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Clinical Trial
. 2025 Dec;21(1):2474775.
doi: 10.1080/21645515.2025.2474775. Epub 2025 Apr 30.

Safety and immunogenicity of PHH-1V booster against SARS-CoV-2 variants, including omicron subvariants: Results from a phase IIb open-label extension study

María Jesús López  1 , Maria Del Mar Vazquez  1 , Melchor Alvarez-Mon  2 , José Ramón Arribas  3   4 , Eunate Arana-Arri  5 , Patricia Muñoz  6   7   8 , Jorge Navarro-Pérez  9 , Rafael Ramos  10   11 , José Molto  4   12 , Susana Otero-Romero  13   14 , Elena Aurrecoechea  15 , Roc Pomarol  15 , Laia Bernad  16   17 , Ignasi Esteban  15 , Raúl Pérez-Caballero  16   17 , Montserrat Plana  4   15 , Júlia G Prado  4   16   17 , Álex Soriano  4   18
Affiliations
Clinical Trial

Safety and immunogenicity of PHH-1V booster against SARS-CoV-2 variants, including omicron subvariants: Results from a phase IIb open-label extension study

María Jesús López et al. Hum Vaccin Immunother. 2025 Dec.

Abstract

SARS-CoV-2 vaccination campaigns on current endemic situation would benefit from vaccine alternatives with easy logistics and accessibility, sustained response and cross-reactivity against emerging variants. Herein, safety and immunogenicity of PHH-1V, adjuvanted recombinant RBD-based vaccine, as fourth dose for the most prevalent SARS-CoV-2 variants in Spain in subjects ≥18 years was investigated for 6 months in HIPRA-HH-2 open-label extension study. Subjects received a fourth dose of PHH-1V after either two BNT162b2 doses plus one PHH-1V dose (cohort 1) or three BNT162b2 doses (cohort 2). As regulatory endpoint, neutralization titers were investigated for PHH-1 V as fourth dose vs BNT162b2 as third dose in subjects receiving previous BNT162b2-based regimens. PHH-1 V immunogenicity (GMT) was investigated against Beta, Delta, and Omicron BA.1, BA.4/5 and XBB.1.5 on Days 14, 98 and 182 post-immunization. Two hundred and eighty-eight subjects received PHH-1V. Neutralizing antibodies against Omicron BA.1 at Day 14 significantly increased after the PHH-1V as fourth booster vs the third BNT162b2 booster (GMT ratio 0.43 (95% CI: 0.28; 0.65; p-value < .0001)). PHH-1V fourth booster induced a significant increase in neutralizing titers vs baseline (GMFR on Day 14 [95% CI]: Beta 6.96 [5.23, 9.25]; Delta 6.27 [4.79, 8.22]; Omicron BA.1 9.21 [5.57, 15.21]; Omicron BA.4/5 11.80 [8.29, 16.80]; Omicron XBB.1.5 5.22 [3.97, 6.87]), remaining significantly higher up to 6 months. The most frequent adverse events were injection site pain and fatigue. As conclusion, PHH-1V booster induced sustained humoral and cellular immune response against Beta, Delta variants and cross reactivity against distant Omicron subvariants and could be an appropriate strategy for implementing heterologous vaccination campaigns.

Keywords: COVID-19; Protein vaccine; SARS-CoV-2; omicron subvariants; vaccine booster.

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Conflict of interest statement

JR Arribas has received consulting fees and payment for participating in advisory boards from Gilead Sciences, MSD, GSK, Eli Lilly, Roche, Pfizer and Sobi; honoraria for lectures and support for meetings and/or travel from MSD.

P Munoz has speaker and/or consultant fees from BioMerieux, Gilead, Pfizer, Tillots, Mundipharma, Roche, Menarini and different scientific societies and nonprofit foundations of Fundación de Ciencias de la Salud, UIMP, Future day Foundation, Fundación Areces.

J Molto has received research funding, consultancy fees, lecture sponsorships and has served on advisory boards for MSD, Gilead Sciences, Viiv Healthcare, and Johnson & Johnson.

A Soriano has received honoraria for lectures from Pfizer, MSD, Angelini, Menarini, Shionogi and Gilead; grants from Pfizer and Gilead.

S Otero-Romer has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed, GSK and MSD; research support from Novartis.

Figures

Figure 1.
Figure 1.
Participants disposition of HIPRA-HH-2 open-label extension study.
Figure 2.
Figure 2.
Comparison of neutralising antibody titre against SARS-CoV-2 Omicron BA.1 variant by PBNA. Representation of mean GMT for adjusted treatment and 95% CI at day 14 post-vaccination for third dose with BNT162b2 vaccine from HIPRA-HH-2 study (third BNT; light grey column) and fourth dose with PHH-1V from HIPRA-HH-2 extension study (fourth PHH; dark grey column).
Figure 3.
Figure 3.
Neutralising antibody levels against SARS-CoV-2 variants by PBNA over time. Representation of mean GMT for adjusted treatment with 95% CI (columns) and mean GMFR from baseline (upper numbers) for all participants from mITT population treated with fourth dose of PHH-1V (n = 190) against SARS-CoV-2 Beta, Delta, Omicron BA.1, omicron BA.4/5 (a) and omicron XBB.1.5 variants (b) at baseline (light grey), day 14 (black), 3 months (dark grey) and 6 months (grey) post-dose. Subjects who reported COVID-19 infections were excluded from the reported day onwards.
Figure 4.
Figure 4.
Total IFN-γ producing T cells upon PBMC re-stimulation with SARS-CoV-2 derived peptide pools by ELISpot. Frequencies of INF-γ+ cells determined by ELISpot assay in re-stimulated PBMC from participants with PHH-1V heterologous booster (cohort 2; n=15) isolated before (baseline), 2 weeks (day 14) and 6 months (day 182) after fourth dose and re-stimulated with RBD Wuhan D614G, RBD 1.351 (beta), RBD B.1.617.2 (delta), RBD omicron BA.1, omicron BA.2, XBB1.5 and Spike (A and B) peptides pools. ***p< .0001, **p< .01, *p< .05.
Figure 5.
Figure 5.
IFN-γ producing CD4+ and CD8+ T-cells upon PBMC re-stimulation with SARS-CoV-2-derived peptide pools by ICS. The frequencies of IFN-γ expressing CD4+ T-cells (a) or CD8+ T-cells (b) are shown. PBMC were isolated from PHH-1V heterologous booster participants (Cohort 2; n= 15) before the immunisation (baseline), two weeks (day 14) and 6 months (day 182) after the fourth dose with PHH-1V, stimulated with RBD Wuhan D614G, RBD 1.351 Beta), RBD B.1.617.2 (Delta), RBD Omicron BA.1, Omicron BA.2 and Spike (A and B) peptides pools, respectively. The cytokine expression in medium-stimulated PBMC was considered as the background value and subtracted from peptide-specific responses. ***p < .0001, **p < .001, *p < .01.
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References

    1. Günl F, Mecate-Zambrano A, Rehländer S, Hinse S, Ludwig S, Brunotte L.. Shooting at a moving target—effectiveness and emerging challenges for sars-cov-2 vaccine development. Vaccines. 2021;9(10):1052. doi: 10.3390/vaccines9101052. - DOI - PMC - PubMed
    1. Alanagreh L, Alzoughool F, Atoum M. The human coronavirus disease covid-19: its origin, characteristics, and insights into potential drugs and its mechanisms. Pathogens. 2020;9(5):331. doi: 10.3390/pathogens9050331. - DOI - PMC - PubMed
    1. Gralinski LE, Menachery VD. Return of the coronavirus: 2019-nCoV. Viruses. 2020;12(2):135. doi: 10.3390/v12020135. - DOI - PMC - PubMed
    1. WHO . Coronavirus (COVID-19) dashboard [internet]. Who.int. [accessed 2023 Oct 18]. https://covid19.who.int/.
    1. Our World in Data . Cumulative confirmed COVID-19 cases and deaths. [accessed 2023 Oct 18]. https://ourworldindata.org/grapher/cumulative-deaths-and-cases-covid-19.

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