? DESCRIPTION (provided by applicant): Measles is a global public health problem, and is one of the leading causes of death in children world-wide. Measles remains endemic in parts of the world such as Africa and Southeast Asia, and imported cases lead to outbreaks affecting tens of thousands of individuals, even in regions that had previously controlled or eliminated the disease. Measles vaccination began in India in the 1980's and the 2-dose schedule was introduced in 2010. Despite these vaccination campaigns, India experiences hundreds of outbreaks yearly. In 2005, 92,000 children died from measles in India, and in 2010 that number had dropped to ~65,000, but still accounts for nearly half of all global measles mortality. The second dose of measles vaccine has further decreased the number of cases, but outbreaks still occur. Even if the two dose schedule works as well as it has in the US and Europe, there will continue to be measles outbreaks in India. Measles vaccine (MV) failure clearly plays a role in global outbreaks, where between 10-50% of cases occur in individuals who had been previously immunized. Even after two doses, measles vaccine has a 2-5% primary failure rate. In India, vaccine failure is likely to be an even greater problem as seroprotection rates < 75% have been documented. Our preliminary data indicates that two doses of measles vaccine is still associated with a failure rate of >6% in southern Indian children. This rate of failure may be high enough to interfere with control and eradication efforts of the most transmissible human virus known. Our objective is to determine the effect of several factors on measles vaccine success and failure in a southern Indian population. To accomplish this, we propose the following Specific Aims: 1) To develop comprehensive immunophenotypes and determine the role of host genetic variation and maternal antibody in measles vaccine success versus failure in southern Indian children (1,000 vaccine recipients, 800 measles cases); 2) To examine the effect of nutrition and vitamin A deficiency on vaccine failure; and 3) To sequence regionally circulating measles isolates and to determine the relationship between measles strain variation on vaccine failure. The proposed aims provide an exciting opportunity to study mechanisms of measles vaccine failure in a region of the world directly impacted by endemic disease. Data obtained from our Aims may: better predict vaccine efficacy, elucidate origins of vaccine failure, and improve our mechanistic understanding of the effect of vitamin A on measles immunity.
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