Elsevier

The Lancet

Volume 401, Issue 10379, 11–17 March 2023, Pages 843-855
The Lancet

Articles
Immunogenicity and safety of BPZE1, an intranasal live attenuated pertussis vaccine, versus tetanus–diphtheria–acellular pertussis vaccine: a randomised, double-blind, phase 2b trial

https://doi.org/10.1016/S0140-6736(22)02644-7Get rights and content

Summary

Background

Bordetella pertussis epidemics persist as transmission remains unabated despite high acellular pertussis vaccination rates. BPZE1, a live attenuated intranasal pertussis vaccine, was designed to prevent B pertussis infection and disease. We aimed to assess the immunogenicity and safety of BPZE1 compared with the tetanus–diphtheria–acellular pertussis vaccine (Tdap).

Methods

In this double-blind, phase 2b trial at three research centres in the USA, healthy adults aged 18–50 years were randomly assigned (2:2:1:1) via a permuted block randomisation schedule to receive BPZE1 vaccination followed by BPZE1 attenuated challenge, BPZE1 vaccination followed by placebo challenge, Tdap followed by BPZE1 attenuated challenge, or Tdap followed by placebo challenge. On day 1, lyophilised BPZE1 was reconstituted with sterile water and given intranasally (0·4 mL delivered to each nostril), whereas Tdap was given intramuscularly. To maintain masking, participants in the BPZE1 groups received an intramuscular saline injection, and those in the Tdap groups received intranasal lyophilised placebo buffer. The attenuated challenge took place on day 85. The primary immunogenicity endpoint was the proportion of participants achieving nasal secretory IgA seroconversion against at least one B pertussis antigen on day 29 or day 113. Reactogenicity was assessed up to 7 days after vaccination and challenge, and adverse events were recorded for 28 days after vaccination and challenge. Serious adverse events were monitored throughout the study. This trial is registered with ClinicalTrials.gov, NCT03942406.

Findings

Between June 17 and Oct 3, 2019, 458 participants were screened and 280 were randomly assigned to the main cohort: 92 to the BPZE1–BPZE1 group, 92 to the BPZE1–placebo group, 46 to the Tdap–BPZE1 group, and 50 to the Tdap–placebo group. Seroconversion of at least one B pertussis-specific nasal secretory IgA was recorded in 79 (94% [95% CI 87–98]) of 84 participants in the BPZE1–BPZE1 group, 89 (95% [88–98]) of 94 in the BPZE1–placebo group, 38 (90% [77–97]) of 42 in the Tdap–BPZE1 group, and 42 (93% [82–99]) of 45 in the Tdap–placebo group. BPZE1 induced broad and consistent B pertussis-specific mucosal secretory IgA responses, whereas Tdap did not induce consistent mucosal secretory IgA responses. Both vaccines were well tolerated, with mild reactogenicity and no serious adverse events related to study vaccination.

Interpretation

BPZE1 induced nasal mucosal immunity and produced functional serum responses. BPZE1 has the potential to avert B pertussis infections, which ultimately could lead to reduced transmission and diminished epidemic cycles. These results should be confirmed in large phase 3 trials.

Funding

ILiAD Biotechnologies.

Introduction

Pertussis or whooping cough is a highly contagious severe respiratory disease caused by Bordetella pertussis. Despite high global vaccination coverage,1 pertussis remains a serious worldwide health problem, with periodic community epidemics and mortality occurring in young infants.2 Even vaccinated adolescents and adults can easily be infected with B pertussis and experience prolonged symptoms; such people can serve as major bacterial reservoirs.3 Because B pertussis is highly infectious,4 pertussis vaccines should ideally prevent not only pertussis disease, but also B pertussis colonising infection and transmission.5

Two types of pertussis vaccines are currently in use: whole-cell vaccines and, more recently, acellular pertussis vaccines (aPVs).6 Many countries began to exclusively use aPVs in the 1990s or early 2000s, and subsequently pertussis infections increased in frequency. Several factors might account for this resurgence,7 but two major contributors are the short duration of aPV-induced immunity8, 9 and the fact that, similar to whole-cell pertussis vaccines, aPVs do not prevent infection with, or human-to-human transmission of, B pertussis.10 In a non-human primate challenge model, use of an aPV did not protect against colonising infection or transmission of B pertussis.11 Animal studies suggest that immunisation with aPVs might prolong nasal carriage of B pertussis11, 12 and therefore increase the bacterial reservoir. By contrast, recovery from B pertussis infection protected primates against subsequent infection and disease when exposed to a second B pertussis challenge.11

Research in context

Evidence before this study

Most high-income countries now use acellular pertussis vaccines (aPVs) for the prevention of whooping cough or pertussis. However, pertussis outbreaks in highly vaccinated populations have shown the limitations of these vaccines. Rapid waning of vaccine-induced immunity and the failure of aPVs to prevent Bordetella pertussis infection and transmission are prevailing hypotheses for the resurgence of pertussis. B pertussis is a strictly mucosal pathogen, but—unlike natural infection—aPVs do not induce mucosal immunity. Vaccines that mimic natural infection could potentially limit acquisition and accelerate clearance of colonising B pertussis. We searched PubMed with the terms “pertussis”, “whooping cough” AND “mucosal vaccine”, “intranasal”, “live attenuated” for studies of mucosal pertussis vaccination up to July 25, 2022, with no language restriction and in various combinations. Our search yielded 276 references, several of which describe novel mucosal anti-pertussis vaccines. However, none of these novel vaccines have reached clinical development, except for the live attenuated vaccine BPZE1. Two articles detailed safety, colonisation, and serum IgG responses after a nasal administration of a single dose of BPZE1 (containing up to 109 colony-forming units) in phase 1 trials.

Added value of this study

This is the first study of the effect of intranasal BPZE1 vaccination compared with the tetanus–diphtheria–acellular pertussis vaccine (Tdap) vaccine in terms of the induction of nasal secretory IgA response. BPZE1 had an acceptable safety profile and was well tolerated. A single BPZE1 dose induced potent nasal secretory IgA against B pertussis antigens. By contrast, Tdap did not consistently induce secretory IgA responses.

Implications of all the available evidence

This study provides the first proof of concept in humans that a single nasal administration of the live attenuated pertussis vaccine BPZE1 can produce a secretory IgA response against B pertussis. Our findings support further development of BPZE1 as a safe next-generation pertussis vaccine that could potentially reduce B pertussis infection and transmission.

An improved vaccine that safely mimics natural infection could ultimately control the spread of pertussis by limiting infection and transmission. The intranasal live attenuated pertussis vaccine BPZE1, which has been developed by genetic inactivation or removal of three major B pertussis toxins, was designed for such a purpose.13 Studies in mice and non-human primates have shown that, in contrast to aPVs, a single BPZE1 dose provides effective protection against both nasal colonising infection and pertussis disease.14, 15 Furthermore, whereas aPV-induced protective immunity starts to wane 6 months after vaccination in mice, no sign of waning immunity was noted for up to 12 months after vaccination with BPZE1.16 Phase 1 clinical studies17, 18, 19 have shown that doses of 103–109 colony-forming units (CFU) of BPZE1 are well tolerated and induce antibody responses to a broad range of B pertussis antigens and Th1-type cellular responses.

In this phase 2b trial we assessed the safety and induction of mucosal and systemic immunity of BPZE1 compared with the tetanus–diphtheria–acellular pertussis vaccine (Tdap) in healthy adults. We also assessed protection against a subsequent re-administration of BPZE1 as an attenuated challenge.

Section snippets

Study design and participants

We did a randomised, double-blind, phase 2b study at three research centres in the USA. We recruited healthy people aged 18–50 years. Participants with childbearing potential could not be pregnant or lactating and had to use an appropriate contraceptive method. Major exclusion criteria included pertussis vaccination in the past 5 years, diagnosis of pertussis in the past 10 years, immunosuppression, acute or chronic pulmonary disease, unwillingness to refrain from tobacco products, routine use

Results

Between June 17 and Oct 3, 2019, 458 people were screened and 300 were enrolled in the study and randomly assigned (figure 1). Follow-up observations were completed on June 24, 2020. Of the 300 participants, 20 (eight in the BPZE1–BPZE1 group, eight in the BPZE1–placebo group, and four in the Tdap–BPZE1 group) were part of the safety cohort that received 107 CFU BPZE1. Among the other 280 participants, one participant was unable to be vaccinated on day 1, leaving 279 participants. Demographics

Discussion

The findings of this randomised, double-blind phase 2b trial suggest that a single nasal administration of the live attenuated pertussis vaccine BPZE1 is safe and well tolerated and induces broad and sustained B pertussis-specific secretory IgA responses. The vaccine also seemed to protect against subsequent colonising infection after an attenuated BPZE1 challenge.

B pertussis is a strictly mucosal respiratory pathogen that primarily infects the upper airways. Mucosal immunity at the site of

Data sharing

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data might be granted after requests have been reviewed.

Declaration of interests

CK, KS, MT, PG, KR, and SN are equity holders in, and current or former employees of or consultants to, ILiAD Biotechnologies. VEM reports leadership of the Pearl institutional review. SN is a former employee of Novartis. AG has received honoraria from Sanofi Pasteur. CL holds patents on the BPZE1 vaccine (licensed to ILiAD Biotechnologies) and reports consulting fees from, and holds equity in, ILiAD Biotechnologies. All other authors declare no competing interests.

References (32)

  • S Esposito et al.

    Pertussis prevention: reasons for resurgence, and differences in the current acellular pertussis vaccines

    Front Immunol

    (2019)
  • MA Witt et al.

    Unexpectedly limited durability of immunity following acellular pertussis vaccination in preadolescents in a North American outbreak

    Clin Infect Dis

    (2012)
  • NP Klein et al.

    Waning Tdap effectiveness in adolescents

    Pediatrics

    (2016)
  • BM Althouse et al.

    Asymptomatic transmission and the resurgence of Bordetella pertussis

    BMC Med

    (2015)
  • JM Warfel et al.

    Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model

    Proc Natl Acad Sci USA

    (2014)
  • V Dubois et al.

    Suppression of mucosal Th17 memory response by acellular pertussis vaccines enhances nasal Bordetella pertussis carriage

    NPJ Vaccines

    (2021)
  • Cited by (0)

    View full text