CHILD-INNOVAC

NASAL VACCINATION AGAINST RESPIRATORY INFECTIONS IN YOUNG CHILDREN

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 Obiettivo del progetto (Objective)

'Respiratory infections are the most frequent cause of childhood morbidity and mortality worldwide. For many respiratory pathogens no vaccine is available, for others classical immunisations remain insufficiently effective. This project concerns the development of novel, nasal vaccines against two major respiratory pathogens, B. pertussis and Respiratory Syncytial Virus (RSV). No vaccine is yet available against RSV, and, although efficacious vaccines against pertussis are widely used, roughly 40 million cases and 200,000-400,000 pertussis-linked deaths are recorded annually, mostly in infants (<6 months) not yet sufficiently protected by the current vaccines. This proposal will yield proof of principle and provide prototypes of multivalent nasal vaccines based on attenuated B. pertussis. The concept is based on the fact that early in life, infants can mount strong anti-B. pertussis T cell responses upon natural infection in contrast to vaccination. Live attenuated B. pertussis BPZE1 has already been constructed and shown to be much more protective in infant mice after a single nasal dose than two doses of current pertussis vaccines. Immunity induced by BPZE1 will be studied in detail, and its genetic and biological stability and safety in various mouse models will be characterised. GMP lots of BPZE1 will be produced and tested for safety in a phase 1 trial in adults as a prerequisite to future trials in the target population. In parallel, human immune responses, in particular memory responses to infection and vaccination will be analysed, which will serve as a basis for immunogenic evaluations of BPZE1. Finally, we will develop BPZE1 as a vector for the presentation of heterologous RSV antigens to the respiratory mucosa. This will be tested in mouse models. A successful outcome of this project should lead to further clinical trials with BPZE1 and to the development of multivalent nasal vaccines able to protect against several respiratory pathogens simultaneously.'

Introduzione (Teaser)

Aiming to provide immunity against two serious respiratory pathogens, an EU-funded study performed a pre-clinical and clinical evaluation of an attenuated Bordetella pertussis vaccine. Results demonstrate that the nasal vaccines are safe to administer, and provides a rapid and long-lasting immune response against whooping cough.

Descrizione progetto (Article)

Respiratory infections such as Pertussis or whooping cough affect 40 million people annually and can be prevented by vaccination. Current vaccination strategies require at least three doses to be given one or two months apart to confer protection. However, vaccination usually starts two months after birth rendering infants below the age of six months highly susceptible to infection.

Despite the immaturity of the immune system at birth, previous studies showed that early vaccination with the whooping cough agent Bordetella pertussis generates a strong immune response. The EU-funded CHILD-INNOVAC project developed an attenuated B. pertussis strain called BPZE1 to be delivered as a nasal live vaccine. This would mimic the natural infection without causing disease.

Pre-clinical testing in various animal models ensured the safety and stability of this vaccine, making it viable for clinical development. Among the most exciting results of the project was the protective effect of BPZE1 in mice against non-related respiratory viruses, such as respiratory syncytial virus (RSV). This intriguing protection was found to correlate with an increase in regulatory T cells, and also with IL-10 and IL-17 production.

Following harmonisation of the study protocols for immunological evaluation, 400 children were enrolled in three countries. In order to evaluate the duration, strength and diversity of the elicited immune responses following vaccination or infection, partners developed assays for the detection of B. pertussis-specific memory T cells and antibody-secreting B cells.

Methods for manufacturing a nasal vaccine for human use were developed and the vaccine was administered to healthy adult male volunteers. Trial objectives included the assessment of safety, tolerability and immune responses of the vaccine as well as the colonisation properties of the modified B. pertussis strain.

By demonstrating the safety of the BPZE1 vaccine, the CHILD-INNOVAC consortium facilitated its good manufacturing practice (GMP) production, toxicology studies and the first-in-man phase I clinical safety trial. These vaccines will be beneficial for neonates by providing long-lasting immunity against respiratory infections especially in developing countries where booster vaccinations may be difficult to implement.