Periodic Reporting for period 2 - VacPath (Novel vaccine vectors to resist pathogen challenge)
Período documentado: 2021-01-01 hasta 2024-10-31
Problem addressed: Infectious diseases are a major burden and constant threat to European populations and economies. While barely perceived as a danger not too long ago, a combination of potential rapid spread of novel pathogens across the globe, as we have seen for SARS-CoV-2, antibiotics resistance, a come-back of “old” pathogens and persistence of “yet to be combatted pathogens” has raised the demand for effective but safe vaccines.
An example of a “yet to be combatted pathogen” is the obligate intracellular bacterium Chlamydia trachomatis. This pathogen is the major cause of sexually transmitted bacterial disease in humans, and poses a world-wide health concern. While responsive to antibiotics, over half of infections are asymptomatic and therefore remain untreated, and also re-infections frequently occur, both urging the need for a prophylactic vaccine. Nevertheless, insufficient knowledge on how to vaccinate against this intracellular pathogen hampers the development of such vaccines.
Overall objectives: In this project, 5 academic and 2 private partners cooperated to educate early stage researchers (ESR) in the diverse aspects of novel vaccine development. These ESR redesigned a protein-based C. trachomatis vaccine of one of the beneficiaries, eliciting humoral responses, to induce also cell-mediated immunity. Different innovative vaccines, based on safe virus-, bacterium-, and plasmid-based vectors, were created which were tested for protective capacity in a preclinical model of C. trachomatis infection. In addition, novel vaccine targets were identified by examining the antigenic landscape on C. trachomatis-infected host cell. Finally, key biological pathways and specific genes linked to vaccine-induced responses were identified. The benefits of this research are not limited to vaccine development for C. trachomatis; results may translate to optimized vectored vaccines for a broad range of intracellular pathogens.
Importance for society: VacPath has contributed towards a new generation of safe vaccines that in future can be exploited to vaccinate against C. trachomatis, or can be adapted to vaccinate against intracellular pathogens of choice. Moreover, of the ten ESR who have or soon will be defending their thesis, four have are continuing a career in academia, three are joining a pharmaceutical company, and three are concurrently evaluating career opportunities in academia as well as in industry. Taken together, this project has educated a new generation of scientists that through the offered, integrated training have been prepared to enter the European task force, in academia or industry, to find creative solutions to address future pathogen-imposed challenges.
An example of a “yet to be combatted pathogen” is the obligate intracellular bacterium Chlamydia trachomatis. This pathogen is the major cause of sexually transmitted bacterial disease in humans, and poses a world-wide health concern. While responsive to antibiotics, over half of infections are asymptomatic and therefore remain untreated, and also re-infections frequently occur, both urging the need for a prophylactic vaccine. Nevertheless, insufficient knowledge on how to vaccinate against this intracellular pathogen hampers the development of such vaccines.
Overall objectives: In this project, 5 academic and 2 private partners cooperated to educate early stage researchers (ESR) in the diverse aspects of novel vaccine development. These ESR redesigned a protein-based C. trachomatis vaccine of one of the beneficiaries, eliciting humoral responses, to induce also cell-mediated immunity. Different innovative vaccines, based on safe virus-, bacterium-, and plasmid-based vectors, were created which were tested for protective capacity in a preclinical model of C. trachomatis infection. In addition, novel vaccine targets were identified by examining the antigenic landscape on C. trachomatis-infected host cell. Finally, key biological pathways and specific genes linked to vaccine-induced responses were identified. The benefits of this research are not limited to vaccine development for C. trachomatis; results may translate to optimized vectored vaccines for a broad range of intracellular pathogens.
Importance for society: VacPath has contributed towards a new generation of safe vaccines that in future can be exploited to vaccinate against C. trachomatis, or can be adapted to vaccinate against intracellular pathogens of choice. Moreover, of the ten ESR who have or soon will be defending their thesis, four have are continuing a career in academia, three are joining a pharmaceutical company, and three are concurrently evaluating career opportunities in academia as well as in industry. Taken together, this project has educated a new generation of scientists that through the offered, integrated training have been prepared to enter the European task force, in academia or industry, to find creative solutions to address future pathogen-imposed challenges.
Work performed: Prior to project start, SSI performed a phase 1 clinical trial, testing the safety and immunogenicity of a recombinant C. trachomatis vaccine antigen, CTH522. CTH522 covers the highly immunogenic Major Outer Membrane Protein (MOMP) variable (VD4) regions of the four most common C. trachomatis sero-variants and elicits excellent humoral responses. With the aim to broaden CTH522-triggered immunity and so target both extra- and intracellular bacteria, we exploited a number of safe virus-(UNIBAS, UDUS), bacterium- (AB, UNISI) and plasmid-based (UU) vaccine vectors, capable of inducing both potent humoral and cell-mediated immune responses. CTH522 was cloned into these vectors, vaccines were verified for integrity and antigen expression, and subsequently produced at a larger scale to test their immunogenicity. After a comprehensive characterization of immune responses triggered by vaccination with a single or combination of different network-developed vaccines, the protective capacity of four selected vaccine combinations was tested in a preclinical model of C. trachomatis infection at SSI. Two vaccines were shown to provide protection to bacterial challenge, i.e. an E. coli Protein Body vector-based vaccine developed at AB and an LCMV vector-based vaccine developed at UNIBAS, based on vaccine-induced humoral and cellular immunity, respectively. Meanwhile, immunopeptidome analyses performed at UU identified a large number of novel C. trachomatis antigens, in part derived from pathogenesis-associated proteins. A selection of these antigens may be utilized to complement developed vaccines. The analysis of RNAseq data at MBT identified a biomarker for successful vaccination with bacterium-based vaccines. Taken together, the results contribute to a novel generation of C. trachomatis vaccines.
During the five years of the project, all ESR extensively collaborated. Antigen constructs, protocols, peptides, antibodies, a Chlamydia strain, gained knowledge, and newly constructed vectored vaccines were shared between beneficiaries, and ESR visited network partners to test their novel vaccines or to provide help with immunizations in challenge experiments. Moreover, the ESR had the opportunity to attend different courses to enhance both their specific and general knowledge of the vaccine field. They presented their research at a variety of meetings, including VacPath meetings, summer schools, national and international conferences. Based on the generated data, so far 6 manuscripts of single organizations and 5 manuscript joint with network partners have been published in prestigious peer-reviewed journals.
During the five years of the project, all ESR extensively collaborated. Antigen constructs, protocols, peptides, antibodies, a Chlamydia strain, gained knowledge, and newly constructed vectored vaccines were shared between beneficiaries, and ESR visited network partners to test their novel vaccines or to provide help with immunizations in challenge experiments. Moreover, the ESR had the opportunity to attend different courses to enhance both their specific and general knowledge of the vaccine field. They presented their research at a variety of meetings, including VacPath meetings, summer schools, national and international conferences. Based on the generated data, so far 6 manuscripts of single organizations and 5 manuscript joint with network partners have been published in prestigious peer-reviewed journals.
Impact: The aim of VacPath has been to develop novel vaccines that elicit both humoral and cellular immunity to the intracellular bacterium C. trachomatis or other intracellular pathogens, including for example SARS-CoV-2. The recent pandemic caused by this virus clearly exemplifies the shortfalls of our current vaccines.
In the first place, while some may induce cellular responses, current vaccines are mainly developed to induce humoral immunity. We can measure such responses and have the knowledge of how to elicit these in an effective manner. The genetic drift of pathogens, however, may rapidly reduce vaccine effectiveness, as we’re currently still observing for SARS-CoV-2. Pathogen escape from cellular immune responses, on the other hand, is not readily achieved at the population level, because the specificity of the cellular response differs in each person and targets a broader range of epitopes. Nevertheless, among other questions, it is unknown how to best induce a cellular response, and which pathogen-derived regions would be best to target. VacPath has contributed to the current state-of-the art in vaccine immunology by providing answers to these questions. In addition, VacPath has educated the next generation of scientists with advanced expertise in this field.
In the second place, as also exemplified by Covid-19, the socio-economic impact of novel vaccine technologies and improved vaccines is tremendous. Without effective vaccines (or treatments) that can protect against contagious and harmful pathogens to which no prior immunity exists, the medical sector cannot handle the drastically increased healthcare demand. Lockdowns affecting education, personal well-being, and the economy as a whole remain the only alternative. Thus, creative vaccine solutions as explored in VacPath are much needed to mitigate the potential devastating effects of current and future (pandemic) pathogens.
In the first place, while some may induce cellular responses, current vaccines are mainly developed to induce humoral immunity. We can measure such responses and have the knowledge of how to elicit these in an effective manner. The genetic drift of pathogens, however, may rapidly reduce vaccine effectiveness, as we’re currently still observing for SARS-CoV-2. Pathogen escape from cellular immune responses, on the other hand, is not readily achieved at the population level, because the specificity of the cellular response differs in each person and targets a broader range of epitopes. Nevertheless, among other questions, it is unknown how to best induce a cellular response, and which pathogen-derived regions would be best to target. VacPath has contributed to the current state-of-the art in vaccine immunology by providing answers to these questions. In addition, VacPath has educated the next generation of scientists with advanced expertise in this field.
In the second place, as also exemplified by Covid-19, the socio-economic impact of novel vaccine technologies and improved vaccines is tremendous. Without effective vaccines (or treatments) that can protect against contagious and harmful pathogens to which no prior immunity exists, the medical sector cannot handle the drastically increased healthcare demand. Lockdowns affecting education, personal well-being, and the economy as a whole remain the only alternative. Thus, creative vaccine solutions as explored in VacPath are much needed to mitigate the potential devastating effects of current and future (pandemic) pathogens.