Moderna has dosed the first participant in the company’s first pivotal registration study of a vaccine candidate beyond its FDA-emergency authorized COVID-19 vaccine—a Phase III trial of its cytomegalovirus (CMV) vaccine candidate mRNA-1647.

The trial (NCT05085366)—dubbed “CMVictory” by the company—is Moderna’s second-ever Phase III study and first to be conducted globally. CMVictory is designed to evaluate the safety and efficacy of a 100 μg dose of mRNA-1647 against primary CMV infection in women ages 16–40 years.

“The study is focusing on women in this particular age range because, in general, that is the age range in which women typically decide to have children,” Lori Panther, MD, MPH, Moderna’s vice president, clinical development, infectious diseases, told GEN.

“In the case of how CMV figures into that, a woman who has a CMV infection during pregnancy is at particular risk of passing that infection on to her infant,” Panther added. “When you look at the total burden of CMV disease impacting an otherwise healthy population, the burden of disease severity is most evident in the children born to women who have had CMV infection.”

According to the U.S. Centers for Disease Control and Prevention (CDC), approximately 1 in 200 infants are born with congenital CMV infection—of which approximately 1 in 5 will consequently have life-altering health conditions that include hearing loss, seizures, and blindness. Those odds increase to approximately 1 in 3 by the time those children reach ages 5 and 6.

Those severe effects plus the unmet medical need, Moderna said, explain why it has prioritized development of a CMV vaccine within its pipeline. Moderna has 37 programs in development across 34 development candidates, including 21 in ongoing clinical studies.

Six mRNAs

mRNA-1647 is a single vaccine consisting of six mRNAs that encode for two proteins on the surface of CMV. Five mRNAs encode the subunits that form the membrane-bound pentamer complex, while the sixth encodes the full-length membrane-bound glycoprotein B (gB). Both the pentamer and gB are essential for CMV to infect barrier epithelial surfaces and gain access to the body, the first step in CMV infection.

According to Moderna, mRNA-1647 is designed to produce an immune response against both the pentamer and gB for the prevention of CMV infection.

“The combination of gB, which has an encouraging history in and of itself, in addition to pentamer, which plays a very important role in viral attachment, is anticipated to be quite effective,” Panther said.

The 100 μg dose was chosen for CMVictory following an interim analysis of safety and immunogenicity data from a Phase II trial (NCT04232280) that also assessed 50 μg and 150 μg dose levels of mRNA-1647.

The interim analysis of that study, conducted one month after receipt of the third vaccination, observed CMV-seronegative participants in mRNA-1647 treatment groups to have neutralizing antibody geometric mean titers (GMTs) against epithelial cell infection that were at least 20-fold higher than the baseline GMT of the CMV-seropositive group—as well as neutralizing antibody GMTs against fibroblast infection that approximated the baseline GMT of the CMV-seropositive group.

CMV-seropositive participants in mRNA-1647 treatment groups were observed to have neutralizing antibody GMTs against epithelial cell infection at least 6.8-fold over baseline, and neutralizing antibody GMTs against fibroblast infection approximately 2-fold over baseline.

CMVictory has an estimated primary completion date of January 29, 2023, according to Moderna has not disclosed when interim data may be released.

Unmet need

Moderna has cited the unmet medical need in CMV, for which no preventive vaccine has been approved. A study published last year in The Journal of Infectious Diseases listed numerous clinical candidates studied in recent years by companies and institutions. They included:

  • Astellas Pharma’s ASP0113—“ASP0113 did not reduce overall mortality or CMV EOD [end-organ disease] by 1-year post-transplant,” according to the conclusion of a Phase III trial (NCT01877655) whose results were published March 19 in EClinical Medicine. (ASP0113 is no longer listed in Astellas’ pipeline).
  • Merck & Co.’s V160—On June 2, a study published in NPJ Vaccines showed Merck’s V160 to be safe and immunogenic in a two-part, double-blind, randomized, placebo-controlled Phase I trial (NCT01986010). However, the specificities and functional properties of V160-elicited antibodies remained undefined, and researchers said further trials were needed to assess whether the vaccine can induce protective anti-CMV immunity in humans.
  • Hookipa Pharma’s HB-101—Hookipa completed enrollment in June in its Phase II trial of HB-101, and has said it expects to report additional safety, immunogenicity, and efficacy data from evaluable patients in the second half of this year, with a final topline data readout planned in the first half of 2023.
  • VBI Vaccines’ VBI-1501—VBI last year completed a Phase I trial of VBI-1501, with data suggesting that the vaccine candidate’s modified gB-G antigen elicited both fibroblast and epithelial cell neutralization.

CMVictory is expected to recruit approximately 8,000 participants, including 6,900 women of childbearing age, from about 150 sites worldwide, starting in the United States.

Moderna isn’t saying how many of that 8,000 are expected to be recruited from the United States. The company has committed that approximately 42% of the U.S. participants to be enrolled will be people of color.

In September, Moderna told investors that roughly half the persons of color are anticipated to be Hispanic or Latinx participants for (23% of planned U.S. participants), followed by Blacks or African Americans (12%), Asians (4%), and others (3%).

In a study published May 21 in the American Journal of Epidemiology, 63% of 9,029 participants studied were CMV seropositive—of which the highest percentages of CMV seropositivity were seen among non-Hispanic Black (88%) and Hispanic (92%) adults compared with non-Hispanic white adults (57%), based on data from the 2016 Health and Retirement Study.

A 2015 study published in Open Forum Infectious Diseases showed CMV seropositivity to be 73% among African American patients studied, vs. 42% for whites, a disparity that persisted across the life span.

“One of the most basic goals of any clinical trial is to have its participants be representative of the population that would benefit from the intervention under study. We know from epidemiological studies that the burden of congenital CMV infection in black communities is twice that of white communities, and we want the demographics of our Phase III trial to reflect the population that is affected by CMV,” Panther said.

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