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In recent years vaccine hesitancy—the delay in acceptance or refusal of available vaccines—has ballooned to become one of the gravest threats to public health across the world. The Covid-19 vaccine is unprecedented both for its pace of development and its potential to reign in a pandemic that has claimed millions of lives, wrecked livelihoods, and halted life as we know it. Yet the success of this scientific breakthrough hinges on societal willingness to vaccinate. What are the conditions under which people are more likely to accept a vaccine? History holds important lessons for this urgent question. This paper points to insights from an analysis of the popular reception of the world’s first ever vaccine, which coined the term itself . Variola vaccinae, the cowpox vaccine attributed to Edward Jenner, provided immunity against the deadly human disease, smallpox, which is to date the only human disease to have been eradicated. The paper draws on case comparisons of the divergent popular responses to the vaccine across subnational units within and between the national units of China and India to show how vaccines are less likely to be resisted if they are ideationally and institutionally embedded.