In this study, we examined the spread of SARS-CoV-2 infection and the dose-dependent efficacy of the COVID-19 vaccine Covishield (Oxford/AstraZeneca). During the period between December 2020 and February 2021, we tested the level of natural infection among individuals by estimating the reactivity of their sera towards SARS-CoV-2 spike (S) and nucleoprotein (N) proteins. The seropositivity of the population in different communities ranged from 17% to 51%, depending on their connectivity to the nearest metropolis Kolkata (population 14.85 million), the disease epicenter. We further found that while 90% of the people administered with two doses of Covishield developed antibody against SARS-CoV-2, only 55% developed antibody after one dose. Primarily those who had developed antibody through natural infection remained seropositive after the first vaccine dose in contrast to those with undetected infection. Our experimental findings not only contribute to a better understanding of COVID-19 epidemiology in India but also pave the way for an effective vaccination strategy involving the individual history of infection.