Evaluating the impact of antiviral post-exposure prophylaxis for health-care workers during orthoebolavirus...

Orthoebolavirus outbreaks place health-care workers (HCWs) at substantial risk, and HCW illness or death can weaken response capacity. The 2026 Bundibugyo virus outbreak in DR Congo highlights the need for deployable countermeasures when species-specific vaccines are unavailable. With candidate antivirals under evaluation, we aimed to estimate the impact of HCW-targeted antiviral post-exposure prophylaxis (PEP) across different readiness, disruption, and allocation scenarios.

We adapted a previously published stochastic branching-process model of orthoebolavirus transmission, representing health care, community, and funeral transmission; time-varying non-pharmaceutical interventions; and HCW-targeted PEP. The model was calibrated to two historical outbreaks using sequential approximate Bayesian computation: the 2013-16 west Africa epidemic, to define a high-burden, reasonable worst-case scenario archetype (west Africa-like archetype); and the 2018-20 North Kivu and Ituri outbreak in eastern DR Congo, to define an archetype with longer transmission under conflict-related response disruption (DR Congo-like archetype). The primary outcome was HCW deaths averted. For both archetypes, we simulated three antiviral deployment readiness scenarios (scenario 1: 100% coverage on day 0; scenario 2: scaled up to 80% coverage over 180 days; and scenario 3: scaled up to 50% coverage over 1 year) and compared their impact on HCW deaths with a scenario of no antiviral. For the DR Congo-like archetype only, we simulated four disruption scenarios: no antiviral PEP, ideal delivery (100% coverage and no dosing delay), delayed dosing with coverage preserved, and delayed dosing with delayed coverage. As a secondary outcome, we assessed number of PEP doses required per HCW death averted under different allocation scenarios.

At baseline (no antiviral PEP), cumulative HCW deaths reached a median of 553 (IQR 208-983) in the west Africa-like archetype by week 60, compared with 61 (19-125) in the DR Congo-like archetype by week 80. Assuming 80% efficacy and 80% coverage with antiviral PEP in the same timeframe in a central analysis, cumulative HCW deaths fell to 200 (68-349; equivalent reduction of 64% [63-66] relative to baseline) in the west Africa-like archetype and 22 (10-44; equivalent reduction of 64% [60-68]) in the DR Congo-like archetype. Under different scenarios of deployment readiness at 80% antiviral efficacy, the median reduction in HCW deaths compared with no PEP was 80% (95% CrI 79-81) in the west Africa-like archetype and 80% (76-84) in the DR Congo-like archetype for scenario 1; 60% (57-62) and 52% (41-58), respectively, for scenario 2; and 19% (16-22) and 22% (7-29), respectively, for scenario 3. In the DR Congo-like operational disruption analyses, an ideal scenario (PEP delivered at 100% coverage without a delay after exposure) averted 83% (79-87) of HCW deaths compared with no antiviral; maintaining 100% coverage but introducing delayed dosing (1-5 days post-exposure) reduced this finding to 50% (40-55) compared with no antiviral. Delayed coverage and dosing resulted in only 35% (25-47) of the ideal scenario impact. At 80% antiviral efficacy with same-day dosing, targeted allocation of recognised high-risk exposures (such as personal protective equipment breaches or direct body-fluid contact) required 44 doses (95% Crl 43-44) per HCW death averted versus 109 doses (85-161) with broad allocation.

HCW-targeted antiviral PEP could substantially reduce HCW deaths during orthoebolavirus outbreaks if efficacious antivirals can be delivered rapidly and high operational coverage is maintained. Comparisons of antiviral use cases and alternative response investments are needed to determine how resources can best support outbreak response.

Gilead Sciences, UK National Institute for Health and Care Research, Oxford Martin School, Miller Institute, EU Global Health EDCTP3, and Coalition for Epidemic Preparedness Innovations.

For the French and Swahili translations of the abstract see Supplementary Materials section.