Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: a phase 1b, double-blind, randomised, placebo-controlled dose-escalation study

Jahnmatz, Maja; Richert, Laura; Al‐Tawil, Nabil; Storsæter, Jann; Colin, Céline; Bauduin, Claire; Thalen, Marcel; Solovay, Ken; Rubin, Keith; Mielcarek, Nathalie; Thorstensson, Rigmor; Locht, Camille; Dager, Lena; Ekholm, Nina; Gustafsson, Margareta; Linde, Åsa; Lång, Cecilia; Năstase, M; Reinholdsson, Ingalill; Sigurdardottir, Erla; Wahlberg, Anneli; Zarea, Izabella; Aktas, Teodora; Andersson, Ingrid; Pihlainen, Eva Hanson; Ljungman, Margaretha; Ringman, Maj; Tecleab, Teghesti; Wehlin, Lena; Allais, Florence; Assuied, Alex; Chêne, Geneviève; Gilbert, Camille; Jean, Delphine; Marec, Fabien Le; Moinot, Laëtitia; Reboud, P; Rousseau, Emilie; Roy, Céline; Schwimmer, Christine; Taïeb, Ludivine; Wallet, Cédrick; Derocle, Gabrielle; Guéguen, Sonia; Lévy-Marchal, Claire; Esperou, Hélène; Debrie, Anne-Sophie; Raze, Dominique; Coutte, Loïc; Diallo, Alpha; Mercier, Noémie

doi:10.1016/s1473-3099(20)30274-7

Cited by 35 publications

(33 citation statements)

References 27 publications

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“…In previous studies a single nasal administration of BPZE1 was shown to provide protection against a B. pertussis challenge in mice [8,10] and non-human primates [9], and was found to be safe, even in severely immunocompromised animals, such as IFN-γ receptor KO mice [22] and MyD88-deficient mice [19]. BPZE1 was also shown to be safe and immunogenic in two human phase I clinical trials [11,12]. Based on the safety and immunogenicity results of the phase Ib study, the 10 9 CFU dose is being used in further clinical development of BPZE1.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies in mice have shown that BPZE1 induces potent mucosal IgA and IL-17-producing tissue-resident CD4 + memory T cells in the nose, which appears to be crucial for long-term protection against nasal colonization by B. pertussis [10]. BPZE1 is now in clinical development and has already successfully completed two phase I studies, which have shown that the vaccine is safe in adult volunteers, and is able to transiently colonize the human nasal cavity and to induce antibody responses to B. pertussis antigens [11,12].…”

Section: Of 16mentioning

confidence: 99%

“…The BPZE1 vaccine strain [8] Working Cell Bank (WCB) was grown in fully synthetic Thijs medium [15] under agitation. After addition of 20% vol/vol of 86% glycerol, aliquots were filled in 1.5-mL cryo-vials and the WCB was stored at −70 • C until further use, as described [11,12].…”

Section: Bacterial Strains and Growth Conditionsmentioning

confidence: 99%

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Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1

et al. 2020

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Current pertussis vaccines protect against disease, but not against colonization by and transmission of Bordetella pertussis, whereas natural infection protects against both. The live attenuated vaccine BPZE1 was developed to mimic immunogenicity of natural infection without causing disease, and in preclinical models protected against pertussis disease and B. pertussis colonization after a single nasal administration. Phase 1 clinical studies showed that BPZE1 is safe and immunogenic in humans when administered as a liquid formulation, stored at ≤−70 °C. Although BPZE1 is stable for two years at ≤−70 °C, a lyophilized formulation stored at ≥5 °C is required for commercialization. The development of a BPZE1 drug product, filled and lyophilized directly in vials, showed that post-lyophilization survival of BPZE1 depended on the time of harvest, the lyophilization buffer, the time between harvest and lyophilization, as well as the lyophilization cycle. The animal component-free process, well defined in terms of harvest, processing and lyophilization, resulted in approximately 20% survival post-lyophilization. The resulting lyophilized drug product was stable for at least two years at −20 °C ± 10 °C, 5 °C ± 3 °C and 22.5 °C ± 2.5 °C and maintained its vaccine potency, as evaluated in a murine protection assay. This manufacturing process thus enables further clinical and commercial development of BPZE1.

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Section: Discussionmentioning

confidence: 99%

Section: Of 16mentioning

confidence: 99%

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Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1

et al. 2020

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“…BPZE1 is now in clinical development and has completed two phase 1 studies in adult human volunteers [104,105]. Two phase 2 studies are currently under way [NCT03541499 and NCT03942406].…”

Section: Live Attenuated Pertussis Vaccinesmentioning

confidence: 99%

“…Interestingly, those subjects that were not colonized by BPZE1 had high pre-existing levels of antibodies to pertactin, filamentous haemagglutinin and fimbriae, suggesting that they had recently been asymptomatically infected with B. pertussis. In the second trial, volunteers with pre-existing antibodies to B. pertussis antigens were excluded, and naso-pharyngeal colonization by BPZE1 could be detected in more than 80% of the volunteers [105]. Furthermore, in the highest dose group (10 9 CFU), all subjects seroconverted.…”

Section: Live Attenuated Pertussis Vaccinesmentioning

confidence: 99%

The Path to New Pediatric Vaccines against Pertussis

Locht

2021

Vaccines

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Whooping cough, or pertussis, mostly caused by Bordetella pertussis, is a respiratory disease that affects all age groups, but severe and fatal pertussis occurs almost exclusively in young children. The widespread use of whole-cell and, more recently, of acellular vaccines has substantially reduced the disease incidence. However, it has not been eliminated in any part of the world and has made a worrisome rebound in several areas. Cocoon and maternal immunization have been implemented in several countries but have their intrinsic limitations. To effectively control pertussis, novel vaccines are needed that protect against disease and prevent B. pertussis infection and transmission, which is not the case for current vaccines. Several approaches are contemplated, including alternative administration routes, such as nasal immunization, improvement of acellular vaccines by adding more antigens and T-cell-promoting adjuvants, and the development of novel vaccines, such as outer membrane vesicles and live attenuated vaccines. Among them, only a live attenuated vaccine has so far been assessed for safety and immunogenicity in preclinical models other than mice and is in clinical development. Before any of these vaccines can be used in neonates, extensive safety and immunogenicity assessment in pre-clinical neonatal models and in carefully designed clinical trials is necessary. The aim of this review is to discuss the current pertussis problem, implemented strategies to resolve it, the value of animal models and novel vaccine approaches.

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