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00925njm 22002777a 4500 dc Corominas Garcia, Júlia author Garriga, Carme author Prenafeta i Amargós, Antoni author Moros, Alexandra author Cañete, Manuel author Barreiro, Antonio author González-González, Luis author Madrenas, Laia author Güell, Irina author Clotet, Bonaventura author Izquierdo-Useros, Nuria author Raïch-Regué, Dàlia author Gallemí, Marçal author Blanco, Julià author Pradenas, Edwards author Trinitè, Benjamin author Prado, Julia G. author Blanch-Lombarte, Oscar author Pérez-Caballero, Raúl author Plana, Montserrat author Esteban, Ignasi author Pastor-Quiñones, Carmen author Núñez-Costa, Xavier author Abu Taleb, Rachel author McSkimming, Paula author Soriano, Alex author Nava, Jocelyn author Anagua, Jesse Omar author Ramos Blanes, Rafel author Martí Lluch, Ruth author Corpes Comes, Aida author Otero Romero, Susana author Martínez Gómez, Xavier author Sans-Pola, Carla author Moltó, José author Benet, Susana author Bailón, Lucía author Arribas, Jose R. author Borobia, Alberto M. author Queiruga Parada, Javier author Navarro-Pérez, Jorge author Forner Giner, Maria José author Ortí Lucas, Rafael author Vázquez Jiménez, María del Mar author Oña Compán, Salvador author Alvarez-Mon, Melchor author Troncoso, Daniel author Arana-Arri, Eunate author Meijide, Susana author Imaz-Ayo, Natale author Muñoz García, Patricia author Villa Martínez, Sofía de la author Rodríguez Fernández, Sara author Prat, Teresa author Torroella, Èlia author Ferrer Soler, Laura author 2023-05 A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated 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. Methods The 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 with ClinicalTrials.gov , NCT05142553 . Findings From 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 < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4+ 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. Interpretation Our 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 http://hdl.handle.net/10256/25470 Medicaments -- Desenvolupament Drug development Medicaments -- Assaigs clínics Drugs -- Testing COVID-19 (Malaltia) COVID-19 (Disease) Vacunes Vaccines Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial