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

Background We report safety, tolerability, and immunogenicity of a recombinant protein RBD-fusion heterodimeric vaccine against SARS-CoV-2 (PHH-1V). Methods A 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. Findings 30 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. Interpretation PHH-1V was safe, well tolerated, and induced robust humoral responses. These data support further exploration of PHH-1V in larger studies. Funding HIPRA [ClinicalTrials.gov][1] Identifier NCT05007509 Evidence before this study We 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 study To 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 evidence These 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. ### Competing Interest Statement LL has received consulting fees from HIPRA, not related to this work and has received institutional grants from HIPRA, AstraZeneca B.V. and Janssen Pharmaceuticals Companies of Johnson & Johnson. AS has received grants from Pfizer and Gilead Sciences and honoraria for lectures for Pfizer, MSD, Gilead Sciences, Shionogi, Angelini, Roche and Menarini. JR has received educational/training fees from AstraZeneca, Boehringer Ingelheim, Janssen-Cilag, MSD Espana S.A., Novartis, LETI Pharma and Lilly. JB has received institutional grants from HIPRA, Grifols, Nesapor Europe and MSD; outside of this work is CEO and founder of AlbaJuna Therapeutics, S.L. NIU has received institutional grants from HIPRA, Grifols, Dentaid, Pharma Mar, Palobiofarma, and Amassence. LF, AP, CG, AB, JC, TP and ET are employed by the Sponsor, HIPRA and some may have stocks. All other authors declare no conflicts of interest. ### Clinical Trial NCT05007509 ### Funding Statement Funding: HIPRA, Avenida de la Selva, Girona, Spain ### 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 HIPRA-HH-1 study was approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) and the Research Ethics Committee (REC) of the Hospital Clinic de Barcelona and was overseen by an independent data safety monitoring board (DSMB). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data collected for the study is available under request to the Sponsor. [1]: http://ClinicalTrials.gov