The ethics of using vaccines to battle cholera: The moral challenge of “Good Enough”

Arthur CaplanNew York University

Langone Medical Centerand

The Center for Vaccine Ethics and Policy

a program of The Division of Medical Ethics NYU Langone Medical Center,

The Wistar Institute Vaccine Center and the Vaccine Education Center of Children’s Hospital of Philadelphia

http://centerforvaccineethicsandpolicy.wordpress.com/

The Challenge of Cholera• Cholera is an infection of the small intestine

that causes a large amount of watery diarrhea.• People get the infection by eating or drinking

contaminated food or water.

• Causes, incidence, and risk factors– Cholera is caused by the bacterium Vibrio cholerae. The bacteria releases a toxin that causes increased release of water from cells in the intestines, which produces severe diarrhea.

The Challenge of Cholera– Cholera occurs in places with poor sanitation, crowding, war, and famine.– Common locations for cholera include:• Africa• Asia• India•Mexico• South and Central America

The Challenge of Cholera• Most cholera patients treated with oral

rehydration salts will survive, but the more severe cases require immediate use of intravenous fluids to counteract their rapid dehydration. Without treatment, the most seriously ill cholera patients can die in as little as 12 hours.

• Infants, children, and the elderly are more likely to die from the disease because they become dehydrated faster than adults

Cholera, Information about Cholera http://www.faqs.org/health/topics/67/Cholera.html#ixzz26eWHOfMD

The challenge of Cholera

• In 2011, cholera cases were reported from all regions of the world. A total of 58 countries reported a cumulative total of 5,898,541 cases including 7,816 deaths with a case fatality rate (CFR) of 1.3%, representing an increase of 85% in number of cases compared with 2010• Reason for jump was outbreak in Haiti

http://www.who.int/wer/2012/wer8731_32.pdf

The outbreak in Haiti• Exploding outbreak of cholera• As of April 23, 2012, the Haitian Ministry of

Health reported 536,943 cases of cholera and 7,112 deaths—the start of the rainy season had accelerated the epidemic

• Poor sanitary systems and sewage• Some evidence introduced by UN personnel

making the management of the outbreak even more complicated

The outbreak in Sierra Leone• As of Sept 13, 2012 sickened more than

17,000 people and killed 250• About two-thirds of the country lacks access

to toilets.• Rain water quickly washes cholera bacteria

into rivers and streams that residents rely on for drinking water

http://www.sacbee.com/2012/09/13/4816888/emergency-aid-for-sierra-leone.html#storylink=cpy

Vaccines• Several oral cholera vaccines have been

developed and are proved to be very safe and effective. Only 2 of these currently marketed.

• One has been used in several mass vaccination campaigns with WHO support, – its use has enabled evidence to be collected on the

effectiveness and implementation of oral cholera vaccines as a public health tool in protecting populations at high risk for outbreaks.

• The same vaccine is licensed in several countries, for use mainly by travellers visiting areas where cholera is endemic.

http://www.who.int/wer/2012/wer8731_32.pdf

Vaccines• The technology for the production of this vaccine

was transferred from Sweden to India via Viet Nam, resulting in the second vaccine which has been licensed in India.

• This new vaccine opens up wider possibilities for public health use in cholera-endemic countries, particularly in Asia, because it is a bivalent O1 and O139 vaccine has no recombinant B subunit and therefore does not need to be diluted in a buffer solution. Both vaccines are whole-cell killed vaccines, 1 with a recombinant B subunit, the other without.

Vaccines• Both are available in limited quantities

• Both are prequalified by WHO and may therefore be purchased by United Nations agencies.

• WHO has never recommended the use of the parenteral cholera vaccine because of its limited protective efficacy (45% for 3 months)

• http://www.who.int/wer/2012/wer8731_32.pdf

Endemic cholera

• Many in India, Bangladesh, Africa and elsewhere have no access to any cholera vaccine for use in an emergency or for endemic cholera

• Cost in lives, morbidity, cost are underreported due to politics, lack of surveillance, other co-morbidities

Emergency vaccination

• Emergency use– Haiti• Initially opposed use, later did use but hard to supply

• Efforts at building stockpiles to respond to outbreaks very slow

Ethical questions that need answers• The vaccine is approved at 2 doses• There is little stockpiled• There is some evidence that one dose or shot

gives some protection• Would it be ethical to test one dose on human

subjects to see if it is protective since in a sudden large epidemic vaccines would only reach a small percentage of people?

• Would one dose be ‘good enough’ in an emergency

Benefits• Find tool for outbreaks in catastrophes

• Prevent waste of resources of it does not work

• Aid in building stockpile

• Reduce cost burden and possibly broaden access to populations facing endemic cholera

• Fuel more research on utility of lower doses, more widely spaced dosing

Worst case/failure• Significant community resistance• Slow recruitment• Adverse event –death• Adverse media coverage• Allegations of use of poor to benefit others • Subjects drop out• Outbreak in middle of study• Inability to disseminate findings• Ambiguous result• Loss of funding to honor commitments to subjects

Subject population for a study ?• Find population where cholera is endemic to

study efficacy of one dose–Poorest of the poor with no access to any

vaccine–How to prepare local community for such a

study–Recruitment -- incentives, options• Length of study• Following refusals?

– Exclusions—HIV, pregnant women

Subject population for a study ?• Find population where cholera is endemic to

study efficacy of one dose–Consent• Can any weight be placed on informed

consent?–Minimize risk by advocating hygiene as part

of recruitment–Can children be recruited?–Prepping the community/nation and world

for a trial

Trial design?• Not in equipoise—some evidence for efficacy

of one dose• Placebo control? Or 2 dose “standard of care”–Consistency with international standards

• Case control• Cluster• Three arm or two arm trial• Pilot studies –On adults first?

Oversight of trial?• Ethics committee approval—local only?

• Subject advocate(s)?• DSMB – Training in bioethics, research ethics–Are Poor represented?– Set and review stopping points?– Level and certainly of evidence to change

vaccine use?

What is owed to subjects??• Some note that a ‘good enough’ study has

benefit for the subjects themselves—diagnosis, community benefit of access to OCV , improved therapy available in community

• Access to efficacious OCV post trial?• Improvement of heath care infrastructure?• Vaccination of communities for how long?• Compensation for harm• Rescue tx

The Center for Vaccine Ethics and Policy

a program of The Division of Medical Ethics NYU Langone Medical

Center, The Wistar Institute Vaccine Center and the Vaccine

Education Center of Children’s Hospital of Philadelphia

http://centerforvaccineethicsandpolicy.wordpress.com/