Safety and Immunogenicity of a Recombinant Protein RBD Fusion Heterodimer Vaccine against SARS-CoV-2: preliminary results of a phase 1-2a dose-escalating, randomized, double-blind clinical trial
Authors: Leal Lorna , Pich Judit , Ferrer Laura , Nava Jocelyn , Martí-Lluch Ruth , Esteban Ignasi , Pradenas Edwards , Raïch-Regué Dàlia , Prenafeta Antoni , Escobar Karla , Pastor Carmen , Ribas-Aulinas Marc , Trinitè Benjamin , Muñoz-Basagoiti Jordana , Domenech Gemma , Clotet Bonaventura , Corominas Júlia , Corpes-Comes Aida , Garriga Carme , Barreiro Antonio , Izquierdo-Useros Nuria , Arnaiz Joan Albert , Soriano Alex , Ríos José , Nadal Marga , Plana Montserrat , Blanco Julià , Prat Teresa , Torroella Elia , Ramos Rafel ,   the HIPRA-HH-1 study group
Published: August 2022

SummaryBackgroundWe report safety, tolerability, and immunogenicity of a recombinant protein RBD-fusion heterodimeric vaccine against SARS-CoV-2 (PHH-1V).MethodsA dose-escalation, phase 1-2a, randomized clinical trial was performed in Catalonia, Spain. Each cohort had one safety sentinel that received PHH-1V vaccine of the corresponding dose, and remaining participants were randomly assigned to receive PHH-1V formulations [10µg (n=5), 20µg (n=10), 40µg (n=10)] or control BNT162b2 (n=5). Two intramuscular doses (0-21 days) were administered. Primary endpoint was solicited events 7 days after each vaccination and secondary-exploratory endpoints were humoral and cellular immunogenicity.Findings30 young healthy adults were enrolled, thirteen were female. Vaccines were safe, well tolerated. The most common solicited events for all groups were tenderness and pain at the site of injection. The proportion of subjects with at least one reported local and/or systemic solicited adverse events (AE) after first or second vaccine dose were lowest in PHH-1V (n=21, 84%) than control group (n=5, 100%). AE were mild to moderate, and no severe AE nor AE of special interest were reported. All participants had a >4-fold change at day 35 in total binding antibodies from baseline. Variants of concern (VOC) alpha, beta, delta and gamma were evaluated using a SARS-CoV-2 pseudovirus-based neutralization assay. All groups had a significant geometric mean fold rise (p<.0001) at day 35 against all studied VOC. Similar results were obtained when a full replicative virus neutralization assay was carried out.InterpretationPHH-1V was safe, well tolerated, and induced robust humoral responses. These data support further exploration of PHH-1V in larger studies.FundingHIPRAClinicalTrials.gov IdentifierNCT05007509Research in contextEvidence before this studyWe searched PubMed up until August 1, 2021, with the terms “SARS-CoV-2”, “COVID-19” and “vaccine”. We initially identified 12,952 results but when added the terms “clinical trial” and “variants” this number decreased to 50. Of these references twelve were clinical trials, and although several vaccines were under development, and the ones that were already approved for administration in the general population described the neutralization effect to the different circulating variants of concern, we could not find any reference to a vaccine developed using variants of concern instead of ancestral Wuhan strain.Added value of this studyTo the best of our knowledge, our study is the first clinical trial to assess the effect as a primary series of a recombinant protein receptor-binding domain fusion heterodimer PHH-1V vaccine against SARS-CoV-2 not including the ancestral strain in its composition. This vaccine contains RBD from B·1·351 (beta) and B·1·1·7 (alpha) variants and is co-formulated with an oil-in-water adjuvant emulsion. In this first-in-human randomized clinical trial, two doses of the SARS-CoV-2 PHH-1V vaccine in a range of 10 to 40 µg/dose were safe and well-tolerated and induced robust humoral immune responses to different circulating variants of concern, including alpha (B1·1·7), beta (B·1·351), delta (B·1·617·2) and gamma (P·1). Additionally, the PHH-1V 40µg dose vaccine elicited moderated cellular immune responses, particularly to variants of concern alpha and delta.Implications of all the available evidenceThese findings indicate that the recombinant protein receptor-binding domain fusion heterodimer vaccine PHH-1V is safe and immunogenic. Phase 2b and Phase 3 clinical trials are ongoing to further investigate its safety and protective efficacy as heterologous booster.