulated by acellular vaccine, even after subsequent booster doses of vaccine.

Finally, data from non-human primate models of disease highlight the functional differences between vaccination and natural pertussis disease. Baboons recovering from a natural pertussis challenge are neither colonized nor do they develop disease upon live pertussis challenge. Animals vaccinated with DTaP are protected from disease, but not from colonization or transmission. Animals vaccinated with whole cell pertussis vaccines are also protected from disease on natural challenge and shed organisms but for a shorter time than those vaccinated with DTaP. Taken together, these data suggest that natural infection with pertussis stimulates the best immunity, with whole cell vaccine offering distinct immunologic advantages over acellular vaccine.

Where does that leave pertussis vaccine development? The first step is to dissect the correlates of protection in the non-human primate model and to compare the key immunologic differences between DTP and DTaP in order to enhance protection against both colonization and disease. The next step will then be to design new vaccines containing novel adjuvants to enhance the immune responses, to investigate the addition of novel pertussis antigens to the existing acellular vaccines, or to generate live attenuated mucosal vaccines that would stimulate the immune response to natural infection. These new approaches will need to be carefully tested. In the interim we will need to continue to use the current vaccines widely and to protect infants prior to immunization with the use of maternal vaccines.

Disclosures: Creech and Edwards report no relevant financial disclosures.