During the 2022 multinational outbreak of monkeypox virus (MPXV) infection, the antiviral drug tecovirimat (TPOXX; SIGA Technologies, Inc., https://www.siga.com) was deployed in the United States on a large scale for the first time. The MPXV F13L gene homologue encodes the target of tecovirimat, and single amino acid changes in F13 are known to cause resistance to tecovirimat. Genomic sequencing identified 11 mutations previously reported to cause resistance, along with 13 novel mutations. Resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment, whereas most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive. The frequency of resistant viruses remains relatively low (<1%) compared with the total number of patients treated with tecovirimat.

BACKGROUND: Rabies expert on demand (REOD) telehealth service is provided by the U.S. Centers for Disease Control and Prevention (CDC) to assist public health practitioners, health providers, and the public to interpret national and international rabies prevention guidelines. REOD is staffed by subject matter experts of the CDC Poxvirus and Rabies Branch to assess each unique situation and provide evidence-based guidance to stakeholders. This study aims to describe the utilization of a rabies telehealth system and provide insight into common consultations. METHODS: A cross-sectional study of the nature of inquiries to REOD was done using the data collected from September 1, 2017 to September 30, 2021. An inquiry tracking form and Microsoft Access database were developed to document all inquiries received. Inquired ones were summarized to determine the frequency of inquiries by month, category, and location. RESULTS: Over a 49-month period, REOD received 5228 inquiries. Peak inquiries (n = 108) occurred during August 2019. The most frequent inquiries received pertained to risk assessment and management of rabies exposures (n = 1109), requests for testing assistance (n = 912), consultation for suspected human rabies (n = 746), rabies exposures and post-bite treatment occurring internationally (n = 310), and consultation for deviations in the recommended pre- and postexposure prophylaxis regimen (n = 300). CONCLUSION: REOD is a global resource for consultation related to managing rabies exposures, diagnostic issues, and rabies control strategies. REOD is a regularly utilized CDC service, as the demand for up-to-date rabies guidance remains high. REOD fulfills a critical role for the interpretation and consultation on rabies prevention guidelines to stakeholder.

Background: During the 2022 multinational outbreak of monkeypox virus (MPXV) clade IIb, the antiviral drug tecovirimat (TPOXX) was deployed in the US on a large scale for the first time ever. The MPXV F13L gene homolog encodes the target of tecovirimat, and single amino acid changes in the F13 protein are known to cause resistance to tecovirimat in orthopoxviruses (OPXV). Method(s): Whole genome metagenomic sequencing and amplicon-based sequencing targeting the F13L gene was used to identify nine mutations previously reported to cause resistance in other OPXV along with ten novel mutations that have been identified from the 2022 mpox outbreak. A cytopathic effect assay, previously established at CDC as part of WHO smallpox research, was adapted to MPXV for tecovirimat phenotype testing of virus isolated from mpox patients. Result(s): As of March 2023, in total, 70 isolates from 40 patients were tested, and 50 of these isolates from 26 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of TPOXX treatment; while isolates with F13 mutations identified by routine surveillance of patients not treated with TPOXX have remained sensitive. Conclusion(s): These data indicate that tecovirimat resistance is developing in immunocompromised patients treated with TPOXX and that for isolates that we have analyzed, the frequency of resistant viruses remain relatively low (< 1%) compared to the total number of patients treated with TPOXX. These findings inform our understanding of when tecovirimat resistance is likely to occur and highlight the need for additional OPXV therapeutics. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

BACKGROUND: No rabies post-exposure prophylaxis (PEP) failure has been documented in humans in the United States using modern cell-culture vaccines. In January 2021, an 84-year-old male died from rabies six months after being bitten by a rabid bat despite receiving timely rabies post-exposure prophylaxis (PEP). We investigated the cause of breakthrough infection. METHODS: We reviewed medical records, laboratory results, and autopsy findings, and performed whole genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close contacts of the patient. RESULTS: Rabies virus antibodies present in serum and cerebrospinal fluid were non-neutralizing. Antemortem blood testing revealed the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, three (0.9%) warranted PEP. CONCLUSION: This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Monkeypox (mpox) is a disease caused by infection with Monkeypox virus (MPXV), an Orthopoxvirus (OPXV) in the same genus as Variola virus, which causes smallpox. During 2022, a global outbreak involving mpox clade IIb was recognized, primarily among gay, bisexual, and other men who have sex with men.* Most affected patients have been immunocompetent and experienced ≤10 rash lesions (1). CDC has recommended supportive care including pain control.(†) However, some patients have experienced severe mpox manifestations, including ocular lesions, neurologic complications, myopericarditis, complications associated with mucosal (oral, rectal, genital, and urethral) lesions, and uncontrolled viral spread due to moderate or severe immunocompromise, particularly advanced HIV infection (2). Therapeutic medical countermeasures (MCMs) are Food and Drug Administration (FDA)-regulated drugs and biologics that are predominantly stockpiled by the U.S. government; MCMs developed for smallpox preparedness or shown to be effective against other OPXVs (i.e., tecovirimat, brincidofovir, cidofovir, trifluridine ophthalmic solution, and vaccinia immune globulin intravenous [VIGIV]) have been used to treat severe mpox. During May 2022-January 2023, CDC provided more than 250 U.S. mpox consultations. This report synthesizes data from animal models, MCM use for human cases of related OPXV, unpublished data, input from clinician experts, and experience during consultations (including follow-up) to provide interim clinical treatment considerations. Randomized controlled trials and other carefully controlled research studies are needed to evaluate the effectiveness of MCMs for treating human mpox. Until data gaps are filled, the information presented in this report represents the best available information concerning the effective use of MCMs and should be used to guide decisions about MCM use for mpox patients.

Monkeypox (mpox) is a zoonotic disease caused by Monkeypox virus (MPXV), an Orthopoxvirus; the wild mammalian reservoir species is not known. There are two genetic clades of MPXV: clade I and clade II (historically found in central and west Africa, respectively), with only Cameroon reporting both clades (1). Human cases have historically been reported from 1) mostly rural, forested areas in some central and west African countries; 2) countries reporting cases related to population migration or travel of infected persons; and 3) exposure to imported infected mammals (2). The annual number of cases in Africa has risen since 2014 and cumulatively surpassed reports from the previous 40 years for most countries. This reemergence of mpox might be due to a combination of environmental and ecological changes, animal or human movement, the cessation of routine smallpox vaccination since its eradication in 1980, improvements in disease detection and diagnosis, and genetic changes in the virus (2). This report describes the epidemiology of mpox since 1970 and during 2018-2021, using data from national surveillance programs, World Health Organization (WHO) bulletins, and case reports, and addresses current diagnostic and treatment challenges in countries with endemic disease. During 2018-2021, human cases were recognized and confirmed in six African countries, with most detected in the Democratic Republic of the Congo (DRC) and Nigeria. The reemergence and increase in cases resulted in its being listed in 2019 as a priority disease for immediate and routine reporting through the Integrated Disease Surveillance and Response strategy in the WHO African region.* In eight instances, patients with mpox were identified in four countries outside of Africa after travel from Nigeria. Since 2018, introductory and intermediate training courses on prevention and control of mpox for public health and health care providers have been available online at OpenWHO.(†)(,)(§) The global outbreak that began in May 2022(¶) has further highlighted the need for improvements in laboratory-based surveillance and access to treatments and vaccines to prevent and contain the infection, including in areas of Africa with endemic mpox.

We report 2 immunocompetent and otherwise healthy adults in the United States who had monkeypox and required hospitalization for viral myocarditis. Both patients were unvaccinated against orthopoxviruses. They had shortness of breath or chest pain and elevated cardiac biomarkers. No immediate complications were observed. They were discharged home after symptoms resolved.

The current worldwide monkepox outbreak has reaffirmed the continued threat monkeypox virus (MPXV) poses to public health. JYNNEOS, a Modified Vaccinia Ankara (MVA)-based live, non-replicating vaccine, was recently approved for monkeypox prevention for adults at high risk of MPXV infection in the United States. Although the safety and immunogenicity of JYNNEOS have been examined previously, the clinical cohorts studied largely derive from regions where MPXV does not typically circulate. In this study, we assess the quality and longevity of serological responses to two doses of JYNNEOS vaccine in a large cohort of healthcare workers from the Democratic Republic of Congo (DRC). We show that JYNNEOS elicits a strong orthopoxvirus (OPXV)-specific antibody response in participants that peaks around day 42, or 2 weeks after the second vaccine dose. Participants with no prior history of smallpox vaccination or exposure have lower baseline antibody levels, but experience a similar fold-rise in antibody titers by day 42 as those with a prior history of vaccination. Both previously naïve and vaccinated participants generate vaccinia virus and MPXV-neutralizing antibody in response to JYNNEOS vaccination. Finally, even though total OPXV-specific IgG titers and neutralizing antibody titers declined from their peak and returned close to baseline levels by the 2-year mark, most participants remain IgG seropositive at the 2-year timepoint. Taken together, our data demonstrates that JYNNEOS vaccination triggers potent OPXV neutralizing antibody responses in a cohort of healthcare workers in DRC, a monkeypox-endemic region. MPXV vaccination with JYNNEOS may help ameliorate the disease and economic burden associated with monkeypox and combat potential outbreaks in areas with active virus circulation.

As of October 11, 2022, a total of 26,577 monkeypox cases had been reported in the United States.* Although most cases of monkeypox are self-limited, lesions that involve anatomically vulnerable sites can cause complications. Ocular monkeypox can occur when Monkeypox virus (MPXV) is introduced into the eye (e.g., from autoinoculation), potentially causing conjunctivitis, blepharitis, keratitis, and loss of vision (1). This report describes five patients who acquired ocular monkeypox during July-September 2022. All patients received treatment with tecovirimat (Tpoxx)(†); four also received topical trifluridine (Viroptic).(§) Two patients had HIV-associated immunocompromise and experienced delays between clinical presentation with monkeypox and initiation of monkeypox-directed treatment. Four patients were hospitalized, and one experienced marked vision impairment. To decrease the risk for autoinoculation, persons with monkeypox should be advised to practice hand hygiene and to avoid touching their eyes, which includes refraining from using contact lenses (2). Health care providers and public health practitioners should be aware that ocular monkeypox, although rare, is a sight-threatening condition. Patients with signs and symptoms compatible with ocular monkeypox should be considered for urgent ophthalmologic evaluation and initiation of monkeypox-directed treatment. Public health officials should be promptly notified of cases of ocular monkeypox. Increased clinician awareness of ocular monkeypox and of approaches to prevention, diagnosis, and treatment might reduce associated morbidity.

Currently, no Food and Drug Administration (FDA)-approved treatments for human monkeypox are available. Tecovirimat (Tpoxx), however, is an antiviral drug that has demonstrated efficacy in animal studies and is FDA-approved for treating smallpox. Use of tecovirimat for treatment of monkeypox in the United States is permitted only through an FDA-regulated Expanded Access Investigational New Drug (EA-IND) mechanism. CDC holds a nonresearch EA-IND protocol that facilitates access to and use of tecovirimat for treatment of monkeypox.() The protocol includes patient treatment and adverse event reporting forms to monitor safety and ensure intended clinical use in accordance with FDA EA-IND requirements. The current multinational monkeypox outbreak, first detected in a country where Monkeypox virus infection is not endemic in May 2022, has predominantly affected gay, bisexual, and other men who have sex with men (MSM) (1,2). To describe characteristics of persons treated with tecovirimat for Monkeypox virus infection, demographic and clinical data abstracted from available tecovirimat EA-IND treatment forms were analyzed. As of August 20, 2022, intake and outcome forms were available for 549 and 369 patients, respectively; 97.7% of patients were men, with a median age of 36.5 years. Among patients with available data, 38.8% were reported to be non-Hispanic White (White) persons, 99.8% were prescribed oral tecovirimat, and 93.1% were not hospitalized. Approximately one half of patients with Monkeypox virus infection who received tecovirimat were living with HIV infection. The median interval from initiation of tecovirimat to subjective improvement was 3 days and did not differ by HIV infection status. Adverse events were reported in 3.5% of patients; all but one adverse event were nonserious. These data support the continued access to and treatment with tecovirimat for patients with or at risk for severe disease in the ongoing monkeypox outbreak.

BACKGROUND: Neglected tropical diseases (NTDs) disproportionately affect populations living in resource-limited settings. In the Amazon basin, substantial numbers of NTDs are zoonotic, transmitted by vertebrate (dogs, bats, snakes) and invertebrate species (sand flies and triatomine insects). However, no dedicated consortia exist to find commonalities in the risk factors for or mitigations against bite-associated NTDs such as rabies, snake envenoming, Chagas disease and leishmaniasis in the region. The rapid expansion of COVID-19 has further reduced resources for NTDs, exacerbated health inequality and reiterated the need to raise awareness of NTDs related to bites. METHODS: The nine countries that make up the Amazon basin have been considered (Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Peru, Surinam and Venezuela) in the formation of a new network. RESULTS: The Amazonian Tropical Bites Research Initiative (ATBRI) has been created, with the aim of creating transdisciplinary solutions to the problem of animal bites leading to disease in Amazonian communities. The ATBRI seeks to unify the currently disjointed approach to the control of bite-related neglected zoonoses across Latin America. CONCLUSIONS: The coordination of different sectors and inclusion of all stakeholders will advance this field and generate evidence for policy-making, promoting governance and linkage across a One Health arena.

On May 17, 2022, the Massachusetts Department of Public Health (MDPH) Laboratory Response Network (LRN) laboratory confirmed the presence of orthopoxvirus DNA via real-time polymerase chain reaction (PCR) from lesion swabs obtained from a Massachusetts resident. Orthopoxviruses include Monkeypox virus, the causative agent of monkeypox. Subsequent real-time PCR testing at CDC on May 18 confirmed that the patient was infected with the West African clade of Monkeypox virus. Since then, confirmed cases* have been reported by nine states. In addition, 28 countries and territories,(†) none of which has endemic monkeypox, have reported laboratory-confirmed cases. On May 17, CDC, in coordination with state and local jurisdictions, initiated an emergency response to identify, monitor, and investigate additional monkeypox cases in the United States. This response has included releasing a Health Alert Network (HAN) Health Advisory, developing interim public health and clinical recommendations, releasing guidance for LRN testing, hosting clinician and public health partner outreach calls, disseminating health communication messages to the public, developing protocols for use and release of medical countermeasures, and facilitating delivery of vaccine postexposure prophylaxis (PEP) and antivirals that have been stockpiled by the U.S. government for preparedness and response purposes. On May 19, a call center was established to provide guidance to states for the evaluation of possible cases of monkeypox, including recommendations for clinical diagnosis and orthopoxvirus testing. The call center also gathers information about possible cases to identify interjurisdictional linkages. As of May 31, this investigation has identified 17(§) cases in the United States; most cases (16) were diagnosed in persons who identify as gay, bisexual, or men who have sex with men (MSM). Ongoing investigation suggests person-to-person community transmission, and CDC urges health departments, clinicians, and the public to remain vigilant, institute appropriate infection prevention and control measures, and notify public health authorities of suspected cases to reduce disease spread. Public health authorities are identifying cases and conducting investigations to determine possible sources and prevent further spread. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.(¶).

Certain laboratorians and health care personnel can be exposed to orthopoxviruses through occupational activities. Because orthopoxvirus infections resulting from occupational exposures can be serious, the Advisory Committee on Immunization Practices (ACIP) has continued to recommend preexposure vaccination for these persons since 1980 (1), when smallpox was eradicated (2). In 2015, ACIP made recommendations for the use of ACAM2000, the only orthopoxvirus vaccine available in the United States at that time (3). During 2020-2021, ACIP considered evidence for use of JYNNEOS, a replication-deficient Vaccinia virus vaccine, as an alternative to ACAM2000. In November 2021, ACIP unanimously voted in favor of JYNNEOS as an alternative to ACAM2000 for primary vaccination and booster doses. With these recommendations for use of JYNNEOS, two vaccines (ACAM2000 and JYNNEOS) are now available and recommended for preexposure prophylaxis against orthopoxvirus infection among persons at risk for such exposures.

OBJECTIVE: To provide epidemiological information on animal and human cases of rabies in the US during 2020 and summaries of 2020 rabies surveillance for Canada and Mexico. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the US during 2020. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided 2020 rabies surveillance data. Data were analyzed temporally and geographically to assess trends in domestic and wildlife rabies cases. RESULTS: During 2020, 54 jurisdictions submitted 87,895 animal samples for rabies testing, of which 85,483 (97.3%) had a conclusive (positive or negative) test result. Of these, 4,479 (5.2%) tested positive for rabies, representing a 4.5% decrease from the 4,690 cases reported in 2019. Texas (n = 580 [12.9%]), Pennsylvania (371 [8.3%]), Virginia (351 [7.8%]), New York (346 [7.7%]), North Carolina (301 [6.7%]), New Jersey (257 [5.7%]), Maryland (256 [5.7%]), and California (248 [5.5%]) together accounted for > 60% of all animal rabies cases reported in 2020. Of the total reported rabid animals, 4,090 (91.3%) involved wildlife, with raccoons (n = 1,403 [31.3%]), bats (1,400 [31.3%]), skunks (846 [18.9%]), and foxes (338 [7.5%]) representing the primary hosts confirmed with rabies. Rabid cats (288 [6.4%]), cattle (43 [1.0%]), and dogs (37 [0.8%]) accounted for 95% of rabies cases involving domestic animals in 2020. No human rabies cases were reported in 2020. CONCLUSIONS AND CLINICAL RELEVANCE: For the first time since 2006, the number of samples submitted for rabies testing in the US was < 90,000; this is thought to be due to factors related to the COVID-19 pandemic, as similar decreases in sample submission were also reported by Canada and Mexico.

OBJECTIVE: To provide epidemiological information on animal and human cases of rabies occurring in the United States during 2019 and summaries of 2019 rabies surveillance for Canada and Mexico. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the United States during 2019. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided data on animals submitted for rabies testing in the United States during 2019. Data were analyzed temporally and geographically to assess trends in domestic and wildlife rabies cases. RESULTS: During 2019, 53 jurisdictions submitted 97,523 animal samples for rabies testing, of which 94,770 (97.2%) had a conclusive (positive or negative) test result. Of these, 4,690 tested positive for rabies, representing a 5.3% decrease from the 4,951 cases reported in 2018. Texas (n = 565 [12.0%]), New York (391 [8.3%]), Virginia (385 [8.2%]), North Carolina (315 [6.7%]), California (276 [5.9%]), and Maryland (269 [5.7%]) together accounted for almost half of all animal rabies cases reported in 2019. Of the total reported rabid animals, 4,305 (91.8%) were wildlife, with raccoons (n = 1,545 [32.9%]), bats (1,387 [29.6%]), skunks (915 [19.5%]), and foxes (361 [7.7%]) as the primary species confirmed with rabies. Rabid cats (n = 245 [5.2%]) and dogs (66 [1.4%]) accounted for > 80% of rabies cases involving domestic animals in 2019. No human rabies cases were reported in 2019. CONCLUSIONS AND CLINICAL RELEVANCE: The overall number of animal rabies cases decreased from 2018 to 2019. Laboratory diagnosis of rabies in animals is critical to ensure that human rabies postexposure prophylaxis is administered judiciously.

OBJECTIVE: In March 2018, the US Department of Defense (DOD) added the smallpox vaccination, using ACAM2000, to its routine immunizations, increasing the number of persons receiving the vaccine. The following month, Fort Hood reported a cluster of 5 myopericarditis cases. The Centers for Disease Control and Prevention and the DOD launched an investigation. METHODS: The investigation consisted of a review of medical records, establishment of case definitions, causality assessment, patient interviews, and active surveillance. A 2-sided exact rate ratio test was used to compare myopericarditis incidence rates. RESULTS: This investigation identified 4 cases of probable myopericarditis and 1 case of suspected myopericarditis. No alternative etiology was identified as a cause. No additional cases were identified. There was no statistically significant difference in incidence rates between the observed cluster (5.23 per 1000 vaccinated individuals, 95% CI: 1.7-12.2) and the ACAM2000 clinical trial outcomes for symptomatic persons, which was 2.29 per 1000 vaccinated individuals (95% CI: 0.3-8.3). CONCLUSIONS: Vaccination with ACAM2000 is the presumptive cause of this cluster. Caution should be exercised before considering vaccination campaigns for smallpox given the clinical morbidity and costs incurred by a case of myopericarditis. Risk of myopericarditis should be carefully weighed with risk of exposure to smallpox.

In March 2015, a patient in Colombia with HIV/AIDS was hospitalized for disseminated ulcers after milking cows that had vesicular lesions on their udders. Vaccinia virus was detected, and the case met criteria for progressive vaccinia acquired by zoonotic transmission. Adherence to an optimized antiretroviral regimen resulted in recovery.

OBJECTIVE: To describe rabies and rabies-related events occurring during 2018 in the United States. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the United States during 2018. PROCEDURES: State and territorial public health departments provided data on animals submitted for rabies testing in 2018. Data were analyzed temporally and geographically to assess trends in domestic animal and wildlife rabies cases. RESULTS: During 2018, 54 jurisdictions reported 4,951 rabid animals to the CDC, representing an 11.2% increase from the 4,454 rabid animals reported in 2017. Texas (n = 695 [14.0%]), Virginia (382 [7.7%]), Pennsylvania (356 [7.2%]), North Carolina (332 [6.7%]), Colorado (328 [6.6%]), and New York (320 [6.5%]) together accounted for almost half of all rabid animals reported in 2018. Of the total reported rabies cases, 4,589 (92.7%) involved wildlife, with bats (n = 1,635 [33.0%]), raccoons (1,499 [30.3%]), skunks (1,004 [20.3%]), and foxes (357 [7.2%]) being the major species. Rabid cats (n = 241 [4.9%]) and dogs (63 [1.3%]) accounted for > 80% of rabid domestic animals reported in 2018. There was a 4.6% increase in the number of samples submitted for testing in 2018, compared with the number submitted in 2017. Three human rabies deaths were reported in 2018, compared with 2 in 2017. CONCLUSIONS AND CLINICAL RELEVANCE: The overall number of animal rabies cases increased from 2017 to 2018. Laboratory diagnosis of rabies in animals is critical to ensure that human rabies postexposure prophylaxis is administered judiciously.

In 2017, a monkeypox outbreak occurred in Likouala Department, Republic of the Congo. Many of the affected individuals were of Aka ethnicity, hunter-gatherers indigenous to Central Africa who have worse health outcomes in comparison with other forest-dwelling peoples. To test the hypothesis that Aka people have different risk factors for monkeypox, we analyzed questionnaire data for 39 suspected cases, comparing Aka and Bantu groups. Aka people were more likely to touch animal urine/feces, find dead animals in/around the home, eat an animal that was found dead, or to have been scratched or bitten by an animal (P < 0.05, all variables). They were also more likely to visit the forest >/= once/week, sleep outside, or sleep on the ground (P < 0.001, all variables), providing opportunities for contact with monkeypox reservoirs during the night. The Aka and possibly other vulnerable groups may warrant special attention during educational and health promotion programs.

Vaccinia virus (VACV) is an orthopoxvirus used in smallpox vaccines, as a vector for novel cancer treatments, and for experimental vaccine research (1). The Advisory Committee on Immunization Practices (ACIP) recommends smallpox vaccination for laboratory workers who handle replication-competent VACV (1). For bioterrorism preparedness, the U.S. government stockpiles tecovirimat, the first Food and Drug Administration-approved antiviral for treatment of smallpox (caused by variola virus and globally eradicated in 1980*(,dagger)) (2). Tecovirimat has activity against other orthopoxviruses and can be administered under a CDC investigational new drug protocol. CDC was notified about an unvaccinated laboratory worker with a needlestick exposure to VACV, who developed a lesion on her left index finger. CDC and partners performed laboratory confirmation, contacted the study sponsor to identify the VACV strain, and provided oversight for the first case of laboratory-acquired VACV treated with tecovirimat plus intravenous vaccinia immunoglobulin (VIGIV). This investigation highlights 1) the misconception among laboratory workers about the virulence of VACV strains; 2) the importance of providing laboratorians with pathogen information and postexposure procedures; and 3) that although tecovirimat can be used to treat VACV infections, its therapeutic benefit remains unclear.

Smallpox vaccine is contraindicated in immunosuppression due to increased risk for adverse reactions (e.g., progressive vaccinia). We describe the first-ever use of tecovirimat as a preemptive vaccinia virus treatment strategy during induction chemotherapy in an active duty member who presented with acute leukemia and inadvertent auto-inoculation after smallpox vaccination.

Monkeypox, caused by a zoonotic orthopoxvirus, is endemic in Central and West Africa. Monkeypox has been sporadically reported in the Republic of the Congo. During March 22-April 5, 2017, we investigated 43 suspected human monkeypox cases. We interviewed suspected case-patients and collected dried blood strips and vesicular and crust specimens (active lesions), which we tested for orthopoxvirus antibodies by ELISA and monkeypox virus and varicella zoster virus DNA by PCR. An ecologic investigation was conducted around Manfouete, and specimens from 105 small mammals were tested for anti-orthopoxvirus antibodies or DNA. Among the suspected human cases, 22 met the confirmed, probable, and possible case definitions. Only 18 patients had available dried blood strips; 100% were IgG positive, and 88.9% (16/18) were IgM positive. Among animals, only specimens from Cricetomys giant pouched rats showed presence of orthopoxvirus antibodies, adding evidence to this species' involvement in the transmission and maintenance of monkeypox virus in nature.

Outbreaks of emerging zoonotic infectious diseases, such as Ebola virus, highly pathogenic avian influenza (H7N9) and Middle East respiratory syndrome, have occurred in recent years, causing infections of these relatively rare diseases among international travellers. An additional emerging zoonosis is monkeypox,1 which was first identified in the Democratic Republic of Congo (DRC) in 1970 but since 2010 has expanded to cause outbreaks among humans in seven additional African countries: Cameroon, Central African Republic, Republic of the Congo, Liberia, Nigeria, Sierra Leone and South Sudan.1,2 Starting in September 2017, a large, ongoing human monkeypox outbreak in Nigeria has caused 269 suspect and 115 confirmed cases from 25 states and 1 territory, including large cities.2

OBJECTIVE To describe rabies and rabies-related events occurring during 2017 in the United States. DESIGN Cross-sectional analysis of passive surveillance data. ANIMALS All animals submitted for laboratory diagnosis of rabies in the United States during 2017. PROCEDURES State and territorial public health departments provided data on animals submitted for rabies testing in 2017. Data were analyzed temporally and geographically to assess trends in domestic and sylvatic animal rabies cases. RESULTS During 2017, 52 jurisdictions reported 4,454 rabid animals to the CDC, representing a 9.3% decrease from the 4,910 rabid animals reported in 2016. Of the 4,454 cases of animal rabies, 4,055 (91.0%) involved wildlife species. Relative contributions by the major animal groups were as follows: 1,433 (32.2%) bats, 1,275 (28.6%) raccoons, 939 (21.1%) skunks, 314 (7.0%) foxes, 276 (6.2%) cats, 62 (1.4%) dogs, and 36 (0.8%) cattle. There was a 0.4% increase in the number of samples submitted for testing in 2017, compared with the number submitted in 2016. Two human rabies deaths were reported in 2017, compared with none in 2016. CONCLUSIONS AND CLINICAL RELEVANCE The overall number of reported cases of animal rabies has decreased over time. Laboratory testing of animals suspected to be rabid remains a critical public health function and continues to be a cost-effective method to directly influence human rabies postexposure prophylaxis recommendations.

Healthcare-associated transmission of monkeypox has been observed on multiple occasions in areas where the disease is endemic. Data collected by the US Centers for Disease Control and Prevention (CDC) from an ongoing CDC-supported program of enhanced surveillance in the Tshuapa Province of the Democratic Republic of the Congo, where the annual incidence of human monkeypox is estimated to be 3.5-5/10,000, suggests that there is approximately one healthcare worker infection for every 100 confirmed monkeypox cases. Herein, we describe a study that commenced in February 2017, the intent of which is to evaluate the effectiveness, immunogenicity, and safety of a third-generation smallpox vaccine, IMVAMUNE((R)), in healthcare personnel at risk of monkeypox virus (MPXV) infection. We describe procedures for documenting exposures to monkeypox virus infection in study participants, and outline lessons learned that may be of relevance for studies of other investigational countermeasures in hard to reach, under-resourced populations.

Reports of 10 suspected cases of monkeypox in Likouala Department, Republic of the Congo, triggered an investigation and response in March 2017 that included community education and surveillance strengthening. Increasing numbers of outbreaks suggest that monkeypox virus is becoming a more prevalent human pathogen. Diverse approaches are necessary for disease control and prevention.

On January 16, 2018, CDC was notified by the Florida Department of Health of potential rabies virus exposure in two persons believed to be residents of Switzerland. Rabies virus infections cause a fatal encephalitis, and persons exposed to the virus are advised to receive postexposure prophylaxis (PEP) as soon as possible (1). On January 10, 2018, a married couple found a bat in a Naples, Florida, shopping mall parking lot and took it to a local veterinary clinic. The woman, estimated to be aged 50–60 years, stated that they were Swiss tourists. No other identifying information was obtained. On January 15, 2018, the bat tested positive for rabies by the direct fluorescent antibody test at the Florida Department of Health public health laboratory. After repeated efforts to identify the couple were unsuccessful, CDC was able to locate the couple by using the national focal point network maintained by World Health Organization (WHO) International Health Regulations (IHR) (2); the two were promptly administered PEP.

OBJECTIVE To describe rabies and rabies-related events occurring during 2016 in the United States. DESIGN Observational study based on passive surveillance data. ANIMALS All animals submitted for rabies testing in the United States during 2016. PROCEDURES State and territorial public health programs provided data on animals submitted for rabies testing in 2016. Data were analyzed temporally and geographically to assess trends in domestic and sylvatic animal rabies cases. RESULTS During 2016, 50 states and Puerto Rico reported 4,910 rabid animals to the CDC, representing a 10.9% decrease from the 5,508 rabid animals reported in 2015. Of the 4,910 cases of animal rabies, 4,487 (91.4%) involved wildlife. Relative contributions by the major animal groups were as follows: 1,646 (33.5%) bats, 1,403 (28.6%) raccoons, 1,031 (21.0%) skunks, 313 (6.4%) foxes, 257 (5.2%) cats, 70 (1.4%) cattle, and 58 (1.2%) dogs. There was a 4.6% decrease in the number of samples submitted for testing in 2016, compared with the number submitted in 2015. No human rabies deaths were reported in 2016. CONCLUSIONS AND CLINICAL RELEVANCE Laboratory testing of animals suspected to be rabid remains a critical public health function and continues to be a cost-effective method to directly influence human rabies postexposure prophylaxis recommendations.

The recent apparent increase in human monkeypox cases across a wide geographic area, the potential for further spread, and the lack of reliable surveillance have raised the level of concern for this emerging zoonosis. In November 2017, the World Health Organization (WHO), in collaboration with CDC, hosted an informal consultation on monkeypox with researchers, global health partners, ministries of health, and orthopoxvirus experts to review and discuss human monkeypox in African countries where cases have been recently detected and also identify components of surveillance and response that need improvement. Endemic human monkeypox has been reported from more countries in the past decade than during the previous 40 years. Since 2016, confirmed cases of monkeypox have occurred in Central African Republic, Democratic Republic of the Congo, Liberia, Nigeria, Republic of the Congo, and Sierra Leone and in captive chimpanzees in Cameroon. Many countries with endemic monkeypox lack recent experience and specific knowledge about the disease to detect cases, treat patients, and prevent further spread of the virus. Specific improvements in surveillance capacity, laboratory diagnostics, and infection control measures are needed to launch an efficient response. Further, gaps in knowledge about the epidemiology and ecology of the virus need to be addressed to design, recommend, and implement needed prevention and control measures.

Rabies is an acute encephalitis that is nearly always fatal. It is caused by infection with viruses of the genus Lyssavirus, the most common of which is Rabies lyssavirus. The Council of State and Territorial Epidemiologists (CSTE) defines a confirmed human rabies case as an illness compatible with rabies that meets at least one of five different laboratory criteria.* Four of these criteria do not depend on the patient's rabies vaccination status; however, the remaining criterion, "identification of Lyssavirus-specific antibody (i.e. by indirect fluorescent antibody...test or complete [Rabies lyssavirus] neutralization at 1:5 dilution) in the serum," is only considered diagnostic in unvaccinated patients. Lyssavirus-specific antibodies include Rabies lyssavirus-specific binding immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies and Rabies lyssavirus neutralizing antibodies (RLNAs). This report describes six patients who were tested for rabies by CDC and who met CSTE criteria for confirmed human rabies because they had illnesses compatible with rabies, had not been vaccinated for rabies, and were found to have serum RLNAs (with complete Rabies lyssavirus neutralization at a serum dilution of 1:5). An additional four patients are described who were tested for rabies by CDC who were found to have serum RLNAs (with incomplete Rabies lyssavirus neutralization at a serum dilution of 1:5) despite having not been vaccinated for rabies. None of these 10 patients received a rabies diagnosis; rather, they were considered to have been passively immunized against rabies through recent receipt of intravenous immune globulin (IVIG). Serum RLNA test results should be interpreted with caution in patients who have not been vaccinated against rabies but who have recently received IVIG.