Prevention of mpox by JYNNEOS vaccination: a case-control study comparing test-negative and alternative-disease control populations

Risk-based vaccine recommendations complicate observational studies of vaccine effectiveness (VE), since recipients and non-recipients may differ in infection risk and likelihood of testing. For JYNNEOS-recommended for men who have sex with men at high mpox risk-prior studies have used differing control populations to estimate VE, with uncertain comparability. We conducted a multi-armed case-control study enrolling mpox cases (N=198), monkeypox virus (MPXV)-negative controls (N=208), and gonorrhea controls (N=155) reported to the California Department of Public Health between November 2022 and October 2024, conducting telephone interviews to capture behavioral risk data typically absent from surveillance and administrative records. Among recipients of 2 pre-exposure JYNNEOS doses, adjusted VE was 89.9% (95% CI, 69.6-96.7%) versus test-negative controls and 92.0% (70.6-97.8%) versus gonorrhea controls. Without behavioral adjustment, however, VE estimates using MPXV-negative controls were lower (50.4-65.4%) than those using gonorrhea controls (61.3-71.3%). Controls diagnosed with an alternative sexually transmitted infection may offer a better comparison group than test-negative controls for JYNNEOS VE studies based on disease surveillance or administrative records, although collection of risk factor data may be necessary to mitigate bias under either design.