A new Oregon Health & Science University and Weill Cornell Medicine 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 study, published yesterday in Science Translational Medicine, finds that CMV lacking a certain viral protein complex — currently considered a critical vaccine target to prevent cross-placental spread — can still be transmitted and cause significant harm to the developing fetus. These findings strongly suggest that additional vaccine targets that could provide superior protection need to be identified and explored.
"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 Daniel Malouli, Ph.D., assistant professor at the OHSU Vaccine and Gene Therapy Institute and senior author of the study. "Ultimately, we hope our research leads to an effective vaccine that can be made widely available."
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 lifelong health complications for the newborn.
CMV is the leading infectious cause of severe neurodevelopmental impairments worldwide, including childhood hearing loss and intellectual disability. 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, Malouli says, 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 which 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," 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. This suggests 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 across the U.S., including co-corresponding author Sallie Permar, M.D., Ph.D., chair of the department of pediatrics at Weill Cornell Medicine and pediatrician-in-chief at New York-Presbyterian Komansky Children's Hospital of Children's Hospital of New York; Klaus Früh, Ph.D., professor at the OHSU Vaccine and Gene Therapy Institute; and lead author Hsuan-Yuan (Sherry) Wang, Ph.D., a post-doctoral scholar in Malouli's lab.
Researchers hypothesized that inducing neutralizing antibodies against CMV's pentameric complex — meaning a combination of multiple viral proteins needed for infection of certain cell types — should also prevent cross-placental spread to the fetus.
The research team tested their hypothesis in non-human primate models. Surprisingly, they found that a virus without 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 at pharmaceutical companies.
Future research by Malouli and 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.
"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," said Permar, of Weill Cornell. "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."
Research reported in this publication was supported by National Institute of Allergy and Infectious Diseases (NIAID) grants P01AI129859, R01AI059457, and R01AI175459; National Institutes of Health (NIH), Office of the Director grants P51OD011092, P51OD011107, U42OD023038, and U42OD010426; NIH S10 High-End Instrumentation grant S10OD01626; Bill and Melinda Gates Foundation grant OPP1036055; and National Center for Advancing Translational Sciences (NCATS) grant UL1TR002553. The contents of this study are solely the responsibility of the authors and do not necessarily represent the official view of the sponsors.
All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regards to this research, OHSU, Louis Picker, Scott Hansen, and Klaus Früh have a substantial financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology and Picker, Hansen, Früh, and Malouli are inventors of technology licensed to Vir. Review details of OHSU's conflict of interest program to find out more about how we manage these business relationships.
