The enormous health and economic impacts of epidemics and pandemics has become one of the defining public policy and health issues in Europe and throughout the world. A new urgency is required to understand, rapidly respond to, and vaccinate against viruses with epidemic and pandemic potential. The major challenge for the modern vaccines is the induction of long-term protective immunity, as clearly demonstrated by fast waning of protection for current COVID-19 vaccines. VICI-DISEASE is an ambitious project which combines existing cutting-edge expertise in a tried and tested consortium, with new advances in this critical field. The consortium’s main objective is to develop a vaccine candidate portfolio and perform a clinical proof-of-concept study, to enable stocks of vaccine candidates ready for further development (Phase 2&3) in case of pandemic outbreaks. The primary candidate will be Nipah virus (NiV), a high-mortality viral disease with no vaccines or treatments. Our vaccine is based on NiV G protein displayed on capsid Virus Like Particle (cVLP), enabled by adapting template processes from our recent COVID-19 vaccine (currently in Phase 3), and expected to provide best-in-class longevity as shown for COVID-19. The VICI-DISEASE consortium’s objective is to develop and perform a clinical proof-of-concept study for • a highly effective (>90% protection), • long-term protective (>2 years), • NiV virus cVLP vaccine, • by adapting template processes established for our COVID-19 vaccine (currently in Phase 3), • within 48 months in a Phase 1/2a clinical study, • to help protect medical workers and the public from future NiV and Hendra virus outbreaks, • and establish a pipeline of novel filovirus vaccines through pre-clinical proof-of-concept studies. We address the call topic by improving pandemic preparedness and response through development of a NiV vaccine to Ph1/2 and two filovirus vaccines to pre-clinical proof-of-concept.

Our aim is to perform pre-clinical and clinical evaluation of a potential Wuhan Coronavirus vaccine candidate. The vaccine will be based on Virus-Like Particle (VLP) display of the SARS-CoV-2 Spike protein antigen. AdaptVac's VLP display technology has been shown to significantly improve vaccine immunogenicity, longevity and efficacy, for a wide range of viral and parasite diseases in pre-clinical studies (including flu and malaria). A unique feature of the technology is its two-component approach. The VLP is generic to all vaccines, and produced at >1g/L yields using E. coli. The disease antigen is produced in any expression system, allowing the most challenging antigens to be successfully produced. The VLP and antigen is then simply mixed, and a spontaneous, irreversible, conjugation occurs under physiological conditions. This results in site-specific, directional, and high-density display of the antigen on the VLP surface. The antigen will be produced using ExpreS2ion's Drosophila S2 insect cells based on the trimetric spike antigen. Furthermore, E. coli and baculovirus will be tested for Spike protein variants. The vaccine candidates will be tested pre-clinically using in vitro viral neutralization assays and possibly animal challenge models as they become available at LUMC. ExpreS2ion will develop the production processes and transfer these for GMP manufacture of the VLP and vaccine antigen, outsourced, to AGC Biologics. Finally, a phase I/IIa study will be performed at Radboud University Medical Center in the Netherlands. A surrogate marker of protection will be established by showing protection in animal models using passive transfer of participant sera, or by in vitro SARS-CoV-2 viral neutralization. This project is focused on delivering a scalable vaccine, ready for testing in the field, which has been shown to be safe in humans and effective in in vitro or animal models.

The 2nd Generation Malaria Vaccine Consortium (MVC-2G) will build on the programmatic use of the first-generation Plasmodium falciparum vaccine, R21 with Matrix-M™, and accelerate the clinical development of the leading second-generation multi-stage P. falciparum malaria vaccine comprising R21 and two novel blood-stage components, RH5.1 and R78C, all formulated in Matrix-M™. It will achieve this through a multi-disciplinary workplan, underpinned by international cooperation, that will accelerate the future achievement of the United Nations’ Sustainable Development Goal 3 (SDG3) in sub-Saharan African countries. Its specific objectives are to: 1. Demonstrate safety and superior efficacy against clinical malaria (over R21/MM alone) of the leading second-generation multi-stage vaccine candidate R21+RH5.1+R78C/MM in a Phase 2b trial in 5-17 month old African infants, in a seasonal setting; 2. In parallel, undertake Phase 1b assessment of the second-generation multi-stage vaccine in African infants to define a 3 or 4 dose delivery schedule that is better aligned with EPI and end-user community expectations, aiming for lower cost of goods and to facilitate improved future uptake of a second-generation product; 3. Demonstrate safety and superior efficacy of the multi-stage vaccine (over R21/MM alone) delivered in an optimised age-based schedule in a multi-site Phase 2b trial in African infants in seasonal and perennial settings; 4. Generate evidence to support use of the multi-stage vaccine in future malaria elimination campaigns by assessment of i) efficacy in adults by CHMI, and ii) safety and immunogenicity in older children; 5. Support the next-generation of early-career African scientists, across all partners in the Consortium, by growing a South-South network to facilitate hands on clinical and laboratory training; and 6. Undertake early engagement with regulators in partner countries to facilitate translation and future registration of this multi-stage vaccine.

Plasmodium vivax is the most widespread malaria and constitutes a significant proportion of human malaria cases. P. vivax accounts for 100-400 million clinical cases each year among the 2.5 billion people living at risk in Latin America, Oceania and Asia. The recently revised Malaria Vaccine Technology Roadmap to 2030 recognises the severity of P. vivax malaria and calls for a vaccine intervention to achieve 75% efficacy over two years – equally weighted with P. falciparum. However, despite this global health need, efforts to develop interventions against this parasite have lagged far behind those for P. falciparum, in large part because of critical bottlenecks in the vaccine development process. These include i) lack of assays to prioritise and down-select new vaccines due to lack of an in vitro P. vivax long-term culture system, and ii) lack of easy access to a safe controlled human malaria infection (CHMI) model to provide an early indication of vaccine efficacy in humans. The Objectives of this MultiViVax proposal will address these critical bottlenecks and shift the “risk curve” in order to better select successful vaccine candidates against multiple lifecycle stages of P. vivax: 1. We will establish a P. vivax CHMI model in Europe for the first time to facilitate the better selection of effective vaccines and remove the current bottleneck for their early-phase clinical testing. 2. We will utilise this CHMI model to identify novel antigens associated with protective blood-stage immunity in humans by taking advantage of recent advances in immuno-screening and parasite RNASeq. 3. We will progress existing vaccines targeting the current leading antigens for both the blood- and transmission-stages along the clinical development pipeline. 4. We will develop novel transgenic parasites for use in assays in order to overcome the current bottleneck in vaccine down-selection caused by the inability to culture P. vivax parasites.