Many HIV vaccine concepts and several efficacy trials have been conducted in the prophylactic and therapeutic fields with limited success. There is an urgent need to develop better vaccines and tools predictive of immunogenicity and of correlates of protection at early stage of vaccine development to mitigate the risks of failure. To address these complex and challenging scientific issues, the European HIV Vaccine Alliance (EHVA) program will develop a Multidisciplinary Vaccine Platform (MVP) in the fields of prophylactic and therapeutic HIV vaccines. The Specific Objectives of the MVP are to build up: 1.Discovery Platform with the goal of generating novel vaccine candidates inducing potent neutralizing and non-neutralizing antibody responses and T-cell responses, 2. Immune Profiling Platform with the goal of ranking novel and existing (benchmark) vaccine candidates on the basis of the immune profile, 3. Data Management/Integration/Down-Selection Platform, with the goal of providing statistical tools for the analysis and interpretation of complex data and algorithms for the efficient selection of vaccines, and 4. Clinical Trials Platform with the goal of accelerating the clinical development of novel vaccines and the early prediction of vaccine failure. EHVA project has developed a global and innovative strategy which includes: a) the multidisciplinary expertise involving immunologists, virologists, structural biology experts, statisticians and computational scientists and clinicians; b) the most innovative technologies to profile immune response and virus reservoir; c) the access to large cohort studies bringing together top European clinical scientists/centres in the fields of prophylactic and therapeutic vaccines, d) the access to a panel of experimental HIV vaccines under clinical development that will be used as benchmark, and e) the liaison to a number of African leading scientists/programs which will foster the testing of future EHVA vaccines through EDCTP

Viral infections diagnosis demands novel, cheaper and rapid technologies to overcome present constraints. Current gold standard for diagnosis of viral infections is based on pathogen-targeted nucleic acid identification; thus, it cannot discern infectious stages from latent ones and it demands time consuming adjustments when mutations occur or new emerging viruses are to be included in the diagnostic protocols. Lately, optomechanics has served to fundamental advancements in physics, from gravitational wave detection to the study of mechanical quantum ground states but it has not yet delivered its full applicability potential. VIRUSCAN aims to apply frontier advancements in optomechanics to the biosensing and diagnostic fields and to create a new interdisciplinary research community with the goal to advance optomechanics, nanoelectromechanics, native mass spectrometry and biophysics towards clinical applications. VIRUSCAN will provide a novel technology capable to identify viral particles and asses their infective potential through the characterization of two physical parameters: mass and stiffness. Stiffness of viral particles has been recently known to act as a regulator of their infectivity at different stages of the virus life cycle. In parallel, advancements in nanoelectromechanical systems have recently demonstrated that stiffness and mass information from nanoscale adsorbates can be disentangled. Targeting intrinsic physical properties of viral particles will allow developing an open platform that will tackle any virus and their mutations. VIRUSCAN will have impact at all levels by: providing a personalized treatment to the patients, reducing the use of not effective antibiotics, increasing safety in blood transfusions, allowing a quick and trustworthy response to emergency situations (e.g. recent EBOLA in West Africa and the ZIKA in Brazil), reducing the spread of viral infections, reducing costs per analysis and screening of a wide range of pathogens.

DEFENDER will address the need for innovative intervention strategies against viruses with epidemic potential, by adopting a comprehensive and integrative platform approach. DEFENDER’s revolutionary Research and Innovation pipeline will focus on preventing virus entry through a host-directed bottom-up approach based on functional genetics in parallel to a top-down virus glycoprotein-centered approach. We will identify novel host dependency and restriction factors, including receptors and proteins involved in viral attachment and binding, endosomal uptake and virus genome uncoating, as targets for antiviral therapy. In parallel, we will use recombinant viral glycoproteins to identify broadly neutralizing nanobodies and novel epitopes for the AI-based design of next generation immunogens and the improvement of therapeutic antibodies. The host bottom-up functional genetic approach will be applied to Nipah, Lassa, Zika, Dengue, Yellow fever, and Chikungunya viruses. Host factors will be identified using a unique arrayed CRISPR perturbation platform, combined with advanced statistical and machine learning approaches and mathematical modelling, mechanistic experiments, and cutting-edge imaging techniques. In parallel, the virus top-down glycoprotein-centered approach will lead to the identification and structural characterization of broadly neutralizing nanobodies targeting conserved epitopes of the glycoproteins of Nipah and Lassa viruses in pre-fusion conformation. DEFENDER will deliver innovative antiviral candidates that induce target degradation, next generation immunogens, and a novel concept to improve the activity of therapeutic antibodies, with proof-of-concept preclinical evaluation in mice. It will define the most vulnerable virus-host interactions, to deliver a robust development pipeline for novel antivirals, therapeutic antibodies, and immunogens and increase antiviral options against a wide range of priority (re-) emerging viruses.

The European XFEL has just entered user operation. With its unparalleled peak brilliance and repetition rate, European XFEL has the potential to further applications in single particle imaging (SPI), thus far limited to large viral particles at X-ray Free-Electron Lasers (XFEL). SPI will allow imaging protein complexes without the need for crystallization. This eventually renders transient conformational states accessible for high resolution structural studies yielding molecular movies of biomolecular machines. A major bottleneck is the wealth of data required to reconstruct a single structure leading to long processing times. This is currently also a problem in electron microscopy (EM). MS SPIDOC will overcome this data challenge by developing a native mass spectrometry (MS) system for sample delivery, named X-MS-I. It will provide mass and conformation selected biomolecules, which are oriented along their dipole axis upon imaging. This will enable structural reconstruction from much smaller datasets speeding up the analysis time tremendously. Moreover, the system features low sample consumption and a controlled low background easing pattern identification. The main objectives of the project are: • Deliver mass and conformation separated biomolecules for SPI. • Orient proteins for SPI. • Image protein complex unfolding • Exploit potential of protein orientation for other applications The MS SPIDOC consortium combines internationally leading expertise in different fields relevant to the project: Instrument design and development, computer simulations as well as working with biomolecules in the gas phase and on SPI are combined to implement the novel sample environment at the next generation XFEL facility. New components and methods will be opened to the market and thereby strengthen the European Research Area (ERA) and industry. This early stage high-risk project will give rise to a new technology with major impact on how to derive structures of biomolecules.

The extraordinary ability of the coronavirus to spread in the environment has established the Covid-19 pandemic as the biggest challenge humanity faces in the XXI century. Covid-19 attacks humans regardless of age, claiming the life of over 8,000 people in a single day, with a devastating death toll exceeding 350,000 in just a few months. The virus is likely to survive for the foreseeable future and disperse further, requiring long-term planning and investment in developing means of detection, protection and cure. Protective measures based on monitoring the dispersion of the coronavirus in the environment and fast screening of individuals has become paramount for ensuring safety of our ageing population and restarting/supporting the worldwide economy. The objective of the ARIADNE project is to develop a multiple-stage analytical platform based on multi-dimensional mass spectrometry instrumentation. Performing direct and instant detection of intact virus particles in breath and in water, and going far beyond that task, this unique analytical platform will push the scientific boundaries in all aspects of analytical sciences centered on mass spectrometry, incorporating a series of potentially disruptive technologies integrated into a single system. ARIADNE integrates state-of-the-art technological advancements in breath sampling and post-ionization methods, new analytical tools for characterization of the protein content of viruses by top-down mass spectrometry, non-destructive ultra-high mass analysis of single particles followed by their soft landing and further processing based on advanced single proteomic workflows. A compact and simplified version of this versatile and powerful analytical platform is also envisaged for advancing the field of real-time breath analytics. Applications extending the analytical capabilities of the system to new viruses, intact bacteria as well as whole human cells will also become accessible.