Tracking high-risk contacts of probable and confirmed cases of Monkeypox virus (MPV) infection has helped document the patterns of secondary transmission of the virus. Between May 19 and July 10, 2022, nationwide, 833 at-risk contacts were reported by cases; 72% were men, and the median age was 36 years. Sexual partners were the group at highest risk of infection, with a secondary attack rate of 21.8%. The secondary attack rate was significantly lower for other types of contact (6.1% for family/friends/neighbors and 1.9% for people living in the same household). The study also showed that among 495 contacts selected to analyze the proportion of vaccinated individuals, 57% received post-exposure vaccination (PEV) with a third-generation smallpox vaccine. The proportion among sexual partners was 68%. The median time intervals between the first or last at-risk contact and vaccination were 11.5 days and 7 days, respectively. Our results show that post-exposure vaccination reduced the risk of secondary infection among contacts, particularly among sexual partners, for whom this risk was nearly four times higher among the unvaccinated compared to the vaccinated. The efficacy of post-exposure vaccination was estimated at 79.3% (95% CI: 51.9–92.1) for all contacts and at 75.8% (95% CI: 35.9–91.8) for sexual partners. Despite the various biases inherent in the study, it provides useful results and insights for evaluating contact tracing and post-exposure vaccination strategies implemented to curb the spread of the virus. It provides initial real-world data on the vaccine efficacy of this strategy using third-generation smallpox vaccines for the prevention of secondary infections with the MKP virus.