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Training network for next generation vaccinologists

Final Report Summary - VACTRAIN (Training network for next generation vaccinologists)

VacTrain, a Marie Curie initial training network (FP7, 2012-2016), consist of 8 academic and industrial partners in vaccine research and development ( VacTrain provided a multidisciplinary and intersectoral research and training programme for 11 young researchers to be trained as vaccinologists. The Early Stage Researchers (ESRs) investigated the molecular, immunological and biochemical properties of several infectious agents using state-of-the-art technologies. In addition, they were trained in the field of biomanufacturing, pharmacoeconomics, regulatory affairs and project management, and attended a number of transferable skill courses. The VacTrain research programme consisted of 4 work packages (WPs). Within these WPs all ESRs have worked together to achieve the overall WP objectives.

WP1: Transcriptional profiling
The goal of WP1 was the application of next generation sequencing (NGS) techniques – specifically transcriptome profiling and antibody repertoire sequencing – in the fields of predictive marker research, vaccine development, vaccine efficacy analysis and generation of high-affinity monoclonal antibodies. Genome-wide transcriptomics was successfully used to identify antigens in Mycobacterium tuberculosis (Mtb)-infected lungs in vivo and genes that predict future sequelae in congenitally cytomegalovirus (CMV) infected newborns. In addition, a newly developed method for paired antibody heavy and light chain sequencing was applied by an ESR to analyze vaccine efficacy of tetanus toxoid (TT) booster immunization. This proof-of-concept project led to the identification, cloning and expression of new high-affinity antibodies against TT. The outcomes of this WP are relevant for the development of an effective vaccine against tuberculosis, a major cause of death. They may also reduce the long-term consequences of congenital CMV infections, which are the most common non-genetic cause of childhood hearing loss and an important cause of neurodevelopmental delays. The establishment of a novel method for paired antibody heavy and light chain sequencing enables easy and rapid generation of monoclonal antibodies for diagnostic and therapeutic applications. This technique is now applied in clinical studies and has the potential to be commercialized for antibody discovery.

WP2: Discovery of antigens and prediction of immunity
The central themes of WP2 were the discovery of antigens able to stimulate protective immune responses in humans and the kinetics and character of protective immune responses against different pathogens. The five involved ESRs focused on the identification of antigens within Mycobacterium tuberculosis (Tb), Staphylococcus aureus (Sa), Borrelia, Cytomegalovirus (CMV), and Influenza A virus (Flu) that stimulate immune responses associated with protection. The overarching idea for each pathogen was to focus on antigens that either were expressed early during infection (Tb, CMV) or expressed during infection by many subspecies (Sa, Borrelia, Flu). In all cases such antigens were identified and their immunogenicity was assessed in vitro by stimulation of PBMC from infected/protected individuals (Tb, CMV) or in vivo in a relevant mouse model (Borrelia, Flu). For the latter two, the chosen antigens were shown to be relevant for use in vaccines as vaccinated mice were protected against several subspecies. In case of Tb and CMV, the in vitro studies confirmed that these antigens had triggered T cell responses in spontaneously protected individuals, indicating their potential in stimulating T cell reactivity when used as vaccine. In the case of Sa, immune escape through antigen variation after vaccination was not seen in the mouse model, hence is not likely to occur in humans after vaccination. The successful identification of antigens with the capacity to induce a highly (cross)protective response are likely to lead to better vaccines than currently available (Borrelia, Flu). In order to overcome current vaccine failures against Tb and CMV, new vaccines critically require the activation of T cells that recognize infected cells early during infection. For both pathogens such antigens have been identified and their immunogenicity has been validated. Incorporation of these antigens in rationally designed vaccines are likely to have serious impact on disease burden. Finally, the appearance of more and more antimicrobials-resistant Sa-strains is a major public health concern and stresses the need for Sa-vaccines. The results from VacTrain support the development of Sa vaccines using one or more of the 10 antigen candidates identified in this WP.

WP3: Testing in models
The main research objective of WP3 was to advance knowledge and technology on the adaptive immune response against four different, highly prevalent human pathogens: CMV, Sa, Flu and the malaria parasite (Plasmodium). Lipid nanoparticle formulations and self-amplifying RNAs have been optimized for vaccine delivery. A unique human decidual culture system has allowed identifying the mechanism of action of CMV-specific antibodies in controlling this virus. Other progress on CMV control was made by applying synthetic long peptides to induce protective CD4 and CD8 based T cell immunity against mouse CMV, a model for human CMV. A breakthrough finding was made in Sa pathogencity by identifying a novel pathogenicity regulon. The finding that a candidate broadly protective Flu vaccine protects in a Flu-Sa co-infection model in mice, further supports the rational to include broadly protective influenza vaccines in pandemic preparedness plans. Finally, several novel liver stage malaria antigens were identified that can be delivered by MVA and adenoviral vectors to elicit powerful T cell responses in the mouse model. The work on Sa, CMV and Plasmodium has resulted in novel vaccine antigen candidates for which the current (end 2016) exploitation state ranges from ready to explore (Sa) to close to clinical testing (Plasmodium). The socio-economic impact of these findings is potentially very high given the high prevalence of these pathogens that remain hard to prevent or treat with currently available anti-microbials or, for malaria, the current vaccine options.

WP4: Testing in humans
The objective of WP4 was to define the correlate of the immune protection seen in a phase 2 randomised controlled trial of cytomegalovirus (CMV) glycoprotein B (gB) vaccine with MF59 adjuvant. Stored sera from this clinical trial were examined. The vaccine boosted neutralising antibodies in natural seropositives but did not induce substantial levels in seronegatives. In neither group was neutralising antibody a correlate of protection. Antibodies that mediate antibody dependent cellular cytotoxicity (ADCC) were found in natural seropositives but were not induced or boosted by the vaccine, so were also not a correlate of protection. Antibody responses to 4 defined antigenic domains within gB were examined. The vaccine boosted immune responses to all four in seropositives, but responses to only one (antigenic domain 2) correlated with protection. The impact of this research is to focus future discovery science on components of the immune system that are protective against CMV infection in humans. The conventional approach to screen for immunogens that induce neutralising antibodies or those that induce ADCC should be redirected towards more detailed examination of epitope-specific responses to gB. We suggest that industrial partners should test immunogens able to induce and to boost antibodies that recognise antigenic domain 2 of gB.

The VacTrain training programme aimed to provide the ESRs with knowledge on the entire process of vaccine development and thereby train vaccine specialists that will contribute to continuing improvement and innovation of vaccine development. After the completion of the VacTrain research and training programmes, resulting in many forms of dissemination (published papers, oral and poster presentations, filing of patents and involvement in public engagement events), we can conclude that all ESRs have matured into independent scientists with an open view on (applied) science. VacTrain has improved their career perspectives and prepared them for a successful career in the vaccine world.