Investigation of an Mpox Outbreak Affecting Many Vaccinated Persons in Chicago, Illinois—March 2023–June 2023

Abstract Background After months of few mpox cases, an increase in cases was reported in Chicago during May 2023, predominantly among fully vaccinated (FV) patients. We investigated the outbreak scope, differences between vaccinated and unvaccinated patients, and hypotheses for monkeypox virus (MPXV) infection after vaccination. Methods We interviewed patients and reviewed medical records to assess demographic, behavioral, and clinical characteristics; mpox vaccine status; and vaccine administration routes. We evaluated serum antibody levels after infection and compared patient viral genomes with MPXV sequences in available databases. We discussed potential vaccine compromise with partners who manufactured, handled, and administered the vaccine associated with breakthrough infections. Results During 18 March–27 June 2023, we identified 49 mpox cases; 57% of these mpox patients were FV. FV patients received both JYNNEOS doses subcutaneously (57%), intradermally (7%), or via heterologous administration (36%). FV patients had more median sex partners (3; interquartile range [IQR] = 1–4) versus not fully vaccinated patients (1; IQR = 1–2). Thirty-six of 37 sequenced specimens belonged to lineage B.1.20 of clade IIb MPXV, which did not demonstrate any amino acid changes relative to B.1, the predominant lineage from May 2022. Vaccinated patients demonstrated expected humoral antibody responses; none were hospitalized. No vaccine storage excursions were identified. Approximately 63% of people at risk for mpox in Chicago were FV during this period. Conclusions Our investigation indicated that cases were likely due to frequent behaviors associated with mpox transmission, even with relatively high vaccine effectiveness and vaccine coverage. Cases after vaccination might occur in similar populations. In May 2023, we investigated an mpox cluster that affected many vaccinated persons. No cause was identified, but cases after 2 mpox vaccine doses were associated with a higher number of sexual partners and milder infections than among unvaccinated persons.