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Mucosal inflammation and pre-existing antibodies define protection and disease outcomes in human Bordetella pertussis challenge

ABSTRACT: Whooping cough, caused by Bordetella pertussis (BP), persists despite widespread vaccination with acellular pertussis (aP) vaccines, which protect against disease but provide incomplete and short-lived immunity against infection and transmission. To define correlates of protection and mechanisms underlying symptom development, we characterized systemic and mucosal immune responses in a North American BP-controlled human infection model (CHIM). Healthy adults, primed in infancy with either whole-cell or aP vaccines, were intranasally challenged with escalating BP doses and classified as symptomatic, asymptomatic, or non-infected. Longitudinal paired blood and nasal samples were analyzed to measure antibody titers, cell subset frequencies, cytokine concentrations, gene expression, and T cell polarization and activation. Non-infected participants exhibited significantly higher pre-challenge serum antigen-specific IgG titers, identifying these antibodies as potential correlates of protection. Only symptomatic individuals developed robust antigen-specific IgG responses post-challenge and displayed pronounced nasal transcriptional inflammation peaking on day 7, characterized by induction of interferon and NF-κB signaling and the presence of HLA-DR⁺ myeloid cells. Systemic responses were modest: plasma cytokine concentrations decreased following challenge regardless of outcome, peripheral blood mononuclear cell transcriptomes remained largely unchanged, and antigen-specific T cell activation and polarization were unaffected. Together, these findings reveal that protection from BP colonization associates with pre-existing serum antibodies, whereas symptom development is driven by localized mucosal inflammation dominated by myeloid cells. The predominance of nasal over systemic immune activation highlights the importance of mucosal immunity in controlling BP and provides critical insights to guide the design of next-generation vaccines aimed at preventing both disease and transmission.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310241 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Mucosal immunity plays a pivotal role in providing comprehensive protection against upper-airway infections and effectively limiting the shedding and transmission of SARS-CoV-2. Despite its critical importance, there remains a notable absence of nasal spray vaccines endorsed for global use by the World Health Organization. This could be due to the inability of current intranasal vaccines to induce strong mucosal and systemic responses in humans, thus urgently entailing a next-generation of intranasal COVID-19 vaccines with novel and safe technologies. In this study, we prepared a two-component intranasal vaccine that combines adenovirus vectors with a self-assembled subunit protein. Specifically, the adenovirus vector expresses the spike protein of XBB.1.5 variant (Ad5XBB.1.5), and were mixed with the recombinant protein that developed derived from the receptor binding domain (RBD) of XBB.1.5 (RBDXBB.1.5-HR). Combination of Ad5XBB.1.5 and RBDXBB.1.5-HR elicited superior humoral and cellular immunity against XBB.1.5-included variants compared with the individual components. Importantly, the STING signaling pathway was found to be crucial for the adjuvant effect of the adenovirus vector. In addition, to increase the broad-spectrum neutralizing capacities, a trimeric protein derived from the BA.5 variant (RBDBA.5-HR) was incorporated to formulate a three-component vaccine (Ad5XBB.1.5+RBDXBB.1.5-HR+RBDBA.5-HR), indicating the utilization of a combination of an adenovirus-vectored and subunit protein vaccines has the potential to serve as a next-generation intranasal vaccine platform. Of note, intranasally delivery of two-component vaccine provided protective immunity against live Omicron XBB.1.16 virus challenge in mice. Furthermore, the combination of adenovirus and subunit protein vaccine demonstrates excellent tolerability and safety in human subjects, and is able to induce enhanced mucosal immunity as well as high levels of sera neutralizing antibody in all participants. These findings underscore its suitability for clinical application in the prevention of SARS-CoV-2 variants encompassing XBB lineages.

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Mucosal inflammation and pre-existing antibodies define protection and disease outcomes in human Bordetella pertussis challenge

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