16 September 2019 - - US-based biotechnology company Moderna, Inc., (NASDAQ: MRNA) has received positive data from the three-month interim analysis of safety and immunogenicity of the Phase 1 study of its investigational cytomegalovirus vaccine (mRNA-1647), the company said.

mRNA-1647 is a wholly owned program in Moderna's prophylactic vaccine portfolio.
Based on these data, Moderna is advancing mRNA-1647 to a dose-confirmation Phase 2 study in the near term.

Preparation has also begun for a pivotal Phase 3 study designed to evaluate the efficacy of mRNA-1647 against primary CMV infection.

The Phase 2 study will test the intended Phase 3 formulation, which contains the same proprietary lipid nanoparticle used in this Phase 1 study.

mRNA-1647 is a vaccine combining six mRNAs in a single vial, which encode for two antigens on the surface of CMV: five mRNAs encoding the subunits that form the membrane-bound pentamer complex and one mRNA encoding the full-length membrane-bound glycoprotein B.

Both the pentamer and gB are essential for CMV to infect barrier epithelial surfaces and gain access to the body. mRNA-1647 is designed to produce an immune response against both the pentamer and gB for the prevention of CMV infection.

The Phase 1 study, which has completed enrollment, is evaluating the safety and immunogenicity of mRNA-1647 in 169 healthy adult volunteers. The study population includes those who were naïve to CMV infection (CMV-seronegative) and those who had previously been infected by CMV (CMV-seropositive).

Participants were randomized to receive either placebo, or 30, 90, 180 or 300 µg of mRNA-1647 on a dosing schedule of 0, 2 and 6 months.

This first planned interim analysis assessed safety and immunogenicity of the first three dose levels (30, 90, and 180 µg) at three months, one month after the second vaccination and before the third vaccination.

Neutralising antibody titers (levels of circulating antibodies that block infection1) were assessed in two assays utilising epithelial cells and fibroblasts, which measure immune response to the pentamer and gB vaccine antigens, respectively.

Seropositive baseline titers are associated with lower rates of congenital CMV transmission.

mRNA-1647 is a two-antigen vaccine designed to protect against CMV infection. It combines six mRNAs in a proprietary LNP in a single vial and encodes for two immuno-dominant proteins of CMV. mRNA-1647 comprises five mRNAs encoding the subunits of the pentamer complex and one mRNA encoding the glycoprotein B target antigen.

The pentamer is important for CMV entry into a variety of cells, including epithelial and endothelial cells, while gB is important for entry into all susceptible cells including fibroblasts.2 A vaccine that produces an immune response against both the pentamer and gB has the potential to prevent CMV entry into cells and thus prevent congenital infections.

Unlike a protein-based vaccine, mRNA-1647 instructs cells to specifically make the pentamer and gB antigens with a structure that mimics the ones presented to the immune system by the virus during a natural infection.

Preclinical data previously published in Vaccine showed that vaccination with mRNA-1647 in animal models elicited potent and durable neutralizing antibody titers.

This randomised, observer-blind, placebo-controlled, dose-ranging study is designed to evaluate the safety and immunogenicity of mRNA-1647 in healthy adults.

The study is investigating a three-dose vaccination schedule (0, 2 and 6 months) of mRNA-1647 at four dose levels (30, 90, 180 and 300 μg) in both CMV-seronegative and CMV-seropositive participants. Primary outcome measures include solicited AEs.

Secondary outcome measures include anti-CMV neutralizing antibody titers against epithelial cell infection and fibroblast cell infection.

The first planned interim analysis of the Phase 1 study includes data from one month after the second vaccination with mRNA-1647 at 30, 90 and 180 µg dose levels.

Forthcoming data from the Phase 1 study will include safety and immunogenicity analyses of the 300 µg dose group as well as data from the third vaccination of all participants at the 30, 90 and 180 µg dose levels. Full Phase 1 data will be presented at a future medical meeting.

Based on these Phase 1 interim data, Moderna is advancing mRNA-1647 into a Phase 2 dose-confirming study in the near term, where the first interim safety and immunogenicity analysis is planned at 0, 2 and 6 months.

This Phase 2 study will test the intended Phase 3 formulation, which contains the same proprietary lipid nanoparticle used in this Phase 1 study.

In parallel, preparation is underway for the pivotal Phase 3 study designed to evaluate mRNA-1647 for the prevention of primary CMV infection in a population that includes women of childbearing age. The design of this Phase 3 study is subject to FDA and global regulatory feedback.