Track 1.
We have identified key antibody epitopes recognized by naturally infected individuals, and these epitopes are included in vaccine construct developed in WP2. The new vaccine construct was able to generate neutralizing antibodies against all the trachoma serovars A, B, C (in addition to serovars giving rise to genital infections), was developed and produced and tested successfully in the guinea pig and mouse models. We also introduced a new adjuvant, CAF10b, which showed to be even more immunogenic than CAF01.
Concerning analysis of the target population, we 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, emphasising 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.
Using this model with our new vaccine construct, we were able to generate both a neutralizing humoral response against all trachoma serovars, as well as a Th1/Th17 CMI response. However, this did not translate into increased protection against an ocular infection with 2x104 bacteria. A strong local immunity, generated by a previous infection, did however protect against a subsequent infection. This indicate that although we have generated the first trachoma subunit vaccine construct ever made, one that is able to induce systemic protective immunity and neutralizing antibodies against all trachoma serovars, the vaccine protocol was not able to direct this immunity into the eye in the NHP model. In fact, when measuring the total antigen specific IgG/IgA level in the eye, preliminary data indicate that all the vaccines were similar and no effect was seen of the topical administration of non-adjuvanted antigen. Another explanation for the lack of protection could be that the NHP model still use an unrealistic high dose, against which all vaccines would fail.
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 (WP6). 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. However, despite scheduling challenges, due to COVID, affecting the overall trial timeline and projections, we succeeded in succesfully completing the trial.
In summary, in TracVac we have generated 1) a vaccine able to induce protective neutralizing antibodies against all trachoma serovars, and 2) developed a vaccine protocol that give strong immunity in the eye, both of which represented the major aims of the TracVac project.
