5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial

The Lancet Infectious Diseases
Oct 2013  Volume 13  Number 10  p823 – 906
http://www.thelancet.com/journals/laninf/issue/current

Online First
Comment
A rare success for cholera vaccines
Saranya Sridhar a, Narendra Kumar Arora b
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2813%2970296-2/fulltext?_eventId=login

Cholera is a truly neglected infectious disease that is endemic in most parts of Africa and Asia. Despite an estimated annual burden of 2—4 million cases,1 it garners public attention only when outbreaks rampage through disaster-struck populations.2 Control of cholera depends on the long-term strategy of improving water quality and sanitation systems, but an effective vaccine conferring durable protection could offer an additional weapon in the depleted armoury of prevention strategies for this disease.

In 2001, WHO prequalified the licensed oral cholera vaccine Dukoral (SBL Vaccin AB, Sweden) for purchase by UN organisations.3 However, this vaccine is expensive, its efficacy lasts for only 2 years,4 and it is primarily used to protect travellers.3 In a technology transfer that should serve as a model for vaccine development, a modified version of the vaccine (Shanchol, Shantha Biotechnics, India) was manufactured and licensed in India in 2009. Shanchol was prequalified by the WHO in 2011. A field trial5 showed 67% cumulative efficacy in the first 2 years after vaccination. At that time, we sounded a note of cautious optimism and awaited the results of longer follow-up since other promising cholera vaccines with similar efficacy had failed to deliver longlasting protection.6

In The Lancet Infectious Diseases, Sujit Bhattacharya and colleagues7 report on whether Shanchol was protective over 5 years in a follow-up of 66 900 participants in a cluster-randomised placebo-controlled trial in Kolkata, India. The whole-cell vaccine containing killed strains from the O1 and O139 serogroups was given in two doses 2 weeks apart to non-pregnant individuals older than 1 year. The vaccine showed 65% (95% CI lower boundary of 52%) cumulative efficacy in the 5 year period for prevention of cholera episodes severe enough for individuals to seek treatment. This cholera vaccine is the first in the long history of cholera vaccine development to show more than 50% efficacy lasting up to 5 years. However, in children aged 1—5 years, who are at greatest risk of disease, the vaccine conferred only 42% cumulative efficacy (95% CI lower boundary of 5%) and too few cases occurred during the fifth year of follow-up to judge whether protection in these children lasted into the fifth year after vaccination. This lower level of protection is compounded by the difficulty of delivering oral vaccination to young children in poor sanitary and hygiene conditions. Nonetheless, we believe this result of an unprecedented level of long-term efficacy will be a giant leap forward for global control of cholera.

Despite this advance, questions remain. How do we improve vaccine efficacy in young children? The cholera community might learn from influenza vaccination, in which live attenuated vaccines are most efficacious in children and killed vaccines most efficacious in adults. Perhaps more effort needs to be placed on development, improvement, and testing of new and old attenuated cholera vaccines.8 A booster dose 2—3 years after the first vaccination might be necessary. Would the vaccine work equally well in areas that are not cholera endemic?

In endemic cholera areas, such as the Kolkata trial site,7 the vaccine might boost existing naturally acquired immunity. This boosting effect is given more credence by trial results showing an increased efficacy in the fourth and fifth year of the study, especially in adults, after a large cholera outbreak in the third year. Whether the vaccine will be equally efficacious in immunologically naive individuals, especially in the context of cholera outbreaks, is unknown. Individuals with HIV infection and those who are pregnant and elderly are the other high-risk populations in whom this vaccine needs to be assessed.

Vaccine efficacy was shown only against the O1 strain circulating in the study population. Efficacy against the O139 strains and newly emergent O1 strains expressing the classical toxins should be investigated.3 Resolution of whether the vaccine can reduce infection or transmission and not just protect against severe disease would help to further strengthen the case for vaccination.

We are only allowed the luxury of posing such questions because today’s study offers the cholera community an effective vaccine conferring durable protection. Despite all these unresolved issues, the need for an affordable cholera vaccine for international use has now been partly fulfilled. The focus now shifts to global policy makers and individual governments as they determine how to translate these study results into effective public good. While we celebrate a rare success story, perhaps the first in the WHO supported Decade of Vaccines collaboration, we need to seize this opportunity to transform global cholera control before we are once again overwhelmed by the next, inevitable, outbreak.

Articles
5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial
Sujit K Bhattacharya, Dipika Sur, Mohammad Ali, Suman Kanungo, Young Ae You, Byomkesh Manna, Binod Sah, Swapan K Niyogi, Jin Kyung Park, Banwarilal Sarkar, Mahesh K Puri, Deok Ryun Kim, Jacqueline L Deen, Jan Holmgren, Rodney Carbis, Mandeep Singh Dhingra, Allan Donner, G Balakrish Nair, Anna Lena Lopez, Thomas F Wierzba, John D Clemens
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2813%2970273-1/abstract

Summary
Background
Efficacy and safety of a two-dose regimen of bivalent killed whole-cell oral cholera vaccine (Shantha Biotechnics, Hyderabad, India) to 3 years is established, but long-term efficacy is not. We aimed to assess protective efficacy up to 5 years in a slum area of Kolkata, India.

Methods
In our double-blind, cluster-randomised, placebo-controlled trial, we assessed incidence of cholera in non-pregnant individuals older than 1 year residing in 3933 dwellings (clusters) in Kolkata, India. We randomly allocated participants, by dwelling, to receive two oral doses of modified killed bivalent whole-cell cholera vaccine or heat-killed Escherichia coli K12 placebo, 14 days apart. Randomisation was done by use of a computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for patients to seek treatment in a health-care facility. We identified culture-confirmed cholera cases among participants seeking treatment for diarrhoea at a study clinic or government hospital between 14 days and 1825 days after receipt of the second dose. We assessed vaccine protection in a per-protocol population of participants who had completely ingested two doses of assigned study treatment.

Findings
69 of 31 932 recipients of vaccine and 219 of 34 968 recipients of placebo developed cholera during 5 year follow-up (incidence 2·2 per 1000 in the vaccine group and 6·3 per 1000 in the placebo group). Cumulative protective efficacy of the vaccine at 5 years was 65% (95% CI 52—74; p<0·0001), and point estimates by year of follow-up suggested no evidence of decline in protective efficacy.

Interpretation
Sustained protection for 5 years at the level we reported has not been noted previously with other oral cholera vaccines. Established long-term efficacy of this vaccine could assist policy makers formulate rational vaccination strategies to reduce overall cholera burden in endemic settings.

Funding
Bill & Melinda Gates Foundation.