Use of a Neonatal-Mouse Model to Characterize Vaccines and Strategies for Overcoming the High Susceptibility and Severity of Pertussis in Early Life

Aispuro, Pablo Martín; Ambrosis, Nicolás Martín; Zurita, María Eugenia; Gaillard, María Emilia; Bottero, Daniela; Hozbor, Daniela Flavia

doi:10.3389/fmicb.2020.00723

Cited by 11 publications

(19 citation statements)

References 61 publications

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“…The failure of current Bp vaccines to prevent transmission and nasal colonization among infants demonstrates limitations of the previous models used to develop these vaccines and emphasizes the necessity of a better understanding of host interactions, especially in highly sensitive newborns ( 20 , 21 , 52 , 53 ). PTx appears to disrupt critical early responses unique to neonates, potentially explaining the specific sensitivity of neonates to Bp .…”

Section: Discussionmentioning

confidence: 99%

“…However, due to the limitations of available models, our understanding of the neonatal response to Bp has resulted in few preventative options in the very young. Thus, extraordinary lengths are often taken to prevent infant exposure, for example by booster vaccinating all their potential contacts, a practice referred to as “cocooning” ( 20 , 21 , 24 )…”

Section: Introductionmentioning

confidence: 99%

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Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis

et al. 2023

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The increased susceptibility of neonates to specific pathogens has previously been attributed to an underdeveloped immune system. More recent data suggest neonates have effective protection against most pathogens but are particularly susceptible to those that target immune functions specific to neonates. Bordetella pertussis (Bp), the causative agent of “whooping cough”, causes more serious disease in infants attributed to its production of pertussis toxin (PTx), although the neonate-specific immune functions it targets remain unknown. Problematically, the rapid development of adult immunity in mice has confounded our ability to study interactions of the neonatal immune system and its components, such as virtual memory T cells which are prominent prior to the maturation of the thymus. Here, we examine the rapid change in susceptibility of young mice and define a period from five- to eight-days-old during which mice are much more susceptible to Bp than mice even a couple days older. These more narrowly defined “neonatal” mice display significantly increased susceptibility to wild type Bp but very rapidly and effectively respond to and control Bp lacking PTx, more rapidly even than adult mice. Thus, PTx efficiently blocks some very effective form(s) of neonatal protective immunity, potentially providing a tool to better understand the neonatal immune system. The rapid clearance of the PTx mutant correlates with the early accumulation of neutrophils and T cells and suggests a role for PTx in disrupting their accumulation. These results demonstrate a striking age-dependent response to Bp, define an early age of extreme susceptibility to Bp, and demonstrate that the neonatal response can be more efficient than the adult response in eliminating bacteria from the lungs, but these neonatal functions are substantially blocked by PTx. This refined definition of “neonatal” mice may be useful in the study of other pathogens that primarily infect neonates, and PTx may prove a particularly valuable tool for probing the poorly understood neonatal immune system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis

et al. 2023

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“…We observed that the higher the antibody titer against a pertussis-specific antigen in a sow, the lower the neonatal antibody response to this antigen in the piglets born to the sow (data not shown). This interference from maternal antibodies present at time of immunization (known as blunting) has been observed in neonatal mice as well as in humans (33)(34)(35). The ratio of the maternal antibodies to vaccine antigens determines the extent of the inhibition, because there may be sufficient B cell epitopes free from maternal antibodies to be bound by the infants' B cells (36).…”

Section: Discussionmentioning

confidence: 99%

Göttingen Minipigs as a Model to Evaluate Longevity, Functionality, and Memory of Immune Response Induced by Pertussis Vaccines

et al. 2021

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Evaluation of the short-term and long-term immunological responses in a preclinical model that simulates the targeted age population with a relevant vaccination schedule is essential for human vaccine development. A Göttingen minipig model was assessed, using pertussis vaccines, to demonstrate that vaccine antigen-specific humoral and cellular responses, including IgG titers, functional antibodies, Th polarization and memory B cells can be assessed in a longitudinal study. A vaccination schedule of priming with a whole cell (DTwP) or an acellular (DTaP) pertussis vaccine was applied in neonatal and infant minipigs followed by boosting with a Tdap acellular vaccine. Single cell RNAsequencing was used to explore the long-term maintenance of immune memory cells and their functionality for the first time in this animal model. DTaP but not DTwP vaccination induced pertussis toxin (PT) neutralizing antibodies. The cellular immune response was also characterized by a distinct Th polarization, with a Th-2-biased response for DTaP and a Th-1/Th-17-biased response for DTwP. No difference in the maintenance of pertussis-specific memory B cells was observed in DTaP- or DTwP-primed animals 6 months post Tdap boost. However, an increase in pertussis-specific T cells was still observed in DTaP primed minipigs, together with up-regulation of genes involved in antigen presentation and interferon pathways. Overall, the minipig model reproduced the humoral and cellular immune responses induced in humans by DTwP vs. DTaP priming, followed by Tdap boosting. Our data suggest that the Göttingen minipig is an attractive preclinical model to predict the long-term immunogenicity of human vaccines against Bordetella pertussis and potentially also vaccines against other pathogens.

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“…Enzyme-linked immunosorbent assay (ELISA). As we previously described (39), plates (Nunc A/S, Roskilde, Denmark) were coated with proteins from bacterial lysates at 3 µg/ml in 0.5 M carbonate buffer pH 9.5, by means of an overnight incubation at 4 ºC. Blocked plates with 3% milk in PBS (2h 37ºC) were incubated with serially diluted samples of mouse serum (1h 37ºC).…”

Section: Groupsmentioning

confidence: 99%

Use of Mucosally Administered Outer Membrane Vesicles Derived fromBordetella pertussisto Diminish Nasal Bacterial Colonization

Rudi,

Gaillard,

Bottero

et al. 2024

Preprint

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Background: We previously identified Bordetella pertussis-derived outer membrane vesicles (OMVs) as a promising immunogen for improving pertussis vaccines. In this study, we evaluated the efficacy of our vaccine prototype in immunization strategies aimed at reducing disease transmission by targeting colonization in the upper airways while maintaining protection against severe disease by reducing colonization in the lower respiratory tract. Methods: We assessed different mucosal administration strategies in a murine model, including homologous 2-dose schedules and heterologous prime-boost strategies combining intramuscular (IM) systemic immunization with mucosal routes (intranasal (IN) or sublingual (SL)). We utilized mucosal c-di-AMP and/or systemic alum adjuvants to formulate the OMV vaccine prototype. A homologous IM immunization schedule and commercial vaccines were used for comparison. Results: All tested heterologous schemes induced higher levels of specific IgG with significant avidity, as well as high levels of IgG1 and IgG2 compared, to corresponding homologous 2-dose schemes via mucosal routes (OMVIN-IN or OMVSL-SL). High IgA levels were observed post-B. pertussis challenge following OMVIN-IN treatments and heterologous treatments where the second dose was administered via a mucosal route. Furthermore, schemes involving the intranasal route, whether in a homologous or heterologous scheme, induced the highest levels of IL-17 and IFN-γ. Accordingly, these schemes showed superior efficacy against nasal colonization than the commercial vaccines. Specifically, homologous intranasal immunization exhibited the highest protective capacity against nasal colonization while maintaining an excellent level of protection in the lower respiratory tract. To enhance the protective capacity against nasal colonization further, we conducted a comparative analysis of formulations containing different adjuvants (c-di-AMP, alum, or a combination of both) administered via homologous intranasal routes. These assays revealed that the use of alum, either alone or in combination with c-di-AMP, did not enhance the immune protective capacity. Conclusions: All the experiments presented here highlight that the use of OMVs, regardless of the scheme utilized, with the exception of OMVSL-SL, outperformed acellular pertussis (aP) vaccines, achieving a greater reduction in bacterial colonization in the upper respiratory tract (p<0.001).

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Use of a Neonatal-Mouse Model to Characterize Vaccines and Strategies for Overcoming the High Susceptibility and Severity of Pertussis in Early Life

Cited by 11 publications

References 61 publications

Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis

Novel murine model reveals an early role for pertussis toxin in disrupting neonatal immunity to Bordetella pertussis

Göttingen Minipigs as a Model to Evaluate Longevity, Functionality, and Memory of Immune Response Induced by Pertussis Vaccines

Use of Mucosally Administered Outer Membrane Vesicles Derived fromBordetella pertussisto Diminish Nasal Bacterial Colonization

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