Novel CMV Vaccine Generates Stronger Response in Key Immune Cells Than Previous Candidate

A messenger RNA (mRNA) vaccine designed to prevent human cytomegalovirus (CMV) elicited long-lasting CMV-specific responses from several types of immune cells, outperforming a previous vaccine concept in multiple measures in a NIAID-supported laboratory study. The findings were published in the Journal of Infectious Diseases.

CMV has been present in much of the global population for centuries. Most people with CMV experience no symptoms and are unaware that they are living with the virus, but CMV is dangerous for people with compromised immune systems and for babies. It is the most common infectious cause of birth defects in the United States. When babies acquire CMV through birth it is called congenital CMV, and it affects about 1 out of every 200 children. Of babies with CMV, about 1 in 5 will experience long-term health effects, including hearing or vision loss, developmental and motor delays, seizures, or microcephaly (a small head). Infants born before 30 weeks' gestational age or with low weight for age that have CMV may be susceptible to additional complications.

There is no preventive vaccine for CMV, and treatment options are limited. An effective CMV vaccine could present needless suffering for millions of babies, and research has been progressing for decades. A recent vaccine candidate was designed to use a laboratory-developed protein from CMV's surface called glycoprotein B (gB)-known to assist CMV in fusing with and entering human cells-to safely teach the immune system how to respond to CMV exposure without causing disease. The vaccine provided about 50% protection from CMV in Phase 2 trials, but that effect was insufficient for the concept to advance to large efficacy studies.

A different, mRNA-based, vaccine is now in a Phase 3 efficacy study in cisgender women with no existing CMV infection. The vaccine was designed to instruct cells to produce the gB protein while also producing a combination of five other glycoproteins on CMV's surface, which like gB are involved in human cell entry.

To better understand how the mRNA vaccine might perform in comparison to gB-based vaccine, researchers examined the immune cells present in blood samples provided by people when they participated in previous studies of each vaccine. The study team performed several assays-laboratory tests-and made the following key observations:

• The mRNA vaccine generated higher levels of antibodies to the five glycoproteins unique to the that vaccine in the form of immunoglobulin G (IgG) antibodies, which are associated with long-term immunity.
• The mRNA vaccine generated more potent signals that the immune system was prepared to deploy antibodies to surround and neutralize-destroy-CMV.
• The gB-based vaccine generated higher levels of IgG antibodies to gB.
• Immune responses to both vaccines were greater in study participants with no existing CMV, but the vaccines still amplified immune system activity in people already living with the virus.

The authors concluded that the mRNA vaccine concept showed promise for better performance than its predecessor in ongoing clinical studies, of which results are expected soon. These results also highlight an opportunity to reformulate the mRNA vaccine to increase the amount of gB proteins it generates, which in tun could improve gB-specific immune responses.

This work was led by Weill Cornell Medicine in collaboration with the Duke Human Vaccine Institute at Duke University Medical Center, Vanderbilt University, Cincinnati Children's Hospital Medical Center, and Moderna, Inc. in Cambridge, Mass. Moderna co-funded the research with NIAID.

Reference: X Hu, et al. Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine. Journal of Infectious Diseases DOI: 10.1093/infdis/jiad593 (2024).