Pertussis resurgence: waning immunity and pathogen adaptation - two sides of the same coin

Abstract

Pertussis or whooping cough has persisted and resurged in the face of vaccination and has become one of the most prevalent vaccine-preventable diseases in Western countries. The high circulation rate of Bordetella pertussis poses a threat to infants that have not been (completely) vaccinated and for whom pertussis is a severe, life-threatening, disease. The increase in pertussis is mainly found in age groups in which immunity has waned and this has resulted in the perception that waning immunity is the main or exclusive cause for the resurgence of pertussis. However, significant changes in B. pertussis populations have been observed after the introduction of vaccinations, suggesting a role for pathogen adaptation in the persistence and resurgence of pertussis. These changes include antigenic divergence with vaccine strains and increased production of pertussis toxin. Antigenic divergence will affect both memory recall and the efficacy of antibodies, while higher levels of pertussis toxin may increase suppression of the innate and acquired immune system. We propose these adaptations of B. pertussis have decreased the period in which pertussis vaccines are effective and thus enhanced the waning of immunity. We plead for a more integrated approach to the pertussis problem which includes the characteristics of the vaccines, the B. pertussis populations and the interaction between the two.

Fig. 1.

(a) Fim and (b) PtxA variants found in B. pertussis populations. Protein variant designations are shown on the left. Dots indicate identical amino acids. Numbering is relative to the N-terminal methionine. Protein variants found in vaccine strains are underlined. The Fim2-2 variant has only been found in one vaccine strain used in The Netherlands.

Fig. 2

[colour online]. Prn variants found in B. pertussis populations. Protein designations are shown on the left. Dots and dashes indicate identical and absent amino acids, respectively. Numbering is relative to the N-terminal methionine of Prn1. The two regions (1 and 2) with five and three amino-acid repeats, respectively, have been blocked. The five amino-acid repeats occur as three variants which have been highlighted. The RGD motif involved in adherence, and protein variants found in vaccine strains, are underlined.

Fig. 3

[colour online]. Relationship between phylogeny and the accumulation of mutations in virulence genes in The Netherlands. The maximum parsimony tree was based on 85 SNPs and 198 Dutch strains isolated between 1949 and 2008. Changes in the alleles for fim3, ptxA, ptxP and prn are indicated. The alleles prn2 and prn3 were combined as they are both non-vaccine types. Based on the four alleles, seven allele types (I–VII) could be distinguished. Coloured dots distinguish allele types and arrows indicate changes between allele types. Whole-cell vaccines used in The Netherlands until 2005 were derived from allele types II and III (blocked). (Adapted from van Gent et al. [25].)

Fig. 4

[colour online]. Temporal trends in strain frequencies and notifications in The Netherlands during 1949–2010. Strain frequencies are indicated by coloured lines. Strains were aggregated into allele types (ATs) defined by the combination of alleles for ptxP, ptxA, prn and fim3 as shown in the top of the graph. No distinction was made between strains with the prn2 and prn3 alleles. ATs are indicated by blocked Roman numerals and allele changes resulting in differences between ATs are indicated. ATs found in one or two periods only, with a frequency lower than 15%, are not shown. If necessary, years were combined to increase the number of analysed strains to at least six. Note that due to this, the x-axis is not proportional. Changes in the vaccination programme are indicated below the x-axis. From 1953 to 2005 a whole cell vaccine (WCV) was used. In 2002, a booster with an acellular vaccine (ACV) was introduced for 4-year-olds and in 2005 the WCV was replaced by an ACV for all age groups. (Adapted from van Gent et al. [25].)