Cholera is an acute diarrheal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. It affects both children and adults and can kill within hours if not properly treated. According to WHO, there are 1.4 to 4.3 million cases and up to 142,000 deaths annually, with a disproportionate burden in Africa and South Asia.
Cholera is a disease of poverty and strikes in settings where there is overcrowding and limited access to safe water and sanitation. Explosive and deadly outbreaks can occur following natural disasters and humanitarian crises when systems break down.
Improvements in water quality, hygiene and sanitation have been recognized as the measures to prevent and control cholera. While effective, these are long-term measures and challenging to implement in low-income countries with limited resources. Oral cholera vaccines can be an effective complementary tool that works for the short- to medium-term, especially during outbreaks when immediate action is needed.
Dukoral, a two-dose inactivated vaccine consisting of killed whole cells of Vibrio cholerae O1 and the B subunit of the cholera toxin, has been on the market since 1991. But it is mainly used in developed countries as a traveler’s vaccine and has not been introduced into developing countries due to its relatively high cost.
IVI’s Cholera Program aims to accelerate the development and introduction of safe, effective, and affordable oral cholera vaccines to combat epidemic and endemic cholera in developing countries.
Through this program, we developed a new low-cost two-dose killed whole-cell oral cholera vaccine. The vaccine (Shanchol) was prequalified by WHO in 2011. Shanchol is currently stockpiled by WHO for emergency use and has been used in countries such as Haiti, South Sudan, Malawi and Ethiopia. Read our story to see how we accomplished bringing a vaccine to WHO prequalification – a major feat that few nonprofit organizations have achieved – and our ongoing efforts to combat cholera in the developing world.
Development of the oral cholera vaccine was made possible due to an international public-private partnership led by IVI with partners from Sweden, Vietnam, India, Korea, and the U.S. In the early 2000s, Vietnam had already developed and licensed its own oral cholera vaccine. But in order for the vaccine to be used globally, it had to be modified to meet the requirements of WHO. Therefore, in collaboration with VaBiotech, the Vietnamese manufacturer of the vaccine, IVI reformulated the vaccine and transferred the technology back to VaBiotech. The modified vaccine (mORC-VAX) was licensed in Vietnam and is now used nationally.
In addition, the technology was transferred to Shantha Biotechnics, a manufacturer in India – a country with a national regulatory authority (NRA) recognized by WHO (a prerequisite for WHO prequalification). IVI worked with Shantha and other partners to perform clinical trials in Kolkata, India to demonstrate that the vaccine was safe and efficacious. Since the vaccine also needed to be affordable to low-income countries, a global access agreement was made in which Shantha agreed to provide the vaccine at an affordable price for the public sector. The pivotal trials conducted in Kolkata showed that two doses of the oral cholera vaccine had a protective efficacy of about 65 percent for up to five years – the first demonstration of strong sustained protection by an oral cholera vaccine.
The vaccine was licensed in India as Shanchol in 2009, and IVI worked closely with Shantha on WHO prequalification, which was obtained in 2011. This was a major achievement for global health and IVI. To date, Shanchol is one of only three WHO-prequalified vaccines that have come about through product development partnerships (PDPs).
Our Work Continues
IVI recognized that more than one manufacturer was needed to ensure a reliable supply of the oral cholera vaccine for the global market. We started working with EuBiologics, a Korean company, in 2010 as our second manufacturing partner. We have been working with Eubiologics to implement the necessary trials for licensure in Korea and to obtain WHO prequalification. As part of the global access agreement, Eubiologics will also provide high-quality affordable vaccines for public-sector use in resource-poor countries.
Substantial progress has been made on the EuBiologics vaccine, Euvichol®. The vaccine was WHO-prequalified in 2015. Once WHO prequalification is achieved, the vaccine can be sold through UNICEF to the global market highlighting the major contribution of Eubiologics and Korea to the fight against cholera.
In 2014, IVI began working with a new partner, Incepta Vaccine Ltd, a Bangladeshi company, for the technology transfer and clinical development of the oral cholera vaccine. Since cholera is endemic in Bangladesh, there is great need for a domestically produced oral cholera vaccine. The partnership with Incepta will help reduce the significant burden of cholera in Bangladesh.
IVI continues to work on optimizing Shanchol™ for use in developing countries. For example, Shanchol consists of a two-dose regimen, but a single-dose regimen would be logistically easier to administer in campaigns for outbreaks and emergency situations. Therefore, a single-dose study was launched in Bangladesh at the beginning of 2014. IVI, with iccdr,b, will assess if one dose of the vaccine is sufficient to provide protection against cholera.
IVI also continues to work in Vietnam, supporting efforts to pave the way for WHO prequalification of mORC-VAX. The Vietnamese NRA was recently recognized by WHO, which means that mORC-VAX could be eligible for WHO prequalification in the near future.
A stockpile using the oral cholera vaccine was established in late 2013 supported by Gavi, the Vaccine Alliance and managed by WHO and other partners. The purpose of the stockpile is to expedite the delivery of cholera vaccines for rapid outbreak response in emergencies and crisis situations. It was used for the first time in 2014 to combat a cholera outbreak in South Sudan. While perceptions have been changing about using a vaccine to fight cholera, more evidence is needed to demonstrate the impact of vaccination and to generate demand for the oral cholera vaccine.
IVI is collaborating with local health authorities and global health groups on introduction of the oral cholera vaccine to provide practical evidence that vaccination works, is feasible, and is well-accepted by the community. We provided technical support to icddr,b for the introduction of the oral cholera vaccine in Bangladesh, a large-scale study that assessed vaccine effectiveness when given through the public health system. The results, published in The Lancet, showed that the vaccine was highly effective and added momentum for cholera vaccination.
With local partners, we introduced the oral cholera vaccine in Nepal, Ethiopia and Malawi, vaccinating more than 180,000 people in 2015. The vaccine was introduced through campaigns in various settings (preventive campaign against endemic cholera in Ethiopia to emergency campaign against an outbreak in flood-stricken Malawi), showing that cholera vaccination is practical and feasible. Despite the progress made, we are still not finished. IVI continues to work on cholera control, increasing vaccine supply and advocating for the use of the vaccine – so that all communities at risk are protected against cholera.
We gratefully acknowledge the Governments of the Republic of Korea and Sweden, Bill & Melinda Gates Foundation, LG Electronics, Kia Motors, Yanghyun Foundation, and Kim & Chang for their support.