Study of BPZE1 Intranasal Pertussis Vaccine (Administered Via VaxINator(TM)), Prime + Boost, in Healthy Adults

• ClinicalTrials.gov Identifier: NCT03942406
• Recruitment Status: Completed
• First Posted: May 8, 2019
• Last Update Posted: July 9, 2020
• Sponsor: ILiAD Biotechnologies
• Collaborator: PPD
• Information provided by (Responsible Party): ILiAD Biotechnologies

Study Description

Brief Summary:

This study evaluates the safety and immunogenicity of the BPZE1 live attenuated pertussis vaccine, intended to prevent nasopharyngeal colonization and pertussis disease, and compares a single (prime) BPZE1 dose or 2-dose (prime + boost) to a single (prime) Boostrix or BPZE1 prime + Boostrix boost. This is a multi-center, randomized, placebo-controlled, and observer blinded trial in healthy adults with a 6 month safety follow-up after the last vaccination.

Condition or disease	Intervention/treatment	Phase
Pertussis; Whooping Cough	Combination Product: BPZE1 pertussis vaccine and VaxINator(TM) Atomization Device	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Phase 2b Study of BPZE1 Intranasal Pertussis Vaccine in Adults to Assess Immunological Response and Safety Profile of 1-Dose (Prime) and 2-Doses (Prime+Boost) Schedule, Compared to a Boostrix™ Prime Dose With or Without a BPZE1 Boost Dose
• Actual Study Start Date: June 15, 2019
• Actual Primary Completion Date: February 14, 2020
• Actual Study Completion Date: June 24, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: BPZE1 Intranasal Prime, BPZE1 Boost; Individual will receive an intranasal dose of BPZE1 via the VaxINator atomization device and a dose of intramuscular (I.M.) placebo. Individuals will receive a boost dose of intranasal BPZE1 via the VaxINator™ atomization device.	Combination Product: BPZE1 pertussis vaccine and VaxINator(TM) Atomization Device; Live attenuated pertussis vaccine administered via the VaxINator(TM) atomization device
Experimental: BPZE1 Intranasal Prime, Placebo Boost; Individual will receive an intranasal dose of BPZE1 via the VaxINator atomization device and a dose of intramuscular (I.M.) placebo. Individuals will receive a boost dose of intranasal placebo via the VaxINator™ atomization device.	Combination Product: BPZE1 pertussis vaccine and VaxINator(TM) Atomization Device; Live attenuated pertussis vaccine administered via the VaxINator(TM) atomization device
Experimental: Boostrix IM Prime, BPZE1 Boost; Individual will receive an intranasal dose of placebo via the VaxINator atomization device and a dose of intramuscular (I.M.) Boostrix (aP vaccine comparator). Individuals will receive a boost dose of intranasal BPZE1 via the VaxINator™ atomization device.	Combination Product: BPZE1 pertussis vaccine and VaxINator(TM) Atomization Device; Live attenuated pertussis vaccine administered via the VaxINator(TM) atomization device
Active Comparator: Boostrix IM Prime, Placebo Boost; Individual will receive an intranasal dose of placebo via the VaxINator atomization device and a dose of intramuscular (I.M.) Boostrix (aP vaccine comparator). Individuals will receive a boost dose of intranasal placebo via the VaxINator™ atomization device.	Combination Product: BPZE1 pertussis vaccine and VaxINator(TM) Atomization Device; Live attenuated pertussis vaccine administered via the VaxINator(TM) atomization device

Outcome Measures

Primary Outcome Measures :

1. Immunogenicity - Mucosal Seroconversion [ Time Frame: 3 months ]
   Proportion of subjects who achieve seroconversion against at least 1 pertussis antigen (PT, FHA, PRN, FIM 2/3, or BPZE1 whole cell extract) in nasal secretions (S-IgA) on Day 29 or 113 (prime or prime + boost)
2. Safety - Solicited AEs [ Time Frame: Through Day 8 following each vaccination ]
   Solicited AEs (local, nasal/respiratory, and systemic reactogenicity events) for 7 days following each vaccination by severity score, duration, and peak intensity.
3. Safety - Laboratory Results [ Time Frame: Through Day 8 following each vaccination ]
   Safety laboratory results (serum chemistry, hematology, coagulation) by FDA toxicity score in the safety lead-in cohort at Day 8 following each vaccination.

Secondary Outcome Measures :

1. Systemic Immunogenicity - seroconversion to 1 or more antigens [ Time Frame: 9 months ]

   Proportion of subjects who achieve seroconversion against pertussis antigen (PT, FHA, PRN, FIM 2/3, or BPZE1 whole cell extract) over baseline (IgG, IgA, and IgG or IgA ELISA when possible) for.

   • At least 1 antigen on each of the Days 29, 85, 113, 169, or 254
   • At least 1 antigen on any of the Days 29, 85, 113, 169, or 254
   • At least any 1 antigen on all Days 29, 85, 113, 169, or 254
2. Systemic Immunogenicity - seroconversion to BPZE1 whole cell extract [ Time Frame: 1 month post each vaccination ]

   Proportion of subjects who achieve seroconversion (IgG ELISA only) against BPZE1 whole cell extract over baseline:

   • On either Day 29 (prime) or 113 (boost)
   • On both Days 29 (prime) and 113 (boost).
3. Systemic Immunogenicity - seroconversion to 2 or more antigens [ Time Frame: 9 months ]

   Proportion of subjects who achieve seroconversion against 2 or more pertussis antigens (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract) over baseline (IgG, IgA, and IgG or IgA ELISA when possible):

   • On each of the Days 29, 85, 113, 169, or 254
   • On any of the Days 29, 85, 113, 169, or 254
   • At least the same 2 antigens on all Days 29, 85, 113, 169, and 254.
4. Systemic Immunogenicity - seroconversion against aP antigens [ Time Frame: 1 month post each vaccination ]

   Proportion of subjects who achieve seroconversion against the acellular pertussis (aP) antigens PT, FHA, and PRN over baseline (IgG, IgA, and IgG or IgA ELISA when possible):

   • On either Day 29 (prime) or 113 (boost)
   • On both Days 29 (prime) or 113 (boost).
5. Systemic Immunogenicity - boosting [ Time Frame: 1 month post boost vaccination ]
   Proportion of subjects who demonstrate boosting for each pertussis antigen (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract) on Day 113. Boost is defined as at least a 2 fold increase from the pre boost sample taken on Day 85 (IgG, IgA, and IgG or IgA ELISA when possible)
6. Systemic Immunogenicity - Geometric Mean Fold Rise [ Time Frame: 9 months ]

   The Geometric Mean Fold Rise (IgG/IgA)against each pertussis antigen (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract):

   • On Days 29, 85, 113, 169, and 254 over baseline (Day 1)
   • On Days 113, 169, and 254 over pre-boost (Day 85)
   • The maximum over baseline on either Day 29 or 85 (post priming response)
   • The maximum over pre-boost (Day 85) on any of the Days 113, 169, or 254 (post boost response)
   • The maximum during the study.
7. Systemic Immunogenicity - Geometric Mean Titer [ Time Frame: 9 months ]

   The Geometric Mean Titer (IgG/IgA) against each pertussis antigen (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract):

   • On Days 29, 85, 113, 169, and 254
   • The maximum on Day 29 or 85 (after priming dose)
   • The maximum after Days 113, 169, or 254 (after boosting dose)
   • The maximum during the study.
8. Mucosal Immunogenicity - seroconversion to any pertussis antigen [ Time Frame: 9 months ]

   Proportion of subjects who achieve seroconversion against any pertussis specific antigen (PT, PRN, FHA, FIM 2/3, or BPZE1 whole cell extract) over baseline in nasal secretions (S-IgA):

   • At least 1 antigen on each of the Days 29, 78, 113, 169, or 254
   • At least 1 antigen on any of the Days 29, 78, 113, 169, or 254
   • At least any 1 antigen on all Days 29, 78, 113, 169, and 254.
9. Mucosal Immunogenicity - seroconversion to BPZE1 whole cell extract [ Time Frame: 1 month post each vaccination ]

   Proportion of subjects who achieve seroconversion against BPZE1 whole cell extract over baseline in nasal secretions (S-IgA):

   • On either Day 29 (prime) or 113 (boost)
   • On both Days 29 (prime) and 113 (boost)
10. Mucosal Immunogenicity - seroconversion against aP antigens [ Time Frame: 1 month post each vaccination ]
    • Proportion of subjects who achieve seroconversion against aP antigens PT, FHA, and PRN over baseline in nasal secretions (S-IgA):
    • On either Days 29 (prime) or 113 (boost)
    • On both Days 29 (prime) and 113 (boost)
11. Mucosal Immunogenicity - seroconversion to 2 or more pertussis antigens [ Time Frame: 9 months ]
    • Proportion of subjects who achieve seroconversion for any 2 or more pertussis antigens (PT, PRN, FHA, or BPZE1 whole cell extract) over baseline in nasal secretions (S-IgA):
    • On each of Days 29, 85, 113, 169, or 254
    • On any of Days 29, 85, 113, 169, or 254
    • At least the same 2 antigens on all Days 29, 85, 113, 169, and 254
12. Mucosal Immunogenicity - Boosting [ Time Frame: 1 month post boost vaccination ]
    Proportion of subjects who demonstrate boosting against each pertussis antigen (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract) on Day 113 in nasal secretions (S-IgA) compared to Day 78 (pre-boost)
13. Mucosal Immunogenicity - Geometric Mean Fold Rise [ Time Frame: 9 months ]
    • The Geometric Mean Fold Rise against each pertussis antigen (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract) in nasal secretions (S-IgA):
    • On Days 29, 78, 113, 169, and 254 over baseline (Day 1)
    • On Days 113, 169, and 254 over pre-boost (Day 78)
    • The maximum over baseline on either Day 29 or 78 (post priming response)
    • The maximum over pre boost on any of the Days 113, 169, or 254 (post boost response)
    • The maximum during the study
14. Mucosal Immunogenicity - Geometric Mean Titers [ Time Frame: 9 months ]
    • The Geometric Mean Titer against each pertussis antigen (PT, FHA, PRN, FIM 2/3, and BPZE1 whole cell extract) in nasal secretions (S-IgA):
    • On Days 29, 78, 113, 169, and 254
    • The maximum on Days 29 or 78 (after priming dose)
    • The maximum after Days 113, 169, or 254 (after boosting dose)
    • The maximum during the study
15. Colonization after Boost [ Time Frame: 1 month post boost vaccination ]
    • Proportion of subjects with positive B. pertussis by bacterial culture of nasal sample on each day and on any of Days 92, 96, and 113.
    • B. pertussis colony counts on each day (Days 92, 96, and 113).
16. Colonization Clearance [ Time Frame: 9 months ]
    Number of subjects who remain culture positive for B. pertussis at Days 78 (following priming) and 254 (following boost).
17. Safety - Unsolicited AEs [ Time Frame: through 6 months from last vaccination ]
    • Unsolicited AEs (eg, treatment-emergent AEs, serious AEs, and suspected unexpected serious adverse reactions) collected for 28 days following each vaccination by Medical Dictionary for Regulatory Activities (MedDRA) classification and severity score.
    • Unsolicited AEs related to vaccination through Day 113 by MedDRA classification and severity score.
    • Serious AEs through 6 months following the last vaccination (or until resolved or stable) by MedDRA classification, relatedness, and severity score.
18. Safety - Vital signs following vaccination [ Time Frame: through 6 months from last vaccination ]
    Vital sign measurements with severity scoring immediately following vaccination.

Other Outcome Measures:

1. Exploratory - Cell-mediated Responses [ Time Frame: 1 month post vaccination ]
   Cell-mediated (eg, B cell, CD4 T lymphocytes + T cell, CD8 T lymphocytes + T cell) responses (eg, cell staining, cytokine production) following stimulation of peripheral blood mononuclear cells collected at baseline, and 8 days post vaccination (prime and boost) to pertussis specific antigens. Results expressed both as absolute values and fold over baseline (per specific assay characteristics).
2. Exploratory - additional mucosal immunity [ Time Frame: 1 month post vaccination ]
   Following the outcomes of the primary and second analyses, additional exploratory endpoints may be tested for systemic or nasal mucosal immunogenicity (IgG or IgA) responses at any time point collected and not already performed in the primary or secondary analysis sets.
3. Exploratory - Geometric Mean Titer IgG for Tetanus and Diptheria [ Time Frame: 1 month post vaccination ]
   The Geometric Mean Titer, expressed for serum IgG ELISA against tetanus and diphtheria on Days 29 and 113.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Is a male or nonpregnant female 18 to 50 years of age, inclusive, on Day 1 (primary vaccination).
2. Is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements.

3. Female subjects must be nonpregnant and nonlactating and meet 1 of the following criteria:

   1. Postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause or documented plasma follicle-stimulating hormone level in the postmenopausal range);

   2. Surgically sterile (ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy).

      NOTE: These procedures and laboratory test results must be confirmed by physical examination, or by subject recall of specific date and hospital/facility of procedure, or by medical documentation of said procedure.

   3. Is of childbearing potential (defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal), agrees to be heterosexually inactive from at least 21 days prior to enrollment and through 3 months after the boosting vaccination or agrees to consistently use any of the following methods of contraception from at least 21 days prior to enrollment and through 3 months after the boosting vaccination:

   i. Condoms (male or female) with spermicide ii. Diaphragm with spermicide iii. Cervical cap with spermicide iv. Intrauterine device v. Oral or patch contraceptives vi. Norplant®, Depo-Provera®, or other FDA approved contraceptive method that is designed to protect against pregnancy.

   NOTE: Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.

4. Has a stable health status as assessed by the investigator, as established by physical examination, vital sign measurements, and medical history.
5. Has access to a consistent and reliable means of telephone contact, which may be in the home, workplace, or by personal mobile electronic device.
6. Is able to understand and comply with planned study procedures.
7. Lives a reasonable distance from the clinical site to be able to travel to and from the clinical site for follow-up visits and agrees to go to the clinical site for evaluation (or provide medical record access if evaluated elsewhere) in the event of an AE.
8. Agrees to stay in contact with the clinical site for the duration of the study, has no current plans to move from the study area, and provides updated contact information as necessary.

Exclusion Criteria:

1. History of being vaccinated in the past 5 years against pertussis.
2. Any significant past reaction to any component of Boostrix (at the discretion of the investigator).
3. Subject reported diagnosis of pertussis in the past 10 years (must be laboratory confirmed or physician diagnosed from medical records).
4. Vital signs by FDA toxicity scoring >1 (may be repeated once during the screening period to allow for inclusion and the most recent measurement taken at baseline).
5. Chronic illness being treated actively and with evidence of recent intervention for worsening or fluctuating symptoms (at the discretion of the investigator).
6. The subject has a history of active cancer (malignancy) in the last 10 years (exception is subjects with adequately treated non melanomatous skin carcinoma, who may participate in the study).
7. Current use of any smoking products and unwillingness to refrain from the use of any smoking products from screening through 28 days after the boosting vaccination.
8. Use of narcotic drugs, evidenced by urine toxicology screen or a history of drug/alcohol abuse within the past 2 years.
9. Has donated blood or suffered from blood loss of more than 450 mL (1 unit of blood) within 60 days prior to screening or donated plasma within 14 days prior to screening.
10. Receipt of immunoglobulin, blood-derived products, systemic corticosteroids, or other immunosuppressant drugs within 90 days prior to Day 1.
11. Asthma, obstructive nasal canal, recurrent or acute sinusitis or other chronic respiratory problems inclusive of the diagnosis of any significant pulmonary disease.
12. History of nasal surgery or Bell's palsy.
13. Use of repeated nasal sprays, Neti pot, routine nasal washing within the past 1 month (more than 2 times per week). Subjects must agree to refrain from use of any of these modalities through Day 113.

14. A temporary exclusion to vaccinate if acute respiratory tract infection or rhinorrhea or temperature >100.4°F (no symptoms for 3 days prior to vaccination day). Subjects may be vaccinated if they stay within the vaccination window (screening [30 days] or at the time of the booster [10 days]).

    NOTE: If a subject exceeds the screening window, they must be reconsented and screening must be reinitiated.

15. Use of corticosteroids in the respiratory tract (eg, nasal steroids, inhaled steroids) within 30 days prior to Day 1.
16. Receipt of a licensed vaccine within the last 30 days prior to Day 1 or planned vaccination during the active study conduct through Day 113. In the case of seasonal influenza, vaccination should not be withheld and is not contraindicated for subject participation. However, vaccination should be planned outside of a 30 day pre- and 30 day post vaccination window whenever possible.
17. Known hypersensitivity to any component of the study vaccines.
18. Participation in any other clinical trial for the testing of an unlicensed product during the previous 6 months or planned during the study conduct.
19. Inability to adhere to the protocol, including plans to move from the area.
20. Personal history or family (first degree) history of congenital or hereditary immunodeficiency.
21. Past or present infection with human immunodeficiency virus, hepatitis B, or hepatitis C by screening test.
22. Any autoimmune or immunodeficiency disease/condition (inherited or iatrogenic).
23. Any neurological disease or history of significant neurological disorder (eg, meningitis, seizures, multiple sclerosis, vasculitis, migraines, Guillain-Barré syndrome [genetic/congenital or acquired]).
24. Any medical condition that, in the opinion of the investigator, might interfere with the evaluation of the study objectives or might affect the safety of the individual, (eg, major depression or history of suicidal attempt).
25. Toxicity grading >1 for screening laboratory test results for kidney, hepatic, and hematologic values (may be repeated once during the screening period to allow for inclusion and the most recent measurement taken at baseline). See Table 13 2 for specifically designated parameters.
26. Body mass index <17 kg/m2 or >40 kg/m2.
27. Frequent contact with children less than 1 year of age (parent, childcare worker, nurse, etc.) or residence in the same household as persons with known immunodeficiency including persons on immunosuppressant therapy.
28. Study team member or first-degree relative of study team member.

Contacts and Locations

Locations

United States, Ohio

Rapid medical Research Inc

Cleveland, Ohio, United States, 44122

United States, Texas

DM Clinical Research

Tomball, Texas, United States, 77375

United States, Utah

Advanced Clinical Research

West Jordan, Utah, United States, 84088

Sponsors and Collaborators

ILiAD Biotechnologies

PPD

Investigators

• Principal Investigator: Mary B Manning, MD; Rapid Medical Research Inc
• Principal Investigator: Barbara Rizzardi, MD; Advanced Clinical Research
• Principal Investigator: Vicki Miller, MD; DM Clinical Research

More Information

Additional Information:

DHHS, FDA, CBER (US). Guidance for industry: Toxicity grading for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials 

Publications:

Althouse BM, Scarpino SV. Asymptomatic transmission and the resurgence of Bordetella pertussis. BMC Med. 2015 Jun 24;13:146. doi: 10.1186/s12916-015-0382-8.

Feunou PF, Ismaili J, Debrie AS, Huot L, Hot D, Raze D, Lemoine Y, Locht C. Genetic stability of the live attenuated Bordetella pertussis vaccine candidate BPZE1. Vaccine. 2008 Oct 23;26(45):5722-7. doi: 10.1016/j.vaccine.2008.08.018. Epub 2008 Aug 30.

Feunou PF, Mielcarek N, Locht C. Reciprocal interference of maternal and infant immunization in protection against pertussis. Vaccine. 2016 Feb 17;34(8):1062-9. doi: 10.1016/j.vaccine.2016.01.011. Epub 2016 Jan 15.

Locht C, Papin JF, Lecher S, Debrie AS, Thalen M, Solovay K, Rubin K, Mielcarek N. Live Attenuated Pertussis Vaccine BPZE1 Protects Baboons Against Bordetella pertussis Disease and Infection. J Infect Dis. 2017 Jul 1;216(1):117-124. doi: 10.1093/infdis/jix254.

Mielcarek N, Debrie AS, Raze D, Bertout J, Rouanet C, Younes AB, Creusy C, Engle J, Goldman WE, Locht C. Live attenuated B. pertussis as a single-dose nasal vaccine against whooping cough. PLoS Pathog. 2006 Jul;2(7):e65. doi: 10.1371/journal.ppat.0020065.

Mielcarek N, Debrie AS, Mahieux S, Locht C. Dose response of attenuated Bordetella pertussis BPZE1-induced protection in mice. Clin Vaccine Immunol. 2010 Mar;17(3):317-24. doi: 10.1128/CVI.00322-09. Epub 2010 Jan 27.

Skerry CM, Cassidy JP, English K, Feunou-Feunou P, Locht C, Mahon BP. A live attenuated Bordetella pertussis candidate vaccine does not cause disseminating infection in gamma interferon receptor knockout mice. Clin Vaccine Immunol. 2009 Sep;16(9):1344-51. doi: 10.1128/CVI.00082-09. Epub 2009 Jul 22.

Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):787-92. doi: 10.1073/pnas.1314688110. Epub 2013 Nov 25.

• Responsible Party: ILiAD Biotechnologies
• ClinicalTrials.gov Identifier: NCT03942406
• Other Study ID Numbers: IB-200P
• First Posted: May 8, 2019
• Last Update Posted: July 9, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by ILiAD Biotechnologies:

pertussis; Bordetella infection; Gram-negative bacterial infection; Respiratory tract infection; Whooping cough; Infection; Respiratory tract disease; Vaccine; Immunological factors; Physiological effects of drugs

Additional relevant MeSH terms:

Whooping Cough; Respiratory Tract Diseases; Bordetella Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections