An article published Online First and in a future edition of The Lancet reports that a low-priced, locally produced oral cholera vaccine has been proven safe and effective in young children in a part of India where the disease is endemic. In anticipation of the results of follow-up studies, this vaccine is now manufactured to WHO standards. It could be introduced across developing nations where cholera remains endemic. The article is the work of Dr John D. Clemens, International Vaccine Research Institute (IVI), Seoul, South Korea, and colleagues. This study was funded by the Bill and Melinda Gates Foundation. Additional funding was provided to the IVI by the Swedish International Development Cooperation Agency and the Governments of South Korea, Sweden and Kuwait.

A prior version of this vaccine had been used in Vietnam, and was effective there. However, it had not been approved for worldwide use because the manufacturing process in Vietnam did not reliably remove cholera toxin from the vaccine. Also, Vietnam’s national regulatory authority is not approved by WHO. To support the use of this cheap oral vaccine, the International Vaccine Institute worked with the Vietnamese manufacturer VaBiotech to improve vaccine quality. In addition,the manufacturing has now been transferred to Shantha Biotechnics (Hyderabad, India), where the national regulatory authority is approved by WHO. The authors evaluated the safety and efficacy of this vaccine in Kolkata, India.

This randomised controlled trial included over 107,000 non-pregnant residents of Kolkata, India, aged 1 year or older. They were cluster-randomised by dwelling to receive two doses of either modified killed-whole-cell cholera vaccine (52,212 people) or heat-killed Escherichia coli placebo (55,562 people), both delivered orally. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholera diarrhoea severe enough for the patient to seek treatment in a health-care facility. The researchers implemented an interim, per-protocol analysis of monitoring for two years. It included individuals who received two completely ingested doses of vaccine or placebo. They evaluated the first episodes of cholera that occurred between two weeks and two years after receiving the second dose.

Overall, 31,932 participants assigned to vaccine received two doses of study treatment and 34,968 in the placebo group. There were 20 episodes of cholera in the vaccine group and 68 episodes in the placebo group. This translates to a 67 percent protective efficacy. The vaccine protected individuals in age-groups of 1 to 4.9 years, 5 to 14.9 years, and 15 years and older. The protective efficacy was significantly similar between age-groups. There was no record of vaccine-related serious adverse events.

The authors explain: “This interim analysis of a double-blind, placebo-controlled trial shows that the modified killed-whole-cell oral vaccine is safe and efficacious, providing nearly 70% protection against clinically significant cholera for at least 2 years after vaccination. Protection was seen in children vaccinated at ages under 5 years, as well as in older individuals.”

They write in conclusion: “Although the protection reported in this trial might itself be sufficient to justify the public health use of the modified killed-whole-cell oral vaccine, the public health value of the vaccine would be increased by demonstration of a longer duration of protection and of vaccine herd protection. Both of these features will be assessed in subsequent follow-up analyses.”

In an associated Comment, Dr Saranya Sridhar, School of Public Health, University of California, Berkeley, CA, USA, mentions the most remarkable feature of this vaccine is the story of its development and how successfully public-private partnerships can work with academics. He says in closing: “This success story ought to be an example for other vaccine initiatives especially against malaria and HIV, to similarly engage industry and academia towards solving an urgent public health need.”

“Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial”
Dipika Sur, Anna Lena Lopez, Suman Kanungo, Allison Paisley, Byomkesh Manna, Mohammad Ali, Swapan K Niyogi, Jin Kyung Park, Banawarilal Sarkar, Mahesh K Puri, Deok Ryun Kim, Jacqueline L Deen, Jan Holmgren, Rodney Carbis, Raman Rao, Nguyen Thu Van, Allan Donner, Nirmal K Ganguly, G Balakrish Nair, Sujit K Bhattacharya, John D Clemens
DOI: 10.1016/S0140-6736(09)61297-6
The Lancet

Written by Stephanie Brunner (B.A.)