Summary of Results
The primary risk factors are using HIV-PrEP and positive rectal STI-PCR since January 2022. The birth year of 1980 or later, registration to primary clinics in the Tel Aviv district and usage of erectile dysfunction medications (in members of the study cohort) are also risk factors for MPXV infection. HIV, Syphilis, and positive pharyngeal PCR for STIs were not associated with MPXV infection.
The highest risk group criteria are HIV-PrEP use or positive rectal STI-PCR or erectile dysfunction medication use (in members of the study cohort) since January 2022. This group represents approximately 1 in 2,100 members in CHS. Their risk is twenty-fold higher than the moderate risk group, with a sensitivity of 88% and NPV of 99.9%. Therefore, the chance of missing a case of infection in the entire moderate to high-risk cohort was 1 in 1,000.
Comparison to known literature
Since the beginning of the current 2022 outbreak of MPXV, almost all cases were identified in men having sex with men (MSM) (7) (9). Some of the characteristics of our study cohort and risk factors we identified are in line with previous reports on the characteristics of infected subjects: the inclusion of males who underwent STI screening; and the identification as risk factors of recent STIs and year of birth before 1980 as a proxy for personal history of smallpox vaccination (7) (9). Assessing some risk factors previously reported requires intrusive questioning of sexual behavior (7) (9). Such questioning is challenging to conduct in many aspects, including the time and cost required for active questioning, possible compromised validity due to personal and cultural reasons, and ethical aspects of the desired balance between medical information and patients' rights for privacy. Therefore, questioning sexual behavior is not a feasible screening tool at the population level for prioritizing vaccines. However, our findings are based on the utilization of medications and laboratory-confirmed diagnoses.
First-generation virus vaccines smallpox vaccine demonstrated 85% cross-protective immunity against MPXV, but this result was obtained more than three decades ago, primarily in Africa and for previous clades (10) (11). The majority of Israeli residents born before 1980 were given the smallpox vaccine. Our results show an adjusted HR of 3.49 (1.43–8.54), translating into estimated vaccine effectiveness of 71% for the 2022 MPXV outbreak.
Based on the known literature, all male CHS members living with HIV were included in our moderate-to-high risk cohort. The proportion of HIV-positive in MPXV infected individuals (16%) is much higher than their proportion in the general population but lower than reported in the UK (24%) (9) and by an international collaborative group (41%) (7). Moreover, HIV was not associated with MPXV infection within the study cohort. This may be explained by the fact that Israeli residents living with HIV are diverse, including persons who immigrated to Israel from countries with endemic HIV.
Limitations
Our study has some noteworthy limitations. The primary limitation is that data is still preliminary, with cases expected to increase significantly. The epidemic is still ongoing, with changes in disease spread within different populations. However, it is critical to make fast prioritization decisions at this epidemic stage, when there is still a high chance of containing the pandemic. Therefore, we believe that although these analyses are preliminary, they carry a high value at this time of global health emergency.
We also believe that our current data represents the underdiagnosis of MPXV in Israel (and probably worldwide) for a few reasons. First, contact tracing for MPXV cases is complicated and sometimes unfeasible. According to current reports, most cases engaged in risky sexual behaviors with multiple partners, many of them anonymous (7). This, along with the long incubation period, makes tracing and identifying subsequent cases almost impossible.
The second cause of potential underdiagnosis is low awareness among healthcare providers. MPXV is a disease with a prodrome similar to many other viral diseases. The clinical course can be nonspecific and difficult to identify, especially in patients with mild disease and few skin lesions. Healthcare providers not working in areas with clusters of cases and large at-risk populations, especially in central, urban Israel, may be less vigilant and easily miss cases. Many cases outside of this central area have likely been missed. Moreover, there may be many symptomatic patients who were not tested for MPXV for various reasons.
Furthermore, we assume that most of the population born before 1980 in Israel has been vaccinated with the smallpox vaccine, though this is not documented in medical records, and we do not have individual data on vaccination status. Vaccination of children in Israel was gradually terminated in the late 1970s'. Therefore, we assume this population was vaccinated, though the actual immunization rate within this age group is unknown. We suggest adopting the age cutoff based on other countries' national smallpox vaccination strategies.
Documented Syphilis infections were rare, a finding we believe to indicate underdiagnosis due to various factors. This may be because many diagnostic tests and therapies for syphilis are administered outside CHS and not reported to CHS. Underdiagnosis may also be due to past infections, with unsatisfactory follow-up, not tested again after Jan 1, 2021.
Another limitation of the current study is that transgender women who may be at moderate to high risk were not included in the study cohort if their current gender was updated in CHS registries.
Implications for Policy
Our findings are significant for vaccine allocation, as mass vaccination with newer generation vaccines is not feasible in the immediate future, and prioritization of the highest risk group is crucial. Accordingly, the Israeli ministry of health (MOH) has adopted a vaccination strategy based on our preliminary findings (Risk-group 1). The vaccination campaign should be coupled with general public health interventions, such as home isolation, sexual health promotion, education, and awareness among healthcare professionals. Implementing these measures promptly may end the epidemic in a short time.