VALIDATE Seminar: The Future Leishmaniasis Vaccines
This seminar explores two novel approaches to leishmaniasis vaccine development, highlighting recent advances and the path towards effective human vaccines. It will be of broad interest across the VALIDATE Network, whatever your pathogen focus, especially for members interested in live attenuated vaccine strategies and the search for biomarkers of protective immunity.
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About the Talks
A New Recombinant Vaccine Formulation for Visceral Leishmaniasis
Dr Ana Paula Fernandes, Center for Technology in Vaccines (CTVacinas), Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
As a neglected disease, visceral leishmaniasis (VL) remains a major cause of morbidity and mortality worldwide. In the absence of prophylactic vaccines, control measures rely on vector and reservoir control, efficient diagnosis, and treatment. The data to be presented report an end-to-end translational study, from antigen discovery to the definition of a vaccine formulation, named VaxLeish, for use in a phase I clinical trial as a therapeutic vaccine. Antigen selection for VaxLeish was based on epitopes derived from the previously well-characterised vaccine candidate antigen A2, together with sequences from a new antigen, Kinetoplast-Associated Protein-like from Leishmania infantum (LinKAP), identified through a reverse vaccinology approach. Similarly to A2, LinKAP contains multiple tandemly repeated amino acid units with highly conserved predicted epitopes across various Leishmania species. CRISPR-Cas9 knockout of the LinKAP gene did not impair parasite growth, differentiation, or infectivity in macrophages, suggesting that LinKAP is not essential for these functions in vitro. Its precise function therefore remains unknown.
A recombinant truncated version of LinKAP induced partial protection when used to immunise mice and hamsters and generated a robust Th1-type immune response. Based on these attributes, we fused the mapped epitopes from A2 and LinKAP into a chimeric antigen, rKAPA2, which was produced under good laboratory practice conditions. So far, VaxLeish (rKAPA2 + Poly ICLC) has been extensively tested in animal models as a prophylactic vaccine, providing evidence that it is highly immunogenic, induces partial protection, and is safe. Several quality attributes of VaxLeish were also defined in line with regulatory requirements.
With future clinical translation in mind, the VaxLeish formulation was also evaluated as a treatment in L. infantum-infected mice and hamsters. Treated animals displayed a shift in T cell responses towards a Th1 profile, evidenced by increased frequencies of IFN-γ+ T cells and reduced IL-10-producing T cells, suggesting a partial reversal of the immunosuppressed T cell responses induced by infection. This profile correlated with a marked reduction in parasite burden in treated animals, supporting the use of VaxLeish not only as a prophylactic vaccine, but also as a therapeutic vaccination strategy for VL.
Based on these findings, we propose that VaxLeish should advance towards clinical trials.
Recent Advances in Leishmania Vaccination Development and Identification of Biomarkers of Protective Immunity
Dr Hira L. Nakhasi, PhD, FASTMH, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
Leishmaniasis is a neglected tropical disease caused by infection with the Leishmania parasite following transmission by an infected sand fly. It results in a range of clinical presentations, from cutaneous leishmaniasis (CL), which can lead to physical disfigurement, to visceral leishmaniasis (VL; kala-azar), which is fatal if left untreated. Millions of people worldwide are at risk of developing leishmaniasis, with an estimated incidence of over 200,000 cases of CL and over 50,000 cases of VL each year. Although progress has been made in reducing the burden of VL in South Asia through elimination programmes, recent outbreaks have been reported in other countries in Africa and South America, as well as in non-endemic areas.
To achieve the global elimination of leishmaniasis, new tools are required, including better surveillance and a safe and effective vaccine. In most cases, asymptomatic infection or successful treatment of VL confers life-long immunity. Moreover, the stability of the Leishmania parasite genome indicates that the development of an effective vaccine may be possible using a live attenuated vaccine strategy. Our laboratory has developed a genetically modified live attenuated dermotropic Leishmania vaccine — the Leishmania major centrin gene-deleted parasite (LmCen-/-) — which has shown safety and efficacy against both cutaneous and visceral forms of leishmaniasis in preclinical studies.
I will discuss progress in advancing the LmCen-/- live attenuated vaccine towards human trials, efforts to identify biomarkers of immunity, and the use of the leishmanin skin test (LST) as a surrogate biomarker of protective cellular immunity.
About the Speakers
Ana Paula Fernandes holds a B.Sc. in Biological Sciences (1986), an M.Sc. in Microbiology (1990) and a Ph.D. in Parasitology from the Federal University of Minas Gerais (UFMG, 1997). She was a research fellow at Harvard Medical School (USA), during master and Ph.D training. She is currently a Researcher Level IA at the National Council for Scientific and Technological Development (CNPq) and a Full Professor at UFMG, where she supervises pos-graduations students in programs in Genetics, Biochemistry and Immunology and Pharmaceutical Sciences.
Her research lines encompass molecular biology, clinical diagnostics, parasitology and immunology, with emphasis on the diagnosis and treatment of infectious and genetic diseases, and vaccine development for infectious agents. She is one of founders of UFMG’s Vaccine Technology Center (now the National Vaccine Center) and has coordinated translational projects leading to licensed products, including the Leish-Tec vaccine for canine visceral leishmaniasis (registered with MAPA) and a rapid test for hepatitis delta (registered with ANVISA). So far, she published more than 180 articles and supervised over 60 master and Ph.D students and post-docs.
Her scientific and innovation contributions have been recognized by multiple honors, including the Peter Muranyi Health Prize (2014, 2023), the “Good Example in Science” award (FAPEMIG/FIEMG/IEL/Rede Globo), the U.S. Embassy “Outstanding Woman” recognition for contributions during the COVID 19 pandemic, the 2022 Inconfidência Medal of Honor, and the 2022 CONFAP Innovative Researcher award. She was also a finalist for the EURO Prize for Innovation in the Public Sector (2023).
Dr Hira L Nakhasi is currently the Director of the Division of Emerging and Transfusion Transmitted Diseases (DETTD) at the Center for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration. As the Director of the DETTD, he is responsible for approving assays to screen blood donors for blood borne pathogens and retroviral diagnostic to ensure USA blood safety. He received his master’s and Ph.D. degrees in biochemistry from the M.S. University of Baroda, India and postdoctoral training at the National Institutes of Health, Bethesda, Maryland and Columbia University, New York, USA. His scientific expertise lies in molecular virology, parasitology, cell biology, immunology and vaccinology. His main research is focused on Leishmania pathogenesis and develop methods to evaluate safety and efficacy genetically modified Leishmania vaccines and diagnostic tools. He has published over 170 publications including reviews and book chapters, being a member of the review committees of several high impact journals, reviewer of grants, and being invited to speak at national and international forums. He is also a member of the several scientific organizations. Over the years he has received numerous awards including US Department of Human and Health Services Distinguished Service Award. He is elected Fellow of American Society of Tropical Medicine and Hygiene. He also has been recipient of several grants from International agencies such as Global Health Initiative and Technologies, Japan; Wellcome Trust UK and National Institutes of Health, USA worth over 10 million dollars for his studies on Leishmania vaccine development.
