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Developing a Chlamydia Trachomatis vaccine

Periodic Reporting for period 3 - TracVac (Developing a Chlamydia Trachomatis vaccine)

Période du rapport: 2020-03-01 au 2021-02-28

Chlamydia trachomatis is the world's leading infectious cause of blindness. WHO estimates globally 146 million active cases of the disease, mainly among children and women. Current control measures are based on "SAFE" strategy, Surgery for trichiasis, Antibiotics, Facial cleanliness and Environmental improvement. WHO supports the alliance for the global elimination of blinding trachoma. This goal will be impossible to reach with the current technology and there is critical need for a vaccine to completely control trachoma in endemic areas and to ensure that trachoma will be fully eliminated as a public health problem. The TracVac project consortium (TRACVAC) is multi-disciplinary and consists of European experts in the field of Infectious Diseases, Clinical Trial, Vaccine R&D and Animal Models. The goal of the project is to help eliminate the global problem of blinding trachoma through the development of a safe and efficacious vaccine. It consist of a two track project strategy.

Track 1: Develop a protective vaccine against ocular Chlamydia trachomatis infections.
The objective is to generate a vaccine that protect against the bacterial strains causing ocular Chlamydia trachomatis infections. To accomplish this, we study naturally protected individuals from endemic regions and identify key epitopes, which will subsequently be incorporated into vaccine constructs and tested for protective efficacy. The aim is to target all the trachoma serovars, and build such a trachoma vaccine construct into a vaccine that is also able to target the genital serovars.

Track 2: Develop and clinical evaluate an immunization protocol for optimal ocular mucosal immunity.
The second main objective is to develop an immunization protocol for optimal ocular mucosal immunity. To do this we will test different vaccination strategies for ocular responses and protection against challenge. Subsequently the best strategy will be tested in a clinical phase I evaluation.
Track 1.
Progress has been made in the identification of key antibody epitopes recognized by naturally infected individuals, and epitopes have been selected to be included in a vaccine construct. This new vaccine construct, with which we aim to generate neutralizing antibodies against trachoma serovars A, B, C (in addition to serovars giving rise to genital infections), has now been developed, produced and tested successfully in the guinea pig and mouse models. It is now scheduled to be tested in the Non-human primate model developed in the TracVac project.
Advances were also made towards developing a toolbox of functional antibody assays to evaluate responses from naturally infected individuals, i.e. a novel high-throughput in vitro neutralisation assay has been developed, and a phagocytosis assay has been developed and published.
PBMCs from patients have been selected for B cell cloning, by which we have identified B cell clones secreting neutralising antibodies.
Concerning analysis of the target population, we have found that in a typical African trachoma endemic population, three typical ocular serovars are in circulation (A, B and Ba) indicating a vaccine will be required to induce protective responses to both B- and C-complex serovars. Unless antibiotic treatment reaches high levels and without socio-economic changes, ocular infections persist in the community and contribute to scarring disease progression, emphasizing the need for a vaccine.

Track 2.
We have established an ocular non-human primate (NHP) challenge model using C. trachomatis serovar B strain. Dose titration experiments have been performed, and a dose for the challenge study has been selected. A vaccine NHP trial has been completed, testing different vaccine adjuvants and immunization schedules. The results showed that although we did achieve neutralizing antibodies in serum, we need to put additional effort into inducing a higher response in the eye. This is now the focus of work package 3.
In preparation for the clinical trial, a toxicology package/safety reporting was completed. GMP manufacturing of the vaccine antigen and adjuvant was completed and send to Imperial College for the clinical trial. The Clinical trial CHLM-02 was approved by the MHRA. Initiation of the trial was delayed due to the COVID-19 situation, and initiated in late September 2020. It is presently running, although scheduling challenges, due to COVID, have affected the overall trial timeline and projections.
TracVac project will significantly accelerate the trachoma vaccine development. The project combines knowledge from clinical development of genital chlamydia vaccine with cutting-edge adjuvant / delivery technologies to address safety and immunogenicity of a trachoma vaccine with the aim of inducing ocular immunity, which is a critical bottleneck for a trachoma vaccine. TracVac will establish an advanced animal mode that will provide safety, immunogenicity and efficacy data for the vaccine. The development of a protective vaccine against trachoma is expected to complement current control measures and be an important tool for the alliance for the global elimination of blinding trachoma. TracVac will contribute to knowledge about novel adjuvants and routes of immunization, which will aid the future development of alternate routes of vaccine administration. TracVac will set up a pipeline leading from preclinical development to initial human trials of vaccines against Chlamydia, paving the way for vaccines with pronounced impact socio-economic impact.
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