According to a study conducted by researchers at Weill Cornell Medicine, an experimental mRNA vaccine against human cytomegalovirus (CMV)a common virus that can infect infants during pregnancy, has elicited some of the most promising immune responses to date of any vaccine candidate against the virus.
The study was published in The Journal of Infectious Diseases.
Cytomegalovirus (CMV): here's what the research says
The study, published in The Journal of Infectious Diseases, provided evidence that the new mRNA vaccine candidate, manufactured by Moderna, Inc., can protect adults from CMV. Therefore, it could potentially prevent women from transmitting the harmful infection to their babies during pregnancy.
Compared to a previously moderately effective vaccine candidate called gB/MF59, the mRNA vaccine elicited better responses in preventing Cytomegalovirus from infecting the epithelial cells that line the mouth and nose and provide the first line of defense against viral infection. The mRNA vaccine was also more effective at inducing the immune system to destroy CMV-infected cells.
“We learned that the new vaccine has the potential to be more effective than a previous CMV vaccine candidate because some of the functional immune responses it elicits are larger in magnitude,” said senior author Dr. Sallie Permar, chair of the Department of Paediatrics. and Nancy C. Padovano Professor of Pediatrics at Weill Cornell Medicine. “An ongoing clinical study will confirm whether these differences lead to greater protection against Cytomegalovirus infection.”
Although healthy adults are largely asymptomatic, one in 200 newborns worldwide is infected with Cytomegalovirus during their mother's pregnancy. “It's the most common congenital infection in the world,” said Permar, who is also pediatrician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center and NewYork-Presbyterian Komansky Children's Hospital.
While the virus rarely causes severe disease in healthy adults, it can cause birth defects and brain damage in newborns infected in utero and deadly infections in immunocompromised adults.
Co-first authors Krithika P. Karthigeyan, a postdoctoral associate in pediatrics at Weill Cornell Medicine, and Xintao Hu, who was part of the research team at the time, also contributed to this research.
Previously, Sanofi and Novartis developed the gB/MF59 vaccine candidate, which targeted glycoprotein B (gB), a sugar-rich viral surface protein that works with other proteins to help Cytomegalovirus attach to and enter human cells. It protected about half of vaccinated individuals from CMV infection in a phase 2 clinical trial conducted by the National Institute of Allergy and Infectious Diseases Vaccine Clinical Trials Network. When the study ended in 2013, it did not advance to phase 3 clinical trials.
Permar and his colleagues used data and patient samples from the phase 2 gB/MF59 study in adolescent girls as a benchmark for evaluating the new mRNA-based vaccine. Using the same technology that produced the company's COVID-19 vaccine, Moderna's CMV vaccine added a second target – a five-unit protein complex that allows the virus to infect the epithelial cells lining the nose and mouth – in addition to glycoprotein B.
In this study, Permar and his team compared the immune responses of individuals vaccinated with gB/MF59 in the Phase 2 study to those immunized with Moderna's mRNA-based Cytomegalovirus vaccine in a Phase 1 clinical trial that ended in 2020. In Specifically, the team compared immune responses in people who were protected against CMV infection after receiving the old vaccine.
The mRNA vaccine, likely because of the additional second target, did a better job of preventing Cytomegalovirus from infecting healthy skin cells. The vaccine stimulated immune cells to produce neutralizing antibodies that block the virus from entering a cell, thus preventing viral replication.
Furthermore, antibody responses induced by the mRNA vaccine could destroy infected cells. In contrast, people vaccinated with the gB/MF59 vaccine produced higher levels of antibodies against gB that had low neutralizing activity but had a strong ability to engulf and eliminate a virus.
The Moderna vaccine has advanced to the first Phase 3 clinical trial for a CMV vaccine candidate, which will help determine whether these differences in immune responses will lead to stronger protection against Cytomegalovirus.
“After more than 50 years of research, we are closer than ever to having a licensed CMV vaccine,” Permar said. “The new mRNA platform has great potential.”
Meanwhile, Permar and his colleagues have developed a preclinical model to test whether similar vaccines protect against fetal cytomegalovirus transmission during pregnancy.
Antibodies that evoke virus-engulfing white blood cells may play an important role in protecting children from potentially serious congenital human cytomegalovirus (HCMV) infections, according to a further study by a Weill Cornell Medicine and NewYork-Presbyterian researcher.
The study, which appeared in the Journal of Clinical Investigation, was the most comprehensive analysis of its kind to date in HCMV research. The researchers examined antibodies in
the blood of 81 mothers infected with cytomegalovirus, comparing the properties of the antibodies in mothers who had passed HCMV and those who had not passed it to their babies.
A key finding was that women in the no-transmission group tended to show higher levels of the white blood cell-evoking mechanism, known as antibody-dependent cell phagocytosis, against cytomegalovirus.
“These findings certainly have implications for the types of immune responses that HCMV vaccines should target,” said senior author Dr. Sallie Permar, the Nancy C. Padovano Professor of Pediatrics and Chair of Pediatrics at Weill Cornell Medicine and a pediatrician chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and NewYork-Presbyterian Komansky Children's Hospital.
The study's first author is Dr. Eleanor C. Semmes, a doctoral physician-researcher in the Department of Molecular Genetics and Microbiology at Duke University School of Medicine.
Cytomegalovirus and related viruses of the herpesvirus family are believed to have infected humans and other mammals for at least tens of millions of years. During this time, these viruses have developed myriad tools and strategies to evade their hosts' immune defenses and establish long-term infections.
HCMV is believed to infect most people in developed countries and virtually all people in developing countries.
Although most infections go unnoticed, cytomegalovirus, as it incubates in the body – throughout life – is believed to subtly promote multiple human ailments, from cancer to heart disease. Additionally, a weak immune system due to HIV, immunosuppressant drugs, or being very old or young can trigger the spread of cytomegalovirus and potentially fatal diseases.
HCMV is maintained in the human population in part through mother-to-child transmission during pregnancy. These congenital cytomegalovirus infections can cause stillbirth, hearing loss, brain development abnormalities, and other conditions in young children; and preventing them is a major public health goal.
Conventional therapeutic strategies based on vaccines and antibodies have so far proven ineffective against congenital HCMV infection, underscoring the need to understand how the immune system can effectively combat this virus.
“Currently, when a mother has an acute cytomegalovirus infection, or is known to have an infected fetus, we have nothing to offer in terms of vaccines or immunotherapies,” Dr. Permar said.
For the study, she and her team used maternal and infant umbilical cord blood samples stored at the Carolinas Blood Bank at Duke University School of Medicine, where Dr. Permar was based at the start of the study. Forty-one of the mothers infected with cytomegalovirus had transmitted the virus to their newborns; the other 40 are not.
A notable discovery concerned “neutralizing antibodies.” These are antibodies that bind to vulnerable sites of the virus and therefore directly interrupt, by neutralizing, the virus's ability to infect cells, reproduce and spread in standard laboratory plate tests.
Normally, vaccines against a virus aim to elicit neutralizing antibodies; previous unsuccessful cytomegalovirus vaccines also did the same. But Dr. Permar and colleagues found that higher levels of HCMV-neutralizing antibodies in maternal blood were not associated with a lower risk of mother-to-child transmission.
They found evidence, however, that mothers who had not transmitted the virus had higher levels of antibody-dependent cellular phagocytosis. This suggests that this indirect mode of antibody immunity, in which antibody proteins use their “tail” sections, called Fc regions, to evoke virus-devouring macrophages and other white blood cells, is a mode from which HCMV is not so able to escape.
“To combat cytomegalovirus, which is so good at evading the immune system, we need to go beyond the simple concept of neutralizing antibodies to consider antibodies that work in other ways,” Dr. Permar said.
The findings are sure to drive HCMV vaccine efforts with newfound speed in the wake of the success of the SARS-CoV-2 vaccine. Dr. Permar and colleagues are currently applying these findings to work with the vaccine company Moderna, which is developing a cytomegalovirus vaccine candidate using the versatile mRNA platform.
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