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Miguel Prudêncio Lab

Plasmodium Infection & Anti-malarial Interventions

The Vision of the Prudêncio Lab is to contribute to a world where the burden of malaria on the planet’s most vulnerable populations is significantly decreased. A distinctive feature of our research lies in approaching fundamental questions pertaining to the biology and immunology of Plasmodium infection from a translational perspective. Our research priorities are, therefore, defined and guided not only by “Why?” and “How?”, but also by “What for?”. With this, we strive to fulfil our Mission of utilizing scientific excellence to deliver a combination of new knowledge and novel antimalarial tools that can be harnessed to combat Plasmodium infection and malaria disease.

Funders

Our research interests span a wide range of topics within the malaria field, with particular emphasis on the hepatic stage of infection by Plasmodium parasites. We are interested in elucidating novel aspects of the biology of Plasmodium infection and host-parasite interactions, investigating co-infections between Plasmodium and other pathogens, developing new drug- and vaccine-based anti-malarial strategies, and developing new experimental strategies to study the different stages of Plasmodium infection.

Our current research focuses on:

Investigating the reciprocal influence of Plasmodium and viral or parasitic co-infections.
Developing and evaluating the activity of novel antiplasmodial compounds.
Addressing current bottlenecks and knowledge gaps in whole-sporozoite vaccination against malaria.
Investigating immunomodulation strategies for enhancement of vaccine efficacy.
Developing a novel whole-sporozoite vaccination strategy.
Generating monoclonal antibodies against human Plasmodium parasites.
Developing novel strategies for assessment of Plasmodium hepatic infection.

Vaccines and other immune-based antimalarial tools

The exploitation of the immune system’s ability to fight infection by Plasmodium has always been a core goal of the Prudêncio Lab. We will continue and expand our efforts in this regard by pursuing three main Objectives:

A) Novel berghei-based vaccines against P. falciparumand P. vivax

Our work employing PbVac and PbViVac (see above) validated the use of “naturally attenuated” rodent P. berghei (Pb) parasites, genetically engineered to express antigens of their human-infective counterparts, as a whole-sporozoite (WSp) vaccination platform against human malaria. We will continue exploring Pb’s amenability to genetic modification to generate and pre-clinically characterize novel stage-transcending vaccine candidates expressing antigens from different phases of the P. falciparum (Pf) and P. vivax (Pv) parasites’ life cycle. Concomitantly, we will proceed our ongoing collaboration with Sanaria, Inc. towards the generation of vialed formulations of the most promising candidates, suitable for parenteral injection.

B) Monoclonal antibodies against vivax

Monoclonal antibodies (mAb) against the Pf circumsporozoite protein (PfCSP), obtained from malaria-naïve individuals immunized with radiation-attenuated sporozoites (RAS) of Pf, have proven a promising approach to Pf malaria prevention. However, the impossibility culturing Pv parasites in the lab renders mAb development against this species extremely difficult. To overcome this, genetically engineered Pb parasites expressing selected Pv antigens will be employed as surrogates of Pv sporozoites in mouse immunization experiments to generate, screen and select hybridomas producing high titers of Pv antigen-specific mAb. These antibodies will then undergo a process of AI-based humanization to deliver highly efficacious human mAbs against Pv, ready for clinical assessment.

C) Enhancement of malaria vaccine efficacy

Several factors are known to influence the efficacy of vaccination in general, and of malaria vaccines in particular. Our existing data offer compelling evidence of a substantial CD8+ T cell-dependent decline in malaria vaccine efficacy with age, in a mouse model of RAS immunization. We will now i) investigate the cellular and molecular mechanisms underlying the observed age-related decline in malaria immunization efficacy in rodents, and (ii) employ the RAS immunization mouse model to devise novel therapeutic strategies targeting cellular immunity to enhance malaria vaccine efficacy in aging populations. In parallel, we are partnering with Novavax AB, the Vaccine Formulation Institute and the University of Oxford to address the largely underexplored issue of whether humoral responses elicited by WSp vaccines can be enhanced using state-of-the-art adjuvant formulations.

Antiplasmodial therapies

Antiplasmodial drugs remain a pivotal cornerstone of malaria control. We will continue striving to enhance the number, scope and efficacy of effective antiplasmodials through:

A) Drug screening, development and repurposing

Over the years, we have collaborated with numerous medicinal chemistry groups on the screening and development of antiplasmodial compounds. We will continue using our well-established in vitro and in vivo models to assess the activity of selected compound libraries and de novo designed molecules against the hepatic, blood and transmission stages of Plasmodium parasites. Among these compound sets are a newly-designed family of ivermectin-based hybrid molecules, and a series of novel specific inhibitors of host aquaporins. In addition, we will continue our previous efforts to assess the potential of drugs that are employed to treat other diseases in malaria-endemic regions to be repurposed for malaria prevention and/or treatment.

B) Antimalarial immunomodulation

In a set of preliminary experiments, we have obtained evidence that specific compounds, currently under clinical development, display immunomodulatory properties that impact the efficacy of antimalarial treatments. We will now unveil the detailed immunological basis of this effect and investigate the ability of these treatments to prevent a subsequent infection by Plasmodium liver or blood stage parasites.

Co-infections

We will expand our efforts to explore the impact of co-infections between Plasmodium and other infectious agents that prevail in malaria-endemic regions. To this end, we will investigate the:

A) Molecular, immunological and pathological crosstalk between gammaherpesviruses, Plasmodiumand cancer

Epstein–Barr virus (EBV) and Pf malaria parasites are well-established etiological agents of endemic Burkitt lymphoma (eBL), the most common pediatric cancer in regions where both pathogens are co-endemic. Our current knowledge about the complex interplay between EBV, Pf malaria, and eBL largely arises from retrospective epidemiological studies that are intrinsically limited by several factors, including the inability to retrospectively infer the exact time of infection with either pathogen and the onset of the molecular events that lead to cancer cell proliferation, the ubiquitous presence of confounding infections or clinical conditions, and the ethical constraints to the collection of relevant tissue specimens and frequent blood sampling. We have established a rodent model of co-infection employing C57BL/6 mice, murine gammaherpesvirus 68 (MHV68) and Pb parasites to show that an infection by Pb reactivates a latent MHV68 infection, and that MHV68 markedly decreases the severity of malaria caused by Pb. We will now (i) investigate the influence of Plasmodium parasites on viral reactivation, and identify targets to inhibit viral proliferation; (ii) elucidate the impact of gammaherpesvirus on Plasmodium infection and malaria, to improve management of severe disease; and (iii) dissect the relative impacts of gammaherpesvirus and Plasmodium on the molecular and immunological events leading to lymphoproliferation, to identify novel eBL prevention strategies.

B) Impact of Leishmaniainfection on malaria susceptibility, progression, and vaccination

Despite their shared geographical prevalence, the mutual interactions between Leishmania and Plasmodium, and their impact on the host’s immune system remain poorly understood. We will seek to unveil the immune interplay between these pathogens, towards understanding how an ongoing Leishmania infection influences the establishment and progression of malaria. We will employ a murine model of (co-)infection to focus on the liver microenvironment shared by Leishmania and Plasmodium during infection by the former and the clinically silent liver stage of the latter’s life cycle. We will carry out an in-depth analysis of the immune landscape in mono- and co-infection animals to unravel how Leishmania modulates the host’s immune response in the context of concurrent infection with the malaria parasite, thereby altering the establishment and progression of the latter. In addition, we will investigate the impact of both acute and chronic Leishmania infections on the immunogenicity and efficacy of WSp malaria vaccination.

2024-2028 European Commission – Horizon Europe

“OptiViVax – Optimising a high efficacy Plasmodium vivax malaria vaccine”

PI: Miguel Prudêncio

2024-2028 Merck KGaA

“Induction of long-lasting premunition against malaria”

PI: Miguel Prudêncio

2021-2025 “la Caixa” Foundation

“Whole-organism vaccines against P. falciparum and P. vivax malaria with enhanced efficacy and scope”

PI: Miguel Prudêncio

2023-2025 Fundação para a Ciência e Tecnologia

“Ivermectin hybrids – potential insecticidal and multistage antiplasmodial drugs for malaria control”

PI: Diana Fontinha

A.M. Mendes, M. Machado, N. Gonçalves-Rosa, I.J. Reuling, L. Foquet, C. Marques, A.M. Salman, A.S.P. Yang, K.A. Moser, A. Dwivedi, C.C. Hermsen, B. Jiménez-Díaz, S. Viera, J.M. Santos, I. Albuquerque, S.N. Bhatia, J. Bial, I. Angulo-Barturen, J.C. Silva, G. Leroux-Roels, C.J. Janse, S.M. Khan, M.M. Mota, R.W. Sauerwein, M. Prudêncio (2018). A Plasmodium berghei sporozoite-based vaccination platform against human malaria. NPJ Vaccines 3: 33.

I.J. Reuling, A.M. Mendes, G.M. de Jong, A. Fabra-García, H. Nunes-Cabaço, G.J. van Gemert, W. Graumans, L.E. Coffeng, S.J. de Vlas, A.S.P. Yang, C.K. Lee, Y. Wu, A.J. Birkett, C.F. Ockenhouse, R. Koelewijn, J.J. van Hellemond, P.J.J. van Genderen, R.W. Sauerwein, M. Prudêncio (2020). Safety and efficacy of a genetically modified rodent malaria parasite against Plasmodium falciparum malaria: an open-label randomized phase 1/2a trial. Science Translational Medicine 12: eaay2578.

D. Moita, T.G. Maia, M. Duarte, C.M. Andrade, I.S. Albuquerque, A. Dwivedi, J.C. Silva, L. González-Céron, C.J. Janse, A.M. Mendes, M. Prudêncio (2022). A genetically modified Plasmodium berghei parasite as a surrogate for whole-sporozoite vaccination against P. vivax malaria. NPJ Vaccines 7: 163, 1-9.

D. Moita, H. Nunes-Cabaço, C. Rôla, B. Franke-Fayard, C.J. Janse, A.M. Mendes, M. Prudêncio (2023). Variable long-term protection by radiation-, chemo-, and genetically-attenuated Plasmodium berghei sporozoite vaccines. Vaccine 41: 7618-7625.

D. Moita, C. Rôla, H. Nunes-Cabaço, G. Nogueira, T.G. Maia, A.S. Othman, B. Franke-Fayard, C.J. Janse, A.M. Mendes, M. Prudêncio (2023). The effect of dosage on the protective efficacy of whole-sporozoite formulations for immunization against malaria. NPJ Vaccines 182: 1-12.

M. Sanches-Vaz, A. Temporão, R. Luis, H. Nunes-Cabaço, A.M. Mendes, S. Goellner, T. Carvalho, L.M. Figueiredo*, M. Prudêncio* (2019). Trypanosoma brucei infection protects mice against malaria. PLoS Pathogens 15: e1008145.

A. Fraga, A.F. Mósca, D. Moita, J.P. Simas, H. Nunes-Cabaço, M. Prudêncio (2023). SARS-CoV-2 decreases malaria severity in co-infected rodent models. Frontiers in Cellular and Infection Microbiology 13: 1307553.

F. Arez, S. Rebelo, D. Fontinha, D. Simão, T.R. Martins, M. Machado, C. Fischli, C. Oeuvray, L. Badolo, M.J.T. Carrondo, M. Rottmann, T. Spangenberg, C. Brito, B. Greco*, M. Prudêncio*, P.M. Alves* (2019). Flexible 3D cell-based platforms for the discovery and profiling of novel drugs targeting Plasmodium hepatic infection. ACS Infectious Diseases 5: 1831-1842.

D. Fontinha, F. Arez, I.R. Gal, G. Nogueira, D. Moita, T.H.H. Baeurle, C. Brito, T. Spangenberg, P.M. Alves, M. Prudêncio (2022). Pre-erythrocytic activity of M5717 in monotherapy and combination in preclinical Plasmodiuminfection models. ACS Infectious Diseases 8: 721-727.

R. Azevedo, M. Markovic, M. Machado, B. Franke-Fayard, A.M. Mendes, M. Prudêncio (2017). A bioluminescence method for in vitro screening of Plasmodium transmission-blocking compounds. Antimicrobial Agents and Chemotherapy61: 202699-16.