Has a decade of maternal pertussis vaccination reduced its effectiveness?

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A recent modeling and meta-analysis study published in the journal Nature communication, The researchers assessed if the maternal vaccine against pertussis, a highly contagious bacterial respiratory infection, reduced effectiveness (‘blunting’) due to prolonged use. They reviewed four studies with up to six years of follow-up and designed a novel mathematical model to assess the short- and long-term effects of immunization on disease transmission dynamics. While unable to rule out a slight decrease in vaccine efficacy (VE), their findings highlight that maternal immunizations are (and will continue to be) essential in preventing pertussis transmission and, more importantly, in saving lives of unvaccinated newborns.

Study: Maternal pertussis vaccination and routine vaccine effectiveness blunted: a meta-analysis and modeling study.  Image credit: Kateryna Kon/ShutterstockStudy: Maternal pertussis immunization and routine vaccine effectiveness blunted: a meta-analysis and modeling study.. Image credit: Kateryna Kon/Shutterstock

Pertussis and the results of global vaccination efforts

Pertussis, also called ‘whooping cough’, is a highly contagious respiratory illness caused by bacteria Bordetella pertussis. Symptoms include a persistent or severe cough, general fatigue and fever, nausea and difficulty breathing. It is characterized by its severe hacking cough from which the name “whooping” is derived. Pertussis infection is most serious in children, especially newborns, and was a significant cause of childhood death before the 1940s.

Fortunately, pertussis is easily preventable with a vaccine. Large-scale vaccination efforts worldwide in the 1940s reduced infection rates by 90% in most countries. Unfortunately, for reasons still unknown, pertussis has been making a comeback over the past two decades. This has spurred a resurgence in pertussis-focused research aimed at evaluating the mechanisms underlying rising infection rates.

Children, especially newborns, are most vulnerable to the disease due to their suboptimal immune development and lack of immunization. To address this, many countries (since 2012) and the World Health Organization (since 2015) have recommended and initiated maternal immunization programs. Vaccination of women during pregnancy has been clinically shown to transfer its protective effects to their unborn babies, resulting in an estimated 70% reduction in neonatal mortality.

“However, the downstream consequences of maternal vaccination, when children receive their routine pertussis vaccine, are poorly understood. In particular, there is a long-standing concern regarding potential immunological blunting, ie, the interference of maternally transferred antibodies with the infant’s immune response.”

Understanding whether current immunization protocols are resulting in blunted immunization, and if so, will allow modification of current immunization policies and may require modification of the vaccine used or the process itself.

About the study

In the current study, researchers conducted a meta-analysis to investigate whether prolonged (2012 to 2023) maternal immunization has reduced vaccine efficacy (VE). Research follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines

Data collection was initiated by aggregating relevant publications from three online databases (PubMed, Web of Science, and Scopus) from database inception to August 25, 2023. This search revealed 374 articles across the database, including 146 duplicate records. Of the remaining 228 publications, abstract screening revealed 69 potential articles, which full-text screening further narrowed to the final sample set – four.

“To be included in our review, studies had to provide an estimate of the relative risk (RR) of pertussis among infants who received at least one dose of primary immunization versus those of unvaccinated mothers. We selected only those studies that used laboratory-confirmed diagnosis of pertussis. .”

Each of the four studies compared at least five pertussis relative risks comparing vaccinated and unvaccinated mothers. Studies were analyzed using two steps – first, to account for the different metrics used in the included studies, standard relative risks were calculated and applied to each included metric. Second, meta-analysis was performed. The meta-regression used here was corrected to account for ‘population’ as a random intercept.

Finally, the researchers developed a novel mathematical model based on the susceptible-exposed-infected-recovery (SEIR) model, explicitly testing for VE accounting for blunting immunization. The model had two outcome measures – 1. “take” (if the initial vaccine fails), and 2. failure to term (loss or reduction of vaccine protection). The model operates within a hierarchical compartmentalization framework consisting of three levels, each with their own ‘path’.

Level 1: “These three possible pathways or segments begin with their mother’s immunization status during pregnancy, followed by an infant’s immunization schedule that is similar to the empirical study.” Level 2: “…newborns can be born to three possible cohorts: to vaccinated mothers whose vaccination was successful, to mothers who failed to vaccinate (ie, those who received the vaccine but whose child was unimmunized), or to unvaccinated mothers.” Level 3: “Each of the three compartments is followed by a compartment for successful primary infant immunization and a compartment for failed primary infant immunization, resulting in sensitizing, or no immunization at all.”

Study results

Exploring the historical landscape of VE in infant pertussis through novel models showed that infant (maternal) vaccination significantly reduced disease incidence. However, consistent with global reports, this was followed by a gradual rebound in pertussis persistence. This is consistent with the previously described “end of honeymoon” effect and is expected in most diseases managed using imperfect but highly efficient vaccines. These results validate the reliability of the model.

Analysis of sample datasets using this model showed that the first vaccine dose in infants after maternal vaccination is highly effective against contracting pertussis, but the second and third doses are much more uncertain, consistent with prior uncertainty regarding the blunted effect. The model demonstrated the presence of a decade-long lag after the introduction of maternal immunization, during which blunted effects are liable to be underestimated in empirical studies.

Encouragingly, quantification of blunt effects suggests that these are small and pale in comparison to the infant mortality savings provided by maternal immunization. These findings support the public health decisions of many countries (55 as of 2021) to continue maternal vaccination efforts and recommend that other countries follow suit.

Conclusion

The current study performed a meta-regression analysis of four epidemiological publications to investigate potential blunting effects of maternal immunization efforts across decades. They developed and applied a mathematical model to explain pertussis relative risk while clearly accounting for vaccine effect blunting.

Their findings reveal the presence of a transient decades-long lag after maternal immunization, characterized by masking and underestimation of blunted effects, thereby explaining previous inconsistencies in the literature. More importantly, the study highlights that although modest VE losses through blunting exist, they are far greater than those from maternal immunized infant mortality savings.

Journal Reference:

  • Briga, M., Goult, E., Brett, TS, & Rohani, P. (2024). Maternal pertussis immunization and routine vaccine effectiveness blunted: a meta-analysis and modeling study. Nature communication, 15(1), 1-11., DOI – 10.1038/s41467-024-44943-7, https://www.nature.com/articles/s41467-024-44943-7



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