Efficacy, Safety, and Immunogenicity of mRNA-1647 Vaccine in Preventing Primary Cytomegalovirus Infection in CMV-Seronegative Females Aged 16-40

The primary objective of this Phase 3, randomized, observer-blind, placebo-controlled study is to demonstrate the **efficacy** of the mRNA-1647 vaccine in preventing primary **Cytomegalovirus (CMV) infection** in CMV-seronegative female participants. Additionally, the study aims to evaluate the **safety** and **reactogenicity** of the mRNA-1647 vaccine when administered on a 3-dose injection schedule in all participants. These objectives are clinically relevant as they address the need for an effective and safe vaccine to prevent CMV infection, which can have significant health implications, particularly in pregnant women and immunocompromised individuals.

Secondary objectives include:

• Evaluating the **immunogenicity** of mRNA-1647 when administered on a 3-dose injection schedule in all participants.
• Assessing the persistence of immunogenicity to mRNA-1647 through 24 months after the third injection in all participants.

The clinical trial involves a total of **5631 participants** and is focused on evaluating the efficacy and safety of the mRNA-1647 vaccine in preventing primary **Cytomegalovirus Infection (CMV)**. The study population consists exclusively of female participants aged between 16 to 40 years. Participants were selected based on their CMV serostatus, with specific cohorts for CMV-seronegative and CMV-seropositive individuals. The trial includes women who are capable of complying with study procedures and have or anticipate having direct exposure to children aged 5 years or younger. Participants are required to provide written informed consent, and those of childbearing potential must adhere to specific contraceptive guidelines. The study does not provide information on the general health status or lifestyle considerations such as diet or physical activity of the participants. The trial population includes a vulnerable group, as indicated by the inclusion of minors and the requirement for parental or legal representative consent where applicable.

The clinical trial is a **Phase 3**, randomized, observer-blind, placebo-controlled study designed to evaluate the efficacy, safety, and immunogenicity of the **mRNA-1647** vaccine in preventing **Cytomegalovirus Infection (CMV)** in healthy participants aged 16 to 40 years. The trial involves a 3-dose injection schedule, with the investigational product being a **solution for injection** administered via **intramuscular use**. The study is expected to span approximately 30 months, with an estimated recruitment start date of September 1, 2021, and an anticipated end date of April 30, 2028.

Participants will undergo a series of study visits, beginning with a screening visit to assess eligibility based on inclusion and exclusion criteria. Key inclusion criteria include being a female aged 16 to 40 years, having the capability to comply with study procedures, and for certain cohorts, being **CMV-seronegative** or **CMV-seropositive** as determined by specific serological tests. The screening visit will also include a urine pregnancy test for females of childbearing potential. Following successful screening, participants will be randomized to receive either the mRNA-1647 vaccine or a placebo, which is **Sodium Chloride 0.9%** solution for injection.

Subsequent study visits will occur at specified intervals to monitor the participants' health and collect data on the primary and secondary endpoints. The primary endpoints include the prevention of primary CMV infection and the assessment of adverse reactions and serious adverse events. Secondary endpoints focus on measuring antigen-specific neutralizing antibody and binding antibody titers at various time points throughout the study. Follow-up visits will be conducted to ensure ongoing safety monitoring and to collect immunogenicity data.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted. Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as non-compliance with study procedures or the occurrence of significant adverse events. The trial is structured to ensure rigorous data collection and analysis, contributing to the understanding of the mRNA-1647 vaccine's potential in preventing CMV infection.

The clinical trial involves the administration of **mRNA-1647**, an experimental vaccine designed to prevent primary **Cytomegalovirus (CMV)** infection. The vaccine is formulated as a **solution for injection** and is administered via the **intramuscular route**. The active substances in mRNA-1647 include mRNA encoding human CMV glycoproteins B, H, L, UL128, UL130, and UL131A, all of which are nucleic acid-based. The dosing schedule for mRNA-1647 consists of a 3-dose injection regimen, with a maximum daily dose of 100 micrograms and a total maximum dose of 300 micrograms over a treatment period of 6 months. The vaccine is produced by MODERNATX, INC. and is not a paediatric formulation.

In addition to the experimental vaccine, the study utilizes **Sodium Chloride 0.9%**, a **solution for injection** serving as a placebo. This solution is also administered intramuscularly. Sodium Chloride, a chemical substance, is provided by FRESENIUS KABI LIMITED. The placebo is relabeled and repackaged for the trial, with no active pharmacological effect intended. The use of Sodium Chloride 0.9% ensures the blinding of the study, allowing for an unbiased assessment of the mRNA-1647 vaccine's efficacy and safety. The placebo is administered over the same 6-month period as the experimental treatment, with no specified maximum daily or total dose, as it serves solely as a comparator.

The efficacy of the mRNA-1647 vaccine in preventing primary **Cytomegalovirus (CMV)** infection will be assessed in a Phase 3, randomized, observer-blind, placebo-controlled clinical trial. The primary endpoint for efficacy evaluation is the occurrence of primary CMV infection, defined as seroconversion from a negative to a positive result for serum IgG. This will be measured using a platform-based automated immunoassay targeting at least one of the four recombinant CMV antigens not encoded by mRNA-1647 (pp150, pp28, pp52, pp38). The assessment will begin 28 days after the third injection.

Secondary endpoints include the measurement of antigen-specific neutralizing antibody (nAb) and binding antibody geometric mean titers (GMTs) or geometric mean concentrations (GMCs) at various timepoints: Day 1, Month 3, Month 7, Month 12, Month 18, Month 24, and Month 30. These measurements will provide additional data on the immunogenicity of the vaccine. The trial will also monitor solicited adverse reactions (ARs) through 7 days after each injection, unsolicited adverse events (AEs) through 28 days after each injection, medically attended adverse events (MAAEs) from Day 1 through 6 months after the last injection, adverse events of special interest (AESIs) from Day 1 through the end of the study (EOS), and serious adverse events (SAEs) from the time of consent through EOS.