Genetically modified live attenuated vaccine against fatal visceral leishmaniasis

No vaccine is currently available for leishmaniasis. An effective vaccine against leishmaniasis will aid in disease elimation

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A neglected disease. Leishmaniasis is a neglected tropical disease caused by different species of the protozoan parasite Leishmania and transmitted by infected sand flies1. Leishmaniasis is a major public health issue affecting more than 12 million people worldwide, with an estimated one billion people at risk2,3. Depending on the clinical manifestation, this disease can remain localized or develop into a systemic infection that can cause long lasting disabilities, and even death1. Leishmaniasis is the second most lethal parasitic disease due to considerable obstacles to universal treatment in many endemic countries, and to the lack of an approved prophylactic vaccine2,4. The development and implementation of an effective vaccination plan is therefore necessary to prevent morbidity and mortality, and to reduce the economic and health care burden of leishmaniasis worldwide.

A new strategy to solve an old problem. Vaccination through leishmanization, injecting low dose of virulent Leishmania (L.) major parasites, in non-exposed areas of the body has been used successfully in endemic areas for protection against re-infection; however this practice has been deemed unfeasible due to safety and standardization issues5. Non-pathogenic live attenuated parasites with a targeted gene deletion can act as a second generation leishmanization to induce protective immunity without causing disease pathology. Funded by the Global Health Innovative Technology (GHIT) Fund, our group used the CRISPR/Cas9 technology to create a genome edited attenuated L. major strain (LmCen-/-) with no antibiotic resistant marker and no detectable off-target mutations4. LmCen-/- parasites cannot divide intracellularly inside of the host cell and do not cause clinical symptoms6.

Does the vaccine work? In our recent paper published in Nature Communications, we have shown that immunization with LmCen-/- does not cause any clinical symptoms in immunocompetent and immunocompromised mice, and it induces a robust and long-lasting protection against challenge with sand flies infected with the cutaneous leishmaniasis species L. major4. Furthermore, our latest paper in Communications Biology showed that vaccination with LmCen-/- parasites promoted protection against sand fly challenge with L. donovani, a species that causes fatal visceral leishmaniasis7. This protection was mediated by a pro-inflammatory immune response, and lead to absence of liver and spleen pathology, compared to non-vaccinated mice7.

From bench to bedside. Our group further developed a Good Laboratory Practices (GLP)-grade LmCen-/- with equal protection as laboratory-grade LmCen-/-7. GLP-LmCen-/- production can be scaled and transferred to Good Manufacturing Practices (cGMP) production for future human clinical trials. We are currently working to advance this candidate vaccine to clinical trials and we have partnered with Gennova Biopharmaceuticals Ltd to manufacture GMP material. With the collaboration of our colleagues at the National Institutes of Health (NIH), we are also developing a Challenge Human Infection Model (CHIM) as part of a Phase 1B or Phase 2 study that can subsequently simplify and reduce the numbers of participants needed for a Phase III clinical trial, which can become prohibitively expensive and take a very long time.

The take home message. Despite its substantial impact on the economy and public health of endemic areas, leishmaniasis is often ignored by the global community as it is the disease of the poor8. A vaccination plan is necessary to control the disease; however, the only effective strategy to date, Leishmanization, has been discontinued due to safety concerns. LmCen-/- provides a safer alternative to Leishmanization, with equivalent long-lasting protection against sand fly challenge in pre-clinical models. LmCen-/- parasites are promising vaccine candidates with broad spectrum efficacy against cutaneous and fatal visceral leishmaniasis, and could become the first approved vaccine for human use.

REFERENCES

  1. McGwire BS, Satoskar AR. Leishmaniasis: clinical syndromes and treatment. QJM. 2014;107(1):7-14.
  2. World Health Organization W. Investing to Overcome the Global Impact of Neglected Tropical Diseases. 2015; https://apps.who.int/iris/bitstream/handle/10665/152781/9789241564861_eng.pdf.
  3. Matlashewski G, Arana B, Kroeger A, et al. Research priorities for elimination of visceral leishmaniasis. Lancet Glob Health. 2014;2(12):e683-684.
  4. Zhang WW, Karmakar S, Gannavaram S, et al. A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing. Nat Commun. 2020;11(1):3461.
  5. Khamesipour A, Dowlati Y, Asilian A, et al. Leishmanization: use of an old method for evaluation of candidate vaccines against leishmaniasis. Vaccine. 2005;23(28):3642-3648.
  6. Selvapandiyan A, Debrabant A, Duncan R, et al. Centrin gene disruption impairs stage-specific basal body duplication and cell cycle progression in Leishmania. J Biol Chem. 2004;279(24):25703-25710.
  7. Karmakar S, Ismail N, Oliveira F, et al. Preclinical validation of a live attenuated dermotropic Leishmania vaccine against vector transmitted fatal visceral leishmaniasis. Comm Biol (In press) 2021.
  8. Kealey A, Smith R. Neglected tropical diseases: infection, modeling, and control. J Health Care Poor Underserved. 2010;21(1):53-69.

Abhay Satoskar

Professor, Ohio State University