Unadjuvanted antenatal pertussis OMV vaccination drives enhanced and durable humoral immunity in offspring.

BACKGROUND: Antenatal-immunization is the primary strategy to protect neonates from pertussis. However, the global shift to acellular vaccines (aP) has raised concerns regarding the duration of transferred immunity, largely due to the Th2-skewed profile they induce. This study evaluates the immunogenicity and protective efficacy transferred to offspring by a novel, unadjuvanted Bordetella pertussis Outer Membrane Vesicle-based vaccine (OMVPreg), which induces a mixed Th1/Th2/Th17 response, compared to the commercial aP vaccine (aPPreg). METHODS: Female mice received a primary two-dose series of aP followed by an antenatal booster of either OMVPreg or aPPreg. Offspring from successive litters were intranasally challenged with B. pertussis at neonatal (day7), infant (day21), and adult (day60) stages. We first characterized the maternal-offspring humoral response and subsequently quantified offspring protection through pulmonary bacterial clearance (log10CFU), correlating these outcomes with antibody kinetics and cellular immune profiles measured by ELISA. RESULTS: Both vaccines were immunogenic in dams, albeit with distinct profiles. The primary two-dose aP schedule, as well as the aPPreg booster, elicited a predominantly IgG1 isotype response (Th2-skewed), whereas OMVPreg induced a mixed IgG1/IgG2a/IgG3 response. This balanced isotype profile was achieved despite prior aP priming, indicating that the OMV booster effectively redirected maternal immunity. The isotype polarization was faithfully transferred to offspring, and IgG-levels in OMVPreg pups remained stable across successive litters, unlike aPPreg pups which showed a significant decline. Upon challenge, OMVPreg offspring exhibited an age-dependent mixed cellular profile: neonates produced higher IFN-γ and IL-22, infants higher IL-17, and adults maintained higher IFN-γ compared to aPPreg counterparts (offspring born shortly after antenatal boost), confirming that OMVs provide essential Th1 signals deficient in aP-boosted offspring. Regarding protection, both vaccines provided equivalent bacterial clearance in early litters (within 12 weeks post-booster). However, in adult offspring from late-born litters (>14weeks), aPPreg-mediated protection waned (4.6 log10 CFU), whereas OMVPreg offspring maintained superior clearance (3.6 log10 CFU; p<0.05). CONCLUSION: Unadjuvanted OMVs effectively modulate the offspring's immune environment, bridging the vulnerability gap left by acellular vaccines. Notably, this was achieved despite prior aP priming, demonstrating that the OMV booster redirects maternal immunity toward a balanced isotype profile and a mixed Th1/Th17-antibody isotype signature response. This translated into long-term protection against severe pulmonary disease in offspring, even as passive maternal antibodies waned.