Format

Send to

Choose Destination
PLoS Negl Trop Dis. 2017 May 12;11(5):e0005527. doi: 10.1371/journal.pntd.0005527. eCollection 2017 May.

A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH.

Author information

1
Centre for Immunology and Infection, Dept. of Biology and Hull York Medical School, University of York, Heslington, York, United Kingdom.
2
Department of Health Sciences, University of York, Heslington, York, United Kingdom.
3
ReiThera Srl (formerly Okairos Srl), Rome, Italy.
4
Keires AG, Bäumleingasse 18, Basel, Switzerland.
5
Agents of Mycoses, Parasitoses and Mycobacterioses, Robert Koch-Institute, Berlin, Germany.

Abstract

BACKGROUND:

Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.

METHODS:

We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.

FINDINGS:

ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.

CONCLUSION:

The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.

TRIAL REGISTRATION:

This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

PMID:
28498840
PMCID:
PMC5443534
DOI:
10.1371/journal.pntd.0005527
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center