John Mekalanos on the Human Importation of Cholera

Special Topic of Cholera Interview, February 2011

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John MekalanosThat is not to say that a new fully pathogenic strain can't de novo emerge from an aquatic environment. But this usually doesn’t happen and maybe the last time it did, it was 1961 in Indonesia (the beginning of the 7th pandemic). Given that this 7th pandemic El Tor strain has unique genetic properties, from all other V. cholerae that caused disease globally before that, it seems likely this strain emerged around this time in that particular location (through virulence gene acquisition) and then spread globally after that even to the present day. My point is that most of this four decade long spread is probably associated with human importation after importation, rather than climatic events as some of my colleagues think. But hey, that’s just my opinion. 

SW: And what's your response to these claims?

Sorry, but the genetic evidence in the case of both the Latin American and Haitian epidemics does not support the idea that this organism, in the form it appeared, crawled out of the aquatic environment as a result of climate change. If strains identical to either the Peru isolate or the Haitian isolate cannot be found in the water BEFORE the epidemic begins, then it seems pretty obvious to me that the two strains were introduced from far away—imported by human activity.

All genetic studies continue to say cholera is imported most of the time with the only exceptions being endemic locales (like Bangladesh and India) where the environment presumably plays some role in maintaining strains between epidemic periods. If human amplification was eliminated there, I think the disease would burn out. Indeed, vaccine studies have suggested that if you decrease the cholera burden in a community, even non-vaccinated folks are protected. This says disease is associated with victims more than the environment. The history of this disease is that cholera gets imported more often than not.

SW: What do you think is the important lesson to take away from this argument of human importation of cholera?

The authorities that make these decisions—the organizations like the WHO, the Pan American Health Organization, the CDC, and anyone else who feels they can weigh in on this—have to realize that when disasters occur and there's no evidence of endemic cholera in the affected location, then authorities should not send humanitarian aid from countries that do have ongoing endemic or epidemic cholera. Or at least they can't send personnel from these regions without at least doing something really aggressive to assure that the people from these countries don't land on the ground without being screened or treated with antibiotics first or, better yet, vaccinated against cholera.

SW: Speaking perhaps naively, why isn't everyone vaccinated, in any case, in this kind of situation?

"When I heard in January 2010 that an earthquake had hit Haiti, the first thing that crossed my mind was 'how long?' I knew cholera would happen, sooner or later, the only question was when."

Vaccination is a big, hot issue now, and there's not a lot of support from those same organizations to make authoritative statements about it. They need to say that if a cholera vaccine was available, then they would recommend its use under these conditions. In my opinion, if everybody who landed in Haiti from a place with endemic cholera had been vaccinated, this disaster would likely have never occurred.

As far as I'm concerned, this was a mistake made decades ago. Honestly, I was in many a committee meeting where this was discussed and people said, "We don't have to worry; it's low risk for cholera to break out there," (there being some new disaster zone). Well, it's low risk, but a huge disaster if it does break out. I'm just flabbergasted by this.

I think this epidemic was avoidable, and all it needed was a little bit of encouragement by the experts in the field a decade or two ago to say that cholera is a problem that can be solved by vaccination of the right people—either of people at risk or of travelers to the environment that is at risk. That policy would have given us a vaccine by now. 

I didn't make any friends telling these people what I really felt. I think the people who made these decisions made some huge mistakes. They were shortsighted, and now they should learn from this and make the correct public statement. They should admit they don't understand enough about this disease to do adequate risk assessment that says no vaccine is needed. Therefore, why not encourage vaccine development and use once available?

Therefore the simplest solution is for the public health community to say clearly  that we need a cholera vaccine with the following characteristics—then list them. Challenge the research community with the task at hand. Tell us they need it for people at risk after disasters, in refugee camp situations, and for travelers to those locales, particularly when those travelers are coming from high-risk countries. I have little doubt that when that is the stated position or policy, that scientists and manufacturers will be motivated to deliver what the public health community needs. 

SW: Is there no vaccine or not enough vaccine, and why?

There really is no vaccine, or at least not one that's widely approved. There's a vaccine approved for use in India, but it's not approved for export to anywhere else in the world and it requires multiple doses to induce immunity. There's a single-dose vaccine that was approved for use in a few European countries for use in travelers but that vaccine ended up having no market, so the company that controlled it licensed it out to another company that currently doesn't have the capacity to produce it.

The estimate is that there might be 200,000 doses of the vaccine in existence. So the idea of immunizing Haiti seems out of the question for now. But why was it out of the question before Haiti happened? Why wasn't it stockpiled? You'll never stockpile this vaccine without a few global health organizations saying it makes sense to do so. And the obvious organization, the one which stands right in the cross hairs, is the WHO. It takes courage to make that statement and stand by it.

By way of full disclosure, I have been involved in developing cholera vaccines so you might say I'm conflicted. However, others have made cholera vaccines too. The problem has not been as much making a safe and effective vaccine. It is getting agencies to say they are willing to use it as part of public policy. After that I'm sure we can figure out how to get that global stockpile made.

But without WHO saying we need it, we want it, if it gets made we will use it, then it will be pretty hard to get somebody to write the check to pay for the program's success. They're the experts the world looks to, yes—but they're making a lot of mistakes in my opinion in setting policies that are basically anti-vaccine when addressing the cholera threat. Let's clean up the water too, but pro-vaccination policy is not anti-water sanitation policy. They are compatible and should be both embraced.

John J. Mekalanos, Ph.D.
Department of Microbiology and Molecular Genetics
Harvard Medical School
Boston, MA, USA

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JOHN MEKALANOS' MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:

Heidelberg JF, et al., "DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae," Nature 406(6795): 477-83, 3 August 2000 with 769 cites. Source: Essential Science Indicators from Thomson Reuters .

ADDITIONAL INFORMATION:

KEYWORDS: CHOLERA, VIBRIO CHOLERAE, GENOME SEQUENCE, GENE FUNCTION, EPIDEMIOLOGY, PATHOGENIC ORIGINS, STRAINS, HAITI, PREDICTION, PROPHYLAXIS, NATURAL DISASTERS, REFUGEE CAMPS, CIVIL WARS, WATER, UNSANITARY CONDITIONS, HUMAN IMPORTATION, UN HUMANITARIAN EFFORT, NEPAL, CLIMATE CHANGE, VACCINATION, WORLD HEALTH ORGANIZATION.

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