A 1-week intradermal dose-sparing regimen for rabies post-exposure prophylaxis (RESIST-2): an observational cohort study.

BACKGROUND: The international health authorities are backing an effort to eliminate canine-mediated rabies in humans by 2030. This effort will require improving access to adequate and timely rabies post-exposure prophylaxis as compliance is low with WHO-recommended regimens (given in four to five visits over 1 month). Access could be substantially improved by an abridged regimen to reduce doses, direct and indirect costs, and improve vaccine equity by better sharing of available vaccine. We aimed to compare rabies virus neutralising antibody titres before and after the fourth visit to determine whether that session was needed or the current regimen could be abridged. METHODS: In this observational cohort study, we measured rabies virus neutralising antibody titres using rapid fluorescent focus inhibition tests in 116 people bitten by dogs with laboratory-confirmed rabies and 20 control individuals. Percentages of circulating plasmablasts were determined by flow cytometry. All individuals had been referred to the rabies prevention clinic at Institut Pasteur in Cambodia and received two intradermal injections of post-exposure prophylaxis on days 0, 3, 7, and 28 (Thai Red Cross regimen) with or without equine rabies immunoglobulin, as per 2010 WHO recommendations. FINDINGS: All individuals had rabies virus neutralising antibody titres considered protective (≥0·5 IU/mL) and plasmablast activation on day 28 before the last injection. The median rabies virus neutralising antibody concentration in the group of individuals bitten by rabies virus-positive dogs was 1·08 IU/mL (IQR 0·37-3·09) on day 7, 26·86 (22·68-49·50) on day 28, and 26·74 (11·78-49·06) on day 42. No significant differences were observed in titres between days 28 and 42, after titres reached a plateau. These titres were reached notwithstanding equine rabies immunoglobulin use, age, sex, nutrition status as indicated by upper-arm circumference in children or BMI in adults, or dog infection status. Titres or plasmablast percentages did not increase between the day of the last injection and 2 weeks later. All patients were alive 1 year after post-exposure prophylaxis. INTERPRETATION: The fourth vaccine session on day 28 provides no additional benefit. Rabies post-exposure prophylaxis can be abridged to a two-dose, three-session, 1 week regimen to improve post-exposure prophylaxis coverage and equity at no risk to patients. FUNDING: Institut Pasteur.

Intradermal rabies post-exposure prophylaxis can be abridged with no measurable impact on clinical outcome in Cambodia, 2003-2014.

Rabies causes 60,000 deaths worldwide annually. Rabies post-exposure prophylaxis is highly effective but often geographically and financially beyond reach in endemic developing countries. We conducted a retrospective study on clinical outcome at ≥6 months in 3318 Cambodians who received intradermal Vero cell vaccine post-exposure prophylaxis after a bite by a rabid or sick-looking but untested dog in 2003-2014. An external expert panel examined verbal autopsy reports to identify rabies deaths. 1739 (93.65%) persons bitten by rabid- and 1066 (72.96%) bitten by sick-looking but untested dogs were traced and 513 were lost to follow-up. Among the former, 1591 (91.49%) and 129 (7.42%) patients referred for 4+ and 3 post-exposure prophylaxis sessions, respectively. Three persons died of probable rabies so that the overall percentage of survival was 99.83% (95% exact confidence interval: 99.49-99.96%) in post-exposure prophylaxis recipients bitten by confirmed rabid dogs. No significant difference was found in survival among patients who received 3 vs. 4+ sessions (with or without rabies immunoglobin). The power of the study, however, was limited. The current four sessions/one month intradermal regimen can be reduced to a three sessions/one week at no detectable added risk to patients, with the limitation of study power at 49%. A clinical follow-up system should be adopted by rabies prevention centers, especially to monitor implementation of an abridged course. The Institut Pasteur in Cambodia regimen will improve vaccine equity by treating 33% more patients with available doses, reduce direct cost of vaccination, transportation and other indirect costs to vaccinees.

Rabies Postexposure Prophylaxis Noncompletion After Dog Bites: Estimating the Unseen to Meet the Needs of the Underserved.

Postexposure prophylaxis (PEP) prevents human rabies and is accessible in Cambodia principally in Phnom Penh, the capital. Timely, affordable access to PEP is a challenge for the mainly rural population. We aimed to identify districts independently associated with PEP noncompletion to position frontline vaccination centers. We analyzed the 2009-2013 database at the Rabies Prevention Center at the Institut Pasteur du Cambodge, Phnom Penh. Logistic regressions identified nongeographic determinants of PEP noncompletion as well as the districts that were independently associated with noncompletion after adjustment for these determinants. The influence of distance by road was estimated using a boosted regression-trees model. We computed a population attributable fraction (rabies index (RI)) for each district and developed a map of this RI distribution. A cartographic analysis based on the statistic developed by Getis and Ord identified clusters of high-RI districts. Factors independently associated with noncompletion were patients' district of residence, male sex, age 15-49 years, initial visit during rice harvest, the dog's status (culled or disappeared), and a prescribed PEP protocol requiring more than 3 PEP sessions (4 or 5). Four clusters of high-RI districts were identified using this analytical strategy, which is applicable to many vaccination or other health services. Positioning frontline PEP centers in these districts could significantly widen access to timely and adequate PEP.