New Study Lends Support to Possible CMV-Glioblastoma Connection

Glioblastoma (GBM) is among the most common and most aggressive malignant primary brain tumors in humans, accounting for approximately 15% of all cases. While brain cancer has many potential risk factors, including smoking and alcohol consumption, researchers have also identified a possible link between GBM and various pathogenic infections such as cytomegalovirus (CMV).

Numerous previous studies have confirmed that CMV nucleic acids and genes are present in more than 90% of some GBM tumors. A new study led by researchers at the California Pacific Medical Center expands on existing research and published articles and explores the connection between CMV and glioma stem-like cells (GSC). According to the study’s authors, existing data supports the idea that long-term, low-level CMV infection may promote the survival, stemness, and proliferation of glioma stem-like cells and could significantly contribute to GBM pathogenesis.

Glioma stem-like cells, like some other malignant tumors, exhibit features of self-renewal and have the ability to initiate and sustain tumor growth, metastasis, and resistance to therapy. Glioma stem-like cells are characterized by resistance to radiation and chemotherapy and are primarily responsible for GBM recurrence.

Based on the hypothesis that a specific CMV gene signature may be associated with GBM pathogenesis, study researchers used glioma cell lines and primary glioma stem-like cells infected with clinical and laboratory CMV strains, and measured relative viral gene expression levels along several time lines, up to 15 weeks post-infection.

Researchers concluded that while CMV gene expression was detected in several infected glioma lines through week five, only CMV-infected glioma stem-like cells expressed viral gene characteristics at the 15 week mark. A significant finding was that CMV-infected glioma stem-like cells outlived their uninfected counterparts, and this extended survival was paralleled by an increased frequency of tumor sphere formation and an increase in stemness regulators, including BMX, a novel CMV target first identified by the California Pacific Medical Center study.

Overall, the data support the theory that long-term, low-level CMV infection plays a critical role in the survival, stemness, and reproduction of glioma stem-like cells and could significantly contribute to GBM development and progression.

Researchers are continuing to study the relationship between CMV, GBM, and other types of cancer, including prostate, colon, and breast cancer. Clinical trials to evaluate the efficacy of CMV-specific cellular immunotherapy for GBM are also underway. With the increasing amount of evidence regarding the CMV-GBM connection, there is also growing interest in exploring vaccination against CMV antigens as a component of emerging immunotherapeutic strategies against GBMs and other malignant tumors.


VBI Partners with Le Classique to Raise CMV Awareness in Canada

VBI is pleased to announce its sponsorship support of Le Classique, a 3-on-3 ball hockey tournament being held in Winnipeg, Canada on February 5th – 8th, 2015. Now in its third year, Le Classique is expected to draw over 2,000 individuals seeking to broaden congenital cytomegalovirus (“CMV”) public awareness.

“Le Classique founders Marc Foidart and Rob Tetrault have combined their love of hockey with a very worthy cause,” said Jeff Baxter, VBI’s President and CEO. “We look forward to supporting Le Classique in their efforts to raise CMV awareness in Winnipeg and throughout Canada.”

Originally founded in Canada, VBI maintains close ties to the country and its people. VBI’s research facilities and the majority of its workforce are located in Ottawa, Ontario. In addition, VBI has participated in several Canadian government sponsored programs which have allowed the company to more quickly advance its product candidates.

CMV is among the most common congenital infections in Canada, causing a host of prenatal developmental delays. Despite its prevalence, awareness of CMV among women of reproductive age remains low. A 2012 study published in Preventative Medicine revealed that only 7% of men and 13% of U.S. women surveyed had heard of congenital CMV.

“Until a vaccine can be developed and deployed, awareness is the best current tool we have to prevent future infections,” said Le Classique founder Rob Tetrault. “Women contemplating pregnancy need to be made aware of the condition so they can understand and better manage potential infection risks.”

100% of the proceeds from Le Classique will be donated to the Canadian CMV Foundation. To make a contribution, or to learn more about Le Classique, visit: http://www.leclassique.ca.


New Study Examines CMV Shedding Patterns in Healthy CMV-Seropositive Children

Cytomegalovirus (CMV) is a highly contagious virus that is spread by direct contact with bodily fluids. To better understand potential transmission risks from contact with the body fluids of children, a recent study monitored weekly and daily CMV shedding patterns in healthy CMV-seropositive children.

While many studies have examined CMV shedding among healthy children, few have collected longitudinal data and none have assessed CMV shedding at weekly or daily intervals.

Researchers selected study participants for longitudinal follow-up from a sample of healthy children aged 0 – 47 months. The participants were selected from the Atlanta, Georgia metropolitan area and did not have a diagnosis of congenital CMV infection. To meet the follow-up criteria, the children had to test positive for anti-CMV IgG; 50 of 161 children qualified. Of these children, researchers enrolled 23 of 25 who also tested positive for CMV DNA in saliva and/or urine. In addition, the study included some CMV-seropositive non-shedders, allowing researchers to assess spontaneous initiation of shedding.

During the course of the study, each child received 12 weekly in-home visits at which field workers collected saliva and urine. During the final two weeks, parents also collected saliva and urine samples daily.

The study found that children who had contracted CMV and were shedding at the first screening visit continued to exhibit occasional shedding in weeks 11 and 12. In addition, children shedding at the screening visit had CMV DNA in 84% of follow-up saliva specimens and 28% of follow-up urine specimens. Median and mean viral loads did not change substantially over time, but shedding occurred at higher viral loads among younger children. These finding suggests that young CMV shedders pose an ongoing risk to pregnant women.

Another significant finding was the surprisingly high viral loads in the saliva of healthy young children. Of the 502 CMV DNA-positive saliva samples collected, nearly half contained greater than 100,000 copies/mL and more than one quarter had greater than 1×106 copies/mL. While several studies have measured CMV viral loads among children with congenital CMV infection, only two previous studies have measured viral loads among healthy children. This is significant because healthy children are most likely to infect pregnant women due to behavioral habits like sharing food or utensils.

Using this data, researchers hope to encourage behavioral changes in women who may be unaware of the risks posed by CMV. CMV infection is a significant cause of birth defects and developmental disabilities, including hearing loss, vision loss, and intellectual disability. Although congenital CMV infection is among the most common causes of developmental delays, few women are aware of the virus and the hygienic strategies needed to prevent transmission.

According to the Centers for Disease Control and Prevention (CDC), simple measures like frequent hand washing after contact with young children, kissing children on the forehead rather than the lips, avoiding the sharing of food or beverages, and disinfecting toys and countertops can help prevent the spread of CMV.

Preventing primary or re-infection of CMV through behavioral changes is of great importance, especially for women of childbearing age. While there is currently no licensed vaccine or established treatment plan for pregnant women, the Institute of Medicine ranks development of a vaccine to prevent CMV as a “highest priority” item.


Researchers Investigate Possible Link between CMV Infection and Atherosclerosis

Acute coronary syndrome (“ACS”) is an umbrella term that describes any condition brought on by sudden, reduced blood flow to the heart. ACS is often caused by atherosclerosis, the accumulation of plaque that can clog arteries.

While there are a number of known hereditary and lifestyle risk factors for ACS, researchers are exploring the role inflammation may play in the development of both ACS and atherosclerosis. One potential cause of inflammation may be cytomegalovirus (“CMV”) infection.

The relationship between CMV and atherosclerosis has been a subject of interest for a number of years. In a 2006 study, coronary plaque specimens from 38 patients who underwent a heart catheterization procedure were divided into an ACS group and a non-ACS group. Using special stains designed to detect CMV, researchers found the ACS group had a higher number of CMV-infected cells. The investigators concluded that CMV in the coronary plaque may be linked to the development of artery blockages.

In a more recent study, researchers examined CMV infection in 105 patients with atherosclerosis who received coronary artery bypass grafts. After adjusting for other risk factors, researchers concluded that patients with a history of ACS were more likely to test positive for CMV. Finally, in a 2012 meta-analysis of 55 prior studies, investigators concluded that CMV infection is associated with the progression of atherosclerosis, especially in Asian populations.

While these studies show that CMV may be linked to the development of atherosclerosis and ACS, the exact mechanism by which CMV affects vascular health is less well understood. Some recent research suggests that CMV and platelets may interact in a way that leads to inflammatory and angiogenic responses, which may exacerbate tissue damage and contribute to the formation of plaque in the inner lining of arteries.

By age 40, between 50% and 80% of U.S. adults will have had a CMV infection. Following the primary infection, the CMV virus typically remains dormant, but it can periodically reactivate, especially in immunocompromised persons.


New Study Explores Breast Milk as Postnatal CMV Transmission Source in Premature Infants

Very low birth weight infants fed breast milk from cytomegalovirus  (“CMV”)-positive mothers may be at an increased risk of developing postnatal CMV infection, says a new study published in JAMA Pediatrics.

Premature infants with very low birth weight (“VLBW”) are particularly vulnerable to CMV infection because of their immature immune systems. CMV infection can cause serious disease and, in some cases, can lead to death.

In one of the largest studies of its kind, investigators evaluated blood transfusions and breast milk as potential CMV transmission sources. 539 infants in three neonatal intensive care units were tested at birth for evidence of congenital CMV infection, and again at regular intervals for ninety days.

29 out of the 539 infants acquired a postnatal CMV infection during the course of the study. Five infants infected with CMV developed severe disease or died. 27 of the 28 CMV infections occurred among infants fed CMV-positive breast milk. No CMV infections were linked to blood transfusion (blood products were CMV-seronegative and leukoreduced).

The study’s investigators estimate that between 10-20% of VLBW infants who are fed CMV positive breast milk from mothers with a history of CMV will develop postnatal CMV infection. In this study, 76% of mothers had been infected with CMV prior to giving birth.

Importantly, despite the potential risk, The American Academy of Pediatrics (“AAP”) Policy endorses routine breast milk feedings, even in CMV seropositive mothers. The AAP Policy suggests that benefits of breast milk feedings may outweigh the risks.


Congenital CMV 101: From Prevention to Treatment

Dr. Michael Cannon, a research epidemiologist at the CDC’s National Center on Birth Defects and Developmental Disabilities, discusses congenital cytomegalovirus. This webinar was originally presented by Dr. Cannon on behalf of the CMV Public Health & Policy Conference.

CMV infection is a major health concern for expecting mothers, with 30,000 U.S. children born with the virus each year. Congenital CMV infection (cCMV) occurs when the virus is transmitted to a baby before birth, often by a mother who is unaware of the infection. While only ten percent of infants congenitally infected with CMV display symptoms, one in six children born with CMV, or more than 5,000 children annually, go on to develop permanent complications including hearing loss, vision loss, and intellectual disabilities.

The number of children impacted by CMV is greater than the number of children affected by fetal alcohol syndrome or Down syndrome. cCMV is responsible for one in five cases of infant hearing loss, and more than $1B per year is spent on persons affected by CMV.

Spread of Infection

CMV is transmitted through direct contact with bodily fluids, most often saliva and urine. CMV seropositive children are a major source of infection due to their high viral loads and shedding. CMV is easily spread among children with infected siblings. Parents with a child who is shedding the virus have a 25 percent chance of infection. Because they work with young children, day care workers are at particularly high risk of infection.

Interventions

Possible interventions to reduce the occurrence of cCMV include prenatal screening, behavioral modification (e.g., the avoidance of behaviors that could result in transmission, like sharing utensils or kissing on the lips), treatment to prevent fetal infection (with antiviral therapies), and early detection and intervention immediately after birth. Currently none of these interventions are routine in the U.S. Utah is the only U.S. state to mandate testing for cCMV in newborns who display hearing loss.

Treatment

Current treatment options for newborns diagnosed with cCMV include antiviral drugs. Antivirals have been shown to have limited and perhaps temporary benefits including the reduction or elimination of CMV viral shedding.

Future Directions

In a 2011 survey published in the journal Pediatrics, many respondents viewed CMV screening favorably, with the majority somewhat or strongly agreeing that they would want to have their newborn tested for CMV, even when it is not performed routinely or if a small payment was required.

While there is currently no vaccine available to treat cCMV, the Institute of Medicine ranks development of a vaccine to treat CMV as a “highest priority” item. In addition, legislatures in two states, Connecticut and Illinois, have considered laws requiring screening for newborns who display signs of hearing loss.

Important Disclaimer: The use or display of content from the Centers for Disease Control and Prevention (CDC) does not imply endorsement or government sanction of any third party causes, ideas, websites, products, or services by the CDC, or by Dr. Cannon.


CMV Organ Transplant Market Overview

Cytomegalovirus (CMV) is among the most common infections following solid-organ transplantation and hematopoietic stem cell transplant procedures, causing disease, transplant complications, and adverse outcomes.

By age 40, between 50 and 80 percent of U.S. adults will have had a CMV infection. Following the primary infection, the CMV virus typically remains dormant, but it can reactivate and cause illness in immunocompromised persons.

Given their immunocompromised state, recipients of organ and stem cell transplant are at particular risk of suffering CMV-related complications. Despite improved CMV awareness and monitoring by transplant physicians, and management with antiviral drugs, the incidence of CMV complications remains high, with estimates ranging from 20 to 70 percent in the first year following transplantation.

CMV complications commonly include pneumonia (shortness of breath, cough), GI disease (abdominal pain, bleeding, diarrhea), CNS disease (altered mental status, cognitive dysfunction), and retinitis (blurring or loss of central vision, scotomata). The type of CMV complications vary by patient population – for instance, CMV pneumonia is more common following stem cell transplant procedures, and CMV retinitis is more common in among persons living with HIV/AIDS.

Complications also relate to the indirect effects of CMV on the patient’s immune system, with a myriad of studies showing that CMV disease increases the incidence of graft rejection, graft injury, and graft failure. Secondary fungal and bacterial infections are also common. CMV infection and disease is associated with longer hospital stays and increased care costs.

Transplant Society Recommendations

In December 2008, a panel of CMV and solid-organ transplant experts met with the Infectious Diseases Section of The Transplantation Society to develop consensus guidelines for managing CMV. First published in 2010, and later revised in 2012, topics covered include CMV diagnosis, risk assessment, prevention, and treatment.

The Transplantation Society recommends that CMV screening be performed before transplantation to guide the treatment approach. The Transplantation Society also suggests that physicians consider administering antiviral medications to patients most at-risk.

To reduce the impact of CMV disease, antivirals are usually begun following the transplant procedure and continued for three to six months or longer. Several antivirals have been evaluated including acyclovir, valacyclovir, ganciclovir, and valganciclovir. Valganciclovir is increasingly being used as the preferred medication for treatment.

Despite significant advances in the prevention and management of CMV, The Transplantation Society has suggested that an effective CMV vaccine, like the one VBI hopes to produce, could satisfy the large need for preventing CMV infection or reactivation post-transplantation.

VBI is developing a prophylactic vaccine to prevent CMV infection – based on preclinical data, VBI has initiated work for GMP manufacturing of its lead candidate for use in formal preclinical and Phase I trials.



Researchers Explore Impact of CMV on Aging and the Immune System

With funding from a five-year, $2.3M NIH grant, researchers at the University of Arizona College of Medicine are studying how cytomegalovirus (CMV) may impact immune system function as we age.

Dr. Janko Nikolich-Žugich, M.D. Ph.D., Chair of the University of Arizona Department of Immunobiology, believes that CMV may cause long-lasting defects in how the immune system responds to infection. In his research, Dr. Nikolich-Žugich describes the immune system as “highly integrated”. He believes that small dysregulations in signaling and cell to cell communication could translate into major deficiencies in overall immune response. The defects may weaken our ability to defend against common viruses, like the flu, as we grow old.

Commenting on a study published by his team this September in the The Journal of Immunology, Dr. Nikolich-Žugich noted that, “Our research group recently showed that infection with only CMV, and no other acute or persistent viruses, causes defects in immune responsiveness to other infections and causes alterations in the naïve T cell receptor repertoire and impaired effector T cell responses.”

T cells are a type of white blood cell that play a key role in adaptive immunity, the system that regulates the body’s response to pathogens. The NIH-sponsored research will seek to elucidate the mechanism by which CMV affects naïve T cell responses, as well as the impact persistent CMV infection has on our immune system. In the U.S., 50 to 80 percent of adults are infected with CMV by the time they are 40 years old.


Universal CMV Screening of Newborns Faces Systemic Challenges

Congenital CMV infection often goes undetected because the majority of affected infants do not present symptoms at birth; routine screening of newborns could allow infected infants to receive better care.

The first law in the U.S. mandating CMV testing took effect in Utah last July. It requires urine or saliva tests for newborns who fail two infant hearing screenings. Lawmakers in Connecticut and Illinois have introduced similar legislation in 2014, but in both states, the bills have so far failed to pass.

Newborn screening tests for illnesses that, while rare, can be treated or managed to minimize impact. Each state runs its own newborn screening program, with the types of testing varying from state to state. In addition to mandatory hearing tests, states rely on a dried blood spot assay which screens for multiple conditions in parallel. While CMV is among the most common congenital infections in the U.S., outside of Utah, CMV testing is not yet required by law.

Challenges to CMV screening are largely practical – CMV viral load is low in blood, and as a result, it is a poor fit for the routine blood tests that are a fixture of newborn screenings today. CMV is best detected using saliva or urine-based assays – however, screening based on urine or saliva has the considerable disadvantage of requiring the establishment of an infrastructure for collecting and transporting specimens – mandating a new and distinct test for all infants would require sweeping legislative changes and could face resistance from an already strained healthcare delivery system. Adding to the challenge, because CMV is a congenital infection, a proper diagnosis can only be made if the CMV virus is detected within a week of birth.

Researchers estimate that, because of onset later in life, only about half of the hearing loss resulting from congenital CMV infection is detected by universal newborn hearing screening. As a result, much of the hearing loss and many other CMV-related disabilities remain undetected for years after birth and are never linked to congenital CMV infection, and are therefore not optimally managed.

Lacking mandatory testing, hospital administrators may consider adopting voluntary screening for congenital CMV, along with a standardized follow-up procedures to monitor the impact of early diagnosis. Each year, approximately 5,000 U.S. infants will develop permanent problems due to CMV, some of them severe, including deafness, blindness, and mental retardation.