Periodic Reporting for period 4 - TracVac (Developing a Chlamydia Trachomatis vaccine)
Período documentado: 2021-03-01 hasta 2022-02-28
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 strategies will be tested in a clinical phase I evaluation.
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 strategies will be tested in a clinical phase I evaluation.
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.
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.
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.