Indian vaccine trial raises spectre of new disease
A new vaccine for Japanese encephalitis is to be tested in Indian children — to the dismay of critics, reports K. S. Jayaraman.
A proposal to test a genetically engineered Japanese encephalitis vaccine in children has alarmed some of India's top virologists. The vaccine could, they say, introduce a new disease or make an existing virus more deadly.
But India's Genetic Engineering Approval Committee (GEAC), which gave clearance for the vaccine trial on 22 May, says that the vaccine manufacturer convinced the committee that the risk is "minimal".
GEAC secretary Ranjini Warrier told SciDev.Net that the committee also took this decision because of the "urgent" need for a Japanese encephalitis (JE) vaccine in India. While the medical community sees the urgency — JE killed more than 800 children in northern India last year — some have reservations about the safety of the vaccine trial.
The trial was originally due to take place last year in Thailand. A senior official of the Thai Ministry of Health told SciDev.Net that the World Health Organization did not support the trial and that it was eventually abandoned for no clear reason. The vaccine manufacturer Acambis declined to reply when asked why it moved the trial to India.
Acambis is a biotechnology company operating in the United Kingdom and the United States. Its vaccine, called ChimeriVax-JE, is made from live, genetically engineered virus that has been weakened so that it cannot cause disease.
A living virus
Scientists created the JE vaccine by replacing the 'envelope' genes of the yellow fever vaccine virus with corresponding genes from the JE virus. This means it contains proteins required for stimulating immunity against JE, but copies itself like the yellow fever virus.
Acambis says the vaccine is virtually the same as the time-tested yellow fever vaccine, except that it has been modified to carry JE genes. The hope is that, like the yellow fever vaccine, the JE vaccine will confer lifetime immunity via a single jab.
The modified vaccine could turn out to be ideal for India, which currently combats JE with a vaccine grown inside the brains of young mice. This is expensive, and India lacks the production capacity to meet the demands of mass vaccination.
What is really worrying scientists, however, is that the vaccine has a yellow fever virus component in it — and yellow fever does not exist in India.
"Almost 80 per cent of the genetic material in ChimeriVax-JE is that of yellow fever virus," says Sudhanshu Vrati, a virologist at the National Institute of Immunology in New Delhi. "So, can we take the risk in bringing a live vaccine based on yellow fever virus into India, which is free of yellow fever?"
Vrati admits that the yellow fever vaccine, in use for 50 years, is one of the world's safest and most efficient. "But once this vaccine virus is genetically manipulated, as in the Acambis vaccine, it no longer remains the same," he says.
"For all practical purposes," says Vrati, "the Acambis vaccine is a new living virus with an altogether new genome that does not exist in the country, and no one knows precisely the risk associated with its use in children."
Another concern, according to Kalyan Banerjee, former director of the National Institute of Virology in Pune, is the threat of recombination — the formation of new combinations of genes — that can lead to the emergence of new viruses. This could occur among 'flaviviruses', the group to which yellow fever, JE, West Nile, dengue and many other viruses belong.
In 1988, scientists analysing the genetics of the Western equine encephalitis virus discovered that it had emerged from the recombination of two 'alpha viruses' — Sindbis virus and Eastern equine encephalitis virus — both mosquito-borne.
In 2004, scientists reported in the Journal of Virology the emergence of a new virus due to the amalgamation of a flavivirus called Modoc with the yellow fever vaccine virus. "There are several examples like this in the literature," Banerjee says.
Vrati agrees. "The risk associated with the emergence of a pathogenic virus during mass vaccination following recombination between ChimeriVax-JE and another flavivirus, however small, cannot be ignored," he says.
The chances of recombination are potentially greater in India than in developed countries, he adds, because there are many other wild-type flaviviruses there as well as the widespread presence of Aedes aegypti mosquitoes, which can transmit these viruses to people when they bite.
Problems would arise, says Banerjee, if a mosquito fed on a vaccinated person and picked up ChimeriVax-JE, and if the vaccine virus recombined with any of the other flaviviruses within that mosquito.
"The resulting recombinant could turn out to be a yellow fever-dengue [combination], a yellow fever-West Nile [combination], a more virulent form of dengue or even a weird virus that can cause a new disease. We do not know," he says.
Acambis's request to launch the vaccine trial in India was discussed at several GEAC meetings since November 2005. But each time, the decision was deferred because the company had not assured GEAC that the vaccine's use would not introduce yellow fever or create recombinant viruses.
At the 22 May meeting, GEAC finally cleared the vaccine, saying the protocol for the trials submitted by the company "is in order and adequate to take care of the concerns expressed in the previous meetings". But some scientists remain sceptical.
According to Acambis, there is no risk of introducing yellow fever to India through the use of its ChimeriVax-JE, as the manufacturing technique "ensures yellow fever virus cannot be generated".
Acambis spokesperson Lindsay Wright said in an email interview that concerns about the "remote and theoretical risk of recombination should not prevent development of new vaccines that provide public health benefit", and that the chance of such recombination "approximates one in 300 million".
Tracking the unexpected
But Banerjee says that even this means that recombination can take place if two viruses are present in a single host.
Vrati, who was consulted by GEAC in the initial stages of Acambis's request for the trial, says the company's argument that ChimeriVax-JE has been shown to be safe when tested in adults in the United States and Australia is irrelevant, since these countries will be using it only for military personnel and adult tourists. "It has not been tested in children anywhere in the world, and so we need more studies before injecting in our children," says Vrati.
But Joseph John, head of virology at the Christian Medical College in Vellore, southern India, feels differently. "We must keep our eyes open and look at the vaccine critically," he says. "If this vaccine takes off, we will have easy access to it if we participate in its development."John says there is "absolutely" no risk of introduction of yellow fever via this vaccine and he does not think there are any "hidden risks" in the vaccine trial. But as in the case of all new vaccines, totally unexpected events might happen and therefore "studies are essential if we are to get the right information," he cautions.