Evaluation of Safety and Immunogenicity of BIMERVAX and Seasonal Influenza Vaccine Coadministration in SARS-CoV-2 and Influenza Vaccinated Adults Aged 65+

The primary objective of this phase II, randomized, double-blind, multi-centre trial is to assess and compare the **safety** and tolerability of BIMERVAX® when coadministered with a seasonal surface antigen, inactivated, adjuvanted influenza vaccine (SIIV) in adults older than 65 years of age who are fully vaccinated against **COVID-19**. This evaluation is clinically relevant as it aims to ensure that the combined administration of these vaccines does not compromise patient safety or increase adverse effects, which is crucial for optimizing vaccination strategies in this age group.

Secondary objectives include:

• To determine and compare the **immunogenicity** measured by means of total antibody against the receptor binding domain (RBD) of the Spike protein of SARS-CoV-2, quantified by electrochemiluminescence immunoassay (ECLIA) at Baseline and Day 28 in cohorts 2 and 3 vaccinated with BIMERVAX®.
• To determine and compare the immunogenicity measured by Influenza strain-specific titres, assessed by haemagglutination inhibition (HAI) at Baseline and Day 28 in cohorts 1 and 3, vaccinated with SIIV.

These secondary objectives are significant as they provide insights into the immune response elicited by the vaccines, which is essential for understanding their efficacy in preventing **SARS-CoV-2** and **Influenza** infections in the target population.

The clinical trial involves a study population comprising **adults aged 65 or older**. Both male and female participants are included, and the trial does not specifically target a vulnerable population. Participants are required to have received at least a primary scheme of an mRNA vaccine, consisting of two doses, with the last dose administered at least six months prior to the start of the trial. Individuals with a history of COVID-19 infection are eligible if the infection occurred more than 30 days before the trial commencement. Participants must also have a negative Rapid Antigen Test at the start of the trial. The study includes adults with pre-existing chronic and stable diseases, provided these conditions are well-controlled. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **phase II**, randomized, double-blind, multi-centre study designed to evaluate the safety and immunogenicity of **BIMERVAX** when coadministered with a seasonal surface antigen, inactivated, adjuvanted influenza vaccine (SIIV) in adults older than 65 years who are fully vaccinated against **COVID-19**. The trial involves a controlled design where participants are randomly assigned to receive either the investigational vaccine, the influenza vaccine, or a placebo, ensuring that neither the participants nor the investigators know which treatment is being administered, thus maintaining the double-blind nature of the study. The trial is expected to last until November 30, 2023, with recruitment having started on July 6, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, vaccination history, and health status. This visit will include a **Rapid Antigen Test** to confirm a negative result for **SARS-CoV-2**. Following successful screening, participants will receive the assigned treatment on Day 0. Subsequent follow-up visits will occur to monitor safety and collect data on immunogenicity, with primary endpoints focusing on the number and characteristics of local and systemic reactions, adverse events, and serious adverse events. Secondary endpoints will evaluate antibody titers and geometric mean fold rise in antibodies.

The expected length of participant involvement is approximately 28 days, with the end-of-study visit marking the conclusion of their participation. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or the inability to comply with study procedures. The trial aims to provide valuable data on the coadministration of these vaccines, contributing to the understanding of their safety and efficacy in the target population.

The clinical trial involves the administration of **BIMERVAX**, an emulsion for injection, which is a COVID-19 vaccine (recombinant, adjuvanted). The active substance in BIMERVAX is the **SARS-CoV-2 virus**, specifically the variants B.1.351-B.1.1.7, spike protein, receptor binding domain fusion heterodimer. This vaccine is administered via **intramuscular injection**. The maximum daily dose is 40 micrograms, with a total dose of 40 micrograms over the treatment period, which is limited to one day. The pharmaceutical form is an emulsion for injection, and the product is manufactured by HIPRA HUMAN HEALTH S.L.

In addition to the experimental vaccine, a **saline solution** is used as a placebo in the study. This placebo is administered in the same manner as the experimental vaccine, via intramuscular injection. The maximum daily and total dose for the placebo is 0.5 milliliters, with the treatment period also limited to one day. The placebo serves as a comparator to evaluate the safety and immunogenicity of the experimental vaccine.

The trial also includes the administration of **Fluad Tetra**, a suspension for injection in a pre-filled syringe. This is an influenza vaccine (surface antigen, inactivated, adjuvanted) containing multiple strains: B/Phuket/3073/2013-like strain, A/Victoria/2570/2019 (H1N1)pdm09-like strain, Influenza virus B/Austria/1359417/2021-like strain, and A/Darwin/9/2021 (H3N2)-like strain. The vaccine is administered via intramuscular injection, with a maximum daily dose of 60 micrograms and a total dose of 60 micrograms over the treatment period of one day. The product is manufactured by SEQIRUS NETHERLANDS B.V.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. Primary endpoints include the evaluation of the number, percentage, and characteristics of solicited local and systemic reactions through Day 7 after vaccination, as well as unsolicited local and systemic adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI) through the end of the study. These parameters will provide insights into the safety profile of the vaccines when coadministered.

Secondary endpoints focus on the immunogenicity of the vaccines. This will be measured by the binding antibodies titre for each individual sample and the geometric mean titre (GMT) for treatment group comparison at Baseline and Day 28. Additionally, the geometric mean fold rise (GMFR) in binding antibodies titre from Baseline to Day 28 will be assessed. Strain-specific hemagglutination inhibition (HAI) antibody titers, expressed as GMT, will also be measured at Baseline and Day 28, along with the GMFR in strain-specific HAI titers elicited at Day 28. These immunogenicity assessments will be conducted to evaluate the response elicited by **BIMERVAX** when coadministered with the seasonal influenza vaccine (SIIV) or when each is administered alone.