Evaluation of Safety and Immunogenicity of PHH-1V81 Booster in Adults Vaccinated Against COVID-19 with mRNA Vaccine, Comparing to Raxtozinameran

The primary objective of this clinical trial is to assess the **safety** and tolerability of a PHH-1V81 booster in adults who have previously received primary vaccination and at least one booster dose of an EU-approved mRNA vaccine. Additionally, the study aims to determine and compare the changes in **immunogenicity** measured by pseudovirus neutralisation assay (PBNA) against the Omicron XBB.1.16 variant at Baseline and Day 14 in the PHH-1V81 vaccine arm versus the Comirnaty arm. These objectives are clinically relevant as they evaluate the potential of the PHH-1V81 booster to provide enhanced protection against COVID-19, particularly against emerging variants.

The secondary objectives include:

• Determining and comparing changes in immunogenicity measured by PBNA against Wuhan, Omicron BA.1, Omicron XBB.1.5 at Baseline and at Days 14, 91, and 182, and Omicron XBB.1.16 at Days 91 and 182, after vaccination in the PHH-1V81 vaccine arm versus the Comirnaty arm.
• Evaluating and comparing the immunogenicity measured by total antibody against the Receptor Binding Domain of the Spike protein of SARS-CoV-2, using an electrochemiluminescence immunoassay (ECLIA) at Baseline and at Days 14, 91, and 182 in the PHH-1V81 vaccine arm versus the Comirnaty arm.
• Assessing the number of adults with SARS-CoV-2 infections ≥14 days in both vaccine arms.
• Assessing the number of COVID-19 severe infections ≥14 days in both vaccine arms.
• Evaluating T-cell mediated responses against the SARS-CoV-2 S glycoprotein at Baseline and at Day 14 for descriptive analysis in a subset of participants from both vaccine arms.

The clinical trial involves **adults** aged 18 years and older who have previously received a primary vaccination scheme and at least one booster dose of an EU-approved mRNA vaccine. The study population includes both male and female participants, and individuals with pre-existing chronic and stable diseases are eligible if their conditions are well-controlled. Participants must have a negative Rapid Antigen Test for **COVID-19 disease** at Day 0 prior to vaccination. The trial does not include a vulnerable population. Participants who are biologically able to have children must adhere to specific contraceptive measures or abstain from activities that could result in pregnancy. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized**, **double-blind**, active-controlled, multi-center, non-inferiority study to evaluate the safety and immunogenicity of a booster vaccination with an adapted recombinant protein RBD fusion homodimer candidate against **COVID-19** in adults. The trial will involve participants who have previously received a primary vaccination and at least one booster dose of an EU-approved mRNA vaccine. The study aims to assess the safety and tolerability of the PHH-1V81 booster and to compare changes in immunogenicity against the Omicron XBB.1.16 variant between the PHH-1V81 vaccine arm and the Comirnaty arm. The trial is expected to commence on November 14, 2023, and conclude by June 30, 2024.

Participants will be involved in the study for a period that includes several key visits. The inclusion visit, or screening, will determine eligibility based on criteria such as age, previous vaccination history, and a negative rapid antigen test for COVID-19. Following the initial vaccination, participants will attend follow-up visits to monitor for solicited and unsolicited local and systemic reactions, as well as serious adverse events. These visits will occur at specified intervals, including Day 7, Day 14, Day 28, Day 91, and Day 182, to assess both primary and secondary endpoints. The end-of-study visit will finalize data collection and ensure participant safety.

The expected length of participant involvement is approximately 7 months, from the initial screening to the final follow-up visit. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable data to the ongoing efforts to combat COVID-19.

The clinical trial involves the administration of two experimental medications. The first medication is **Comirnaty Omicron XBB.1.5**, a COVID-19 mRNA vaccine (nucleoside modified) produced by BioNTech Manufacturing GmbH. This vaccine is presented as a **dispersion for injection** and contains the active substance **raxtozinameran**, a nucleic acid. The vaccine is administered via the **intramuscular** route at a dosage of 30 micrograms per dose. The maximum daily and total dose is 30 micrograms, with a treatment period of one day. This formulation is not a pediatric formulation and is used as a comparator in the trial.

The second experimental medication is a recombinant protein vaccine, described as **SARS-CoV-2 Virus, Variants B.1.351-B.1.1.7, Spike Protein, Receptor Binding Domain Fusion Heterodimer**. This vaccine is formulated as an **emulsion for injection** and is also administered via the **intramuscular** route. The active substance is a structurally diverse substance classified as a vaccine. The dosage for this vaccine is 40 micrograms per dose, with a maximum daily and total dose of 40 micrograms, and a treatment period of one day. This vaccine is used as the test product in the trial.

Both vaccines are administered as part of a Phase IIb/III, double-blind, randomized, active-controlled, multi-center, non-inferiority clinical trial. The trial aims to assess the safety and immunogenicity of a booster vaccination in adults previously vaccinated against COVID-19. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the measurement of **neutralisation titre** against the Omicron XBB.1.16 variant, which will be determined using a pseudovirus neutralisation assay (PBNA). This will be reported as inhibitory concentration 50 (IC50) and expressed as reciprocal concentration for each individual sample, as well as geometric mean titre (GMT) for treatment group comparison at Baseline and Day 14. Additionally, the trial will evaluate the number, percentage, and characteristics of solicited and unsolicited local and systemic reactions, adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESI), and medically attended adverse events (MAAE) through various timepoints, including Day 7, Day 28, and the end of the study.

Secondary endpoints will further explore the neutralisation titres against multiple SARS-CoV-2 variants, including Wuhan, Omicron BA.1, Omicron XBB.1.5, and Omicron XBB.1.16. These will be measured at Baseline and Days 14, 91, and 182. The study will also assess the percentage of subjects experiencing a ≥4-fold increase in neutralizing antibody titres, geometric mean fold rise (GMFR) in neutralising antibodies, and binding antibodies titre for treatment group comparison. Additional analyses will include the percentage of subjects with a ≥2-fold increase in total binding antibody titres, the number of confirmed COVID-19 cases and severe cases from ≥14 days post-vaccination, and T-cell-mediated response to the SARS-CoV-2 S glycoprotein as measured by whole PBMC stimulation by ELISpot at Baseline and Day 14 in a subset of participants. These assessments will provide comprehensive data on the immunogenicity and efficacy of the booster vaccination.