Rutgers scientists have developed a new approach to stopping viral infections: a so-called live attenuated replication-defective DNA virus vaccine that uses a compound known as centanomycin to create a modified virus for vaccine development.
The method was tested to produce a weakened or “attenuated” version of murine cytomegalovirus, a common virus that has been altered so that it cannot reproduce or replicate inside a cell. A virus with defective DNA replication is unable to replicate its genome, its essential genetic material. As a result, it is unable to produce infectious progeny virus in infected cells and is thus restricted primarily to the site of inoculation.
The researchers say that when the weakened virus particles are injected into animals, they stimulate the host’s immune system to recognize the invading live virus particles as foreign, killing the virus whenever it is encountered.
A new approach published in Cell report methodsit has been shown to effectively stop viral infections in laboratory animals.
“We found this method to be safe; the weakened virus infects certain cells without spreading further and alerts the host to produce specific neutralizing antibodies against it,” said Dabboo Jaijian, a research associate in the Department of Microbiology at Rutgers New Jersey Medical. School and author of the study. “We see this as a new method that we hope will accelerate the development of a vaccine against many untreated viral infections in humans and animals.”
The method is called a live attenuated DNA virus vaccine because it specifically targets DNA viruses – such as cytomegalovirus, varicella and herpes simplex viruses, which reproduce by making copies of their own DNA molecules – and uses a modified DNA virus to fight them . Developing a method that can quickly and easily generate live, replication-defective, attenuated viruses will speed vaccine development against diseases caused by DNA viruses, the researchers said.
The researchers showed the method to be effective in mice against several DNA viruses, including human cytomegalovirus, murine cytomegalovirus, and herpes simplex virus 1 and 2.
“One of the main advantages of our technology is the safety provided by robust inhibition of viral replication and the fact that progeny viruses are not produced,” said Jaijian. “Our technology can be easily applied to any DNA virus to produce live attenuated replication-defective viruses for vaccine development.”
Not all viruses reproduce this way. The COVID-19 virus, SARS-CoV-2, for example, is known as an RNA virus because it makes new copies of itself through its RNA. The COVID vaccines use this. RNA, which is short for ribonucleic acid, is used to make proteins in SARS-CoV-2.
The DNA virus vaccine method works specifically with DNA viruses because the researchers treat the cytomegalovirus particles intended for use in the vaccine with centanomycin. The compound is known as a DNA binder because it attaches to the DNA of organisms, including the DNA of viruses, blocking reproduction.
The team aims to eventually test this method in humans with the goal of treating cytomegalovirus and other DNA virus infections.
Cytomegalovirus is a common virus in people of all ages, according to the US Centers for Disease Control and Prevention (CDC). A healthy person’s immune system usually prevents the virus from causing illness. However, cytomegalovirus infection can have serious consequences in immunocompromised patients and organ transplant patients. Congenital infection is also a major cause of birth defects in newborns.
The virus is spread through body fluids, including blood, saliva, urine, semen and breast milk. According to the CDC and the World Health Organization, approximately 50 percent of adults worldwide have been infected with cytomegalovirus. One in three children in the United States contracts the virus before the age of five.
For the experiment, the researchers grew cytomegalovirus samples in their laboratory, purified them, and then infused them with centanomycin. After injection into a laboratory mouse, the weakened virus infects cells but does not spread. Over time, the mice’s immune systems developed enough antibodies to shut down the virus and eliminate the infection.
The analysis confirmed that the treated viral cells were not toxic to other cells in the mouse’s body.
The researchers are continuing to test the method on other medically important viruses, including guinea pig cytomegalovirus as a model to test the effectiveness of the vaccine in guinea pigs, with the intention of moving to clinical trials to test the method’s effectiveness in humans.
Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number U01HL150852. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.
Hua Zhu, assistant professor of microbiology at the New Jersey Medical School, also participated in the study. Other scientists involved in the study include Moses Lee, a professor in the Department of Chemistry at Georgia State University in Atlanta, and Kavita Govindasamy, an assistant professor at the New Jersey Center for Science, Technology and Mathematics at Kean University in Union, New Jersey.