1. The ethics of using vaccines to battle cholera: The moral challenge of “Good Enough” Arthur Caplan New York University Langone Medical Center and 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/

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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?

19. 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?

20. 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

21. 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/