ABSTRACT
The HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial to compare the immunogenicity and safety of a heterologous booster with PHH-1V adjuvanted recombinant vaccine versus a homologous booster with mRNA vaccine. Interim results showed a strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 after dosing. Here we report that these humoral and cellular responses after PHH-1V dosing are sustained up to 6 months. These results are observed both when including or not participants who reported SARS-CoV-2 infection and in a high-risk population ([≥]65 years). Additional analysis revealed a non-inferiority of PHH-1V booster in eliciting neutralizing antibodies also for SARS-CoV-2 Omicron XBB.1.5 when compared to mRNA vaccine after 6 months. The PHH-1V vaccine provides long-lasting protection against a wide variety of SARS-CoV-2 emerging variants to prevent severe COVID-19. ClinicalTrials.gov Identifier: NCT05142553
Subject(s)
COVID-19ABSTRACT
The SARS-CoV-2 pandemic made evident that we count with few coronavirus-fighting drugs. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety and tolerability profiles. We began elaborating a list of 116 drugs previously used to treat other pathologies or characterized in pre-clinical studies with potential to treat coronavirus infections. We next employed molecular modelling tools to rank the 44 most promising inhibitors and tested their efficacy as antivirals against a panel of alpha and beta coronavirus, e.g., the HCoV-229E and SARS-CoV-2 viruses. Four drugs, OSW-1, U18666A, hydroxypropyl-beta-cyclodextrin (HbetaCD) and phytol, showed antiviral activity against both HCoV-229E (in MRC5 cells) and SARS-CoV-2 (in Vero E6 cells). The mechanism of action of these compounds was studied by transmission electron microscopy (TEM) and by testing their capacity to inhibit the entry of SARS-CoV-2 pseudoviruses in ACE2-expressing HEK-293T cells. The entry was inhibited by HbetaCD and U18666A, yet only HbetaCD could inhibit SARS-CoV-2 replication in the pulmonary cells Calu-3. With these results and given that cyclodextrins are widely used for drug encapsulation and can be safely administered to humans, we further tested 6 native and modified cyclodextrins, which confirmed {beta}-cyclodextrins as the most potent inhibitors of SARS-CoV-2 replication in Calu-3 cells. All accumulated data points to beta-cyclodextrins as promising candidates to be used in the therapeutic treatments for SARS-CoV-2 and possibly other respiratory viruses.
Subject(s)
Coronavirus InfectionsABSTRACT
Summary 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 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 endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies against the ancestral Wuhan-Hu-1 strain and different variants of SARS-CoV-2 after the PHH-1V or the BNT162b2 boost, the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides and the safety and tolerability of PHH-1V as a boost. 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 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1·68 (p<0·0001) and 0·87 (p=0·43) for the ancestral Wuhan-Hu-1 strain; 0·61 (p<0·0001) and 0·57 (p=0·0064) for the beta variant; 1·01 (p=0·89) and 0·52 (p=0·0003) for the delta variant; and 0·59 (p=<0·0001) and 0·56 (p=0·0026) for the omicron 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, elicits a strong and sustained neutralizing antibody response against Wuhan-Hu-1 strain, and a superior one concerning the previous circulating beta and delta SARS-CoV-2 variants, as well as the currently circulating omicron. 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.