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BPZE1 is a live, attenuated pertussis vaccine derived from B. pertussis strain Tohama I modified by genetic removal or inactivation of 3 B. pertussis toxins: pertussis toxin, dermonecrotic toxin, and tracheal cytotoxin. This Phase 2a study evaluated the safety and immunogenicity of liquid or lyophilized BPZE1 vaccine administered intranasally by needleless tuberculin syringe or mucosal atomization device (VaxINatorFifty healthy male and non-pregnant female participants 18-49 years of age were enrolled. Participants were randomized 3:3:3:1 to a single lyophilized dose of 10Across all groups, 35/50 (70 %) experienced at least one local adverse event (AE) and 31/50 (62 %) experienced at least one systemic AE, with similar AE frequencies observed between the highest 10Lyophilized BPZE1 vaccine was well tolerated and immunogenic at the highest dose (10

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 &le, &minus, 70 &deg, C. Although BPZE1 is stable for two years at &le, C, a lyophilized formulation stored at &ge, 5 &deg, 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 &minus, 20 &deg, C &plusmn, 10 &deg, C, 5 &deg, 3 &deg, C and 22.5 &deg, 2.5 &deg, 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.

Summary Background 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. Methods 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 . Findings 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. Interpretation 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. Funding ILiAD Biotechnologies.

Decades of peer reviewed evidence demonstrate that: 1)Bordetellapertussisand pertussis toxin are potent adjuvants, inducing asthma and allergic sensitization in animal models of human disease, 2)Bordetella pertussisoften colonizes the human nasopharynx, and is well documented in highly pertussis-vaccinated populations and 3) in children, a history of whooping cough increases the risk of asthma and allergic sensitization disease. We build on these observations with six case studies and offer a pertussis-based explanation for the rapid rise in allergic disease in former East Germany following the fall of the Berlin Wall; the current asthma, peanut allergy, and anaphylaxis epidemics in the United States; the correlation between the risk of asthma and gross national income per capita by country; the lower risk of asthma and allergy in children raised on farms; and the reduced risk of atopy with increased family size and later sibling birth order. To organize the evidence for the pertussis hypothesis, we apply the Bradford Hill criteria to the association between Bordetella pertussisand asthma and allergicsensitization disease. We propose that, contrary to conventional wisdom that nasopharyngealBordetella pertussiscolonizing infections are harmless, subclinicalBordetella pertussiscolonization is an important cause of asthma and diseases of allergic sensitization.

Background In a Phase 2b, multi-center, placebo-controlled, randomized study, intranasal BPZE1 induced mucosal and serum antibodies to pertussis antigens and protected against subsequent colonization following attenuated challenge with BPZE1 3 months later. BoostrixTM also induced serum but not mucosal antibodies and did not protect against BPZE1 challenge. We have evaluated the induction of serum bactericidal activity (SBA) for Bordetella pertussis by BPZE1 or Boostrix vaccination. A previous study showed that Boostrix induction of SBA is dependent on Prn whereas B. pertussis infection induces SBA targeting Prn and other antigens. Methods A convenience set of subjects who had a broad range of Prn and PT IgG serum concentrations from treatment groups who received BPZE1+BPZE1 or Boostrix+Placebo (Day 1 and 85 vaccination) were randomly selected to assess SBA using B. pertussis strain B1917. Three timepoints (baseline, 28 days following first and second vaccination) were analyzed and interpolated 50% killing titers determined. The relationship to Prn IgG concentration was assessed. Results BPZE1 and Boostrix elicited similar and significant increases in SBA following vaccination. BPZE1 and Boostrix elicit anti-Prn IgG, with Boostrix eliciting higher concentrations. A greater SBA response relative to PRN IgG was observed for BPZE1 compared to Boostrix. SBA-Prn correlations were high post-Boostrix (0.74) as previously reported; correlation was lower (0.35) following BPZE1, suggesting the involvement of broader antigenic protection beyond Prn alone. Table of GMT and GMFR in SBA and Prn IgG Conclusion In this exploratory investigation, the novel intranasal live-attenuated pertussis vaccine BPZE1 induced SBA titers that were similar to Boostrix using a B. pertussis strain representative of current disease isolates. SBA-Prn correlations were high post-Boostrix, consistent with prior reports showing Prn is the acellular vaccine antigen that mediates SBA. In contrast, BPZE1 bactericidal antibodies appear broader than Prn which may be important given the global rise of Prn-deficient B. pertussis strains. Disclosures All Authors: No reported disclosures

Summary The resurgence of pertussis may originate from inefficient vaccine-mediated protection against infection by Bordetella pertussis. Here, we show that the live attenuated vaccine BPZE1 is safe in nonhuman primates and induces robust protection against both B. pertussis disease and infection., Evidence suggests that the resurgence of pertussis in many industrialized countries may result from the failure of current vaccines to prevent nasopharyngeal colonization by Bordetella pertussis, the principal causative agent of whooping cough. Here, we used a baboon model to test the protective potential of the novel, live attenuated pertussis vaccine candidate BPZE1. A single intranasal/intratracheal inoculation of juvenile baboons with BPZE1 resulted in transient nasopharyngeal colonization and induction of immunoglobulin G and immunoglobulin A to all antigens tested, while causing no adverse symptoms or leukocytosis. When BPZE1-vaccinated baboons were challenged with a high dose of a highly virulent B. pertussis isolate, they were fully protected against disease, whereas naive baboons developed illness (with 1 death) and leukocytosis. Total postchallenge nasopharyngeal virulent bacterial burden of vaccinated animals was substantially reduced (0.002%) compared to naive controls, providing promising evidence in nonhuman primates that BPZE1 protects against both pertussis disease and B. pertussis infection.

BACKGROUND: The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1. METHODS: We performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified. RESULTS: All BPZE1 vaccinees showed robust B. pertussis–specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1–specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1. CONCLUSION: The breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT02453048, NCT00870350. FUNDING: ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.

While a number of endogenous risk factors including age and genetics are established for Alzheimer’s disease (AD), identification of acquired, potentially preventable or treatable causes, remains limited. In this paper, we review three epidemiologic case studies and present extensive biologic, immunologic and anatomic evidence to support a novel hypothesis that Bordetella pertussis (BP), the bacterium better known to cause whooping cough, is an important potential cause of AD. Cross-cultural documentation of nasopharyngeal subclinical BP colonization reflecting BP-specific mucosal immunodeficiency, proximate anatomy of intranasal mucosal surfaces to central nervous system (CNS) olfactory pathways, and mechanisms by which BP and BP toxin account for all hallmark pathology of AD are reviewed, substantiating biologic plausibility. Notably, respiratory BP infection and BP toxin secreted from subclinical BP colonization can account for the initiation and accumulation of amyloid β plaques and tau tangles. Additional mechanisms consistent with the immunobiologic effects of subclinical BP colonization include microglial activation and inflammation, atrophy and neurodegeneration, excitotoxicity, distinctive anatomic distribution and sequential spread of disease, impaired glucose utilization, and other characteristic CNS pathology of AD. We conclude by assessing the evidence for causation against the Bradford Hill criteria, and advocate for further investigation into the potential role of BP in the etiology of AD.

We discuss the correlation between the incidence of acute clinical Bordetella pertussis infection and celiac disease in children < 2 years of age during the Swedish celiac disease epidemic of the 1980s and 1990s.

It is established that (1) subclinical Bordetella pertussis colonization of the nasopharynx persists in highly vaccinated populations, and (2) B. pertussis toxin is a potent adjuvant that, when co-administered with neural antigens, induces neuropathology in experimental autoimmune encephalomyelitis, the principle animal model of multiple sclerosis. Building on these observations with supporting epidemiologic and biologic evidence, we propose that, contrary to conventional wisdom that subclinical pertussis infections are innocuous to hosts, B. pertussis colonization is an important cause of multiple sclerosis.