Under the Microscope / Prof William Reville: If asked to name a deadly virus, most people would nominate the HIV virus that causes Aids, and some would mention the Ebola virus or the Sars virus. But few would mention the rotavirus, even though it kills more children annually than HIV/Aids.
Rotavirus causes vomiting and diarrhoea and infects most children in their early years. The diarrhoea can be so bad that, untreated, it can kill the child by shock from dehydration. An estimated 610,000 children die annually from rotavirus - 5 per cent of all deaths younger than five years. The good news is that vaccines have just been tested that promise to effectively tackle this deadly disease. The story is outlined by Roger Glass, a leading epidemiologist, in Scientific American, April 2006.
Viruses are tiny biological entities made from protein and nucleic acid. The nucleic acid is either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and contains the information content (genes) of the virus. The protein forms a protective coat around the nucleic acid. The rotavirus is a spherical particle (about 70 billionths of a metre across) and looks like a wheel when seen in the electron microscope - hence the name, derived from the Latin rota for "wheel".
In 1973 it was discovered that rotavirus infects children causing diarrhoea. The route of transmission is faecal-oral. A virus - bearing droplet landing on a baby's thumb quickly gets into the mouth, from where the viruses soon reach the small intestine. They infect the cells of the intestinal lining where they replicate themselves at great speed, killing the infected cells. The infected intestinal cells are shed and are excreted in floods of fluid as diarrhoeal bursts. If rehydration therapy is not given the child can lose up to 10 per cent of body weight and enter shock within a couple of days.
I have a personal interest in human rotavirus. I carried out most of my research using the electron microscope. In 1980 I was approached by Michael Mahony of the department of paediatrics in Cork University Hospital and asked to examine normal and diarrhoeal infant stools in the electron microscope at UCC. I was excited to see the first ever image of the rotavirus in Cork. We (MJ Mahony, RG Barry, WJ Reville) published the results in the Irish Medical Journal, Vol 74, 171-173, 1981.
Although nearly all children under five everywhere contract rotavirus, most deaths occur outside of North America and Europe, in locations where access to medical rehydration therapy is limited. The 10 countries where rotavirus diarrhoea is deadliest are India, Pakistan, China, Nigeria, Congo, Ethiopia, Afghanistan, Bangladesh, Indonesia and Tanzania.
Children who survive their first rotavirus infection remain unharmed in the long term and are very unlikely to suffer rotavirus diarrhoea again. This is because they have acquired natural immunity against the virus and, if challenged again by the virus, automatically produce antibodies to inactivate the pest. It was clear from the start that the only hope of successfully combating this disease was to develop a vaccine that would imitate this natural immunity.
The principle of vaccination is to fool the immune system into thinking it is under attack by using a form of the infectious micro-organism that poses no threat, eg in the case of a virus either an inactivated virus, or a form weakened to such an extent it cannot trigger disease. The immune systems reacts to the inactivated/attenuated agent (vaccine) and produces antibodies just as it would against the active virus itself.
The pharmaceutical companies were emboldened to invest huge resources in developing rotavirus vaccines because the potential market is enormous. GlaxoSmithKline tested an oral vaccine in 1983 based on a weakened strain of bovine rotavirus. Trials in Finland showed the vaccine reduced the chance a vaccinated child would develop severe diarrhoea by 88 per cent. However, later trials in Africa and Peru gave inconsistent results. Malnutrition and poor general conditions affect a child's response to vaccination. The company put the vaccination programme on hold.
In 1991 Wyeth Ayerst (now Wyeth Pharmaceuticals) was given permission to test another vaccine, called RotaShield, an attenuated molecular hybrid of monkey and human rotavirus. Large-scale tests in the US, Finland and Venezuela demonstrated the vaccine's efficacy and safety. However, in 1999 several infants suffered a serious complication called intussusception after vaccination, whereby a short segment of intestine folds into a nearby region to cause a blockage. This painful condition must be quickly reversed with an enema and, in rare cases, causes death. The vaccination programme, the product of 15 years work and several hundred million dollars, was shelved.
Researchers suspected that the intussusception problem was related to the monkey strain of rotavirus. GlaxoSmithKline (GSK) and Merck independently started huge trials - GSK using an attenuated human rotavirus (Rotarix) and Merck a hybrid bovine-human rotavirus (RotaTeq). Those trials, the largest and most expensive safety trials ever conducted, have now been completed. The new vaccines offer 85- to 98 per cent protection against rotavirus diarrhoea and do not increase the natural incidence of intussusception.
These vaccines cost several hundred million dollars each to develop and so they will, at least initially, be expensive. Efforts must be made to make them affordable to the many millions of children born annually in the poorest and most vulnerable regions. With help from a committed world the principal killer of children in the developing world should be eliminated by effective vaccination within 10 years. This will be a wonderful demonstration of the power of science-based technology to do good.
William Reville is associate professor of biochemistry and public awareness of science officer at UCC