A biotechnology company based in Massachusetts announced positive 7-month interim safety and immunogenicity data after the 3rd and final vaccination in the Phase 1 study of its investigational cytomegalovirus (CMV) vaccine candidate, mRNA-1647.

The findings published by Moderna, Inc. on January 9, 2020, builds on the previously reported 3-month interim analysis during September 2019.

“Prevention of CMV in women of childbearing age is an urgent unmet need. mRNA-1647 is the first mRNA vaccine for an infectious disease to enter a Phase 2 clinical trial,” said Stéphane Bancel, Moderna’s CEO, in a press release.

This is important news since there is currently no approved vaccine for the prevention of CMV infection.

The mRNA-1647 vaccine comprises 6 mRNAs encoding 2 antigens in 1 vaccine and is designed to protect against CMV infection.

Of the 6 mRNAs, 5 encode the subunits of the CMV pentamer complex and 1 mRNA encodes the glycoprotein B (gB) protein, both of which are highly immunogenic.

Both pentamer and gB proteins are essential for CMV to enter epithelial cells, which is the first step in CMV infection.

mRNA-1647 is designed to produce an immune response to both pentamer and gB antigens to prevent CMV infection.

CMV is a common pathogen and member of the herpesvirus family, which includes herpes simplex virus types 1 & 2, varicella-zoster virus, and Epstein-Barr virus.

For most people, CMV infection is not a serious health problem, said the Centers for Disease Control and Prevention (CDC) in May 2019.

However, certain groups are at high-risk for serious complications from CMV infection:

Infants infected in utero (congenital CMV infection)

Very low birth weight and premature infants

People with compromised immune systems.

Congenital CMV infection results when infected mothers transmit the virus to their unborn child, and it is the leading infectious cause of birth defects in the United States with approximately 25,000 newborns in the U.S. infected every year.

Birth defects occur in approximately 20 percent of infected babies and include neurodevelopmental disabilities such as hearing loss, vision impairment, varying degrees of learning disability and decreased muscle strength and coordination.

CMV is spread through saliva, breastmilk, mucus, and urine and is common in healthy babies and toddlers; as a result, young children can be a major source of infection for pregnant women, and others, says the CDC.

The 2nd interim analysis of the Phase 1 trial reports safety and immunogenicity of the first three dose levels (30, 90 and 180 µg) through seven months (one month after the third vaccination) and the highest dose level (300 µg) through three months (one month after the second vaccination).

Neutralizing antibody titers were assessed in two assays utilizing epithelial cells and fibroblasts, which measure the immune response to pentamer and gB antigens, respectively.

Safety data were consistent with those reported at the three-month interim analysis. The vaccine was generally well-tolerated and there were no vaccine-related serious adverse events (SAEs).

The most common solicited local adverse reaction (AR) across all vaccinations was injection site pain (54-100% of a given treatment group). The most common solicited systemic ARs reported overall were headache, fatigue, myalgia, and chills.

Fever was reported in 0-55% of CMV-seronegative treatment groups and in 8-67% of CMV-seropositive treatment groups.

The most common Grade 3 solicited ARs were in CMV-seropositive participants and were fatigue (0-27% of a given treatment group), chills (0-27% of a given treatment group) and fever (0-33% of a given treatment group).

In general, the highest solicited systemic AR rates were reported after the second vaccination, were more frequent in the CMV-seropositive compared to the CMV-seronegative group, and tended to correlate to dose.

As reported in the previous interim analysis, one related Grade 4 adverse event (AE) has been observed, which was an isolated lab finding of elevated partial thromboplastin time (PTT), which was elevated at baseline (Grade 1) and self-resolved on the next lab test with no associated clinical findings.

In the CMV-seronegative group at 7 months:

Neutralizing antibody titers continued to increase after the third vaccination in both epithelial cell and fibroblast assays.

Neutralizing antibody titers against epithelial cell infection was greater than 10-fold higher than CMV-seropositive baseline titers at the 90 and 180 µg dose levels after the third vaccination, compared to 3-fold to 5-fold higher after the second vaccination.

Neutralizing antibody titers against fibroblast infection increased to 1.4-fold higher than CMV-seropositive baseline titers at the 90 and 180 µg dose levels after the third vaccination, compared to titers that were comparable to CMV-seropositive baseline titers after the second vaccination.

In the CMV-seropositive group at 7 months:

Neutralizing antibody titers continued to increase after the third vaccination in both epithelial cell and fibroblast assays.

Third vaccination boosted neutralizing antibody titers against epithelial cell infection to levels of 22-fold to 40-fold over baseline across treatment groups, compared to 10-fold to 19-fold over baseline after the second vaccination.

Third vaccination boosted neutralizing antibody titers against fibroblast infection to levels of 4-fold to 6-fold over baseline across treatment groups, compared to 2-fold to 4-fold over baseline after the second vaccination.

Samples from a subset of CMV-seronegative participants from the 30, 90 and 180 µg dose levels demonstrated T-cell reactivity against the gB antigen at all doses. Pentamer-based T-cell assays remain in development.

This interim analysis also reports the first data from the 300 µg dose level through 3 months (one month after the second vaccination), which continued to show consistent dose-dependent increases in neutralizing antibodies against epithelial cell infection and against fibroblast infection in both CMV-seronegative and CMV-seropositive participants.

Safety and tolerability at the 300 µg dose level were comparable to that observed at the 180 µg dose level.

“These data are significant because they show that after a 3rd dose, mRNA-1647 continues to increase durable immune responses that exceed the levels of those with natural CMV infection,” said Tal Zaks, M.D., Ph.D., chief medical officer at Moderna.

“There is no approved vaccine to prevent CMV infection despite repeated attempts over the last 50 years.”

“With mRNA-1647, which encodes for both the pentamer and gB antigens, we believe we can significantly reduce the burden of CMV infection, including in women of childbearing age, concluded Dr. Zaks in the press release.

A 12-month interim analysis is planned, which will report safety and immunogenicity through six months after the third vaccination.

Separately, Moderna said the 1st participant has been dosed in the randomized, observer-blind, placebo-controlled, dose-confirmation Phase 2 study, which will investigate the safety and immunogenicity of mRNA-1647 in approximately 252 healthy adults in the U.S. at three dose levels (50, 100 and 150 μg) in both CMV-seronegative and CMV-seropositive participants administered in a 3-dose vaccination schedule (0, 2 and 6 months).

This Phase 2 study will test the intended Phase 3 formulation, which contains the same proprietary lipid nanoparticle (LNP) used in the Phase 1 study. The first interim analysis will evaluate safety and immunogenicity at three months (one month after the second vaccination) and is intended to inform Phase 3 dose selection. mRNA-1647 is the first mRNA vaccine for an infectious disease to enter a Phase 2 clinical trial.

With the seven-month Phase 1 data and the launch of the Phase 2 study, the Company is actively preparing for a global randomized, observer-blind, placebo-controlled Phase 3 pivotal study to evaluate the efficacy of mRNA-1647 against primary CMV infection.

Moderna has solicited and received Type C meeting feedback from the FDA on the preliminary design of the pivotal trial, which will evaluate the prevention of primary CMV infection in a population that includes women of childbearing age.

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

Moderna is advancing messenger RNA (mRNA) science to create a new class of transformative medicines for patients. To learn more visit ModernATX.

Cytomegalovirus Vaccine news published by Precision Vaccinations.