Vaccinology and applied Microbiology

To overcome antimicrobial resistance (AMR) compromising global public health, novel strategies to develop next generation vaccines against AMR pathogens are required. However, the development of effective vaccines is challenging for bacterial infections occurring at mucosal sites, in particular in the gastrointestinal (GI) tract. In this context, Helicobacter pylori is listed as high priority AMR pathogen and the most common chronic bacterial infection affecting half of the world’s population with a high risk to progress into gastric cancer. Previous failures in H. pylori vaccine development approaches suggest that induction of mucosal immunity is required for protection. Thus, Vax2Muc will develop a rational prophylactic lead candidate against H. pylori in a straight-forward manner and directly evaluate this candidate for safety and immunogenicity in a phase I clinical trial, serving as proof-of-concept for novel vaccine technologies developed in Vax2Muc. To induce long-term protective mucosal immune responses sustained by tissue resident memory T cells, we will apply our previously identified vaccine antigens, combined with potent adjuvants for a systemic prime, and implemented in an innovative oro-mucosal film for a mucosal pull. Vax2Muc will further advance GMP manufacturing, and investigate and progress novel vaccine technologies and strategies tailored for mucosal application. We will evaluate our lead candidate and alternative approaches in pre-clinical mouse and pig models to define meaningful correlates of immunity and protection, which are still lacking for most of GI/AMR infections. Thus, Vax2Muc will deliver (i) a prophylactic vaccine candidate against H. pylori as PoC, and (ii) a wealth of knowledge and technologies that can be translated into the clinical development pipeline and are broadly applicable for various GI/AMR mucosal pathogens to significantly benefit the challenging field of mucosal vaccination and finally reduce disease burden from AMR/GI diseases.

Funding Agency: EU HORIZON EUROPE

The aim of the project is to conduct the critical preclinical studies and production steps to validate and further develop our adjuvant candidate bis-(3´,5´)-cyclic dimeric adenosine monophosphate (c-di-AMP) for its implementation as adjuvant in a clinical phase I trial of a hepatitis C virus (HCV) candidate vaccine.

Funding Agency: Helmholtz Validation Fund (Initiative and Networking Fund)

Our project aims at addressing two key problems: 1) the paucity of vaccine adjuvants currently on the market, and 2) the lack of a prophylactic vaccine against hepatitis C virus-caused diseases. To address both of these, we plan to conduct a clinical phase I trial of an HCV candidate vaccine comprising HCV antigens formulated with our adjuvant candidate c-di-AMP.

Funding Agency: Helmholtz Validation Fund (Initiative and Networking Fund)

The HZI and the CIGB (Center for Genetic Engineering and Biotechnology, Havana, Cuba) are conducting a scientific collaboration aimed at developing and optimizing novel vaccine candidates. The adjuvant "cyclic di-adenosine monophosphate" (c-di AMP or CDA) was developed and patented by the HZI. It will be used as an immune booster to improve the immunogenicity, effectiveness and applicability of the antigens produced and developed by the CIGB. The aim of the cooperation is in particular to develop CDA:

1. as an adjuvant for the induction of adaptive immune responses against antigens of vaccine candidates for the immunotherapy of chronic infectious diseases and
2. as an enhancer of innate immunity as part of the pre- / post-exposure prophylaxis (PEP) of SARS-CoV2, to develop a suitable vaccine formulation for the CIGB.

By combining the expertise, intellectual property and know-how of both partners in vaccine development, the existing vaccine candidates will be improved and a stronger impact and a wider scope of application will be achieved. To intensify the German-Cuban interaction and scientific and strategic discussions in the field and to enable vaccine development specifically for therapeutic vaccine applications, as well as to achieve a technology transfer between scientists from Germany and Cuba, various workshops and bilateral laboratory courses will be carried out.

Funding Agency: BMBF - Federal Ministry of Education and Research

The ISIDORe consortium, made of the capacities of European ESFRI infrastructures and coordinated networks, proposes to assemble the largest and most diverse research and service providing instrument to study infectious diseases in Europe, from structural biology to clinical trials. Giving scientists access to the whole extent of our state of the art facilities, cutting edge services, advanced equipment and expertise, in an integrated way and with a common goal, will enable or accelerate the generation of new knowledge and intervention tools to ultimately help control SARS CoV 2 in particular,and epidemic prone pathogens in general, while avoiding fragmentation and duplication among European initiatives. Such a global and interdisciplinary approach is meant to allow the implementation of user projects that are larger, more ambitious and more impactful than the EU supported transnational activities that the consortium is used to run. Our proposition is ambitious but achievable in a timely fashion due to the relevance and previous experience of the partners that we have gathered and that have complementary fields of expertise, which addresses the need for an interdisciplinary effort. Leveraging all these existing strengths to develop synergies will create an additional value and enhance Europe capacity for controlling emerging or re-emerging and epidemic infectious diseases, starting with the COVID 19 pandemic. Such a global and coordinated approach is consistent with the recommendations of the One Health concept and necessary to make significant contributions to solving complex societal problems like epidemics and pandemics.

Groups:
Vaccinology and applied Microbiology - Prof. Dr. Carlos A. Guzmán
Compound Profiling and Screening - Prof. Dr. Ursula Bilitewski

Homepage:https://isidore-project.eu/

Funding Agency: EU HORIZON EUROPE

The major aim of this project is to develop an advanced vaccine platform to promote protective mucosal immunity by co-delivery of mRNAs encoding antigen(s) and human endogenous adjuvants. This requires to adopt the nanocarrier design for co-delivery of different mRNAs with distinct expression kinetics. The approach encompasses the selection of relevant antigen and endogenous adjuvants for mucosal vaccination, and a proof-of-concept study with a vaccine-relevant antigen showing stimulation of protective immunity against a viral infection. The major aim will be achieved by fulfilling the following three specific tasks:

1. Development of a core-shell nanocarrier platform for mRNA co-delivery.
2. Selection/optimization of endogenous adjuvant candidate mRNAs and proof-of-concept for tailored immunostimulation.
3. Development of a formulation for mucosal mRNA nanocarrier vaccination and proof-of-concept for protective immunity.

Groups:
Vaccinology and applied Microbiology - Prof. Dr. Carlos A. Guzmán
Biological Barriers and Drug Delivery - Prof. Dr. Claus-Michael Lehr

Funding Agency: Other

In this project, we aim to identify protective bacterial antigens by the use of a bioinformatics approach. We will use P.aeruginosa and E.coli as model organisms to identify fully conserved peptides, and link selected synthetic peptides to a carrier protein to render them immunogenic. The design of an epitope-focused vaccine, which is anticipated to exhibit an improved immunogenic precision level, promises to result in a vaccine with a greater efficacy and safety profile, because it does not involve cell-derived material or biological processes for production.

Groups:
Vaccinology and applied Microbiology - Prof. Dr. Carlos A. Guzmán
Molecular Bacteriology - Prof. Dr. Susanne Häußler
Structure and Function of Proteins - Prof. Wulf Blankenfeldt
Chemical Biology - Prof. Dr. Mark Brönstrup
Structural Infection Biology - Prof. Dr. Michael Kolbe

Funding Agency: Other

The overall aim of the project is the validation of modular bead-based assay systems as a tool for research institutes. In this context, the subproject aims a validating the developed bead assays to be used for the analysis of murine as well as human samples derived from infected individuals (SARS-CoV-2 and influenza). Furthermore, the usability of the improved beads (e.g. enhanced number of analytes, adaptation of selected analytes) for the identification of early predictors for the expected course of the infection or the success of prophylactic immune interventions will be assessed. These analyses will be corroborated by using samples derived from mouse models for specific risk groups (elderly and metabolic dysfunction). These experimental approaches will essentially contribute to the validation as well as improvement of the bead assays. The gained results will further contribute to the overall knowledge on infections with SARS-CoV-2 and the respective course of the infection, its diagnosis and possible treatment strategies.

Funding Agency: BMBF - Federal Ministry of Education and Research

The strategic goals of the EU-funded INCENTIVE project are to advance knowledge of the underlying mechanisms of poor responsiveness to influenza vaccines (IVs) and to develop two next-generation universal IVs. This is a partnership between Indian, European and US groups that address the global health and economic challenge posed by influenza infections. The objectives include: performing comprehensive profiling of responders and non-responders to licensed IVs in infants, children, adults and elderly in phase IV trials in Europe and India to identify the mechanisms of vaccine responsiveness; advancing the development of two next-generation vaccines by providing a proof-of-concept for vaccine efficacy in non-human primates for an antigen presenting cell-targeted nucleic acid vaccine and developing a computationally-optimized vaccine up to phase II clinical trials and vaccine efficacy in a controlled human challenge; identifying predictive biomarkers of responsiveness to vaccination for new diagnostics; implementing technology transfer; and performing a health systems and investment analysis.

Partners:

• Helmholtz Centre for Infection Research (HZI)
• Public Health Foundation of India (PHFI)
• Translational Health Science and Technology Institute (THSTI)
• Université libre de Bruxelles (ULB)
• University of Bergen (UiB)
• University of Oslo (UiO)
• Center for the Evaluation of Vaccination (UA-CEV)
• Leiden University Medical Center (LUMC)
• Institut Pasteur (IP)
• ASA Spezialenzyme GmbH (ASA)
• Barcelona Institute for Global Health (ISGlobal)
• BIOASTER
• University of Georgia (UGA)
• HVP Stichting
• EuroVacc Foundation (EVF)
• Human Vaccines Project (HVP Inc.)
• Indian Institute of Technology Madras (IITM)
• Seth Gordhandas Sunderdas Medical College (GSMC) and the King Edward Memorial (KEM) Hospital
• National Institute of Immunology (NII)

Coordinator: Carlos A. Guzmán, Helmholtz Centre for Infection Research (HZI)

Homepage:https://www.incentive-h2020.eu/

Funding Agency: EU HORIZON2020

Spontaneous resolution of hepatitis B virus (HBV) infection is characterised by neutralising antibodies and HBV-specific T cell responses, elements which are lacking in chronic HBV infection. The EU-funded TherVacB project aims to overcome immune tolerance in chronic HBV infection and the virus’s resistance to cure. The interdisciplinary consortium will employ a heterologous prime-boost therapeutic vaccination scheme with proven efficacy in preclinical models of hepatitis B to target and activate B and T cell responses; thereby, TherVacB hopes to produce vaccine components and prepare a first-in-human application. To provide a clinical proof of concept of the therapeutic hepatitis B vaccine in patients with chronic hepatitis B, the consortium will establish a patient registry and perform a multicentre phase Ib/IIa clinical trial of the vaccine's safety and potency to induce immune control of chronic HBV infection.

Homepage:https://www.thervacb.eu/

Funding Agency: EU HORIZON2020

Through the collaborative work in this project, we plan to develop and test an optimized protein sequence with favorable antigenic and stability profile, to be used as a template conferring more long-term neutralization capabilities when used with standard seasonal influenza vaccination.

Groups:
Vaccinology and applied Microbiology - Prof. Dr. Carlos A. Guzmán
Computational Biology for Infection Research – Prof. Dr. Alice McHardy
Structure and Function of Proteins - Prof. Wulf Blankenfeldt

Funding Agency: Global Grand Challenges of the Bill & Melinda Gates Foundation

Paving the way towards individualized vaccination

Exploring multi-omics big data in the general population based on a digital mHealth cohort

Rationale
Novel vaccines for an increasing number of pathogens are becoming available. Yet, there is a natural limit to effectiveness, safety and acceptability with regard to combining vaccines and adding new ones to existing vaccination schedules. Therefore, vaccination schedules need to become more individualized to address this challenge and optimize their efficiency.

Objectives
The aim of the i.Vacc project is to identify new multi-omics profiles for susceptibility to respiratory infections that have a higher predictive value than existing stratifications for vaccination recommendations and that provide a conceptual basis for personalized vaccination strategies. The study is designed to target influenza infections with particular variability in hostsusceptibility, pathogen antigen profile and ranging vaccine effectiveness. The study will also include other respiratory viral infections and susceptibility to infections in general. We aim at complementing GNC data with genomics and proteomics to predict susceptibility to respiratory infections, using machine learning approaches, and at exploring the predictive potential of further molecular biomarkers, using sorted immune cell populations and high-resolution interaction proteomics. We expect that biomarkers identified in this project and validated in clinical studies will be instrumental in advancing personalized vaccine strategies. Furthermore, this study will support future translation of the PIA application from the research follow-up to extra-mural clinical patient monitoring (e.g. immunosuppressed patients).

Study Design
The project uses data from the German National Cohort (GNC) (see also our study center in Hannover), specifically from the subcohort ZIFCO (see also www.info-pia.de).

Leader: Prof Dr Gérard Krause

Groups:
Epidemiology- Dr. Berit Lange
Vaccinology and applied Microbiology- Prof. Dr. Carlos A. Guzmán

Homepage:https://info-pia.de/projekte/i-vacc/

Principal Investigators:

• Gerard Krause (Coordinator; Epidemiology, German National Cohort (NAKO), digital mHealth), Department of Epidemiology, HZI
• Alice McHardy (Bioinformatics), Department of Computational Biology for Infection Research, BRICS – Braunschweig Integrated Centre of Systems Biology
• Lothar Jänsch,( Proteomics), Research Group Cellular Proteome Research, HZI
• Thomas Illig (Genomics), Department of Human Genetics, Medical School Hannover
• Frank Klawonn (Biostatistics), Institute for Information Engineering, Ostfalia University of Applied Sciences

HZI-Project Partners:      

• Carlos A. Guzmán (Vaccinology)
• Peggy Riese (Vaccinology)
• Stephanie Trittel (Vaccinology)
• Gisa Gerold (Functional proteomics)
• Andreas Bremges (Bioinformatics)
• Tobias Kerrinnes (NAKO)
• Yvonne Kemmling (NAKO)
• Stefanie Castell (Epidemiology, NAKO)

Funding Agency: Ministry for Science and Culture of Lower Saxony