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Review 1: "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 1: "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
Description

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 (Clinicaltrials.gov 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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: The present pre-print of Younis et al is considered a reliable study since the claims are generally supported by the data and the methods applied. Overall, the work is clearly and accurately presented. In particular, the authors designed the study in detailed manner taking into consideration sex and age differences as well as the relative control group. The participants, who constituted a sufficient number to derive the results, participated in the majority of the study throughout its duration, increasing the reliability of the results. Moreover, the data supported previous findings regarding safety and immunogenicity of the candidate ChAd63-KH vaccine. However, the biggest limitation was the loss of samples due to the special conditions prevailing in the study area, which could have added value to the study because of the information they would have given important information regarding the way the ChAd63-KH works as a therapeutic agent and its inability to cure PKDL. Nevertheless, the authors discuss the weaknesses and limitations of the study and suggest alternative approaches. They also discuss the results based on both their own previous studies and recent literature on the induction of immune responses against inoculation with adenovirus vaccines. As a conclusion decision-makers should consider the claims in this study actionable with limitations based on the methods and data.

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