Safety and immunogenicity of the protein-based PHH-IV 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.

BackgroundA 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 with ClinicalTrials.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{middle dot}68 (p<0{middle dot}0001), 1{middle dot}31 (p=0{middle dot}0007) and 0{middle dot}86 (p=0{middle dot}40) for the ancestral Wuhan-Hu-1 strain; 0{middle dot}62 (p<0{middle dot}0001), 0{middle dot}65 (p<0{middle dot}0001) and 0{middle dot}56 (p=0{middle dot}003) for the Beta variant; 1{middle dot}01 (p=0{middle dot}92), 0{middle dot}88 (p=0{middle dot}11) and 0{middle dot}52 (p=0{middle dot}0003) for the Delta variant; and 0{middle dot}59 (p=<0{middle dot}0001), 0{middle dot}66 (p<0{middle dot}0001) and 0{middle dot}57 (p=0{middle dot}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-{gamma} on day 14. There were 458 participants who experienced at least one adverse event (89{middle dot}3%) in the PHH-1V and 238 (94{middle dot}4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79{middle dot}7% and 89{middle dot}3%), fatigue (27{middle dot}5% and 42{middle dot}1%) and headache (31{middle dot}2 and 40{middle dot}1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10{middle dot}14%) for the PHH-1V group and 30 (11{middle dot}90%) for the BNT162b2 group (p=0{middle dot}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.