In the years following the COVID-19 pandemic, Europe and several other regions have witnessed an alarming resurgence of whooping cough, also known as pertussis. Once thought to be largely controlled through routine childhood immunisation, the disease has re emerged at levels not seen for decades in some countries. This unexpected comeback has puzzled public health experts, especially as vaccination coverage has remained high in many affected regions.
A new perspective article published in EMBO Molecular Medicine sheds light on why pertussis has returned and why existing vaccines may no longer be sufficient to control it. Written by Camille Locht of the University of Lille, Inserm and the Institut Pasteur de Lille, the article titled “Pertussis before, during and after Covid-19” examines how pandemic restrictions temporarily suppressed the disease and how deeper immunological weaknesses have since become visible.
When pandemic controls silenced a highly contagious disease
Pertussis is among the most contagious respiratory infections known, rivalled only by measles in its ability to spread rapidly through populations. During the COVID-19 pandemic, however, reported cases of pertussis dropped dramatically across Europe and other regions. Social distancing, face masks, reduced travel, and school closures disrupted transmission chains so effectively that infant deaths from pertussis virtually disappeared during this period.
Yet this disappearance was temporary. As COVID-19 restrictions were lifted, other respiratory viruses rebounded almost immediately, while pertussis showed a delayed but dramatic return. By early 2024, countries such as Denmark and the Czech Republic reported their largest pertussis outbreaks in decades. Similar trends were observed in other European countries and in parts of Asia, indicating that the resurgence was not confined to Europe.
The delayed rebound raised critical questions. Vaccine coverage had not declined significantly, particularly in high-income countries. This suggested that the resurgence was not driven by hesitancy or access issues but by deeper biological and epidemiological factors that had been masked during the pandemic years.
A disease that never fully went away
Long before the COVID-19 pandemic, pertussis incidence had already been increasing in many countries. This trend was particularly noticeable in regions that had replaced older, whole-cell pertussis vaccines with newer, acellular pertussis vaccines. While acellular vaccines are safer and better tolerated, their long-term effectiveness has been increasingly scrutinized.
The article highlights that pertussis cases have been rising steadily even in populations with high childhood immunisation rates. This pattern contradicted expectations based on classical herd immunity models, suggesting that existing vaccines might be preventing severe disease without fully interrupting transmission.
Adding to the concern is a shift in age distribution. Whereas infants were once the primary group affected, recent outbreaks show a growing burden among adolescents and older children. These age groups often experience milder symptoms but can unknowingly transmit the bacterium to vulnerable infants.
How modern vaccines shaped the current problem
A central argument of the article is that three key limitations of current acellular pertussis vaccines have contributed to the resurgence. The first is bacterial adaptation. Bordetella pertussis has evolved in response to vaccine-induced immune pressure, leading to the emergence of strains that lack pertactin, one of the antigens targeted by acellular vaccines. These strains are now widespread in several countries.
The second limitation is the rapid waning of immunity. Studies from Australia, Canada, and other regions have shown that protection from acellular vaccines declines significantly within a few years after vaccination. This leaves adolescents and adults susceptible to infection even if they were fully vaccinated in childhood.
The third and most consequential limitation is that acellular vaccines do not effectively prevent infection or transmission. While they protect individuals from severe symptoms, they allow the bacterium to colonise the nasal passages. This silent carriage enables ongoing community spread, undermining herd immunity and allowing outbreaks to persist.
The missing piece of immunity in the nose
Understanding why acellular vaccines fail to block transmission requires a closer look at mucosal immunity. Natural pertussis infection induces strong immune responses in the lining of the respiratory tract, including the production of secretory IgA antibodies and specialized tissue-resident memory T cells that produce IL-17.
These immune cells act as local sentinels, rapidly clearing bacteria from the nose and upper airways. In contrast, injected acellular vaccines primarily stimulate systemic antibody responses and favour a T helper 2 immune profile. This response protects against disease but does not generate robust mucosal defences.
Animal studies and recent human data suggest that acellular vaccines may even suppress the development of these local immune responses. As a result, vaccinated individuals can remain effective carriers of Bordetella pertussis, sustaining transmission despite high vaccination rates.
A new generation of vaccines enters the spotlight
Recognising these limitations, researchers have been exploring alternative vaccine strategies designed to induce mucosal immunity. Among various experimental approaches, the live attenuated nasal vaccine candidate BPZE1 stands out as the most advanced.
BPZE1 is engineered to mimic natural infection without causing disease. Key toxins are removed or genetically inactivated, while essential antigens are preserved. Administered intranasally, the vaccine colonises the nasopharynx transiently, triggering strong local and systemic immune responses.
Preclinical studies in mice and non-human primates have shown that a single dose of BPZE1 induces durable mucosal immunity, including IL-17-producing tissue-resident memory T cells. Importantly, vaccinated animals showed reduced bacterial carriage.
Evidence from human clinical trials
BPZE1 has progressed through multiple phases of human clinical testing. Early phase trials demonstrated that the vaccine is safe and capable of inducing immune responses in healthy adults. Later studies showed that BPZE1 could prevent infection following controlled exposure to Bordetella pertussis.
In a phase II trial comparing BPZE1 with standard acellular vaccines, nasal immunisation generated strong secretory IgA responses and significantly reduced bacterial load upon re-exposure. In contrast, injected acellular vaccines failed to prevent colonisation.
More than 600 individuals, including children and adolescents, have now received BPZE1 without major safety concerns. Ongoing trials are evaluating its performance in populations previously primed with acellular vaccines, a critical step given the widespread use of these vaccines over the past two decades.
Reference
Locht, C. (2025). Pertussis before, during and after Covid-19. EMBO Molecular Medicine, 17(4), 594 to 598. https://doi.org/10.1038/s44321-025-00199-2
