Study reveals key insights for preventing cytomegalovirus spread to fetuses

A new Weill Cornell Medicine and Oregon Health & Science University co-authored study provides critical insight for the development of a vaccine that can more effectively block the spread of cytomegalovirus, or CMV, across the placenta to babies before they are born.

CMV is one of the most common viruses and most people don't even know they've been infected. However, it carries significant risks to the developing fetus, including lifelong health complications such as hearing loss, developmental delays and neurological impairment. An effective vaccine would help protect babies from future health impacts.

The new study, published March 12 in Science Translational Medicine, finds that CMV lacking a certain viral protein complex - thought to be a critical vaccine target to prevent cross-placental spread - can still be transmitted and cause significant harm to the developing fetus. These results strongly suggest that additional vaccine targets providing superior protection need to be identified and explored.

As a pediatric health care provider, I am passionate about giving children the best possible start to a full and healthy life, so it's heartbreaking to see a child undergo this infection and face devastating and potentially life-long complications. These findings are exciting because they bring us one step closer to the development of an effective vaccine, which we hope can protect pregnant women and babies around the world."

Dr. Sallie Permar, co-corresponding author, chair of the Department of Pediatrics and the Nancy C. Paduano Professor in Pediatrics at Weill Cornell Medicine and pediatrician-in-chief at NewYork-Presbyterian Komansky Children's Hospital of Children's Hospital of New York

Stopping cross-placental spread

CMV is a common virus that can infect people of all ages, and over half of adults have been infected with this virus by age 40. While a CMV infection can cause mild flu-like symptoms, most people show no signs of disease and aren't aware that they have caught the virus.

However, infection during pregnancy can pose a substantial risk of transmission to the developing fetus which can result in life-long health complications for the newborn.

CMV is the leading infectious cause of severe neurodevelopmental impairments including childhood hearing loss and intellectual disability worldwide. According to the Centers for Disease Control and Prevention, about 1 in 200 babies born in the United States will contract a congenital CMV infection, and about 20% of them will go on to develop severe birth defects or suffer from long-term neurologic or other health problems.

Strategies to prevent parent to fetus transmission are urgently needed, says senior author Dr. Daniel Malouli, assistant professor at the OHSU Vaccine and Gene Therapy Institute, but despite more than four decades of clinical research, no effective vaccine has been developed. This lack of progress is largely due to a gap in understanding on what virus/host interactions allow CMV to cross the placenta in human patients.

"More robust information on the interactions between the virus and the human host is crucial for the selection of promising targets that can be used for the development of an effective vaccine," Dr. Malouli said. "The data uncovered in our research go against commonly held assumptions in the field of CMV vaccine development and indicate that some of the most widely used vaccine targets may provide insufficient protection from cross-placental spread suggesting that other CMV proteins may need to be included in future vaccine designs to block these transmission events."

One step closer to an effective vaccine

The study was a collaborative effort among researchers, including Dr. Klaus Früh, professor at the OHSU Vaccine and Gene Therapy Institute, and lead author Hsuan-Yuan (Sherry) Wang, Ph.D., a post-doctoral scholar in the group of Dr. Malouli.

Researchers hypothesized that inducing neutralizing antibodies against CMV's pentameric complex, a combination of multiple viral proteins needed for infection of certain cell types, should also prevent cross-placental spread to the fetus.

In the now published study, the research team tested this hypothesis in their non-human primate models. Surprisingly, they found that a virus devoid of the pentameric complex was still able to cross the placenta and harm the fetus, indicating that other targets need to be investigated — urgent work of high importance for ongoing vaccine development programs of various pharmaceutical companies.

Future research by the team will leverage the existing models used in this study to further understand virus-host interactions required for cross-placental transmission, and identify new, more effective vaccine targets.

"We hope that our work can pave the way for the selection of more promising vaccine targets, which we will test in future studies," said Dr. Malouli. "Ultimately, we hope our research leads to an effective vaccine that can be made widely available."