Virus World

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children's National Hospital faculty. 

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children's National and the study's senior author, presented the teams' findings Nov. 8, 2019, during a second-annual symposium jointly held by Children's National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children's National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings. According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person's immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person's missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body's infection-fighting white blood cells, the Children's National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3). Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

• Three patients were treated for active CMV, and the T-cells resolved their viremia.
• Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
• Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses. 

"These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections. Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients." Michael Keller, M.D., pediatric immunologist at Children's National and the lead study author.

No other emerging pathogen is known to have jumped so frequently from species to species. A virus that killed a six-year-old boy in 1965 has also infected bonobos and chimpanzees in an unprecedented case of viral ‘ping-pong’ between species.

James Chodosh at Harvard Medical School in Boston, Massachusetts, Donald Seto at George Mason University in Manassas, Virginia, and their colleagues reconstructed the history of a long-stored sample of adenovirus, a type of virus that causes colds and other illnesses. By tracking the small changes that accumulated in the virus’s genome when it infected new species, the researchers found that it had previously lived in bonobos (Pan paniscus), chimpanzees (Pan troglodytes) and humans.

The analysis also showed that the pathogen was remarkably similar to an adenovirus recently identified in two groups of primates that had never come into contact with each other: bonobos in the San Diego Zoo in California and chimpanzees in a primate research facility in Louisiana. The results suggest that the transmission of adenoviruses to humans from other animals might have an important role in the emergence of pathogens that could harm human health.

The original findings were published in the Journal of Virology: https://doi.org/10.1128/JVI.00564-19

Large-scale study to identify human adenovirus genotypes in Singapore leads to discovery of four new adenovirus strains and increase in strains linked to severe diseases. Researchers suggest use of antiviral therapies and adenovirus vaccines, and routine monitoring of adenovirus strains.

Human adenovirus (HAdV) infections in Singapore and Malaysia have caused severe respiratory disease among children and adults in recent years, but scientists still don't know whether these outbreaks are due to new or re-emerging virus strains. In the first large-scale study to systematically identify HAdV strains in Singapore, scientists led by Duke-NUS Medical School have discovered four new strains and found an increase in two strains linked to severe diseases. Using a genotyping algorithm to study HAdV infections among patients from two large public hospitals in Singapore, the researchers tested over 500 clinical samples from paediatric and adult patients. "We detected four new HAdV strains closely related to a strain isolated from an infant in Beijing during an epidemic in 2012-2013," said the study's lead author, Dr Kristen Coleman, from the Emerging Infectious Diseases (EID) Programme at Duke-NUS Medical School. "Our results also highlight an increase in HAdV types 4 and 7 among the paediatric population over time. Importantly, patients with weakened immune systems and those with HAdV types 2, 4 or 7 were more likely to experience severe disease."

Adenoviruses are a family of viruses with over 50 known strains that can infect people of all ages and most commonly infect the respiratory system. The sore throat and fever associated with the common cold are among the symptoms brought about by different adenovirus strains. In some cases, particularly in patients with weakened immune systems, adenoviruses can cause severe respiratory symptoms, including pneumonia, or more life-threatening conditions like organ failure. "The high prevalence and severity of HAdV type 4 infections identified in our study is intriguing," stated Dr Gregory Gray, senior and corresponding author of the study, who is a professor in the EID Programme at Duke-NUS and member of the Duke Global Health Institute at Duke University, USA. "Upon its discovery in the 1950s, HAdV type 4 was largely considered restricted to and controlled by vaccine in the US military population, with rare detections among civilians. Singapore would benefit from more frequent studies of clinical HAdV genotypes to identify patients at risk for severe disease and help guide the use of new antiviral therapies."

Given the study results, the authors suggest public health officials and clinicians in Singapore consider using antiviral therapies and adenovirus vaccines. Furthermore, they recommend Singapore and other countries considering new HAdV treatment and control measures conduct periodic and routine adenoviral genotype surveillance to collect the data needed to make informed, evidence-based decisions.

Published in J. Infectious Disease (Sept. 30, 2019):

https://doi.org/10.1093/infdis/jiz489