B-cell responses after intranasal vaccination with the novel attenuated Bordetella pertussis vaccine strain BPZE1 in a randomized phase I clinical trial.
Despite high vaccination coverage, pertussis is still a global concern in infant morbidity and mortality, and improved pertussis vaccines are needed. A live attenuated Bordetella pertussis strain, named BPZE1, was designed as an intranasal vaccine candidate and has recently been tested in man in a phase I clinical trial. Here, we report the evaluation of the B-cell responses after vaccination with BPZE1. Forty-eight healthy males with no previous pertussis-vaccination were randomized into one of three dose-escalating groups or into a placebo group. Plasma blast- and memory B-cell responses were evaluated by ELISpot against three different pertussis antigens: pertussis toxin, filamentous haemagglutinin and pertactin. Seven out of the 36 subjects who had received the vaccine were colonized by BPZE1, and significant increases in the memory B-cell response were detected against all three tested antigens in the culture-positive subjects between days 0 and 28 post-vaccination. The culture-positive subjects also mounted a significant increase in the filamentous haemagglutinin-specific plasma blast response between days 7 and 14 post-vaccination. No response could be detected in the culture-negatives or in the placebo group post-vaccination. These data show that BPZE1 is immunogenic in humans and is therefore a promising candidate for a novel pertussis vaccine. This trial is registered at ClinicalTrials.gov (NCT01188512).
Jahnmatz M
，Amu S
，Ljungman M
，Wehlin L
，Chiodi F
，Mielcarek N
，Locht C
，Thorstensson R
... -
《-》
Heterologous prime-boost immunization with live attenuated B. pertussis BPZE1 followed by acellular pertussis vaccine in mice.
Pertussis is a severe and life-threatening infectious disease. Two successive generations of vaccines have strongly reduced its incidence over the last 70 years. However, despite excellent global vaccine coverage, it is still not under control and constitutes today the most frequent vaccine-preventable childhood disease. New vaccination approaches are therefore needed. Here, we provide preclinical proof of concept for a heterologous prime-boost strategy, using the live attenuated Bordetella pertussis vaccine candidate BPZE1 to prime infant and neonatal mice intranasally and a currently available acellular pertussis vaccine (aPV) as a booster. Intranasal vaccination with BPZE1 provided strong protection against challenge in neonatal mice, which could be boosted with a single dose of aPV. Furthermore, BPZE1 priming induced a strong Th1/Th17 response, which was maintained after repeated aPV administrations, in contrast to non-primed mice, in which aPV administrations resulted in Th2 skewing. In addition to T cell responses, intranasal administration of BPZE1 to infant or neonatal mice also primed antibody responses to B. pertussis antigens, with a strong preference of the IgG2a over the IgG1 isotypes, which was not seen in non-primed animals. Finally, neonatal BPZE1 priming strongly enhanced aPV-induced protection against B. pertussis challenge. These results lend support for a heterologous prime-boost strategy to control pertussis by using BPZE1 early in life and considering the current aPV administrations as booster vaccinations, thereby bridging the gap from birth to the first aPV immunizations and avoiding aPV-mediated Th2 skewing. A first-in-man clinical trial on BPZE1 has recently been successfully completed, which provides hope that these findings may be translated into human applications in the future.
Feunou PF
，Kammoun H
，Debrie AS
，Locht C
... -
《-》
Long-term immunity against pertussis induced by a single nasal administration of live attenuated B. pertussis BPZE1.
Duration of vaccine-induced immunity plays a key role in the epidemiology and in the pattern of transmission of a vaccine-preventable disease. In the case of whooping cough, its re-emergence has been attributed, at least partly, to the waning of immunity conferred by current pertussis vaccines. We have recently developed a highly attenuated live vaccine, named BPZE1, which has been shown to be safe and to induce strong protective immunity against Bordetella pertussis infection in mice. In this study, we evaluated the long-term immunogenicity and protective efficacy induced by a single intranasal dose of BPZE1. Up to 1 year after immunization, BPZE1 showed significantly higher efficacy to protect adult and infant mice against B. pertussis infection than two administrations of an acellular pertussis vaccine (aPV). B. pertussis-specific antibodies were induced by live BPZE1 and by aPV, with increasing amounts during the first 6 months post-immunization before a progressive decline. Cell-mediated immunity was also measured 1 year after immunization and showed the presence of memory T cells in the spleen of BPZE1-immunized mice. Both cell-mediated and humoral immune responses were involved in the long-lasting protection induced by BPZE1, as demonstrated by adoptive transfer experiments to SCID mice. These data highlight the potential of the live attenuated BPZE1 candidate vaccine as part of a strategy to solve the problem of waning protective immunity against B. pertussis observed with the current aPV vaccines.
Feunou PF
，Kammoun H
，Debrie AS
，Mielcarek N
，Locht C
... -
《-》
Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: a phase 1b, double-blind, randomised, placebo-controlled dose-escalation study.
Long-term protection and herd immunity induced by existing pertussis vaccines are imperfect, and a need therefore exists to develop new pertussis vaccines. This study aimed to investigate the safety, colonisation, and immunogenicity of the new, live attenuated pertussis vaccine, BPZE1, when given intranasally.
This phase 1b, double-blind, randomised, placebo-controlled, dose-escalation study was done at the phase 1 unit, Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden. Healthy adults (18-32 years) were screened and included sequentially into three groups of increasing BPZE1 dose strength (107 colony-forming units [CFU], 108 CFU, and 109 CFU), and were randomly assigned (3:1 within each group) to receive vaccine or placebo. Vaccine and placebo were administered in phosphate-buffered saline contained 5% saccharose as 0·4 mL in each nostril. The primary outcome was solicited and unsolicited adverse events between day 0 and day 28. The analysis included all randomised participants who received a vaccine dose. Colonisation with BPZE1 was determined by repeatedly culturing nasopharyngeal aspirates at day 4, day 7, day 11, day 14, day 21, and day 28 after vaccination. Immunogenicity, as serum IgG and IgA responses were assessed at day 0, day 7, day 14, day 21, day 28, 6 months, and 12 months after vaccination. This trial is registered at Clinicaltrials.gov, NCT02453048.
Between Sept 1, 2015, and Feb 3, 2016, 120 participants were assessed for eligibility, 48 of whom were enrolled and randomly assigned (3:1) to receive vaccine or placebo, with 12 participants each in a low-dose, medium-dose, and high-dose vaccine group. Adverse events between day 0 and day 28 were reported by one (8%, 95% CI 0-39) of 12 participants in both the placebo and low-dose groups, and two (17%; 2-48) of 12 participants in both the medium-dose and high-dose groups, including cough of grade 2 or more, oropharyngeal pain, and rhinorrhoea and nasal congestion. During this time, none of the participants experienced any spasmodic cough, difficulties in breathing, or adverse events following immunisation concerning vital signs. The tested doses of BPZE1 or placebo were well tolerated, with no apparent difference in solicited or unsolicited adverse events following immunisation between groups. Colonisation at least once after vaccination was observed in 29 (81%; 68-93) of 36 vaccinated participants. The tested vaccine doses were immunogenic, with increases in serum IgG and IgA titres against the four B pertussis antigens from baseline to 12 months.
The tested vaccine was safe, induced a high colonisation rate in an adult population, and was immunogenic at all doses. These findings justify further clinical development of BPZE1 to ultimately be used as a priming vaccine for neonates or a booster vaccine for adolescents and adults, or both.
ILiAD Biotechnologies.
Jahnmatz M
，Richert L
，Al-Tawil N
，Storsaeter J
，Colin C
，Bauduin C
，Thalen M
，Solovay K
，Rubin K
，Mielcarek N
，Thorstensson R
，Locht C
，BPZE1 study team
... -
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
