Periodic Reporting for period 3 - TracVac (Developing a Chlamydia Trachomatis vaccine)
Reporting period: 2020-03-01 to 2021-02-28
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.
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.
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.