A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis.

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][1]). We aimed to enrol 100 participants (male and female aged 12-50 years) with uncomplicated PKDL of ≥ six months duration. ChAd63-KH (7.5x1010 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 ≥ 90% 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. ### Competing Interest Statement PMK and CJNL are co-inventors of a patent that covers the gene insert used in ChAd63-KH. No other conflicts of interest are declared. ### Clinical Trial NCT03969134 ### Funding Statement The clinical trial was funded by a Wellcome Trust Translation Award (WT108518MA; https://wellcome.ac.uk). Additional support for transcriptomics studies was provided by a Wellcome Trust Senior Investigator Award (to PMK; WT104726) and by the TRANSVAC2 program supported by the European Union Horizon 2020 Research and Innovation programme under grant agreement No. 730964 (TNA1802-02; https://www.transvac.org). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The LEISH2b study (Clinicaltrials.gov ID: [NCT03969134][1]) was approved by the Sudan National Medicines and Poisons Board, and the Ethical Review Committees of the Institute of Endemic Diseases, University of Khartoum and the Department of Biology, University of York. LEISH2b was sponsored by the University of York. The study was conducted according to the principles of the current revision of the Declaration of Helsinki 2008 and ICH guidelines for GCP (CPMP/ICH/135/95). All participants provided written informed consent before enrolment. Consent forms are available accompanying the published protocol 32. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Processed gene expression data are available as supplementary material. Raw gene expression data will be available from GEO on publication. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03969134&atom=%2Fmedrxiv%2Fearly%2F2024%2F04%2F11%2F2024.04.11.24305597.atom