Has a decade of maternal pertussis vaccination reduced its effectiveness?

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

Study: Maternal pertussis immunization and the blunting of routine vaccine effectiveness: a meta-analysis and modeling study. Image Credit: Kateryna Kon / Shutterstock

Pertussis and the results of global immunization efforts

Pertussis, colloquially called ‘whooping cough,’ is a highly contagious respiratory illness caused by the bacteria Bordetella pertussis. Its symptoms included chronic 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 obtained. Pertussis infections are most severe in children, especially newborns, and were a significant cause of childhood mortality before the 1940s.

Thankfully, pertussis is easily preventable via vaccines. Global large-scale immunization efforts in the 1940s reduced transmission rates by 90% in most countries. Unfortunately, for reasons hitherto unknown, pertussis has been staging a comeback over the past two decades. This has prompted a resurgence into pertussis-centric research aimed at evaluating the mechanisms underpinning rising transmission rates.

Infants, especially newborns, are the cohort most vulnerable to the disease, given their suboptimal immune development and lack of immunization. To counter this, numerous nations (since 2012) and the World Health Organization (since 2015) have recommended and initiated maternal immunization programs. Vaccinating women during the gestation period has been clinically revealed to transfer its protective effects to their unborn infants, resulting in an estimated 70% reduction in newborn mortality.

“However, the downstream consequences of maternal immunization, when infants receive their routine pertussis vaccines, are poorly understood. Specifically, there has been long-standing concern regarding potential immunological blunting, i.e., the interference of maternally transferred antibodies with the infant immune response.”

Understanding if current vaccination protocols are resulting in immunization blunting, and if so, to what extent, will allow for the revision of present immunization policies and may require an overhaul of the vaccines used or the process itself.

About the study

In the present study, researchers conducted a meta-analysis to investigate if prolonged (2012 to 2023) maternal immunization has reduced vaccine effectiveness (VE). The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Data collection was initiated by collating relevant publications from three online databases (PubMed, Web of Science, and Scopus) from database initiation till August 25, 2023. This search revealed 374 articles across databases, 146 of which were duplicate records. Of the 228 remaining publications, abstract screening revealed 69 potential articles, which full-text screening further narrowed down 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 in infants having received at least one dose of their primary immunization from vaccinated vs. unvaccinated mothers. We selected only those studies that used laboratory-confirmed diagnosis of pertussis.”

Each of the four included studies reported at least five pertussis relative risk estimates in comparing vaccinated and unvaccinated mothers. Study analyses were carried out using two steps – Firstly, to account for different metrics used in the included studies, standard relative risks were calculated and applied to each included metric. Secondly, the meta-analyses were carried out. The meta-regression used herein was corrected to account for ‘population’ as a random intercept.

Finally, researchers devised a novel mathematical model based on the Susceptible-Exposed-Infected-Recovery (SEIR) model, explicitly testing for VE accounting for immunization blunting. The model had two outcome measures – 1. failure in “take” (if the primary vaccine failed), and 2. failure in duration (loss or reduction of vaccine protection). The model works in a hierarchical compartmentalization framework comprising three levels, each with their own ‘paths.’

Level 1: “These three possible paths or compartments start from their mother’s immunization status during pregnancy, followed by an infant immunization schedule that resembles that of the empirical studies.” Level 2: “…newborns can be born in three possible compartments: from vaccinated mothers whose immunization succeeded, mothers whose immunization failed (i.e., who received the vaccine but whose infant remained unprotected), or 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, thereby becoming susceptible, or no immunization thereby also becoming susceptible.”

Study findings

Exploring the historical landscape of VE in infant pertussis via the novel model revealed that infant (maternal) immunization substantially decreased 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 yet highly efficient vaccines. These results validate model reliability.

Analyzing the sample dataset using this model revealed that the first vaccine dose in infants following maternal immunization is highly effective against pertussis contraction, but the second and third doses are much more uncertain, consistent with previous uncertainty regarding blunting effects. The model demonstrated the presence of a decade-long lag phase following the introduction of maternal immunization, during which time blunting effects are liable to be underestimated in trial studies.

Encouragingly, quantifying the blunting effects suggests that they are minor and pale compared to the infant mortality-saving that maternal immunization provides. These findings support the public health decisions of many countries (55 as of 2021) to continue maternal immunization efforts and recommend that other nations follow suit.

Conclusions

The present study conducted a meta-regression analysis of four epidemiological publications to investigate the potential blunting effect of decade-long maternal immunization efforts. They further devised and implemented a mathematical model to interpret pertussis relative risk while explicitly accounting for vaccine efficacy blunting.

Their findings reveal the presence of a transient decade-long lag phase following maternal immunization, characterized by the masking and underestimation of blunting effects, thereby explaining previous inconsistencies in the literature. More importantly, the study highlights that while moderate levels of VE loss via blunting do exist, they are far outweighed by the infant mortality savings that maternal vaccination provides.