The Hop-On NOSEVAC modeling activity (proposed as WP8) aims at developing mathematical and quantitative modeling platforms for nasal vaccines research, to help in the deep understanding, prevention and reduction of nasal colonization and infection by respiratory pathogens. The Hop-On modeling activity brings added value to the NOSEVAC project by combining biological data and theoretical modeling frameworks to deliver a stronger and more robust quantitative analysis of the processes involved both in the mode of action and efficacy of bivalent RNA- and protein-based nasal vaccines against bacterial and viral infection, respectively. Mathematical, bio-statistical and computational modeling will offer a unique opportunity to gather sets of data from pre-clinical and clinical investigations to accelerate the development of the next generation nasal vaccines against nasal colonization/infection by pathogens, and implicitly also aid in preventing and limiting antibiotic resistance. The data and integrative models generated by NOSEVAC and the Hop-On NOSEVAC modeling activity in animal, human and in vitro studies will act synergistically to guide policy makers and funders towards rational decisions on supporting further nasal vaccine development. Modeling tools and frameworks developed for the respiratory pathogens under the focus of NOSEVAC could also be applied to study other pathogens and obtain useful knowledge for other vaccines. By expanding the toolbox of methods, descriptive and predictive models, we will contribute to the global effort in vaccine development and pandemic preparedness.

Malaria remains a serious health concern worldwide, with P. falciparum considered one of the deadliest human parasites. Yet, the currently approved vaccine against malaria (RTS,S/AS01) offers limited protection due to challenges in vaccine development. Using current advances made in understanding immunity to address some of the existing challenges, this proposal aims to develop a more efficacious vaccine against P. falciparum by targeting multiple developmentalstages(sporozoite, liver and blood-stage). In this project, combinations of 1) highly promising whole parasite vaccination approach targeting the liver (late-arresting GAP), 2) RTS,S (provided by GSK) and 3) mRNA versions of clinically evaluated and partially protective blood stage vaccine candidates (Rh5, AMA1-DiCo [sporozoite and blood stage]) will be evaluated in preclinical and small-scale human trials to discern the optimal combination for further clinical investigations. To inform a rational design of future vaccine candidates, CAPTIVATE will analyse the vaccine-induced immune response to acquire a full understanding of malaria protective immunity and develop an advanced immunology in-silico platform. While immunity to blood stage malaria is relatively well understood, the mechanisms of adaptive protective immunity for pre-erythrocytic malaria vaccine candidates are less well-established. CAPTIVATE addresses this critical knowledge gap by combining state-of-the-art preclinical and clinical (CHMI) in vivo malaria vaccine efficacy models with an innovative in-silico platform comprising TCR/VDJ sequencing and artificial intelligence predictions, to identify such mechanisms. CAPTIVATE assembles a unique combination of European experts in their respective fields (malaria modelling in primates, clinical vaccine testing, in-silico modelling of immune responses, innovative omics approaches) in an integrated interdisciplinary approach aimed at bringing the next generation malaria vaccines to the clinic.

The availability of effective malaria vaccines is a historic landmark, “a breakthrough for science, child health and malaria control” that “could save tens of thousands of young lives each year” [WHO 2021]. But substantial implementation challenges need to be addressed to realise this potential. In many areas where malaria vaccines will soon be introduced, EPI coverage is suboptimal, especially in the second year of life. Introduction of malaria vaccines is also an opportunity to strengthen delivery of basic vaccines because a) additional immunisation visits will be required to administer 3 doses of malaria vaccine between the ages of 5 and 9 months and a fourth dose at about 2 years, and b) in areas with highly seasonal malaria, annual intensification of vaccine delivery may be advantageous to optimize malaria impact, both providing opportunities for catch-up of other vaccines, and c) recognition of the importance of malaria may lead to be less mistrust of malaria vaccines, as observed during pilot implementations; such positive attitudes could be leveraged to promote vaccination in general. The purpose of this project is to support national immunization and malaria programmes in 14 countries in West and Central Africa with highly seasonal malaria, to optimize delivery and uptake of malaria vaccines, and to exploit the opportunities to strengthen delivery of other vaccines. This will be achieved through a programme of implementation research, adapting delivery approaches to local situations, and sharing information about what works best. The project, which builds on a network of 13 countries that was established through the EDCTP-funded OPT-SMC project, coordinated by the University of Thiès in Senegal, the LIH, TDR, LSHTM, CAPM, MMV and WHO, will provide grants and technical assistance to national programmes to enable them to monitor vaccine introduction and identify barriers to uptake, and develop, implement, and evaluate strategies to address these barriers.

Malaria killed about 640 thousand people in 2020, largely young children in Africa. Rapid recent progress has led to two anti-sporozoite vaccine developers planning WHO prequalification applications in 2022. These include the new high efficacy R21/Matrix-M vaccine, to be supplied at the required large scale, and led by partners in this consortium. In parallel, recent progress with transmission-blocking malaria vaccines has led to substantial efficacy in a first direct skin feeding field trial. This opens up the prospect of a two-stage vaccine targeting both sporozoites and sexual-stage parasites that should have a major impact on malaria transmission, thereby enabling regional elimination and ultimate eradication. We propose here to develop such a vaccine assessing both established virus-like particle (VLP) vaccines in potent saponin adjuvants and also exciting new thermostable mRNA vaccines expressing the parasite antigens now showing high efficacy. Importantly, we will adopt new VLP design technologies, e.g. SpyCatcher bonding, that allow bivalent antigen display, to enable a single vaccine to protect against both the Plasmodium falciparum parasite, which causes most deaths, and the more widespread Plasmodium vivax parasite. A lead vaccine candidate will be down-selected based on well-studied pre-clinical efficacy models and induction of functional transmission-blocking antibodies, prior to GMP manufacture and a clinical trial in year 4. The consortium brings together academics, non-profits and a wide range of companies with both leading technologies and access to small and very large scale GMP manufacturing capacity. This programme builds on the recent success of several partners in the R21/Matrix-M programme and aims to accelerate the malaria eradication agenda by providing the first vaccine to tackle both major malaria parasite species, and confer both individual and community protection on the way to eradication.

Although vaccination is an effective way to reduce the huge disease burden associated with diarrhoea caused by enteric pathogens, many attempts to develop vaccines for shigellosis and ETEC infections have failed and a number of current approaches are too complex and costly to provide an adequate solution for LMICs. This Consortium is dedicated to advancing a radically new approach against Shigella and ETEC based not on the immunodominant, but highly variable Shigella LPS O-antigen, target of almost all past and current vaccine development efforts. There are four pillars on which the ShigETEC vaccine has been designed: (i) Elimination of the LPS O-antigen to allow recognition of multiple antigens on the cell surface that are shared among different serotypes of Shigella and are increasingly being recognized as important in protection from shigellosis. These antigens are also closely related to those of ETEC and may also help in protecting against that pathogen as well. (ii) Elimination of the invasiveness of Shigella by disruption of the invasion complex resulting in a much safer/less reactogenic oral vaccine that can take advantage of gut mucosal immunity, possibly allowing administration of high vaccine doses and therefore addresses the low immunogenicity seen with other live attenuated vaccine candidates. (iii) Addition of detoxified toxin antigens of ETEC that will induce neutralizing/blocking antibodies to these critical virulence factors. (iv) Rational molecular design of ShigETEC will allow future generations of vaccines to include additional antigens for other pathogens. The work programme entails manufacture of clinical trial material, first-in-human testing for safety and immunogenicity in non-endemic adults, a sero-epidemiology study to learn about natural immune response to the vaccine, and importantly testing the vaccine in endemic populations. The Consortium comprises partners from EU and Bangladesh that bring along highly complementary expertise.