Study design and participants
This observational, retrospective population-based cohort study was based on data obtained from the electronic medical records of Clalit Health Services (CHS) members, a large healthcare organization that covers approximately 52% of the entire Israeli population. The study commenced on July 31, 2022, when the MVA vaccination campaign was initiated in CHS. Participants were followed until August 10, 2022, the last date with confirmed infections on the data extraction date, August 15, 2022.
The primary endpoint was MPXV infection diagnosis, determined by a laboratory-confirmed real-time polymerase chain reaction (RT-PCR) test.
The cohort included all CHS members estimated to be at moderate to high risk for MPXV infection. The a-priori definition of inclusion criteria in the moderate to high-risk cohort was based on a previously reported study in CHS (6).
The moderate to high-risk cohort included all CHS male members who answered one or more of the following criteria: (a) dispense of HIV-Pre Exposure Prophylaxis medication (HIV-PrEP) since January 1, 2021; (b) at least one rectal or pharyngeal PCR-Sexually Transmitted Infection (STI) test from January 1, 2021; (c) aged 25-46 who received the Human Papilloma Virus (HPV) vaccine; and (d) HIV-positive. Participants with a follow-up shorter than a week from vaccination or infected on the vaccination day were excluded.
Data extraction
The following data were extracted for each participant: age, geographical district of the primary healthcare clinic, population sector, score for socioeconomic status, utilization of primary healthcare services, vaccines utilization, history of HIV/AIDS, STIs detected in rectal, pharyngeal, or urine PCR tests, blood test for Syphilis screening (TPHA), and dispense of HIV-PrEP and PDE5-inhibitors (Sildenafil, Tadafil, or Vardenafil.
Statistical analysis
Descriptive statistics were used to characterize the study participants. The geographical district was classified as Tel Aviv versus other districts, as Tel Aviv is the Israeli epicenter of the LGTBQ+ community. The population sector was classified as the general Jewish sector versus two minority sectors: Israeli- Arabs and Jewish-Ultraorthodox, and the sociodemographic status score was categorized as below the median versus median score or higher.
The study cohort was assembled at time zero, defined as the day of the first MVA vaccinations in CHS. To avoid immortal time bias (7), we performed a time-dependent analysis in which a time-varying covariate was used to indicate the vaccination date for each vaccinated subject. In this analysis, vaccinated participants were transferred from the 'unvaccinated' risk set to the 'vaccinated' risk set when vaccinated, modifying their vaccination status from unvaccinated to vaccinated. Consequently, the follow-up of vaccinated patients started at the end of the immortal period.
The association between MVA vaccination and MPXV infection was estimated using univariable and multivariable Cox proportional-hazards regression models with time-dependent covariates, adjusted for sociodemographic and clinical factors.
Analyses were conducted in R statistical software version 3.5.0 (R Project for Statistical Computing). All reported p-values are two-tailed.
Sensitivity Analyses
Two sensitivity analyses were performed. The first sensitivity analysis included only individuals who were defined as eligible for the MVA vaccine per the Israeli MOH guidelines at the time of the study: (a) Males aged 18 – 42 who were dispensed HIV-PrEP, or (b) Males aged 18 – 42 who were diagnosed with HIV and also were diagnosed with recorded one or more of the following STIs since January 1, 2022: active Syphilis, Chlamydia, or Gonorrhea. The maximum age of 42 was determined based on the last year (1980) when smallpox vaccines were administered in Israel to all newborns.
The second sensitivity analysis evaluated VE only in the highest risk group. As detailed by a study in CHS (6), the highest risk group was identified based on the characteristics of N=58 individuals infected with MPXV before the vaccination campaign commenced. The high-risk group included participants of the study cohort who answered one or more of the following criteria in the period from January 1, 2022, and until July 18, 2022 : (a) dispense of HIV-PrEP (b) at least one recent positive rectal or pharyngeal test result for NE Gonorrhea or Chlamydia, (c) recent dispense of PDE5-inhibitors, and (d) history of Syphilis infection. This group was shown to have a 23-fold higher risk for MPXV infection than the rest of the cohort, with a sensitivity of 93.1% for capturing MPXV cases diagnosed before the vaccination campaign commenced (6).