Pertussis Vaccine Candidate Based on Outer Membrane Vesicles Derived From Biofilm Culture

Abstract

Outer membrane vesicles (OMV) derived from Bordetella pertussis—the etiologic agent of the resurgent disease called pertussis—are safe and effective in preventing bacterial colonization in the lungs of immunized mice. Vaccine formulations containing those OMV are capable of inducing a mixed Th1/Th2/Th17 profile, but even more interestingly, they may induce a tissue-resident memory immune response. This immune response is recommended for the new generation of pertussis-vaccines that must be developed to overcome the weaknesses of current commercial acellular vaccines (second-generation of pertussis vaccine). The third-generation of pertussis vaccine should also deal with infections caused by bacteria that currently circulate in the population and are phenotypically and genotypically different [in particular those deficient in the expression of pertactin antigen, PRN(-)] from those that circulated in the past. Here we evaluated the protective capacity of OMV derived from bacteria grown in biofilm, since it was observed that, by difference with older culture collection vaccine strains, circulating clinical B. pertussis isolates possess higher capacity for this lifestyle. Therefore, we performed studies with a clinical isolate with good biofilm-forming capacity. Biofilm lifestyle was confirmed by both scanning electron microscopy and proteomics. While scanning electron microscopy revealed typical biofilm structures in these cultures, BipA, fimbria, and other adhesins described as typical of the biofilm lifestyle were overexpressed in the biofilm culture in comparison with planktonic culture. OMV derived from biofilm (OMVbiof) or planktonic lifestyle (OMVplank) were used to formulate vaccines to compare their immunogenicity and protective capacities against infection with PRN(+) or PRN(-) B. pertussis clinical isolates. Using the mouse protection model, we detected that OMVbiof-vaccine was more immunogenic than OMVplank-vaccine in terms of both specific antibody titers and quality, since OMVbiof-vaccine induced antibodies with higher avidity. Moreover, when OMV were administered at suboptimal quantity for protection, OMVbiof-vaccine exhibited a significantly adequate and higher protective capacity against PRN(+) or PRN(-) than OMVplank-vaccine. Our findings indicate that the vaccine based on B. pertussis biofilm-derived OMV induces high protection also against pertactin-deficient strains, with a robust immune response.

Integrating proteomic data with metabolic modelling provides insight into key pathways ofBordetella pertussisbiofilms

“…Prn was found to be downregulated in biofilm cells. This is contrasted by previous results that have found an increase in Prn in B. pertussis biofilm cells (14, 16–18). However, it should be noted that de Gouw et al .…”

“…As one of the three ACV components, the change identified supports the hypothesis that the planktonic based ACV may not protect as efficiently against cells in the biofilm condition. The utility of biofilm related proteins as novel vaccine antigens has been demonstrated previously (14, 16, 84). This study provides additional targets that may be explored further in addition to identifying key metabolic pathways that may be crucial to disrupting the biofilm lifestyle.…”

“…Additional models were generated with proteomic expression data from a separate study. To our knowledge, there are 5 studies that have compared protein expression of B. pertussis biofilm cells with their planktonic counterpart (14)(15)(16)(17)(18). Of these, only one study by de Gouw et al (14) has publicly available global proteomic expression data of planktonic and biofilm cells and thus was chosen for the production of iMAT models.…”

“…Development of the vaccine has been based on planktonic studies and may not be entirely representative of the infection cycle. Although proteomic comparisons have been performed between biofilm and planktonic B. pertussis cells (14)(15)(16)(17)(18), little is known about the metabolic reactions that are altered while in the biofilm state. In response to changes in environment, the most widely studied regulator of gene expression in B. pertussis is the Bordetella virulence gene (Bvg) system (19).…”

Biological Nanoparticles in Vaccine Development

“…As mentioned, OMV-based vaccines currently exist for the prevention of Hib and MenB infections. Recent literature has focused on the development of OMV vaccines for influenza ( Rappazzo et al, 2016 ; Watkins et al, 2017b ), malaria ( Scaria et al, 2019 ), pertussis ( Raeven et al, 2020 ; Carriquiriborde et al, 2021 ), Lyme disease ( Klouwens et al, 2021 ), plague ( Carvalho et al, 2019 ; Wang X. et al, 2020 ), and SARS-Cov-2 ( Gaspar et al, 2021 ; Thapa et al, 2021 ; van der Ley et al, 2021 ). Due to the inherent flexibility and capability of the OMV platform, there is interest in expressing heterologous antigens from different pathogens on the same OMV to create novel combined vaccines ( König et al, 2021 ).…”