Richard Smith: Working to make cholera a disease of the past

richard_smith_2014Until last year the Cholera Hospital in Dhaka, Bangladesh, could have a thousand admissions a day before and after the monsoon. On a calm day now it still has hundreds. Not all the patients, many of them children, have cholera but many do. Many of the children also have malnutrition, sometimes severe. In order to cope the doctors used to have to erect a tent in the car park and fill it with cholera cots that were inches apart. A cholera cot has a hole in the middle to help management of the profuse diarrhoea that is the hallmark of cholera. As the tent was dark my immediate thought on entering the tent was of pictures of the Crimea with Florence Nightingale, the lady with the lamp, attending the dying soldiers. But few die in the Dhaka Cholera Hospital as the nurses and doctors are so adept at treating the disease, and tremendous improvements in the hospital mean that the tent hasn’t been needed in 2016.

Epidemic in Naples

In the epidemics of the past cholera would kill on a huge scale. Axel Munthe, the Swedish physician, described in his book The Story of San Michele an epidemic in Naples in the 19th century.

“I described in the first letter how,
half -faint from the stench of carbolic acid in the
empty train I stepped out on the deserted Piazza
late in the evening, how I passed in the streets
long convoys of carts and omnibuses filled with
corpses on the way to the cholera cemetery, how
I spent the whole night amongst the dying in the
wretched fondaci of the slums.…..
How much easier it would have been for them
and for me, thought I, if only their agony was
not so long, so terrible! There they were lying
for hours, for days in stadium algidum, cold as
corpses, with wide-open eyes and wide-open
mouths, to all appearances dead and yet still alive.
Did they feel anything, did they understand any-
thing? So much the better for the few who could
still swallow the tea-spoonful of laudanum one of
the volunteers of the Croce Bianca rushed in
to pour into their mouths. It might at least finish
them off before the soldiers and the half-drunk
heccamorti came at night to throw them all in
a heap in the immense pit on the Camposanto
dei Colerosi. How many were thrown there alive?
Hundreds, I should say. They all looked exactly
alike, I myself was often unable to say if they
were dead or alive. There was no time to lose,
there were dozens of them in every slum, the or-
ders were strict, they all had to buried in the

Cholera now

Epidemics still occur in low income countries, including Bangladesh.

Cholera is endemic in Bangladesh (as it is in 50 low income countries), with some 300 000 cases and 4500 deaths a year. Every medical student knows that clean water and sanitation remove the threat of cholera, but installing clean water and sanitation throughout Bangladesh, a country where water is as common as dry land and where the heavy rains of the monsoon last for four months is a formidable challenge. Dhaka is a city of some 20 million people where a third live in densely populated slums, often without clean water or sanitation. The city is expected to grow to 30 million by 2030 with 50% living in slums.

The alternative to clean water and sanitation is a vaccine, and vaccines have been available since the late 19th century, but early generation vaccines given parenterally proved unsatisfactory  when clinical trials  were finally done in the 1960s and 1970s. Recognition of the importance of intestinal mucosal immunity in preventing cholera led the development of orally administered cholera vaccines. In order to introduce into a national prevention programme a safe, effective, cheap, and easily administered vaccine is needed. Icddr,b (formerly the International Centre for Diarrhoeal Disease, Bangladesh) has been working on this since the 1980s, but the goal now seems close.

Oral vaccines

In 2001 the World Health Organisation prequalified (WHO jargon for approved) a Swedish oral vaccine, Dukoral, whose safety and efficacy were shown in the 1980s by  icddr,b. Because of high cost and challenges in administration it’s used mainly by people from high income countries visiting low income countries where they may contract cholera. Next a vaccine produced in Vietnam was transferred to India and licensed as Shanchol. A large trial in Kolkata in West Bengal (Bangladesh was once East Bengal) showed that the vaccine was safe and gave 65% protection after five years. But could the vaccine work effectively in real world conditions in Bangladesh with its high risk of cholera?

Icddr,b conducted a cluster randomised trial led by Dr Firdausi Qadri, among almost 270 000 people aged over 1 year in 90 clusters in Dhaka. These were the poorest people, those at highest risk of cholera. The trial used two doses of the Shanchol vaccine, and it was given by government workers, making it more likely that if the intervention was effective the programme could be scaled across Bangladesh. The trial had three arms; vaccination alone; vaccination plus encouragement to wash hands and drink water treated with chlorine; and no intervention. The main outcome measure cholera with severe dehydration, the type that kills.

During the two years after vaccination there were 528 episodes of cholera and 226 of the episodes were associated with severe dehydration: 106 in the group who received no intervention; 65 in the group who received only vaccination; and 55 in the group who were vaccinated and encouraged to wash their hands and drink treated water. Overall protection against severe was 37% in those simply vaccinated and 45% in those vaccinated and encouraged to wash their hands and drink treated water. But among those who received two doses of the vaccine protection was 53% in the first group and 58% in the second group.

The authors concluded that the Shanchol vaccine was effective in real world conditions and that encouragement to wash hands and drink treated water offered little extra advantage. (For reasons of cost and low expectation that it would produce much effect the trial did not include a group who did not receive vaccination but were encouraged to wash hands and drink treated water, but these are clearly good things to do.)

The next step was a trial conducted by icddr,b among nearly 205 000 individuals to see whether a single dose of vaccine would be as protective as a double dose. It was, except, as had been found in other trials, among children under five. It’s obviously easier and cheaper to deliver one dose of vaccine rather than two, and this trial opens up the possibility that those over five might be offered one dose of vaccine and those under five two doses. It also shows that even with a programme offering two does there would be benefit among those receiving only one dose, as will inevitably happen.

Another icddr,b trial has shown that the Shanchol vaccine is stable even in the high temperatures of Bangladesh, an important finding that will simplify distribution of the vaccine.  

Local vaccines

Bangladesh has a burgeoning pharmaceutical industry, and there are now two oral cholera vaccines (Cholvax and Hillchol) that have been manufactured in Bangladesh and are now in phase I/II trials. This should bring down the cost of the vaccine still further, and the hope is that WHO will prequalify the vaccines early next year.

Much of what is needed will then be in place to start a national programme of vaccination. Perhaps it will eventually be possible to stop transmission of cholera in Bangladesh (as a natural marine organism it cannot be eradicated), as has happened in high income countries including Italy;  the Dhaka Cholera Hospital will then never again need to erect the tent in the car park, can shrink in size, and concentrate on treating the other causes of diarrhoea.

Richard Smith was the editor of The BMJ until 2004. 

Competing interest: RS is the chair of the board of icddr,b