The Potential of Moderna's mRNA Platform for Developing a Vaccine to Fight CMV

It is natural to think that a viral infection will always manifest itself as an illness or disease until either the body has cleared it or the virus kills its host.  In fact, there are many viruses whose success relies on their ability to enter our bodies and hide without causing an acute illness or alerting our immune systems.  These sleeper viruses then periodically wake up and use their host to spread silently to their contacts. The herpes family of viruses are masters of this tactic, and Cytomegalovirus, or CMV, is a member of this family. CMV is estimated to live silently within 60 percent of the U.S. and similar populations – and in nearly 80 percent of people worldwide. 

However, while harmless to most people with healthy immune systems, CMV is the number one cause of babies being born with severe damage to their brains, eyes and ears and associated lifelong disabilities.  This so-called congenital CMV infection occurs in one in every 200 babies born in the US.  One in 10 of these babies will have problems at birth. There are an estimated 20,000 to 40,000 babies born each year in the U.S. with CMV infection, of which approximately 6,000 will develop permanent health problems, including as many as 400 deaths.  CMV can also reactivate in immunosuppressed people such as those receiving transplants and cause them to lose their transplant or die.

The impact of CMV can be devastating and it is much like Zika, but far more common. The microcephaly, deafness, blindness, seizures and intellectual disability caused by CMV result in a huge personal and emotional burden on families, not to mention the cost to individuals and health systems for the lifelong care of these children.

So how do we prevent congenital CMV?  Well it is hard, firstly, because CMV is almost always an asymptomatic infection in healthy adults. Infected mothers do not feel ill and typically won’t learn of their baby’s infection until an ultrasound is done. Secondly, pregnant women are typically not screened for CMV because there is currently no vaccine or treatment.

Moderna is working to change that, using its messenger RNA (mRNA) platform to create a CMV vaccine that directs cells to safely produce and express antigenic proteins that trigger the body’s immune system to produce antibodies that can neutralize the virus and prevent infection.  

Moderna currently has a Phase 1 study for a CMV vaccine, mRNA-1647, and in newly published data in the scientific journal Vaccine, Moderna demonstrated the potential of its mRNA vaccine platform to develop novel vaccines both for pregnant women and transplant patients. (Additional clinical trial information can be found here.)

CMV uses two proteins to attach to and enter the body’s cells: one is a protein called gB, or glycoprotein B, and the other is a complex protein made of five proteins assembled together, called the Pentameric Complex (PC). gB is important for entering fibroblasts and PC is important for entering epithelial cells (the cells that line our skin, nose and mouth). If our vaccine is effective in blocking these proteins, then the expectation is that CMV cannot enter the cells and therefore cannot cause congenital infections.

In the study, Moderna’s mRNA encoding CMV glycoproteins gB and PC were put into its delivery system. When this vaccine was given to mice and non-human primates it produced high levels of very specific and durable antibodies that are able to neutralize CMV.

In the study, Moderna delivered six mRNAs which then correctly assembled within the cell to make the pentamer protein and the gB protein – these in turn induced the body to produce an immune response against these key CMV proteins. This was the first time that encoded mRNA was used to create the pentamer complex directly in an animal – and showed that when brought together with gB in a multi-valent vaccine it was possible to neutralize infection across a wide variety of cells.

The search for a CMV vaccine has been ongoing for the past 40 years, and it remains a “silent” global burden and a key priority for those of us fighting viruses and infectious disease. Creating a vaccine that prevents congenital CMV would help prevent devastating outcomes for children and families – and we are hugely encouraged by what we have been able to achieve with the combination of encoded mRNA and our platform.  If this is repeated in clinical trial and the vaccine is shown to prevent CMV infection, then we could be on our way to helping the body to be ready to recognize and repel this silent invader before it can cause disease and disability.   

This work also provides important confirmation of the ability of mRNA, designed and delivered in this way, to induce immune responses to complex antigens.  This in turn opens the door to tackling an array of potentially preventable diseases that up until now have been difficult to address with conventional technology.

The paper in Vaccine can be found here.

Other sources of information on CMV can be found at:
https://www.cdc.gov/cmv/index.html
https://www.nationalcmv.org/home.aspx
http://www.congenitalcmv.org/index.asp