Abstract
Bordetella pertussis is the agent of pertussis, also referred to as whooping cough, a disease that remains an important public health issue. Vaccine-induced immunity to pertussis wanes over time. In industrialized countries, high vaccine coverage has not prevented infection and transmission of B. pertussis, leading to periodic outbreaks in people of all ages. The consequence is the formation of a large source for transmission to children, who show the highest susceptibility of developing severe whooping cough and mortality. With the aim of providing protection against both disease and infection, a live attenuated pertussis vaccine, in which three toxins have been genetically inactivated or removed, is now in clinical development. This vaccine, named BPZE1, offers strong protection in mice and non-human primates. It has completed a phase I clinical trial in which safety, transient colonization of the human airway and immunogenicity could be demonstrated. In mice, BPZE1 was also found to protect against inflammation resulting from heterologous airway infections, including those caused by other Bordetella species, influenza virus and respiratory syncytial virus. Furthermore, the heterologous protection conferred by BPZE1 was also observed for non-infectious inflammatory diseases, such as allergic asthma, as well as for inflammatory disorders outside of the respiratory tract, such as contact dermatitis. Current studies focus on the mechanisms underlying the anti-inflammatory effects associated with nasal BPZE1 administration. Given the increasing importance of inflammatory disorders, novel preventive and therapeutic approaches are urgently needed. Therefore, live vaccines, such as BPZE1, may offer attractive solutions. It is now essential to understand the cellular and molecular mechanisms of action before translating these biological findings into new healthcare solutions.
Highlights
Despite of the use of efficacious vaccines, Bordetella pertussis is still one of the leading causes of neonatal morbidity and mortality worldwide [1]
Given that immunity induced by B. pertussis infection decreases later than vaccine-induced immunity [7], and that newborns are capable of inducing a strong Th1 response upon infection [8], a live attenuated pertussis vaccine candidate has been developed to be administered by nasal inoculation [9]
A single nasal administration of BPZE1 in infant mice was associated with stronger protection than that induced by two inoculations of acellular pertussis vaccines (aPV) [9] and was lasting substantially longer [13, 14]
Summary
Despite of the use of efficacious vaccines, Bordetella pertussis is still one of the leading causes of neonatal morbidity and mortality worldwide [1]. In addition to B. pertussis, BPZE1 protects mice against lung infection by other Bordetella species, this was not observed after vaccination with aPV [9, 12, 19]. In a mouse lethal challenge model, BPZE1 reduced both death and lung colonization induced by B. bronchiseptica [19] These protective effects depend on two distinctive mechanisms. An additional administration of BPZE1 improved survival of the influenza-infected mice and further decreased the inflammatory cytokine levels Since this protective mechanism did not rely on adaptive immunity, these observations suggest that BPZE1 could induce trained innate immunity, which has been shown to be based on epigenetic reprogramming of monocytes [21]. This may lead to transcriptional programs that rewire the intracellular immune
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