New Delhi, July 27: The death of a patient receiving gene therapy in the US and new laboratory studies have raised safety concerns over a virus used to ferry genes in India’s first HIV vaccine trial in Pune.
The virus, called the adeno-associated virus (AAV), has been used in the US for a decade in trials to deliver corrective genes into patients suffering from arthritis, hemophilia and Parkinson’s disease.
The US Food and Drug Administration (FDA) announced on Thursday that a patient with arthritis who had received gene therapy using AAV had taken ill and died. The FDA did not specify the illness but said that it was related in time to the second injection of the product.
The agency has stopped the arthritis trial as a precautionary measure, and is reviewing all ongoing trials involving any use of AAV.
India’s first trial of a candidate vaccine against HIV conducted last year by the National AIDS Research Institute (NARI), Pune, was also based on AAV. It was developed by Targeted Genetics, a US-based biotechnology company, also involved in the arthritis trial.
Thirty adults participated in the Pune trial as part of a three-country study to evaluate the vaccine’s safety. The trial, also conducted in Belgium and Germany, concluded earlier this year, and researchers have said the vaccine has had no serious side effects.
A Targeted Genetics official said no serious adverse effects have ever been observed in trials involving AAV. The clinical course the patient experienced has never been seen as a consequence of exposure to AAV used in gene therapy or naturally occurring AAV, the official said.
But safety concerns about AAV have also emerged after independent studies by Mark Sands at the Washington University, St. Louis, and his colleagues suggest that AAV slips in sections of its own genetic material into mouse genes and triggers liver cancer.
“Our finding is rather disturbing. It raises serious safety concerns,” Sands, an associate professor of medicine told The Telegraph. “I think it’s time to step back, and do long-term toxicity studies with AAV in a large number of animals,” Sands said.
However, other researchers point out that AAV is a common virus and a majority of adults have been exposed to it. “It has never been associated with cancer or any other disease in humans,” said Patricia Fast, director of medical affairs with the International AIDS Vaccine Initiative (IAVI), an organisation spearheading the effort to develop a vaccine against HIV.
Over the past 11 years, AAV has been used in 27 trials involving more than 500 people, and cancer has never emerged as an issue, Fast said. A company spokesperson told The Telegraph that the illness and death in the arthritis trial was “not a tumour incident”.
Scientists said the implications of these developments on the Pune trial remain unclear. In the coming weeks, investigators will try and determine what might have caused illness in the patient who received the AAV.
NARI scientists also point out — and Sands at Washington University concedes — that there are stark differences in the way that the laboratory mice and the humans received AAV. The mice had received intravenous injections, but the humans got the virus in their muscles.
“The mice received much larger doses of the virus than any human has been given,” a NARI scientist, who requested anonymity, said.
The laboratory studies linking AAV with liver tumours in mice appear in today’s issue of the journal Science.
IAVI has said there are differences in the AAV product used in the arthritis and HIV vaccine trials. “The AAV-based AIDS vaccine underwent very extensive safety studies in hundreds of small animals as well as non-human primates before it was introduced into humans,” IAVI said in a statement to The Telegraph. “Data is complete on the first part of the safety study and no serious vaccine-related adverse events have occurred,” it said.
However, IAVI and NARI officials said they will continue to follow up volunteers of the trials for five years, regularly checking them to ensure that they have had no serious consequences to the candidate vaccine.