The Lancet: 116E rotavirus vaccine development

The Lancet
Jun 21, 2014 Volume 383 Number 9935 p2099 – 2184

Vaccine development and developing countries
The Lancet
Participation of patients in medical research requires that a balance is struck—between anticipated benefits and potential harms of the new treatment being assessed, and with a view to the broader value of evidence accrued for guiding clinical practice and future research. Tensions can arise, however. Research in low-income settings has sometimes been perceived to be of greater potential benefit to those in high-income countries, where a drug may be marketed after licensing. In an extreme case, at the time of an outbreak of influenza A H5N1 virus in 2006—07, researchers in Indonesia were unable to share clinical samples with their counterparts in high-income countries, owing to a perceived lack of reciprocity for the benefits of research. This disappointing, and unusual, event underscores the need for a shared and participatory agenda in health research.

In today’s Lancet, Nita Bhandari and colleagues present an excellent example of successful clinical research in a developing country. They report a phase 3 clinical trial of Rotavac, an oral 116E strain rotavirus vaccine, in India. They document an efficacy of about 54% against severe rotavirus gastroenteritis in infants. Drawing on funding and technical support from Indian and international sources, development of this vaccine against an attenuated human—bovine reassortant virus has taken some 30 years to come to fruition.

Although oral rotavirus vaccines—the licensed Rotarix and RotaTeq—have been available for some years, Rotavac has the potential to be a powerful and affordable vaccination option. India has a larger burden of rotavirus deaths than any other country, with most rotavirus admissions occurring in the first year of life. Rotavac can therefore be expected to be of great benefit in reducing childhood mortality from diarrhoea, contingent on future licensing and introduction in India, and subject to ongoing monitoring of adverse events including intussusception. Availability of an additional rotavirus vaccine could also prove to be of benefit in other developing countries.

In an accompanying Viewpoint, Maharaj Bhan and coauthors describe the collaborative international process which led to the development of Rotavac. They discuss the economic landscape for vaccine development that has influenced the vaccine’s creation and will continue to affect its provision alongside competing vaccines. In a Comment in this issue, Brian Greenwood discusses the ethics of randomised vaccine trials. The setting in which a vaccine is to be used, for instance a low-income country, is expected to affect the protection achieved and necessitates rigorous evaluation. In what circumstances, however, is it appropriate for people in a trial’s control group to be denied a vaccine of expected health benefit in order to establish efficacy in those allocated by chance to an experimental group? Again the question of balance comes into play, which could involve provision of another licensed vaccine to people in the control group. Questions of this nature will continue to exercise researchers and policy makers, especially in resource-poor countries.

Vaccines cross borders readily given their relative ease of administration and durable effects. Not only have vaccines contributed to long-term health gains in high-income countries and the decisive eradication of smallpox, but vaccination campaigns in developing countries have played an important part in reducing neonatal mortality. Yet the ongoing setbacks in the global mission to control poliomyelitis, which have included violent targeted opposition to polio vaccination projects in Pakistan, emphasise the political dimension of health programmes and of vaccination in particular.

There is no shortage of disease targets in need of vaccines. Although development of vaccines against HIV continues to pose serious challenges for both basic and clinical researchers, vaccines against malaria and dengue (both infectious diseases that cause major burdens of morbidity and mortality concentrated in developing countries) are in advanced stages of clinical assessment. In the future, while development of new vaccines will remain costly in terms of time and research effort, the Rotavac story could prove inspiring for a world planning new health aspirations and challenges for the post-MDG era—a combination of research creativity and entrepreneurial ingenuity shaping future medical treatments brought about by and for the people of developing countries.

The use of a placebo in vaccine trials
Brian Greenwood
Injecting an infant, who cannot consent, with a saline solution that can do no good is not an activity that anyone would want to undertake lightly, yet this is what happens frequently in the course of paediatric vaccine trials. When the efficacy and safety of a novel vaccine is being assessed for the first time, societies, ethics committees, and parents accept this course of action on the grounds that although the vaccinated infant cannot derive any benefit from participating in the trial, other infants might do so in the future.

116E rotavirus vaccine development: a successful alliance
Shabir A Madhi, Umesh D Parashar
In The Lancet, Nita Bhandari and colleagues’ study1 about the efficacy of the new 116E rotavirus vaccine in Indian infants offers an opportunity to address the substantial lag in translation of scientific progress for the benefit of the world’s most vulnerable population. Vaccination is considered to be second only to access to potable water in its potential cost-effectiveness as a health-care strategy for improving child health. Most childhood deaths from vaccine-preventable diseases, such as Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and rotavirus, happen in low-income countries.

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial
Nita Bhandari PhD a, Temsunaro Rongsen-Chandola MSc a, Ashish Bavdekar DNB b, Jacob John MD c, Kalpana Antony MBA d, Sunita Taneja PhD a, Nidhi Goyal DPH a, Anand Kawade MD b, Prof Gagandeep Kang PhD c, Sudeep Singh Rathore MBBS a, Sanjay Juvekar PhD b, Prof Jayaprakash Muliyil DrPH c, Alok Arya MPharm a, Hanif Shaikh MPharm b, Vinod Abraham MPH c, Prof Sudhanshu Vrati PhD e, Michael Proschan PhD f, Robert Kohberger PhD g *, Georges Thiry PhD h, Roger Glass PhD f, Prof Harry B Greenberg MD i, George Curlin MD f, Krishna Mohan PhD j, G V J A Harshavardhan BVSc j, Sai Prasad MBA j, T S Rao PhD k, John Boslego MD m, Dr Prof Maharaj Kishan Bhan MD for the India Rotavirus Vaccine Group
Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India.
We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6—7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6—7 weeks, 10 weeks, and 14 weeks. Infants’ families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry—India (CTRI/2010/091/000102) and (NCT01305109).
4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53•6% (95% CI 35•0—66•9; p=0•0013) and 56•4% (36•6—70•1; p<0•0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37—97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1•5 in the vaccine group and 3•2 in the placebo group, with an incidence rate ratio of 0•46 (95% CI 0•33—0•65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product.
Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants.
Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.

Team science and the creation of a novel rotavirus vaccine in India: a new framework for vaccine development
Maharaj K Bhan, Roger I Glass, Krishna M Ella, Nita Bhandari, John Boslego, Harry B Greenberg, Krishna Mohan, George Curlin, T S Rao
In The Lancet, findings from Nita Bhandari and colleagues’ phase 3 clinical trial1 show the safety and efficacy of the 116E rotavirus vaccine against severe rotavirus gastroenteritis in Indian infants. The vaccine has an efficacy similar to that of two licensed oral rotavirus vaccines—RotaTeq (Merck) and Rotarix (GlaxoSmithKline)—when tested in low-income settings.2,3 However, the timeline of development has been unique and unconventional. The vaccine was not the product of a major multinational manufacturer, but rather, the result of work by team science, based in India.