Christian Medical College, Vellore
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Gagandeep Kang is a physician-scientist who has made outstanding contributions to understand and improve child health through her research in enteric diseases and vaccinology, all conducted at a small medical school in Vellore, India. She has built a strong inter-disciplinary research program that uses careful and detailed field epidemiology with molecular tools for characterization of infectious agents and host response to infection to understand and change factors that affect transmission, development and prevention of enteric infections and their sequelae. Observational, interventional and mechanistic studies on enteric infection and nutrition have demonstrated the complex relationships between gut function and physical and cognitive development.
Professor Kang's key and comprehensive contributions to rotavirus research have significantly informed our understanding of disease and vaccine performance in children who live in challenging environmental conditions. She conducted the largest single birth cohort study on rotaviral infections in the world demonstrating that protection after natural infection is lower in India than in developed countries, which has important implications for control of disease by vaccination. Prior to this seminal paper in rotavirus epidemiology, it was believed that two prior infections with rotavirus provided complete protection against subsequent disease, forming the basis of rotavirus vaccine development. The data showed that in India, rotavirus infections occur early, reinfection is more common than previously believed, and the rate of protection against severe diarrhoea and diarrhoea of any severity was low, predicting that the rotavirus vaccines would not work as well as in industrialized countries. A modelling study using these data estimated 50% vaccine efficacy in poor environmental condition and in fact, this level of efficacy has subsequently been reported in trials in India as well as studies from Asia and Africa.
From geographic information systems to map viruses in the community to cost of illness studies, Professor Kang designed and ran the studies which resulted in India becoming the only low-income country with comprehensive disease burden estimates for which cost-effectiveness of vaccination for multiple clinical outcomes could be predicted and resulted in oral rotavirus vaccines being the first completely new vaccine since the pentavalent vaccine to be rolled out across India from 2016 to 2019.
In parallel, Professor Kang’s group identified an unusual strain, G10P, which was then being developed as a vaccine candidate, was found to infect neonates in both the neonatal nursery and the community. Careful community based studies by Gagandeep’s group demonstrated that infection with the G10P strain in the neonatal period did not protect children from homotypic or heterotypic infection or gastroenteritis. This was controversial at the time, but the strain was subsequently withdrawn as a vaccine candidate. However, the unique predilection of G10P for the neonatal gut led to a series of studies that continue to inform our understanding of enteric infection biology today. Whole genome sequencing conducted in India demonstrated that the virus had eight genes from bovine rotaviruses and three from human viruses. Further work by a graduate student Sasirekha Ramani, in the laboratories of Mary Estes and BV Prasad at Baylor, where Gagandeep had done her post-doctoral training, demonstrated that the G10P strain was unusual in having an internal sialic acid binding site on the VP8* protein and this also bound to type II glycans and that infection was influenced by anti-glycan antibodies and breast milk oliogosaccharides.
For rotavirus vaccines, Professor Kang established the first accredited laboratory for evaluation of clinical specimens for trials, outside the US. The laboratory has now supported vaccine developers and studies in China, Brazil, Nepal, Myanmar, Sri Lanka, Maldives, Malawi, Zimbabwe and Uganda. In trying to understand why oral vaccines do not work well in developing countries, Professor Kang began to work with polio vaccines, because unlike for rotavirus, there is a correlate of protection for poliovirus. Testing the hypothesis that removal of competing enteric pathogens might permit better take of oral poliovirus vaccines, the group collaborated with Nick Grassly from Imperial College on a clinical trial in Vellore that showed that despite azithromycin removing bacteria and decreasing inflammation, immunogenicity was not enhanced.
Questioning the role of mucosal versus systemic immune responses in poliovirus vaccination also led to an open-label controlled trial of inactivated polio vaccine (IPV) in Indian children previously immunized with OPV which measured shedding after challenge with serotype 1 and 3 bivalent OPV to assess intestinal immunity. The substantial boost in intestinal immunity conferred by a supplementary dose of IPV indicated a role for this vaccine in supplementary immunisation activities to accelerate eradication and prevent outbreaks of poliomyelitis. These data resulted in a WHO recommendation for the use of IPV in travellers from endemic areas to rapidly increase intestinal immunity and prevent transmission.
Professor Kang has a deep interest in the interactions between the external and internal environments, and many complementary studies have tried to investigate the sequelae of enteric infections or find ways to ameliorate them. Trying to measure the quality of the external envrionment led to estimation of poverty using different scales, which can be complicated when agreement is low and can not be replicated across communities. In several interventional studies, her group has attempted to interrupt transmission by focusing on safe water and has generally failed, as in a study where children in households provided safe water for two years showed not difference in rates of acquistion of cryptosporidiosis. Othe studies focused on nutritional interventions, with supplementation in adults or probiotic treatment in children which did support the role of complementary therapy in restricting disease-induced damage and longer term consequences.
Using high quality clinical research Professor Kang has addressed and continues to address critical issues in enteric infections and vaccine development. Her world class laboratory in Vellore is now a reference laboratory for WHO in India and the South East Asian Region as well as a centre for teaching and research. The research community recognises her ability to identify compelling problems of child survival, and attack these with the best scientific tools that laboratory medicine has to offer. Along the way, she has served as a role model for young investigators, especially women, and has helped the next generation participate in what is her own passion for science and discovery in the cause of improving child survival.