A randomized, double-blind phase 2b trial to evaluate efficacy of ChAd63-KH for treatment of post kala-azar dermal leishmaniasis

Abstract

In a recent phase 2a clinical trial, the candidate leishmaniasis vaccine ChAd63-KH was shown to be safe and immunogenic in Sudanese patients with post kala-azar dermal leishmaniasis (PKDL). However, its value as a stand-alone therapeutic was unknown. To assess the therapeutic efficacy of ChAd63-KH, we conducted a randomized, double-blind, placebo-controlled phase 2b trial (ClinicalTrials.gov: NCT03969134). Primary outcomes were safety and efficacy (≥90% improvement in clinical disease). Secondary outcomes were change in severity grade and vaccine-induced immune response. 86 participants with uncomplicated PKDL of ≥6 month duration were randomized to receive ChAd63-KH (7.5 × 10¹⁰ viral particles, once by the intramuscular route) or placebo. 75 participants (87%) completed the trial as per protocol. No severe or serious adverse events were observed. At day 90 post-vaccination, 6/40 (15%) and 4/35 (11%) participants in the vaccine and placebo groups, respectively, showed ≥90% clinical improvement (risk ratio [RR] 1.31 [95% confidence interval (CI), 0.40-4.28], p = 0.742). There were also no significant differences in PKDL severity grade between study arms. Whole-blood transcriptomic analysis identified transcriptional modules associated with interferon responses and monocyte and dendritic cell activation. Thus, a single vaccination with ChAd63-KH showed no therapeutic efficacy in this subset of Sudanese patients with PKDL.

Keywords: Leishmania; adenovirus; clinical trial; post kala-azar dermal leishmaniasis; therapeutic; vaccine.

Graphical abstract

Figure 1

Study CONSORT diagram Solid boxes indicate participants to primary outcome at day 90 post-vaccination (Vx). Treatment was offered per protocol from day 90 (see main text). Dotted boxes were outside the trial window for primary outcome and represent scheduled follow-up to provide or monitor standard of care. LTFU, lost to follow up

Figure 2

Adverse events associated with the LEISH2b trial Data are shown for local and systemic adverse events judged to be possibly, probably, likely, or definitely associated with Vx. Data are shown as proportions of participants in the study (n = 86). Only grade 1 AEs (mild, yellow; 26 vs. 17 events overall in vaccine vs. placebo groups) and grade 2 AEs (moderate; orange; 17 vs. 10 events overall in vaccine vs. placebo groups) were observed. See Tables S2–S5 for full details.

Figure 3

Clinical improvement in LEISH2b participants (A) Clinical improvement by study arm (n = 40 and n = 35 for vaccine and placebo groups, respectively). Participants were categorized based on degree of improvement at different times post-Vx. Color key indicates improvement category. No significant differences were detected at any time point or over time (Fisher’s exact test; see main text). (B) Distribution of overall PKDL grades by study arm (n = 40 and n = 35 for vaccine and placebo groups, respectively). Participants were scored for PKDL grade at Vx (day 0) and at indicated days post-Vx. Color key indicates grades. No significant differences were detected at any time point or over time (Fisher’s exact test; see main text).

Figure 4

WBTA of vaccine response WBTA was conducted on blood drawn prior to and 1 day post-Vx. Data are shown for 50 vaccinated participants (19 F, 31 M; 9 adult, 41 adolescent). (A) g:Profiler analysis of 311 upregulated genes. Representative enriched pathways are numbered: (1) GO0003725, double-stranded RNA binding; (2) GO0001730, 2′-5′-oligoadenylate synthetase activity; (3) GO0042379, chemokine receptor binding; (4) GO0019221, cytokine-mediated signaling pathway; (5) GO0034097, response to cytokine; (6) GO0045089, positive regulation of innate immune response; (7) GO0051607, defense response to virus; (8) GO0034341, response to type II interferon; (9) GO0071357, cellular response to type I interferon; (10) REAC:R-HAS-1, cytokine signaling in immune system; (11) TF:M00772, IRF motif; and (12) TF:M10080, STAT2 motif. Full details are provided in Table S6. (B) Significantly enriched immune-related modules were identified applying the CERNO test on the adjusted p value-ranked lists of genes generated by DeSeq2 (see Table S6 for module gene lists). Bars represent the proportions of significantly upregulated (red), downregulated (blue), or unchanged (gray) genes. The significance of module activation is proportional to the intensity of the bar, while the effect size is proportional to its width. Only the top 35 modules (of 57; see Table S6) are shown for clarity. No DEGs, and hence no modules, were identified in patients receiving placebo.