Júlia Corominas, Carme Garriga, Antoni Prenafeta, Alexandra Moros, Manuel Cañete, Antonio Barreiro, Luis González-González, Laia Madrenas, Irina Güell, Bonaventura Clotet, Nuria Izquierdo-Useros, Dàlia Raïch-Regué, Marçal Gallemí, Julià Blanco, Edwards Pradenas, Benjamin Trinité, Julia G. Prado, Oscar Blanch-Lombarte, Raúl Pérez-Caballero, Montserrat Plana, Ignasi Esteban, Carmen Pastor-Quiñones, Xavier Núñez-Costa, Rachel Abu Taleb, Paula McSkimming, Alex Soriano, Jocelyn Nava, Jesse Omar Anagua, Rafel Ramos, Ruth Martí Lluch, Aida Corpes Comes, Susana Otero Romero, Xavier Martinez Gomez, Carla Sans-Pola, José Moltó, Susana Benet, Lucía Bailón, Jose R. Arribas, Alberto M. Borobia, Javier Queiruga Parada, Jorge Navarro-Pérez, Maria José Forner Giner, Rafael Ortí Lucas, María del Mar Vázquez Jiménez, Salvador Oña Compán, Melchor Alvarez-Mon, Daniel Troncoso, Eunate Arana-Arri, Susana Meijide, Natale Imaz-Ayo, Patricia Muñoz García, Sofía de la Villa Martínez, Sara Rodríguez Fernández, Teresa Prat, Èlia Torroella, Laura Ferrer, Institut Català de la Salut, [Corominas J, Garriga C, Prenafeta A, Moros A, Cañete M, Barreiro A] HIPRA, Amer, Girona, Spain. [Otero Romero S] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Unitat Docent, Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosis Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Martinez Gomez X] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Unitat Docent, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Sans-Pola C] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Spain. Grup de Recerca de Farmacologia Clínica, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
SummaryBackgroundA SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and welltolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration.MethodsThe HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine —either heterologous (PHH-1V group) or homologous (BNT162b2 group)— in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered withClinicalTrials.gov,NCT05142553.FindingsFrom 15 November 2021, 782 adults were randomly assigned to PHH-1V (n=522) or BNT162b2 (n=260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1·68 (p+and CD8+T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89·3%) in the PHH-1V and 238 (94·4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79·7% and 89·3%), fatigue (27·5% and 42·1%) and headache (31·2 and 40·1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10·14%) for the PHH-1V group and 30 (11·90%) for the BNT162b2 group (p=0·45), and none of the subjects developed severe COVID-19.InterpretationOur interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe.FundingHIPRA SCIENTIFIC, S.L.U.