Hugh Pennington on the Zika virus
‘The recent cluster of cases of microcephaly and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a public health emergency of international concern.’ The statement by Margaret Chan, director-general of the World Health Organisation, on 1 February was very precise. It wasn’t about the spread of Zika virus itself, but about the possible complications of an infection caused by it. The ‘neurological disorders’ are cases of Guillain-Barré syndrome, victims of which have paralysis ascending from their legs, sometimes leading to respiratory failure, and loss of feeling with a ‘glove and stocking’ distribution. It isn’t rare. Neither is microcephaly. I looked after people with it when I was a nurse in a hospital for the intellectually disabled (established 150 years ago as the Asylum for Idiots and Imbeciles of the Seven Northern Counties). Congenital microcephaly is a devastating condition. Children with it will at best have severe intellectual impairment for the whole of their lives. But 90 per cent of Guillain-Barré syndrome sufferers recover. As a houseman in London, I looked after a totally paralysed pregnant patient. Her delivery was fast and uneventful. Recovery started at once. A month later only her eyelids remained weak.
So far, the link between microcephaly, the Guillain-Barré syndrome and a Zika infection is only one of coincidence. But it has been known for years that in many cases of Guillain-Barré syndrome, the sufferer will have had a recent history of infection, and that infections during pregnancy can cause microcephaly. Rubella is the best-known example, but it is very unlikely that it has anything to do with the current problem. A successful and vigorous immunisation campaign eradicated the virus in Brazil. The last baby with congenital rubella syndrome was born on 12 September 2009.
Chan had no choice whether or not to make her declaration. The incidence of congenital microcephaly in Brazil and its possible cause(s) requires urgent investigation, and Guillain-Barré syndrome is not a trivial condition. Even so, she had to measure her words with care. The WHO was criticised for overreaction when it declared the worldwide spread of swine flu a pandemic in 2009, and for tardiness in its response to Ebola in West Africa.
For the moment big questions remain. How strong is the evidence that the mothers of babies with microcephaly have been infected with the Zika virus? Do all the microcephaly cases have similar brain abnormalities? When during gestation did they develop? Can the Zika virus be isolated from these children? Are any other microbes involved? Why do current reports emphasise microcephaly in Brazil and Guillain-Barré syndrome in Colombia? Has the genome sequence of the Zika virus changed recently? The last of these questions is technically the easiest and cheapest to answer. Results and analyses should begin to arrive within weeks. On 3 February the UK Medical Research Council announced that as much as £1 million has been made available through its Rapid Response scheme to fast-track Zika research.
To understand Zika’s past, present and future, compare it with yellow fever, one of the great plagues of the past. It was fear of yellow fever that drove politicians and charities to action: about 15 per cent of cases develop a haemorrhagic fever clinically similar to Ebola, and as lethal as Asiatic smallpox. The Rockefeller Foundation deserves most of the credit for defeating it. By 1950 it had withdrawn from research and fieldwork on the virus because it believed all the necessary discoveries had been made. Scientifically it was the right decision. But in its New York labs the foundation continued research on different but similar viruses. It reported that new viruses discovered in African forests during the investigation of yellow fever appeared to simulate the epidemiology of yellow fever, and that it was possible they were responsible for hitherto unrecognised infections. It said that one of the new agents, the Zika virus, was related to the West Nile and dengue viruses.
The co-discoverers of the Zika virus were the pathologist George Dick and the entomologist and epidemiologist Alexander Haddow, who worked together for the Colonial Medical Service at the Yellow Fever Institute in Entebbe. Haddow was a mosquito man. To study their biting habits he used human bait. Dick was a virus hunter, and used monkeys as his bait. In the 1940s, looking for yellow fever, they chose the accessible Zika forest near Entebbe because a monkey that had been shot there was found to have the virus. Zika became one of the most intensively studied forests in Africa, even though yellow fever virus wasn’t found again there until 1972, when there was a brisk outbreak in monkeys.
On 18 April 1947, in a cage high on a tree in the forest, rhesus monkey number 766 developed a fever. Its serum was introduced into the brains of mice. They fell ill. This was the Zika virus. Haddow wanted to know more about the high-flying mosquitoes and their viruses and built a 120 foot steel tower in the forest to capture them. The best time and place to find Zika virus was in the evening, 80-100 feet above the forest floor. The first reported case of human infection with the Zika virus was in 1964. Another Entebbe virologist, David Simpson, had a 36-hour fever, some back pain, a headache and a rash. Three days later he had recovered apart from some spots.
For many years the Zika virus was thought to be unimportant. There was no evidence to suggest that it could do anything more than cause an illness like Simpson’s. In fact a Zika infection almost certainly caused no symptoms at all in the majority. Antibody studies in Nigeria in the early 1970s found that 40 per cent of people had been infected at some time in the past; people in India and South East Asia had also been infected, with the same very mild consequences.
In 2007 things began to change. A big Zika outbreak occurred on Yap Island in Micronesia in the south-western Pacific. The symptoms were mild: a rash, sore eyes and joint pain. Alarm bells rang because the outbreak was by far the biggest that had been recorded to date – it was estimated that well over half the residents had been infected – and because the virus had travelled so far to get to Yap. There was fear that it might spread to the Americas. Another big Zika outbreak began in late 2013 in French Polynesia. This time a number of cases of Guillain-Barré syndrome were reported that seemed to be associated with the virus.
In May 2015 the first confirmed indigenous cases of Zika virus infection were reported in north-east Brazil. Since then it has spread across the country, and so far has appeared in Mexico, Haiti, Puerto Rico, Barbados, Central America, Paraguay and other South American countries, though not yet Bolivia, Peru, Chile, Uruguay or Argentina. None of this is a surprise. The mosquito that spreads it, Aedes aegypti, which also spreads dengue and yellow fever, is not under control. It occurs in all American countries with tropical or sub-tropical regions. Dengue is currently on the rampage in Brazil: in 2015 there were 1.6 million suspected cases (almost certainly a large underestimate) and 839 deaths.
The Rockefeller Foundation committed itself to the eradication of yellow fever in 1915. Apparent success in South America came quite quickly. Aedes aegypti is very urban, but in the early years of the campaign it wasn’t necessary to get rid of it completely in order to make yellow fever disappear; if Aedes aegypti bred in fewer than 5 per cent of houses that was good enough. But after twenty years the virus returned, infecting the generation that had been born since its initial disappearance and so lacked immunity against it. The Brazilian Government Decree No. 8675 of 4 February 1942 made the eradication of Aedes aegypti an official objective. The aquatic habitats of its larvae were chemically treated; final eradication required the use of DDT. The mosquito had gone from Brazil by 1958, and together with most South American countries it was certified free of Aedes aegypti by the Pan American Health Organisation. The next step was to eradicate it throughout the Americas. The US signed up but at first did nothing, in spite of the occurrence of the mosquito in nine Southern states. (Mexico’s minister of health pointedly presented the US surgeon general with a transparent plastic block containing the embedded corpses of the ‘last two Aedes aegypti in Mexico’.) An eradication programme started in 1964 in Texas and southern Florida, but little enthusiasm was shown by politicians, public health professionals or the public: the money, they said, could be better spent. The programme was finally brought to an end after the election of Richard Nixon, a casualty of Republican meanness, US citizens’ objections to mosquito searchers entering their property, and growing opposition to DDT.
In 1976 the mosquito returned to Brazil, almost certainly from the north. There is no conclusive evidence that it came from the US, but it’s possible. Fertilised females don’t fly far – probably no further than 800 metres – but the eggs are tough and larvae travel well in water carried in small containers. Even though dengue appeared in Brazil in 1981, the attempt to eradicate Aedes aegypti was dropped, to be replaced in 1986 with a control policy. The yellow fever fear-factor has gone: an effective and safe vaccine was developed by Max Theiler of the Rockefeller Foundation in the 1930s.
Now the mosquito is thriving again. The pressing issue is the possible link between the Zika virus and microcephaly. It hasn’t been reported in accounts of other Zika virus outbreaks. But viruses like Zika can mutate very fast. West Nile virus is related to Zika. After its initial discovery it remained quiet for years. Then in the mid-1990s it became nastier: there were epidemics in North Africa and Southern Europe, and it caused severe brain disease. It took off in New York in 1999, and spread rapidly across the US. Could Zika spread in the US? Yes. Aedes aegypti occurs in Florida, most southern states including Texas and New Mexico, and has been found in California. It would be very easy for someone travelling in South America to be infected without realising, return to the US carrying the virus, then be bitten by a mosquito which flies off eventually to infect someone else.
Infected travellers will be returning to the UK every day. But the likelihood of catching it from one of them is remote. It is theoretically possible to get it from a blood transfusion from an asymptomatic recent returnee but the risk of that is extremely low. (Donors returning from countries with Zika now have to wait 28 days before giving blood.) There is even less chance of transmission by a British mosquito. The Asian tiger mosquito, Aedes albopictus, has transmitted Zika virus in laboratory experiments. It has been spreading across the world during the last three decades and is now well established in southern Europe as well as North and South America. In 2007 it was the vector of an outbreak of Chikungunya (caused by a virus unrelated to Zika) with 197 cases in Italy. Aedes albopictus usually moves from country to country in used car tyres. A well-studied incursion into the Netherlands was associated with the import of Dracaena sanderiana, ‘lucky bamboo’, from China. There was a panic; sightings of the mosquito were made all over the country. None was verified. The climate was too cold for the mosquito to establish itself. It is the same, so far, in the UK.
Aedes aegypti has been a vector for disease in Britain only once, in 1865. Yellow fever-infected mosquitoes flew off the ship Hecla on its arrival in Swansea after a six-week voyage from Cuba and caused an outbreak in the town that killed 15. Two of Hecla’s crew had died just before the boat left Cuba, three died during the voyage, and another on the day the ship arrived. It’s unlikely that these circumstances will be repeated.
Developing a safe Zika vaccine will take years. Max Theiler was lucky with his yellow fever vaccine: it contains live virus that has never mutated back to virulence. If Zika does cause brain abnormalities one would have to be certain that any vaccine virus, especially a live one, didn’t do the same. The immunology of viruses closely related to Zika is complex. There are four serotypes of dengue. Infection with one of them will give you lifelong immunity to it, but it will also make you more likely to develop a more severe haemorrhagic illness if you are infected with another serotype.
The quickest way to stop Zika in Brazil will be to attack the mosquitoes. Sexual transmission from person to person has happened, but on the grand scale of things isn’t important. The Olympics are near. Insecticides and GM are being used – male mosquitoes which have been genetically modified to cause their offspring to die have been shown to reduce Aedes aegypti populations by 90 per cent. Past experience with Aedes control shows that what works best is a combination of source reduction (by removing or covering water containers, and treating water to kill larvae), indoor and outdoor insecticide spraying, and community education. It may be that biological controls will be used as well: larvivorous fish, big water-fleas and Toxorhynchites, a mosquito with vegetarian adults which emerge from larvae that live off the larvae of other mosquitoes.
If Zika virus behaves like urban yellow fever, transmission should stop when 95 per cent of houses are free of breeding Aedes aegypti. But dengue transmission continues unabated in Brazil. As things stand, the mosquito is unlikely to be staying away from that many houses.