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.

Autor:	Corominas J; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Garriga C; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Prenafeta A; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Moros A; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Cañete M; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Barreiro A; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., González-González L; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Madrenas L; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Güell I; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Clotet B; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain.; Infectious Diseases and Immunity, Faculty of Medicine, Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Carrer de la Sagrada Família, 7, 08500, Vic, Spain., Izquierdo-Useros N; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain., Raïch-Regué D; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain., Gallemí M; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain., Blanco J; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain.; Infectious Diseases and Immunity, Faculty of Medicine, Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Carrer de la Sagrada Família, 7, 08500, Vic, Spain.; Germans Trias i Pujol Research Institute (IGTP), Carretera de Canyet, s/n, Badalona, Spain., Pradenas E; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain., Trinité B; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain., Prado JG; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain.; Germans Trias i Pujol Research Institute (IGTP), Carretera de Canyet, s/n, Badalona, Spain., Blanch-Lombarte O; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain., Pérez-Caballero R; IrsiCaixa AIDS Research Institute, Carretera de Canyet, s/n, Can Ruti Campus, 08916, Badalona, Spain., Plana M; AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ del Rosselló, 149, 08036, Barcelona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain., Esteban I; AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ del Rosselló, 149, 08036, Barcelona, Spain., Pastor-Quiñones C; AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ del Rosselló, 149, 08036, Barcelona, Spain., Núñez-Costa X; Veristat, LLC, Barcelona, Spain.; Veristat, LLC, Toronto, Canada.; Veristat, LLC, Pickmere, UK., Taleb RA; Veristat, LLC, Barcelona, Spain.; Veristat, LLC, Toronto, Canada.; Veristat, LLC, Pickmere, UK., McSkimming P; Veristat, LLC, Barcelona, Spain.; Veristat, LLC, Toronto, Canada.; Veristat, LLC, Pickmere, UK., Soriano A; Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C. de Villarroel, 170, 08036, Barcelona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain., Nava J; Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C. de Villarroel, 170, 08036, Barcelona, Spain., Anagua JO; Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C. de Villarroel, 170, 08036, Barcelona, Spain., Ramos R; Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Biomedical Research Institute, Girona (IdIBGi), Catalan Institute of Health, Carrer del Dr. Castany, s/n, 17190, Salt, Girona, Spain.; Department of Medical Sciences, School of Medicine, University of Girona, Plaça de Sant Domènec, 3, 17004, Girona, Spain., Lluch RM; Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Biomedical Research Institute, Girona (IdIBGi), Catalan Institute of Health, Carrer del Dr. Castany, s/n, 17190, Salt, Girona, Spain.; Department of Medical Sciences, School of Medicine, University of Girona, Plaça de Sant Domènec, 3, 17004, Girona, Spain., Comes AC; Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Biomedical Research Institute, Girona (IdIBGi), Catalan Institute of Health, Carrer del Dr. Castany, s/n, 17190, Salt, Girona, Spain., Romero SO; Hospital Universitari Vall d'Hebron, Pg. de la Vall d'Hebron, 119, 08035, Barcelona, Spain.; Unitat Docent Vall d'Hebron, Universitat Autònoma de Barcelona, Plaça Cívica, 08193, Bellaterra, Barcelona, Spain.; Department of Neurology/Neuroimmunology, Centro de Esclerosis Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Pg. de la Vall d'Hebron, 119, 08035, Barcelona, Spain., Gomez XM; Hospital Universitari Vall d'Hebron, Pg. de la Vall d'Hebron, 119, 08035, Barcelona, Spain.; Unitat Docent Vall d'Hebron, Universitat Autònoma de Barcelona, Plaça Cívica, 08193, Bellaterra, Barcelona, Spain., Sans-Pola C; Hospital Universitari Vall d'Hebron, Pg. de la Vall d'Hebron, 119, 08035, Barcelona, Spain.; Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Plaça Cívica, 08193, Bellaterra, Barcelona, Spain.; Clinical Pharmacology Research Group, Vall d'Hebron Institut de Recerca, Pg. de la Vall d'Hebron, 119, 08035, Barcelona, Spain., Moltó J; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain., Benet S; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, Spain., Bailón L; Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, Spain., Arribas JR; Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, IdiPAZ, C. de Pedro Rico, 6, 28029, Madrid, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain., Borobia AM; Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, IdiPAZ, C. de Pedro Rico, 6, 28029, Madrid, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029, Madrid, Spain.; Spanish Clinical Research Network - SCReN, Spain., Parada JQ; Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, IdiPAZ, C. de Pedro Rico, 6, 28029, Madrid, Spain.; Spanish Clinical Research Network - SCReN, Spain., Navarro-Pérez J; Hospital Clínico Universitario Valencia, Av. de Blasco Ibáñez, 17, 46010, València, Spain., Forner Giner MJ; Hospital Clínico Universitario Valencia, Av. de Blasco Ibáñez, 17, 46010, València, Spain., Lucas RO; Hospital Clínico Universitario Valencia, Av. de Blasco Ibáñez, 17, 46010, València, Spain., Jiménez MDMV; Hospital Regional Universitario de Málaga, Av. de Carlos Haya, 84, 29010, Málaga, Spain., Compán SO; Hospital Regional Universitario de Málaga, Av. de Carlos Haya, 84, 29010, Málaga, Spain., Alvarez-Mon M; Hospital Universitario Príncipe de Asturias, Av. Principal de la Universidad, s/n, 28805, Alcalá de Henares, Madrid, Spain., Troncoso D; Hospital Universitario Príncipe de Asturias, Av. Principal de la Universidad, s/n, 28805, Alcalá de Henares, Madrid, Spain., Arana-Arri E; Scientific Coordination, Biocruces Bizkaia HRI, Osakidetza, Cruces Plaza, 48903, Barakaldo, Bizkaia, Spain., Meijide S; Scientific Coordination, Biocruces Bizkaia HRI, Osakidetza, Cruces Plaza, 48903, Barakaldo, Bizkaia, Spain., Imaz-Ayo N; Scientific Coordination, Biocruces Bizkaia HRI, Osakidetza, Cruces Plaza, 48903, Barakaldo, Bizkaia, Spain., García PM; Instituto de Investigación Sanitaria Hospital Gregorio Marañón, C. del Dr. Esquerdo, 46, 28007, Madrid, Spain.; CIBER Enfermedades Respiratorias- CIBERES (CB06/06/0058), Madrid, Spain., de la Villa Martínez S; Instituto de Investigación Sanitaria Hospital Gregorio Marañón, C. del Dr. Esquerdo, 46, 28007, Madrid, Spain., Fernández SR; Instituto de Investigación Sanitaria Hospital Gregorio Marañón, C. del Dr. Esquerdo, 46, 28007, Madrid, Spain., Prat T; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Torroella È; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain., Ferrer L; HIPRA, Avinguda de la Selva, 135, 17170, Amer, Girona, Spain.
Jazyk:	angličtina
Zdroj:	The Lancet regional health. Europe [Lancet Reg Health Eur] 2023 May; Vol. 28, pp. 100613. Date of Electronic Publication: 2023 Apr 14.
DOI:	10.1016/j.lanepe.2023.100613
Abstrakt:	Background: 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. Funding: HIPRA SCIENTIFIC, S.L.U. Competing Interests: The authors of this manuscript declare: J Blanco has received institutional grants from HIPRA, 10.13039/501100016387Grifols, and MSD, royalties for licensed patent from AlbaJuna, honoraria for lectures from FLS Science and CIBER, supporting for meeting and/or travel from 10.13039/100016016Gilead Sciences, and unpaid independent COVID-19 monitoring from GMCSC (Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19) and unpaid participation in COVID-19 advisory group for CCAC (Comitè Científic Assessor de la COVID-19). Outside of this work, J Blanco is the CEO, founder and shareholder of AlbaJuna Therapeutics, S.L. J Corominas, C Garriga, A Barreiro, L González-González, L Madrenas, I Güell, D Raïch-Regué, J G Prado, T Prat, E Torroella, B Trinité, L Ferrer, M Cañete and A Prenafeta have received funding from HIPRA. The funding from HIPRA to R Ramos was paid to his institution. A Soriano has received grants from 10.13039/100004319Pfizer and 10.13039/100005564Gilead Sciences, consulting fees from 10.13039/100004319Pfizer, MSD and 10.13039/501100005612Shionogi, and honoraria for lectures for 10.13039/100004319Pfizer, MSD, 10.13039/100005564Gilead Sciences, 10.13039/501100005612Shionogi, 10.13039/501100006546Angelini, and Menarini. B Trinité declares royalties by an institutional agreement and consulting fees for HIPRA, and is an unpaid member in advisory board for the Health Department of the 10.13039/501100002809Generalitat de Catalunya. N Izquierdo-Useros, D Raïch-Regué and M Gallemí declare institutional grants from HIPRA, Pharma Mar, 10.13039/501100016387Grifols, Dentaid, Palobiofarma, Mynorix and Amassence. N Izquierdo-Useros and M Gallemí have received speaking honoraria from FLS Science. JR Arribas has received consulting fees and payment for participating in advisory board from 10.13039/100005564Gilead Sciences, MSD, GSK, Eli Lilly, 10.13039/100004337Roche, 10.13039/100004319Pfizer and Sobi, honoraria for lectures and support for meetings and/or travel from MSD. A Borobia has received grants from GSK, Moderna and Janssen, speaking honoraria for Janssen, 10.13039/100005564Gilead Sciences and 10.13039/100004319Pfizer, and payment for participating in advisory board for 10.13039/100004319Pfizer, Janssen and MDI. PM García has received consulting fees and speaking honoraria from 10.13039/100005564Gilead Sciences, Mundipharma and 10.13039/100004319Pfizer, payment for expert testimony and participated in advisory board for 10.13039/100005564Gilead Sciences and received support for meeting and/or travel from 10.13039/100004319Pfizer. S Otero-Romero has received speaking honoraria from Genzyme, Biogen-Idec, Novartis, Roche, and MSD. Julia G Prado declares institutional grants from 10.13039/501100016387Grifols. J Corominas, C Garriga, A Prenafeta, A Moros, M Cañete, A Barreiro, L González-González, L Madrenas, I Güell, T Prat, E Torroella and L Ferrer are employees of HIPRA. Some of these authors may have stocks of HIPRA. Several patent applications have been filed by HIPRA SCIENTIFIC S.L.U. and Laboratorios HIPRA, S.A. on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the novel recombinant RBD fusion heterodimer PHH-1V. A Barreiro, J Corominas, A Prenafeta, L González-González, L Madrenas, L Ferrer, E Torroella, T Prat and C Garriga are the inventors of these patent applications. N Izquierdo-Useros is a patent inventor with no economical compensation for Pharma Mar and Mynorix. The other authors have no relevant conflicts of interest to declare. (© 2023 The Author(s).)
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