Live Attenuated Pertussis Vaccine BPZE1 Protects Baboons Against Bordetella pertussis Disease and Infection

Abstract

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.

Keywords: baboon model; live attenuated vaccine; pertussis.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Baboon nasopharyngeal colonization by BPZE1 and leukocytosis. A, Four baboons (solid red line) and 3 baboons (dashed green line) were inoculated with 109 colony-forming units (CFU) and 1010 CFU of BPZE1, respectively, and nasopharyngeal bacterial loads were measured at weekly intervals, as indicated, with a limit of detection of 10 CFU/mL. B, White blood cell (WBC) counts were determined at the indicated time points. Blue, red, and green bars indicate WBC counts of noninfected animals, baboons inoculated with 109 CFU BPZE1, and baboons inoculated with 1010 CFU BPZE1, respectively. Results are presented as geometric mean with geometric standard error of the mean.

Figure 2.

Serum antibody responses of BPZE1-inoculated baboons. Immunoglobulin G (IgG) (A) and immunoglobulin A (IgA) (B) titers were measured against filamentous hemagglutinin (FHA) (upper panels), pertussis toxin (PT) (middle panels), and pertactin (Prn) (lower panels) at the indicated time points after administration of BPZE1. Each symbol represents an individual animal. Blue, red, and green symbols indicate antibody titers of noninfected animals, baboons inoculated with 109 colony-forming units (CFU) BPZE1, and baboons inoculated with 1010 CFU BPZE1, respectively.

Figure 3.

BPZE1-induced protection against challenge with Bordetella pertussis strain D420. Juvenile baboons were nasally vaccinated with 109 colony-forming units (CFU) (red symbols) or 1010 CFU BPZE1 (green symbols) or left untreated (blue symbols). Seven weeks after vaccination, all animals were infected with >1010 CFU B. pertussis D420, and white blood cell (WBC) (A) counts were determined at the indicated time points after challenge. Blue, red, and green bars indicate WBC counts of nonvaccinated animals, baboons vaccinated with 109 CFU BPZE1, and baboons vaccinated with 1010 CFU BPZE1, respectively. B, Nasopharyngeal colonization by B. pertussis D420 was monitored at indicated time points. Each symbol represents an individual animal. C, Total bacterial burden was estimated as area under the curve of (B) in nonvaccinated baboons (Control), baboons vaccinated with 109 CFU BPZE1 (109), or baboons vaccinated with 1010 CFU BPZE1 (1010). Results are presented as geometric mean with geometric standard error of the mean. **P < .01.

Figure 4.

Booster effect of Bordetella pertussis D420 challenge in BPZE1-vaccinated baboons. Immunoglobulin G (IgG) (A) and immunoglobulin A (IgA) (B) titers were measured against filamentous hemagglutinin (FHA) (upper panels), pertussis toxin (PT) (middle panels), and pertactin (Prn) (lower panels) at the indicated time points after challenge with B. pertussis D420. Each symbol represents an individual animal. Blue, red, and green symbols indicate antibody titers of nonvaccinated animals, baboons vaccinated with 109 colony-forming units (CFU) BPZE1, and baboons vaccinated with 1010 CFU BPZE1, respectively.