Safety and immunogenicity of PHH-1V as booster vaccination through the Omicron era: results from a phase IIb open-label extension study up to 6 months

Background Phase IIb HIPRA-HH-2 study results showed that PHH-1V as first booster dose elicited a strong and sustained neutralising antibody response against various SARS-CoV-2 variants. Here, we report the safety and immunogenicity of a fourth booster dose of PHH-1V against the most prevalent Omicron SARS-CoV-2 variants in Spain. Methods The HIPRA-HH-2 open-label extension study ([NCT05142553][1]) evaluated the safety and immunogenicity of PHH-1V as a fourth booster dose in subjects aged ≥18 years and followed for 6 months. Subjects received a fourth dose of PHH-1V 6–12 months after a previous regime of either two doses of BNT162b2 plus a third dose of PHH-1V (Cohort 1) or three doses of BNT162b2 (Cohort 2). Primary regulatory endpoint evaluated the neutralisation titres (GMT) against Omicron BA.1 on Day 14 of PHH-1V used as fourth dose in Cohort 2 vs the BNT162b2 used as third dose in initial HIPRA-HH-2 study. The immunogenicity of PHH-1V as fourth dose was also investigated by GMTs against Beta, Delta, and Omicron BA.1, BA.4/5 and XBB.1.5 on Days 14, 98 and 182 post-immunisation in the overall study population and in Cohorts 1 and 2 versus baseline. Safety of the fourth dose was also assessed. Findings From September 2022, 288 subjects received PHH-1V as a fourth dose (Cohort 1 n=106; Cohort 2 n=182). A significant increase in neutralising antibodies against Omicron BA.1 subvariant at Day 14 was observed from the third homologous booster with mRNA vaccine compared to the fourth heterologous booster with PHH-1V (1739.02 vs 4049.01; GMT ratio 0.43 (95% CI: 0.28; 0.65; p-value < 0.0001). PHH-1V used as fourth booster induced a statistically significant increase in neutralising antibody titres 14 days after immunisation for all variants compared with baseline [GMFR on Day 14 (95%CI) was 6.96 (5.23, 9.25) for Beta variant; 6.27 (4.79, 8.22) for Delta variant; 9.21 (5.57, 15.21) for Omicron BA.1 variant; 11.80 (8.29, 16.80) for Omicron BA.4/5 variant and 5.22 (3.97, 6.87) for Omicron XBB.1.5 variant]. Titres remained significantly higher compared with baseline at 3 and 6 months post-vaccination. Cohort comparison revealed no significant differences at 14, 98 and 182 days post-vaccination. The most frequent adverse events were injection site pain (Cohort 1: 84.0%; Cohort 2: 77.5%) and fatigue (Cohort 1: 17.9%; Cohort 2: 29.1%). No subjects experienced severe COVID-19 infection. Interpretation The PHH-1V vaccine as a booster induced a potent and sustained neutralising antibody response against previous circulating Beta, Delta variants and Omicron BA.1, BA.4/5, and XBB.1.5 subvariants in subjects previously vaccinated with three doses regardless of previous regimen. These findings suggest that PHH-1V could be an appropriate strategy for upcoming heterologous vaccination campaigns. Funding HIPRA SCIENTIFIC, S.L.U (HIPRA), Spain. Unmet needs Immunity against SARS-CoV-2 will continue to increase in the community through widespread vaccination and infection. Despite this, at the individual level, the humoral response against new variants is diminished in both vaccinated and infected individuals. Booster strategies have demonstrated a reduction in the risk of not only COVID-19 infection but also of long COVID-19 or persistent post-COVID manifestations. Furthermore, heterologous booster strategies for vaccination regimens offer broad neutralising responses. However, available evidence regarding new platforms beyond mRNA-based vaccines is currently limited. Evidence before this study The PHH-1V vaccine elicits high and long-lasting levels of neutralising antibodies against all COVID-19 variants studied, as well as a strong cellular immunity response, when used as a heterologous booster in previously vaccinated individuals receiving mRNA and viral vector vaccines. However, safety and immunogenicity data on a fourth booster dose of PHH-1V against the most prevalent Omicron variants in Spain were not available at the time of the study period. Added value of this study The PHH-1V dimeric adjuvanted vaccine delivered as a fourth booster dose can induce a potent and significant neutralising antibody response against previous circulating Beta, Delta variants and Omicron BA.1, BA.4/5, and also against XBB.1.5 subvariants from Day 14 through Day 182 compared with baseline regardless of the primary vaccination received (two doses of BNT162b2 plus a third dose of PHH-1V (Cohort 1) or three doses of BNT162b2 (Cohort 2)) and confirm the higher response of PHH-1V when used as a heterologous fourth-dose booster. This open-label extension study also demonstrated that PHH-1V is well tolerated and safe irrespective of the prior booster vaccination received. Implications of all the available evidence These data confirm the advantages of heterologous booster vaccination with PHH-1V and the broad-spectrum response of the PHH-1V vaccine against the different emerging variants of COVID-19, suggesting that PHH-1V could be an appropriate booster for upcoming heterologous vaccination campaigns. ### Competing 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 non-profit foundations of Fundacion de Ciencias de la Salud, UIMP, Future day Foundation, Fundacion 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. L Riera-Sans is full time employee of HIPRA. ### Clinical Trial NCT05142553 ### Funding Statement This study was funded by HIPRA SCIENTIFIC, S.L.U (HIPRA), Spain. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was reviewed and approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) as well as Independent Ethics Committee from the Hospital Clinic de Barcelona (HCB/2021/1110) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the corresponding author [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05142553&atom=%2Fmedrxiv%2Fearly%2F2024%2F04%2F12%2F2024.04.09.24305540.atom