From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE.
Rhea N. Coler,Malcolm S. Duthie,Kimberly A. Hofmeyer,Jeffery Guderian,Lakshmi Jayashankar,Julie Vergara,Tom Rolf,Ayesha Misquith,John D. Laurance,Vanitha S. Raman,H. Remy Bailor,Natasha Dubois Cauwelaert,Steven J. Reed,Aarthy C. Vallur,Michelle Favila,Mark T. Orr,Jill A. Ashman,Prakash Ghosh,Dinesh Mondal,Steven G. Reed +19 more
TLDR
The vaccine candidate was shown to be safe and induced a strong antigen‐specific immune response, as evidenced by cytokine and immunoglobulin subclass data, which provide a strong rationale for additional trials in Leishmania‐endemic countries in populations vulnerable to VL.Abstract:
Key antigens of Leishmania species identified in the context of host responses in Leishmania-exposed individuals from disease-endemic areas were prioritized for the development of a subunit vaccine against visceral leishmaniasis (VL), the most deadly form of leishmaniasis. Two Leishmania proteins—nucleoside hydrolase and a sterol 24-c-methyltransferase, each of which are protective in animal models of VL when properly adjuvanted— were produced as a single recombinant fusion protein NS (LEISH-F3) for ease of antigen production and broad coverage of a heterogeneous major histocompatibility complex population. When formulated with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE), a Toll-like receptor 4 TH1 (T helper 1) promoting nanoemulsion adjuvant, the LEISH-F3 polyprotein induced potent protection against both L. donovani and L. infantum in mice, measured as significant reductions in liver parasite burdens. A robust immune response to each component of the vaccine with polyfunctional CD4 TH1 cell responses characterized by production of antigen-specific interferon-γ, tumor necrosis factor and interleukin-2 (IL-2), and low levels of IL-5 and IL-10 was induced in immunized mice. We also demonstrate that CD4 T cells, but not CD8 T cells, are sufficient for protection against L. donovani infection in immunized mice. Based on the sum of preclinical data, we prepared GMP materials and performed a phase 1 clinical study with LEISH-F3+GLA-SE in healthy, uninfected adults in the United States. The vaccine candidate was shown to be safe and induced a strong antigen-specific immune response, as evidenced by cytokine and immunoglobulin subclass data. These data provide a strong rationale for additional trials in Leishmania-endemic countries in populations vulnerable to VL.read more
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Journal ArticleDOI
Status of vaccine research and development of vaccines for leishmaniasis.
Portia M. Gillespie,Coreen M. Beaumier,Coreen M. Beaumier,Ulrich Strych,Ulrich Strych,Tara Hayward,Peter J. Hotez,Maria Elena Bottazzi +7 more
TL;DR: Leishmaniasis is a vector-borne neglected tropical disease caused by a protozoan parasite of the genus Leishmania and transmitted to humans by the bite of a sand fly, and both VL and CL vaccines have been shown to be cost-effective in economic modeling studies.
Journal ArticleDOI
The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: first-in-human trial.
Rhea N. Coler,Tracey A. Day,Ruth D. Ellis,Franco M. Piazza,Anna Marie Beckmann,Julie Vergara,Tom Rolf,Lenette L. Lu,Galit Alter,David A. Hokey,Lakshmi Jayashankar,Robert L. Walker,Margaret A Snowden,Thomas J. Evans,Ann M. Ginsberg,Steven G. Reed +15 more
TL;DR: A tuberculosis vaccine containing an immunity-potentiating agent stimulated strong immune responses in a first-in-human trial and demonstrated an acceptable safety profile and indicated that the GLA-SE adjuvant drives a functional humoral and T-helper 1 type cellular response.
Journal ArticleDOI
A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH
Mohamed Osman,Anoop Mistry,Ada Keding,Rhian Gabe,Elizabeth Cook,Sarah Forrester,Rebecca C. Wiggins,Stefania Di Marco,Stefano Colloca,Loredana Siani,Riccardo Cortese,Deborah F. Smith,Toni Aebischer,Paul M. Kaye,Charles J.N. Lacey +14 more
TL;DR: The first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells, and results support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL are reported.
Journal ArticleDOI
Update on Chlamydia trachomatis Vaccinology.
TL;DR: Recent findings are summarized and formulations, including antigens, adjuvants, routes, and delivery systems for immunization, primarily explored in the female mouse model, are discussed, with the goal of implementing a vaccine against C. trachomatis genital infections.
Journal ArticleDOI
A Review of Leishmaniasis: Current Knowledge and Future Directions.
Sarah Mann,Katherine Frasca,Sara Scherrer,Andrés F. Henao-Martínez,Sabrina Newman,Poornima Ramanan,José Antonio Suárez +6 more
TL;DR: In this paper, the authors summarize the current knowledge of the epidemiology, clinical manifestations, diagnosis, and treatment of cutaneous, mucosal, and visceral leishmaniasis.
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