Why whooping cough keeps coming back despite widespread vaccination

Pertussis is a vaccine-preventable respiratory disease that can be life-threatening in infants, yet it persists with epidemics every 3-5 years and notable surges in 2012-2016 and after COVID-19. In the EU/EEA in 2023, 52% of reported cases were in adults, who often go undiagnosed and act as a reservoir for vulnerable infants. Understanding the immune reasons for this persistence matters for clinicians, policymakers, and vaccine developers.

This narrative review stems from discussions at the April 2025 Global Pertussis Initiative meeting in Istanbul. It synthesizes mostly murine and baboon data, plus growing human evidence, on innate, B-cell, and T-cell responses to infection and vaccination, and on how bacterial evolution undermines control.

The authors identify five drivers of endemicity: extreme contagiousness, waning immunity, pathogen adaptation, limited mucosal protection, and asymptomatic transmission. Natural immunity is variable and may last up to about 20 years, while vaccine immunity typically wanes within 3-10 years. Infection generates IgG1 and nasal IgA, but IgG appears late, and T cells matter more for clearance. Th1 (IFN-γ) and Th17 (IL-17) CD4+ cells, including tissue-resident memory cells in the lungs and nose, drive clearance and protect against nasal colonization. In baboons, infection prevents colonization and transmission, whereas aP vaccination does not. aP vaccines favor Th2 responses and more IgG4 after boosting, while wP vaccines induce Th1/Th17 responses, stronger innate activation, and broader antibody diversity. Priming type and later subclinical exposure (hybrid immunity) shape booster responses. B. pertussis also evades immunity through toxins, complement-evasion factors, regulatory T cells, and intracellular survival in macrophages. Evolving strains show shifts in ptxP, ptxA and prn alleles, higher pertussis toxin production, pertactin-deficient variants, and macrolide resistance linked to 23S rRNA mutations. Post-pandemic "immunity debt," reduced immunization, and improved surveillance may also contribute.

Implications: current vaccines remain essential, particularly maternal immunization, which markedly reduces infant disease; modest antibody blunting in infants of vaccinated mothers is of uncertain clinical relevance. Future vaccines should induce durable Th1/Th17, mucosal, and tissue-resident memory responses, ideally reducing transmission, alongside sustained surveillance of antigenic and antibiotic-resistance changes.

Caveats: this is a expert-meeting narrative review, not a systematic analysis. Much mechanistic evidence comes from animal models, and the text provided is truncated before later sections on strain evolution and vaccine development.