Abstract and Introduction
Recent reemergence of pertussis (whooping cough) in highly vaccinated populations and rapid expansion of Bordetella pertussis strains lacking pertactin (PRN), a common acellular vaccine antigen, have raised the specter of vaccine-driven evolution and potential return of what was once the major killer of children. The discovery that most circulating B. pertussis strains in the United States have acquired new and independent disruptive mutations in PRN is compelling evidence of strong selective pressure. However, the other 4 antigens included in acellular vaccines do not appear to be selected against so rapidly. We consider 3 aspects of PRN that distinguish it from other vaccine antigens, which might, individually or collectively, explain why only this antigen is being precipitously eliminated. An understanding of the increase in PRN-deficient strains should provide useful information for the current search for new protective antigens and provide broader lessons for the design of improved subunit vaccines.
Bordetella pertussis, the causative agent of pertussis (whooping cough), continues to reemerge in countries that have high vaccine coverage, such as the United States, and has accelerated since the switch during the mid-1990s from whole-cell pertussis (wP) formulations comprising many partially characterized bacterial proteins to the less reactogenic 1–5 component acellular pertussis (aP) vaccines.[1,2] These aP vaccines, including DTaP (diphtheria, tetanus, and aP for children) and Tdap (tetanus, diphtheria, and aP for adolescents and adults), protect against disease, but this protection wanes rapidly and does not prevent colonization or transmission of the pathogen.[3–5] In this background of suboptimally performing aP vaccines, many countries have noted the emergence and expansion of strains specifically lacking pertactin (PRN), a membrane bound autotransporter, and 1 of up to 5 B. pertussis protein antigens included in the vaccines.[6–11]
PRN-deficient B. pertussis strains have recently been reported in countries using aP vaccines, including the United States, Australia, Sweden, Italy, Norway, the United Kingdom, France, Belgium, Finland, the Netherlands, and Japan. The frequency of PRN-deficient strains has been variable, but these strains have risen to dominance in the United States (85%), Australia (>80%), Sweden (69%), and Italy (55%).[7–11] Lower frequencies were reported from Japan, which showed a major decrease from a prevalence of 41% during 2008–2010 to 8% during 2014–2016 and correlated with a change to aP vaccine formulations that exclude PRN.[6,11–12] Denmark, which uses the monocomponent pertussis toxin (PT) vaccine, had no reports of PRN-deficient isolates before 2012, and the 4 PRN-deficient strains detected since have been associated with human migration from countries with PRN in their vaccines. Limited data are available from the predominantly developing countries that use wP vaccines to enable a robust comparison between the effects that aP and wP have on the selection of PRN. A sequencing study of the only 2 clinical isolates reported from India, which still uses wP, showed that the isolates still retained the broadly encountered PRN gene allele prn-1. Considered together, these observations provide a strong correlation between the use of aP vaccines containing PRN and the appearance and increase to prominence of PRN-deficient strains.
Lineages of all bacteria are constantly evolving, but increasing to dominance alone is not conclusive evidence of a causal relationship between use of PRN-containing aP vaccines and loss of PRN. A PRN mutation could be carried along with a strain that is increasing in dominance because of 1 or many other mutations. However, the appearance of a wide variety of PRN mutations, each arising from a diversity of B. pertussis lineages over time, provides additional strong evidence in favor of vaccine-driven selection on PRN in particular. Although insertions of IS481 at multiple genomic locations are the most common PRN mutation, there is a large diversity of disruptions to PRN expression, including deletions within the signal sequence, promoter inversion, transversions resulting in a stop codon, deletions resulting in a stop codon, and full-gene deletion.[2,6,12] The variety of genomic lesions that have led to loss of PRN indicates that numerous independent selection and expansion events have occurred in most of the lineages now circulating in many countries using aP vaccines. Providing more direct experimental data, such as murine models aimed at investigating PRN-deficient B. pertussis infection, have demonstrated an overall defect in colonization in unvaccinated mice, but advantages in both colonization and competition in assays using aP-vaccinated mice.[14–16]
Together, these observations strongly support the hypothesis that loss of PRN confers a fitness advantage over wildtype B. pertussis particular to the aP vaccinated populations in which they are arising. However, there are 4 other antigens included in aP vaccines that are not being disrupted or lost. Why are the other vaccine antigens not being mutated at similar rates? What are the characteristics of PRN that might lead to the loss of this antigen in particular? Understanding multiple possible explanations, and distinguishing between them where possible, will be useful for ongoing efforts to improve vaccines to control B. pertussis spread and disease.
Emerging Infectious Diseases. 2021;27(6):1561-1566. © 2021 Centers for Disease Control and Prevention (CDC)