Safety and immunogenicity of the live-attenuated hRVFV-4s vaccine against Rift Valley fever in healthy adults: a dose-escalation, placebo-controlled, first-in-human, phase 1 randomised clinical trial.
Isabel Leroux-Roels, Chittappen Kandiyil Prajeeth, Amare Aregay, Niranjana Nair, Guus F Rimmelzwaan, Albert D M E Osterhaus, Simone Kardinahl, Sabrina Pelz, Stephan Bauer, Valentino D'Onofrio, Azhar Alhatemi, Bart Jacobs, Fien De Boever, Sharon Porrez, Gwenn Waerlop, Carine Punt, Bart Hendriks, Ellemieke von Mauw, Sandra van de Water, Jose Harders-Westerveen, Barry Rockx, Lucien van Keulen, Jeroen Kortekaas, Geert Leroux-Roels, Paul J Wichgers Schreur
{"title":"Safety and immunogenicity of the live-attenuated hRVFV-4s vaccine against Rift Valley fever in healthy adults: a dose-escalation, placebo-controlled, first-in-human, phase 1 randomised clinical trial.","authors":"Isabel Leroux-Roels, Chittappen Kandiyil Prajeeth, Amare Aregay, Niranjana Nair, Guus F Rimmelzwaan, Albert D M E Osterhaus, Simone Kardinahl, Sabrina Pelz, Stephan Bauer, Valentino D'Onofrio, Azhar Alhatemi, Bart Jacobs, Fien De Boever, Sharon Porrez, Gwenn Waerlop, Carine Punt, Bart Hendriks, Ellemieke von Mauw, Sandra van de Water, Jose Harders-Westerveen, Barry Rockx, Lucien van Keulen, Jeroen Kortekaas, Geert Leroux-Roels, Paul J Wichgers Schreur","doi":"10.1016/S1473-3099(24)00375-X","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans.</p><p><strong>Methods: </strong>A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 10<sup>4</sup> (low dose), 10<sup>5</sup> (medium dose), or 10<sup>6</sup> (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00.</p><p><strong>Findings: </strong>Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months.</p><p><strong>Interpretation: </strong>The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use.</p><p><strong>Funding: </strong>The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.</p>","PeriodicalId":49923,"journal":{"name":"Lancet Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":36.4000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lancet Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/S1473-3099(24)00375-X","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/25 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans.
Methods: A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 104 (low dose), 105 (medium dose), or 106 (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00.
Findings: Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months.
Interpretation: The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use.
Funding: The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.
期刊介绍:
The Lancet Infectious Diseases was launched in August, 2001, and is a lively monthly journal of original research, review, opinion, and news covering international issues relevant to clinical infectious diseases specialists worldwide.The infectious diseases journal aims to be a world-leading publication, featuring original research that advocates change or sheds light on clinical practices related to infectious diseases. The journal prioritizes articles with the potential to impact clinical practice or influence perspectives. Content covers a wide range of topics, including anti-infective therapy and immunization, bacterial, viral, fungal, and parasitic infections, emerging infectious diseases, HIV/AIDS, malaria, tuberculosis, mycobacterial infections, infection control, infectious diseases epidemiology, neglected tropical diseases, and travel medicine. Informative reviews on any subject linked to infectious diseases and human health are also welcomed.