# Revisiting Whooping Cough: Global Drivers and Implications of Pertussis Resurgence in the Acellular Vaccine Era

## TL;DR

Whooping cough is coming back despite high vaccination rates, driven by waning immunity, evolving bacteria, and antibiotic resistance, requiring new strategies for control.

## Contribution

The paper introduces a three-driver framework for pertussis resurgence: waning aP immunity, vaccine-driven evolution, and macrolide resistance.

## Key findings

- Waning and non-sterilizing immunity from acellular vaccines allows B. pertussis transmission.
- Genomic evolution of B. pertussis includes dominance of the ptxP3 lineage and PRN− strains.
- Macrolide-resistant clones like MT28-Shanghai are emerging under combined vaccine and antibiotic pressure.

## Abstract

Background: Whooping cough caused by Bordetella pertussis is re-emerging despite high vaccination coverage, with rising incidence in adolescents and adults in the acellular vaccine (aP) era. This narrative review synthesizes evidence on the drivers of this paradox and their implications for pertussis control. Methods: We conducted a structured (but not fully systematic) literature search and narrative synthesis of PubMed, Web of Science, and Embase for publications from January 2000 to February 2025 using terms related to “Bordetella pertussis,” “pertussis resurgence,” “acellular vaccine,” “waning immunity,” “ptxP3,” “pertactin-deficient,” “macrolide resistance,” and “whole-genome sequencing.” English-language, peer-reviewed studies, surveillance reports, genomic analyses, and immunological investigations were included. About 1900 records met broad eligibility criteria and were screened, and key studies were selected for narrative synthesis. Results: The resurgence appears to result from three convergent factors: (1) waning and non-sterilizing aP-induced immunity, which allows bacterial colonization and transmission; (2) vaccine-driven genomic evolution of B. pertussis, marked by global dominance of the ptxP3 lineage and widespread pertactin-deficient (PRN−) strains; and (3) emergence of macrolide-resistant clones, exemplified by the MT28-Shanghai strain. Whole-genome sequencing (WGS) has been central for defining these processes and clonal sweeps under combined vaccine and antibiotic pressure, supporting a three-driver framework of waning aP immunity, vaccine-driven evolution, and macrolide resistance. Conclusions: Pertussis resurgence illustrates pathogen adaptation to human interventions. Effective mitigation requires WGS-integrated global surveillance, re-evaluation of vaccine formulations to keep pace with antigenic change, and strengthened antibiotic stewardship, alongside development of next-generation vaccines that induce durable mucosal immunity and block transmission.