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Review 2: "A Randomized Double-blind Phase IIb Trial to Evaluate the Efficacy of ChAd63-KH for the Treatment of Post Kala-azar Dermal Leishmaniasis"

Overall, reviewers state that regardless of the negative results the study is well-performed and informative.

Published onMay 21, 2024
Review 2: "A Randomized Double-blind Phase IIb Trial to Evaluate the Efficacy of ChAd63-KH for the Treatment of Post Kala-azar Dermal Leishmaniasis"
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key-enterThis Pub is a Review of
A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis
A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis

Summary Background In a recent Phase IIa 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.Methods To assess the therapeutic efficacy of ChAd63-KH, we conducted a “window of opportunity” randomized, double-blind, placebo-controlled trial ( registration: NCT03969134). We aimed to enrol 100 participants (male and female aged 12-50 years) with uncomplicated PKDL of ≥ six months duration. ChAd63-KH (7.5×1010 viral particles) or saline placebo was administered once intramuscularly. Primary outcomes were safety and efficacy. Safety was determined by adverse event monitoring. Efficacy was the proportion of participants at 90 days post-vaccination with ζ90% improvement in clinical disease. Participants failing to reach this clinical endpoint were offered a standard of care (AmBisome®). Secondary outcomes included changes in PKDL severity grade and measurements of vaccine-induced immune response.Findings Between 4th April 2020 and 17th June 2022, 86 participants (66 adolescents, 20 adults; 47% female, 53% male) were enrolled and randomised to receive ChAd63-KH 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 (RR 1.31 [95% CI, 0.40 to 4.28], p=0.742). There were also no significant differences in PKDL grade between study arms. Whole blood transcriptomic analysis identified transcriptional modules associated with interferon responses and monocyte and dendritic cell activation, confirming vaccine reactogenicity.Interpretation Single dose administration of ChAd63-KH vaccine had no therapeutic efficacy in this subset of Sudanese PKDL patients. Further studies are needed to evaluate whether this vaccine would have therapeutic benefit using alternate dosing regimens or in combination with standard chemotherapy or immune modulation, and whether it has efficacy as a prophylactic vaccine for cutaneous or visceral leishmaniasis.Funding This study was funded by the Wellcome Trust.Research in context Evidence before this study A leishmaniasis vaccine candidate was developed employing chimpanzee adenovirus 63 (ChAd63) to deliver genes encoding two Leishmania antigens, KMP-11 and HASPB1. This vaccine (ChAd63-KH) was previously evaluated for safety and immunogenicity in a Phase I healthy volunteer study and a Phase IIa study in Sudanese patients with post kala-azar dermal leishmaniasis (PKDL). It was shown to be safe and immunogenic, warranting further clinical studies to evaluate efficacy as a stand-alone therapeutic in PKDL patients.Added value of this study This clinical trial was designed to evaluate the safety and efficacy of ChAd63-KH in PKDL patients with persistent disease (dermal lesions for ≥ 6 months). If successful, single dose vaccination would significantly improve treatment options currently available to patients. The safety of ChAd63-KH was confirmed, with no severe or serious adverse events observed in trial participants. Approximately 13% of participants had ζ90% improvement in their PKDL over the course of 90 days follow up post vaccination, but this did not differ between vaccine and placebo arms, indicating that this reflected spontaneous cure rather than vaccine efficacy. Immune monitoring using whole blood transcriptomics confirmed the previously reported ability of this vaccine to induce immune responses in humans.Implications of all the available evidence This study indicates that as a stand-alone treatment, single dose vaccination with ChAd63-KH was unable to overcome the immune dysfunction that maintains persistent PKDL. A similar “high bar” has also been encountered in therapeutic vaccine trials for other persistent diseases. Given previous success with other forms of immunochemotherapy in PKDL, future therapeutic vaccine studies in PKDL might also benefit from combining ChAd63-KH vaccination with additional chemotherapy or immune modulation. The prophylactic efficacy of this vaccine against different types of leishmaniasis also remains to be evaluated.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.


Review: The authors report on the results of an important Phase IIb trial in which they evaluated adult and adolescent patients with post-kala azar dermal leishmaniasis of at least 6 months' duration after double-blind administration of a single dose of the ChAd62-KH vaccine. Given the significant challenges with current management, an effective vaccine for this indication would be a significant advancement in control of the disease as well as transmission of the parasite given that patients with this condition are infectious to biting sand flies. Unfortunately, the results of this clinical trial were negative, in that the primary objective was not met. Given the unbelievable challenges of conducting this study amid a global pandemic, a coup, and a civil war, these results are doubly disappointing.

Overall, the paper is extremely well written, clear, and comprehensive. Despite the negative findings, it is important to report the results, nevertheless. I have only a few minor comments, as outlined below:

  1. According to the stated sample size calculations, the study would have been sufficiently powered if 100 participants had been enrolled. Not surprisingly due to the turmoil in Sudan, this was not achievable; however, the underenrollment was not mentioned in the Discussion as a potential reason for why lack of efficacy wasn't seen. I completely understand, given the totality of the evidence, that it would have been unlikely that efficacy would have been seen if the full sample size had been enrolled; however, this could be discussed. Furthermore, in the description of the sample size calculation, a spontaneous cure rate of <2% was assumed whereas it appears that in fact, in the placebo arm, this was >10%. This wasn't commented upon as another potential explanation for the lack of efficacy (it also wasn't discussed why it was so much higher than assumed, and why the spontaneous cure rate for sample size calculation was estimated to be that low).

  2. Introduction, Lin 112: suggest "or paromomycin" instead of "and".

  3. Several instances of abbreviations not being defined are found throughout the manuscript (e.g., "IMP", "UVB", etc.).

  4. Methods: the composition of the placebo is not described.

  5. Results, Lines 307-308: repetition of Lines 298-299.

  6. Results, Line 306: spell out "mths".

  7. Results, Line 320: what do the p values refer to? Please clarify (e.g., local and systemic AEs?).

  8. Results, Lines 324-327: was the "itching" considered to be a hypersensitivity reaction to dying parasites? It might be interesting to postulate upon this either here or in the discussion.

  9. Discussion, Line 383: I'd recommend deleting "DNA" from this sentence since viral vectored vaccines aren't usually referred to as DNA vaccines.

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