Pertactin-Deficient Bordetella pertussis, Vaccine-Driven Evolution, and Reemergence of Pertussis

Longhuan Ma; Amanda Caulfield; Kalyan K. Dewan; Eric T. Harvill

Disclosures

Emerging Infectious Diseases. 2021;27(6):1561-1566. 

In This Article

Unique Features of PRN Among Vaccine Antigens

PRN is conserved in B. pertussis, B. parapertussis, and B. bronchiseptica under the same Bordetella virulence gene regulatory system, suggesting that PRN has a more general role in pathogenesis that is not restricted to the human-specific B. pertussis. However, there are 16 other autotransporter genes identified in the genome of B. pertussis, 5 of which are disrupted by frameshift mutations.[27] Park et al.[28] observed that autotransporters, as a group, are much more highly mutated or lost than other virulence factors. There appears to be no major loss in in vitro growth or in vivo fitness that prevents the expansion of B. pertussis strains lacking PRN, indicating that the functional contributions of PRN in pathogenesis might be redundant or that complementary functions, potentially mediated by other autotransporters, might be compensating for any deficiencies caused its loss. This finding can be contrasted with PT, which requires a complex operon to assemble and another to export, has a central and nonredundant role in the pathogenesis of B. pertussis, and has no paralogs in the genome that can replace it. This finding is consistent with the rarity of clinical isolates lacking PT, compared with the abundance of PRN-deficient strains.[29–31] For these and potentially other reasons, it might be that loss of PRN can be tolerated, but loss of PT would result in a more serious fitness defect.

Examination of the location and conformation of the different acellular vaccine components showed that most antibody functions directed against these antigens occur away from the bacterial surface. Both PT and the mature surface-associated filamentous hemagglutinin (FHA)[32] are secreted and diffuse away into the surrounding host environment. Therefore, antibodies directed against released FHA and PT would primarily neutralize toxin function by binding to the secreted molecules in the surrounding milieu, or to molecules in the process of being shed, mitigating potential surface-directed antibody effects. These antibodies do not effectively localize to the bacterial surface and thus do not facilitate complement activation or fragment crystallizable region (FcR)–mediated phagocytosis that would result in direct bacterial killing (Figure 1, panel A).[33,34] Fimbriae (FIM), although generally anchored to the bacteria, might extend more than a cell length away from the cell surface. Because FIM are composed of repeated structures with many copies of the same antigenic molecule, most FIM antibodies would be bound to parts of the structure extended >1 micron from the bacterial membrane, which is an enormous distance for highly reactive complement components to travel. Antibodies bound to fimbria would not be arrayed on a 2-dimensional surface required to optimally bind and activate complement or FcRs (Figure 1, panel B).[35]

Figure 1.

Model for various roles of antibodies against antigens in acellular pertussis vaccine. A) Antibodies against PT and FHA neutralize secreted virulence factors and mitigate disease progression but are not targeted to the bacterial surface. B) Antibodies attaching to fimbriae poorly activate the complement system far from the bacterial membrane. C) Antibody-PRN complex induces strong bactericidal activity via multiple synergistic functions. This complex activates complement to form a MAC, activates complement to deposit components such as C3b that opsonize the bacterial surface, and binds FcRs on phagocytes to activate phagocytosis. PRN labels indicate strains specifically lacking PRN. Bp, Bordetella pertussis; CR1, complement receptor type 1; FcR, fragment crystallizable region; FHA, filamentous hemagglutinin; MAC, membrane attack complex; PRN, pertactin; PT, pertussis toxin.

However, PRN is the only aP vaccine antigen that remains closely associated with the outer membrane. When cognate antibodies bind PRN, they become arrayed on the bacterial surface in a conformation that is particularly effective in binding and activating complement component C1q. The subsequent complement cascade that is activated rapidly deposits component in the adjacent membrane that opsonizes the cell and assembles into a membrane attack complex to lyse the bacterial membrane.[33–36] The combination of the array of antibodies, bolstered by the complement components cleaved and activated in the immediate vicinity, would effectively opsonize the bacteria for efficient phagocytic killing (Figure 1, panel C).

The model we provide (Figure 1), although largely hypothetical, is consistent with evidence that aP vaccination is effective in preventing severe disease (by binding and neutralizing a key factor that mediate aspects of disease) but is much less effective in preventing nasopharyngeal colonization. Most antibodies, similar to those directed against secreted PT/FHA or distal FIM, do not effectively target and kill the bacteria. This model would also explain why loss of PRN might enable partial evasion of aP-induced immunity, and is also consistent with human surveys that showed that 3-component aP vaccines containing PT, FHA, and PRN were more efficacious than 2-component vaccines lacking PRN.[37,38]

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