Cholera vaccination in Haiti: evidence, ethics, expedience.

Hinman, Alan R. ; Farmer, Paul ; Papers, Jean-William 等

The cholera epidemic in Haiti will be a year old in October and is far from under control. As cases spiked across the country during the summer rainy season, the ranks of cholera relief workers grew thin. Too few patients reach healthcare facilities with enough time to be sure that treatment--simple rehydration in most cases--can restore them to health. Access to clean water and to modern sanitation is dwindling. We must redouble existing efforts at cholera prevention and care--case-finding and treatment, water and sanitation projects, education and surveillance--while simultaneously integrating vaccination into die ongoing response. Even prior to this epidemic it was clear that waterborne pathogens posed great risks to communities across the country, including those not affected directly by the January 2010 earthquake. All steps to protect Haiti's vulnerable population needed, and still need, to be taken.

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One of these steps is vaccination. Oral cholera vaccines have been proven safe, effective, and deliverable in resource-poor epidemic settings. They can help protect poor communities that lack clean water and modern sanitation, and they bring collective as well as individual benefits. There is no evidence to suggest, as some have warned, that adding vaccination to the cholera response would take resources from other pillars of prevention and care, such as case-finding, treatment, and water and sanitation efforts. Yet, cholera vaccines remain unavailable in Haiti to date. We propose a vaccine demonstration in urban and rural Haiti, with a discussion of ethical considerations and possible objections. The Haitian cholera epidemic is the largest the world has seen in recent history; Haiti deserves nothing less than a comprehensive, integrated response using all of the tools in the armamentarium, including oral cholera vaccine.

Background

Founded in the aftermath of the largest and most successful slave revolt in history, modern-day Haiti is marred by extreme poverty, political unrest, a high burden of disease, and weak infrastructure. Haiti's chronic afflictions were exacerbated when a magnitude 7.0 earthquake devastated its capital, Port-au-Prince, and the surrounding regions on January 12, 2010, killing an estimated 220,000 people and displacing some 1.3 million more. Massive rescue and relief efforts ensued: UN agencies, multilateral organizations, bilateral aid agencies, and nongovernmental organizations rushed from around the world to help. These relief efforts averted substantial suffering and death, and the outpouring of solidarity--an estimated 50 percent of American households donated to the earthquake relief and recovery efforts--was heartening. But acute relief did little to address the profound deficiencies of Haiti's public health infrastructure, and the often chaotic and splintered response to the quake complicated the situation in other ways. To help realize lasting improvements, NGOs and international aid groups must work with and be coordinated by the government, the only institution charged with providing rights to all Haitian citizens.

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As aid workers shifted from immediate rescue and relief to the longer road of reconstruction, challenges such as providing safe shelter, food, clean water, and sanitation in the IDP camps remained. Today, nearly 600,000 people still live in internally displaced persons (IDP) camps, which fill most of the open spaces in the beleaguered capital. Before the earthquake, Haiti had poor health indices, including the highest infant (57/1,000) and maternal mortality (620/100,000) rates in the region, and one of the lowest immunization rates in the world (53 percent). Now, pathologies that often crop up among displaced populations, such as diarrhea and respiratory infections, have become common in the IDP camps and elsewhere in the ruined city. Water is no longer provided for free in most IDP camps, increasing the risk of outbreaks of waterborne disease. But there have been notable achievements, too. Prostheses and wheelchairs have become more common, although, as before the quake, long-term rehabilitation and follow up was limited; ongoing efforts to control HIV and tuberculosis continue, and seem to have prevented the spike in new infections that some had predicted. Thanks to effective immunization efforts in Haiti and elsewhere in the Western Hemisphere, measles did not play the same deadly role after the earthquake as it has in many other similarly disrupted settings.

Although the quake brought new attention, and new-resources, to Haiti's "acute-on-chronic" health problems, emergency relief could not replace public health infrastructure. The great majority of those living in rural regions have never enjoyed access to potable water; in 2001 the Water Poverty Index named Haiti the most water-insecure country out of the 147 that were ranked. In March 2011, with a million people still unhoused, the US Centers for Disease Control and Prevention (CDC) predicted that cholera was "very unlikely to occur." But in late October, ten months after the earthquake, a surge of patients with profuse watery diarrhea presented themsleves at healthcare facilities in the Artibonite River basin. Cholera, never previously documented on Haitian soil, had come to Haiti.

The waterborne bacterium Vibrio cholerae causes profuse, watery diarrhea in an estimated 3 million to 5 million people worldwide each year, killing more than 100,000 of them. Typically spread by ingestion of contaminated water or food, the disease may have been introduced in Haiti when untreated human waste from a camp housing peacekeepers from cholera-endemic countries leaked into the Artibonite River. Laboratory analysis of a sample from central Haiti revealed that the strain active in Haiti is practically identical to strains circulating in South Asia. Cholera is frequently imported into non-endemic areas without causing outbreaks of disease, but in this case widespread use of river water for drinking, bathing, and washing--in the absence of safe water supplies--facilitated the spread of cholera throughout the Artibonite basin and, before long, the whole of Haiti. The lack of immunity in the population made individuals especially vulnerable to infection.

Within weeks, cholera spread throughout the country's ten departments. As of September 18, the Haitian health ministry reported 452,189 cases and 6,334 deaths (and these are official figures, which almost certainly underreport the actual number of cases and deaths). The initial case-fatality rate of 7 percent--among the highest recorded in recent history--has dropped to 1.7 percent nationally, though regions vary between 0.8 percent and 7.7 percent. But the disease is far from under control: after a decline in cases from January to April of 2011, there was a resurgence of cases across the country' beginning in May. Such seasonal variation in incidence--rising in the rainy season, falling somewhat in the dry season--is likely to continue as cholera becomes endemic in Haiti. Now, more than 600 new cases, and more than 10 deaths, are reported every day, making this the largest cholera epidemic the world has seen in decades. On the western third of Hispaniola, cholera seems here to stay.

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Cholera Prevention and Care

Comprehensive and integrated prevention and care can curb the spread of cholera and the suffering and death it causes, even in settings with minimal medical infrastructure. Active case finding and treatment with oral rehydration and/or (for moderate and severe cases) intravenous rehydration and antibiotics can bring case-fatality rates well below one percent. Building water treatment systems and providing point-of-use purification technologies can substantially reduce transmission, as can improving waste management and installing modern sanitation infrastructure. National surveillance and education campaigns can increase the efficacy of these interventions. Finally, safe and effective oral cholera vaccines exist and could be delivered alongside the other components of prevention and care. To date, however, vaccination campaigns have not been rolled out in Haiti. During any epidemic of cholera, we should deploy all tools in the medical and public health arsenal. During the epidemic in Haiti, the largest in recent history and one that shows no signs of slowing, vaccination is an essential complementary intervention as water and sanitation infrastructure are strengthened in the long term.

Cholera Vaccines

Older cholera vaccines were injectable, caused local side effects, and produced limited protection for a short period. But two oral cholera vaccines, Dukoral (~US$6/dose) and Shanchol (~US$1.85/dose), developed in the last two decades, are easier to administer and offer approximately 70 percent protection for two to three years after two doses given two weeks apart. Observed so-called "herd immunity" effects suggest that additional community-level protection would come with large-scale immunization. Cross-country studies that include herd immunity indicate the cost effectiveness of cholera vaccination in resource-poor settings. Both vaccines have been successfully administered to hundreds of thousands of persons in multiple randomized controlled trials, and have excellent safety profiles. But oral cholera vaccines are not magic bullets: Dukoral has the disadvantage of requiring ingestion of 150 ml of a buffer solution (75 ml for children 2-5 years of age) at the time of vaccination. Refrigerated storage is recommended for both vaccines, though ongoing studies are testing their stability at higher temperatures. Currently there are only an estimated 400,000 doses of both vaccines available, but production could be ramped up rapidly with increased demand.

Increasingly, global health policymakers have endorsed the use of oral cholera vaccines in endemic and epidemic settings. In March 2010, the WHO endorsed vaccination in conjunction with other control priorities in endemic settings: it suggested local health authorities consider integrating reactive vaccination with treatment, water, and sanitation efforts in epidemic settings depending on health infrastructure. In April of 2011, the WHO's Strategic Advisory Group of Experts on Immunization (SAGE) launched a working group on vaccination in humanitarian emergencies. Their report concluded that "not vaccinating [in Haiti] may have cost lives and represents a lost opportunity to gather more experience in responding to outbreaks in non-endemic situations as well as innovative use of vaccination strategies to control outbreaks." Most recently, in July, the Technical Advisory Group (TAG) of the Pan-American Health Organization (PAHO), the regional arm of the WHO, suggested that "cholera vaccination be considered as an important complementary tool for the control and prevention of cholera on the island of La Hispaniola."

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Current Proposal

To examine the efficacy of integrating vaccination into the ongoing response to cholera in Haiti, the authors and a group of Haitian and American colleagues working in government ministries, aid agencies, multilateral organizations, nongovernmental organizations, and research universities have proposed an urban and rural vaccine pilot using the 200,000 available doses of Shanchol. Although its health system was weakened by the 2010 earthquake, Haiti could accommodate a large-scale demonstration of reactive vaccination because there are sufficient health providers--nurses, doctors, pharmacists, community health workers--in country to deliver the two-dose course effectively. GHESKIO, an NGO, would run the urban pilot in the Port-au-Prince slum Cite de Dieu; Zanmi Lasante (the Haitian branch of Partners In Health) would run the rural pilot in Bocozel, located in the Artibonite River valley. The Haitian Ministry of Health would supervise the project, along with external cholera experts and public health officials. If this demonstration were deemed successful, we would suggest the production of cholera vaccine be ramped up to supply a larger campaign across Haiti--integrated, perhaps, with ongoing childhood immunization efforts--and the development of a global strategy (possibly including a stockpile) for prevention and control of endemic and epidemic cholera around the world. Strengthening the immunization program and creating an international stockpile would be intended consequences of the pilot roll-out.

The Ethics of Cholera Vaccination in Haiti

Should this demonstration project move forward? If it proves effective, should the government of Haiti and international partners implement a nationwide vaccination campaign? Ethical principles, such as "do no harm" and patient autonomy, can help answer these questions and also guide program design.

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"Do no harm"--primum non nocere, in Latin--is a cornerstone of medicine and public health. Before assuring that a vaccine will benefit individuals, we must be certain that it will do them no harm. Many health interventions have side effects; patients must be aware of any risks associated with a vaccine, and must decide, along with their health care providers, that the expected benefits outweigh potential harm.

According to the WHO, Shanchol is a safe vaccine with no significant side effects. A number of randomized controlled trials have confirmed the safety of the vaccine on hundreds of thousands of people in South Asia, Southeast Asia, and Africa. Most recently, from February-April of 2011, 263,737 doses of Shanchol were delivered in Dhaka, Bangladesh and no adverse events have been recorded.

In addition to ensuring that individual participants would not face harmful side effects, a vaccine campaign must be careful not to disrupt or have adverse consequences on families or communities. For example, could, as some have suggested, a demonstration project that vaccinates only a specific population trigger resentment among those who are not vaccinated? Experience suggests this would not be the case: previous clinical trials of oral cholera vaccine, and of other vaccines and medical interventions, have not commonly led to such social frictions, even though they have not included everyone. Indeed, the introduction of a novel diagnostic or preventative or therapeutic invariably occurs in stages, with blanket coverage a rare achievement except in the case of a few vaccines. A demonstration project is the first step toward a universal vaccination campaign. If successful, vaccine production could be increased and delivery scaled nationwide.

In addition to avoiding harmful consequences, a vaccine demonstration must be designed to maximize potential benefits for its participants. Abundant evidence suggests that Shanchol is effective in endemic and epidemic settings. Protection begins 7-10 days after receiving the second dose and lasts at least 2-3 years. After an epidemic in Vietnam, on open, controlled trial using an earlier variant of the vaccine found 66 percent protective efficacy for people of all ages 8-10 months after receiving two doses; three to five years after vaccination, protection remained at 50 percent. A randomized controlled trial in Kolkata, India, that vaccinated 31,932 people in 2006 found a 67 percent protective efficacy during an interim report two years after vaccine courses were completed. In addition to protecting individuals who are immunized, large-scale vaccination confers further protection--herd immunity--on the general population. By reducing the number of people who become infected, vaccination decreases production of viable cholera organisms deposited into the environment through fecal contamination.

The WHO has not fully recommended reactive use of cholera vaccine--that is, vaccinating during an ongoing epidemic--but recent studies suggest efficacy in epidemic settings, especially when integrated with the other pillars of prevention and care. A case-control study of reactive vaccination during an outbreak in Vietnam found a protective efficacy of 76 percent. A modeling exercise suggested that, if widespread vaccination had been launched during the 2008-2009 Zimbabwe epidemic, 40 percent of both cases and deaths could have been averted. Two recent models of the epidemic in Haiti have predicted substantial benefits from vaccination: one estimated that 10 percent coverage would avert 63,000 cases and 900 deaths; the other estimated that 30 percent coverage would lead to a 55 percent reduction in cases. The positive results of these past vaccination campaigns and modeling exercises makes a strong case that cholera vaccination would significantly help, not hurt, populations that receive it.

In addition to "do no harm," the principle of autonomy demands that health interventions not encroach on the self-determination of individuals. Participants in vaccination campaigns must not he coerced, nor should extravagant claims of efficacy be made. All must be free to decline participation without fear of retribution. Providing sufficient and balanced information about the vaccine to potential participants, many of whom may be illiterate, is a precondition of autonomous decision-making. Maintaining privacy with respect to the decision to participate is also necessary to safeguard participants' autonomy. That said, a lack of access to effective vaccines during the world's largest cholera outbreak must also be seen as an ethical challenge. We are doing harm by failing to act.

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Vaccination and Social Justice

In addition to principles from medical ethics--autonomy and "do no harm," for example--an honest appraisal of the cholera epidemic in Haiti must consider global inequities, such as the lack of access to the fruits of modern medicine among poor communities around the globe. The poor quite literally embody many of the ethical challenges inherent in medicine and public health. For example, the question of rationing health care--a political flashpoint in discussions of US healthcare reform--reaches its logical end when considering the gap in access to healthcare between the rich and poor worlds. Each year OECD countries spend about US$4,000 on healthcare per person {the United States spends more than US$8,000); low-income countries spend an estimated US$27 per person. At times the disjuncture between debates within medical ethics and the pathologies of poverty brings to mind George Bernard Shaw's Pygmalion: "Have you no morals?" the governor asks, to which Doolittle answers: "Can't afford them, governor. Neither could you if you was as poor as me."

Social justice grapples with inequities in the distribution of resources, including those dedicated to health care. For example, John Rawls' "difference principle," which has been extended by Thomas Pogge and others to a global level, demands preferential treatment of the most disadvantaged members of society. Is it just, Pogge asks, that an estimated 18 million people around the world die prematurely front poverty-related causes every year? We live in a world in which pathogens move freely across borders while the fruits of medical research, including vaccines, arc blocked at customs. Cholera is a poignant example of this contradiction: the disease was introduced in Haiti from without, yet not all of the tools in the armamentarium are available to protect Haitians from infection.

Cholera prevention and care ought to follow the contours of Rawls' difference principle; that is, caregivers ought to make a preferential option for the poor. Invariably, the poorest members of society bear the highest burden of disease while having the least access to medical care, prevention services, clean water, and modern sanitation. Cholera fatalities occur when people lack access to simple rehydration; it is no surprise that the vast majority of the more than 6,000 Haitians who have perished in the cholera epidemic were extremely poor before they became sick. Aggressive case-finding and prompt treatment can bring case-fatality rates below one percent. Strengthening water and sanitation infrastructure can slow the spread of cholera and prevent epidemics of waterborne disease in the future. No private or NGO initiatives can replace a robust public water supply. However, rebuilding the water and sanitation systems in Haiti will take resources and time, and an estimated 600 Haitians contract cholera every day. Integrating vaccination into the cholera response could provide poor, vulnerable Haitians with some degree of protection from cholera infection. Vaccination campaigns could target the places in which water and sanitation infrastructure is weakest: urban slums and rural areas. In other words, integrating vaccination into the ongoing cholera response could provide the greatest benefits to those least well off.

Because only 200,000 closes of Shanchol are currently available, some have argued that it isn't fair to protect some people if you can't protect everyone. (20 million doses would be needed to vaccinate the entire population.) We believe this logic is specious and circular Shantha has only produced only 200,000 doses of Shanchol because there is insufficient demand for more; there is insufficient demand because the 200,000 available doses are too few for a large immunization campaign, and so forth. The proposed demonstration could be a way to break the cycle: if deemed successful, the Haitian government and international partners could order more doses, Shantha could increase production, and the vaccination campaign could be scaled up nationally.

Such "limited good" arguments are, in this case, more a manifestation of neglect than a legitimate cause for concern. It was not difficult to predict the explosive spread of cholera back in late October of 2010, and had vaccines been ordered then, millions of doses would currently be available. Millions of doses can still rapidly be made available if we order them. The moral point is that Haitians lack access to an affordable, safe, and effective vaccine that could protect them from a debilitating and sometimes deadly illness that was unwittingly introduced by relief workers seeking to help after the earthquake.

Conclusion

One unintended consequence of the injunction to "do no harm" is a bias towards inaction among the institutions that govern the landscape of global health. If an organization does nothing, it is unlikely to be blamed for hurting anyone. The tendency of bureaucracies to attend to their own self-perpetuation as much as they attend to their stated goals, as sociologist Max Weber noted, compounds this inertia. Bill Foege, who masterminded smallpox eradication in India, noted that "we frequently worry about the problems of commission, but we fail to even think about the greater harm that gets done through the problems of omission." The cost of inaction is high when attempting to control an explosively infectious disease like cholera. Had a large-scale vaccination campaign begun soon after cholera hit Haiti in late October 2010, perhaps large numbers of cholera cases and fatalities could have been averted. Perhaps also healthcare providers would not be spending millions of dollars every month treating patients admitted with severe watery diarrhea.

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Some uncertainty' is endemic to the field of medicine and public health. We can never know everything about an intervention, and the consequences--favorable and unfavorable--it will have among individuals and populations before delivering it. Foege said, "If we had to wait until we could be absolutely certain that we could eliminate smallpox, then we never would have been able to do it. HIV/AIDS came along and it would so have complicated the eradication process that it might have become impossible." Integrating vaccination into the ongoing response to cholera in Haiti is the ethical and expedient thing to do. Although its healthcare system was weakened by the 2010 earthquake, Haiti could accommodate a large-scale vaccination campaign because there are still large immunologically naive populations, and there are sufficient healthcare providers in country to deliver the two-dose course effectively. If the demonstration were deemed successful, we would suggest production of cholera vaccine be ramped up for use across Haiti--perhaps in conjunction with childhood immunization programs--and in other countries (and possibly for the development of a global stockpile). Yellow fever and meningococcal vaccine stockpiles have helped reduce the incidence of those diseases, and a cholera vaccine stockpile could be developed in the same way: a coalition of donors guarantee the purchase of necessary doses; manufacturers expand production capacity; and healthcare providers integrate vaccination with delivery of care and other prevention services.

By mid-October 2011, one year after cholera hit Haiti, nearly 7,000 Haitians will have perished in the epidemic. But next year, and the year after that, need not continue this grim trajectory. Our response must be comprehensive and integrated; we must move rapidly, and together.

ALAN R. HINMAN (1), PAUL FARMER (2), (3), (4), JEAN-WILLIAM PAPERS (5), (6), LOUISE C. IVERS (2), (3), (4) FERNET LEANDRE (4), (7), JONATHAN L. WEIGEL (2), (4), MARK L. ROSENBERG (1)

AFFILIATED INSTITUTIONS:

(1) The Task Force for Global Health, Decatur, GA; (2) Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA; (3) Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA; (4) Partners In Health, Boston, MA; (5) Center for Global Health, Weill Cornell Medical College, New York, NY; (6) GHESKIO Centre, Port-au-Prince, Haiti; (7) Zanmi Lasante (Partners In Health), Cange, Haiti.