Dr. John D Clemens’ Acceptance Speech
2010 Albert B. Sabin Gold Medal Award
I would like to express my deep appreciation to the Sabin Institute for this really great
honor. I feel humbled to be receiving an award commemorating one of the great heroes
of vaccinology, Albert Sabin, and to be in the company of past recipients of this award,
all of whom I greatly admire, and many of whom have been my friends and mentors. And
special thanks to my friend, colleague and mentor, Jan Holmgren, for his overly generous
introduction.
The world has benefitted greatly from innovative approaches to the development of
vaccines and the recent global commitment to tackle the world’s most neglected diseases.
A good example is cholera, a dehydrating diarrheal disease that can cause terrifying
epidemics and can take an otherwise healthy person to a state of hypovolemic shock and
death within a span of hours. I entered the world of international health research through
work on cholera, and the challenges of controlling cholera through vaccination have
continued to fascinate and occupy me for the last 30 years.
As a medical resident at Case Western Reserve University Hospitals, I had the privilege
to train under Professor Charles C.J. Carpenter, a giant in US medical academia and
global health, who, as a young physician working in Calcutta had made fundamental
advances in the way that we rehydrate patients with cholera, dramatically reducing the
case-fatality rate of the disease.
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Chuck was innovative in his approach to medical education and encouraged his residents
to take elective time to work abroad in developing countries.
In 1978 I eagerly seized this opportunity with the help of Dr. Tom Butler, then a young
faculty member at Case. Tom suggested that I take my elective at the Cholera Research
Laboratory in Dhaka, Bangladesh, under the supervision of its Scientific Director, Dr.
Bucky Greenough, who had been Tom’s mentor at Johns Hopkins. Before long, my wife,
Bonnie, who was then a pediatric resident at Case, and I were off to Bangladesh. Though
we spent only 6 weeks working in Dhaka, it was a life-changing experience for both of us,
giving us a taste of the excitement of conducting research on cholera in the midst of the
world’s busiest diarrhea hospital.
Following my residency, my career veered toward mainstream, academic internal
medicine, working with Dr. Alvan Feinstein’s Clinical Epidemiology Unit at Yale. In
1983, while at Yale, I received an intriguing phone call from Dr. David Sack, then a
young faculty member at Johns Hopkins and a Dhaka alumnus. David asked whether I
would be interested to direct a new diarrheal diseases project in Dammam, Saudi Arabia
operated by the Dhaka Centre, which was then called ICDDR, B. My wife and I, ever
eager to pursue adventurous overseas opportunities, traveled to Dhaka to obtain Saudi
visas for the visit, but for reasons that included a certain amount of political intrigue, the
visas were never issued. However, at the end of our visit to Dhaka, Bucky Greenough,
who by then had become the Director of the Centre, mentioned that there was another
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possible job opportunity—leading a field trial of killed oral cholera vaccines in Matlab,
Bangladesh.
The trial in Bangladesh was to be the first-ever trial of the efficacy of an oral cholera
vaccine in the field. Following nearly a century of use, the old injectable cholera
vaccines had been abandoned as public health tools by the WHO in the late 1970s as a
result of disappointing results in well-controlled trials. At the same time, mucosal
immunologists had demonstrated that the problem with the older generation, injectable
cholera vaccines was that they failed to elicit sufficient mucosal secretory IgA antibodies
against cholera, which are now known to be the primary basis for immune protection
against cholera. Importantly, this research found that oral presentation of antigens is the
most efficient way of eliciting this mucosal secretory immunity, which led to a flurry of
activity in the development of oral cholera vaccines.
By the early 1980s, the lead oral cholera vaccine candidate was one developed by
Professor Jan Holmgren at the University of Gothenburg. The vaccine consisted of the B
subunit of cholera toxin, which Jan had biochemically defined years earlier, as well as a
mixture of killed vibrio whole cells, the latter not very different from the constituents of
the old injectable vaccines. After careful consideration, WHO had selected Jan’s B
subunit-killed whole cell oral cholera vaccine for testing in a large-scale field trial in
Bangladesh.
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In 1983 Bonnie and I left New Haven with our two young daughters for our new home in
Dhaka, where we were to live for the next five years. For the entire family, life in
Bangladesh was an amazing experience, and the job of leading this trial was an
extraordinary opportunity. My training at Yale had equipped me well to deal with the
rarified aspects of trial design and methods, but the experience in Bangladesh educated
me on the practical realities of conducting a large scale field trial in a developing
country—including hiring and training some 500 staff, purchasing a fleet of speedboats
to traverse the riverine field area, renovating a field research station, and engaging in the
challenging politics of large-scale field trials.
The Bangladesh trial enrolled about 90,000 adults and children. Subjects were assigned to
one of two killed oral cholera vaccines—one, Jan Holmgren’s B subunit-killed whole
cell oral vaccine, and another containing the same killed vibrio whole cells without B
subunit— or to a placebo. The B subunit-containing vaccine conferred 85% protection
against cholera and cross-protection against ETEC diarrhea in the short-term, and 50%
protection against cholera over three years of follow-up. At the time, these were quite
stunning findings for a cholera vaccine. And buttressed by other studies, the Bangladesh
trial provided the basis for international licensure of the oral B subunit-killed whole cell
vaccine by the Swedish producer SBL. Unfortunately, due to its expense, this vaccine
has been marketed primarily for travelers and has yet to be deployed for the poor in
cholera-endemic countries.
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But behind the scenes, rather quietly, a parallel development was taking place that was to
ultimately yield an oral cholera vaccine for the poor. In the 1980s, the late Professor
Dang Duc Trach, then Deputy Director of the National Institute of Hygiene and
Epidemiology in Hanoi, Vietnam, contacted Jan about acquiring the know-how for
producing the second oral vaccine that we had tested in Bangladesh, a vaccine that
contained killed whole cells but not the B subunit. In the Bangladesh trial, this killed
whole cell-only oral vaccine had been less protective in the short-term but equally
protective in the long-term as the B subunit-killed whole cell vaccine.
Trach, who believed that there was a great need for a vaccine to control the high burden
of cholera in Vietnam, reasoned that this simple oral vaccine could be cheaply produced
in Vietnam and would be easy to deploy. At his invitation, I travelled to Hanoi from my
home in Dhaka in 1986 to discuss the results of the Bangladesh cholera vaccine trial. It
was a wonderful discussion, though Vietnam was quite isolated from most of the Western
world at that time and still had a great deal of bitterness towards the U.S. government.
Upon reflection, I think that this visit probably was my first taste of what Peter Hotez has
termed “Vaccine Diplomacy.” Not long after this visit, Jan and I lost touch with Trach,
but some seven years later, after I had returned to the United States and was working at
NIH, Dr. Bernard Ivanoff of the WHO mentioned to me that he had heard that the
Vietnamese were making great progress with the killed oral cholera vaccine. Bernard
suggested that we travel to Hanoi to meet with Trach. Trach described to us how he had
directed the production of an oral killed whole cell vaccine; had tested it in nearly 70,000
people in the city of Hue, Vietnam; and had found it to be safe and about 60% protective.
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He also informed us that he thought he could produce the vaccine for under 25 cents per
dose.
Bernard and I were incredibly excited by this news, but recognized that helping Trach
move forward with the vaccine would require a team effort, and immediately enlisted the
help of both Jan and Dr. Roger Glass, then at CDC. We first helped Trach further analyze
the Hue data so that it could be published internationally; and the resulting paper was
published in The Lancet, with a very positive editorial. As well, we realized that if the
vaccine were to be accepted internationally, it would have to be tested in a conventional
randomized, double-blind clinical trial, as the Hue study was an open study.
Dr. Duane Alexander, then Director of the National Institute of Child Health and Human
Development, where I worked at NIH, provided generous support and encouragement for
this trial, and with further support from the Swedish government and from the WHO, we
organized a randomized, placebo-controlled trial of this vaccine in the coastal city of Nha
Trang, Vietnam where cholera had been highly endemic.
The Nha Trang trial was truly massive, enrolling about 350,000 people. But sadly
Murphy’s Law prevailed: cholera completely disappeared the moment we started
vaccinating. We thus conducted one of the largest trials of vaccine safety ever done.
Thankfully, the vaccine was safe, but without hard efficacy data, it seemed that this
attractive Vietnamese vaccine would never see the light of day outside of Vietnam.
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Unexpectedly, the creation of the International Vaccine Institute (IVI) in Seoul, Korea in
the mid-1990s provided a platform that resurrected our hopes for an inexpensive and
effective oral cholera vaccine for the developing world. This Institute was initiated by the
United Nations Development Programme (UNDP), and was developed to meet an urgent
need for a vaccine research and development organization focused on vaccines against
diseases of the poor.
UNDP opened a competitive bid for the right to host an IVI among countries in the AsiaPacific region. Korea applied, hoping to repay the world for all of the assistance that it
had received during and after the terrible days of the Korean War. Critical to the ultimate
selection of Korea as the host country was the strong support of Korea’s then President,
Kim Young-Sam, ably assisted by his advisor, Ban Ki-Moon, who is now Secretary
General of the United Nations.
In 1997 the IVI came into being as an autonomous, legally established international
organization, with signatures at the UN by Korea’s then Minister of Foreign Affairs, Mr.
Hong Soon-young, and Professor Barry Bloom, the Chairman of IVI’s inaugural Board of
Trustees.
In 1999 I had the good fortune to be selected as IVI’s first Director. As Jan mentioned in
his introduction, a breakthrough came later that year, when IVI was awarded a grant from
the Bill and Melinda Gates Foundation, called DOMI or Diseases of the Most
Impoverished, to support research to accelerate the development and introduction of
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vaccines against neglected enteric infections such as cholera. Under DOMI, further
development of the Vietnamese oral killed whole cell cholera vaccine was selected as a
top priority.
However, early on in the DOMI Program we realized that the world would not likely
accept the Vietnamese vaccine because the Vietnamese national regulatory authority was
not approved by the WHO. It was therefore necessary for us to find an alternative
producer. And Trach, who truly had a global vision and whose aim was to make his
inexpensive effective vaccine available to the entire world, embraced the plan of
technology transfer.
In 2004 we organized a meeting in Hanoi with Dr. Varaprasad Reddy, President of a
company called Shantha Biotechnics in India, to craft a technology transfer agreement
whereby Shantha in India, where the regulatory authority was WHO-approved, would
receive the vaccine from the Vietnamese producer, which by that time had changed its
name to VaBiotech.
IVI’s vaccine process development department, led by Rodney Carbis, was to coordinate
the technology transfer. However, Rodney’s group immediately encountered an
important obstacle: the Vietnamese vaccine was not produced by methods that were in
compliance with WHO standards for killed oral cholera vaccines. This necessitated a
substantial modification of the vaccine by Rodney’s group, including selection of
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different strains, the use of different manufacturing methods, and implementation of new
quality control assays.
Thus modified, this oral killed whole cell cholera vaccine was tested by IVI and
Vietnamese scientists in Vietnam and was found to be safe and immunogenic.
To achieve licensure in India, IVI initiated clinical trials in Kolkata, with the strong
collaboration and support of Professor NK Ganguly, Director of the Indian Council of
Medical Research, and Dr. Sujit Bhattacharya, Director of the National Institute of
Cholera and Enteric Disease (or NICED) in India.
In 2006 a pivotal randomized, placebo-controlled efficacy trial of a 2-dose regimen of
this newly reformulated vaccine was initiated in nearly 70,000 children and adults
residing in dense, urban slums in Kolkata, India. The trial found that during the first three
years of follow-up the vaccine conferred sustained 70% protection against cholera,
establishing a new benchmark for cholera vaccines.
Gratifyingly, the vaccine was recently described by The Lancet as the world’s first
affordable oral cholera vaccine.
On the basis of this trial, the vaccine has been licensed in India under the trade name,
Shanchol, an important first step. But of course our goal was not merely
commercialization of the vaccine in India, but making it available to the poor through
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public sector programs both inside and outside of India. Crucial to this goal was a
revision of WHO’s recommendations on oral cholera vaccines, which in the past had
been lukewarm at best.
In November 2009, the WHO Scientific Advisory Group of Experts or SAGE considered
recent data on cholera and cholera vaccines, and determined that the data were indeed
sufficient to warrant a major revision in WHO’s position.
A WHO position paper in 2010 now recommends the use of oral cholera vaccines for the
control of both endemic and epidemic cholera. This is an important first step, and both
India and Bangladesh are now piloting the use of Shancol.
We still have a ways to go, including gaining WHO pre-qualification for the Shantha
vaccine, generating a larger global supply by transfer of the vaccine to additional
producers, and identifying how to finance purchase of this vaccine for the poor, but we
feel there is good reason for optimism, and we hope that you will stay tuned.
Thank you for indulging me by allowing me to tell this somewhat wondering saga of
cholera vaccines, but I think that the saga does illustrate how people working together in
a multinational collaboration—in this case Bangladesh, India, Sweden, the U.S., and
Vietnam—can overcome major obstacles to developing vaccines for the poor, even ones
like cholera vaccines, which are commercially unattractive.
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Before closing, I would like to acknowledge several additional people and organizations
who contributed greatly to this cholera vaccine story:
The Government of Korea has been an unwavering supporter of the IVI and its work,
including direct support by the current president, President Lee Myung-bak, and the First
Lady, Kim Yoon-ok, as well as by Presidents and First Ladies from the previous two
administrations.
Professors Cho Wan-Kyoo and Park Sang-Dai, who have worked so hard to land the IVI
in Korea and make it succeed, deserve great credit not only for the success of the killed
oral cholera vaccine but for the success of IVI as a global contributor.
The IVI could never have undertaken an ambitious program like this cholera vaccine
program without the guidance of its Board of Trustees, led by its current Chairman,
Professor Ragnar Norrby, and his predecessors, Professors Samuel Katz and Barry
Bloom, and of its suburb Scientific Advisory Group, now led by Professor Robert Black
and previously led by Professor Margaret Liu, who is now the Vice Chairman of our
Board.
Literally hundreds of dedicated staff of the major organizations have been involved in
this story-- the ICDDR,B in Bangladesh, The National Institute of Hygiene and
Epidemiology in Vietnam, the University of Gothenburg in Sweden, the National
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Institute of Cholera and Enteric Diseases and Shantha in India, NIH in the US, the IVI in
Korea, and the World Health Organization—have contributed in essential ways.
The Bill and Melinda Gates Foundation deserves special thanks, as do the governments
of Sweden and the United States, for their extraordinary generosity as donors without
whose support the killed oral cholera vaccine story would have stalled a long time ago.
And of course, my gratitude goes to my family, which has provided loving support to me
during my highly itinerant professional career.
Again, thanks so much for this great honor.
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