Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure-Minnesota, 2021.

BACKGROUND: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture-based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies 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 patient contacts. RESULTS: Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that 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, 3 (0.9%) warranted PEP. CONCLUSIONS: This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture-based 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.

Tecovirimat Resistance in Mpox Patients, United States, 2022-2023.

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.

Epidemiology of Human Mpox - Worldwide, 2018-2021.

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.

Interim Clinical Treatment Considerations for Severe Manifestations of Mpox - United States, February 2023.

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.

Myocarditis Attributable to Monkeypox Virus Infection in 2 Patients, United States, 2022.

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.

Interim Guidance for Prevention and Treatment of Monkeypox in Persons with HIV Infection - United States, August 2022.

Monkeypox virus, an orthopoxvirus sharing clinical features with smallpox virus, is endemic in several countries in Central and West Africa. The last reported outbreak in the United States, in 2003, was linked to contact with infected prairie dogs that had been housed or transported with African rodents imported from Ghana (1). Since May 2022, the World Health Organization (WHO) has reported a multinational outbreak of monkeypox centered in Europe and North America, with approximately 25,000 cases reported worldwide; the current outbreak is disproportionately affecting gay, bisexual, and other men who have sex with men (MSM) (2). Monkeypox was declared a public health emergency in the United States on August 4, 2022.† Available summary surveillance data from the European Union, England, and the United States indicate that among MSM patients with monkeypox for whom HIV status is known, 28%-51% have HIV infection (3-10). Treatment of monkeypox with tecovirimat as a first-line agent is available through CDC for compassionate use through an investigational drug protocol. No identified drug interactions would preclude coadministration of tecovirimat with antiretroviral therapy (ART) for HIV infection. Pre- and postexposure prophylaxis can be considered with JYNNEOS vaccine, if indicated. Although data are limited for monkeypox in patients with HIV, prompt diagnosis, treatment, and prevention might reduce the risk for adverse outcomes and limit monkeypox spread. Prevention and treatment considerations will be updated as more information becomes available.

Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol - United States, May-August 2022.

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.

Use of JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) for Preexposure Vaccination of Persons at Risk for Occupational Exposure to Orthopoxviruses: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

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.

Ocular Monkeypox - United States, July-September 2022.

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.

Monkeypox Outbreak - Nine States, May 2022.

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.¶.

Severe Monkeypox in Hospitalized Patients - United States, August 10-October 10, 2022.

As of October 21, 2022, a total of 27,884 monkeypox cases (confirmed and probable) have been reported in the United States.§ Gay, bisexual, and other men who have sex with men have constituted a majority of cases, and persons with HIV infection and those from racial and ethnic minority groups have been disproportionately affected (1,2). During previous monkeypox outbreaks, severe manifestations of disease and poor outcomes have been reported among persons with HIV infection, particularly those with AIDS (3-5). This report summarizes findings from CDC clinical consultations provided for 57 patients aged ≥18 years who were hospitalized with severe manifestations of monkeypox¶ during August 10-October 10, 2022, and highlights three clinically representative cases. Overall, 47 (82%) patients had HIV infection, four (9%) of whom were receiving antiretroviral therapy (ART) before monkeypox diagnosis. Most patients were male (95%) and 68% were non-Hispanic Black (Black). Overall, 17 (30%) patients received intensive care unit (ICU)-level care, and 12 (21%) have died. As of this report, monkeypox was a cause of death or contributing factor in five of these deaths; six deaths remain under investigation to determine whether monkeypox was a causal or contributing factor; and in one death, monkeypox was not a cause or contributing factor.** Health care providers and public health professionals should be aware that severe morbidity and mortality associated with monkeypox have been observed during the current outbreak in the United States (6,7), particularly among highly immunocompromised persons. Providers should test all sexually active patients with suspected monkeypox for HIV at the time of monkeypox testing unless a patient is already known to have HIV infection. Providers should consider early commencement and extended duration of monkeypox-directed therapy†† in highly immunocompromised patients with suspected or laboratory-diagnosed monkeypox.§§ Engaging all persons with HIV in sustained care remains a critical public health priority.

Progressive Vaccinia Acquired through Zoonotic Transmission in a Patient with HIV/AIDS, Colombia.

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.

Preemptive Tecovirimat Use in an Active Duty Service Member Who Presented With Acute Myeloid Leukemia After Smallpox Vaccination.

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

Epidemiologic and Ecologic Investigations of Monkeypox, Likouala Department, Republic of the Congo, 2017.

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 Manfouété, 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.

Seroprevalence and Risk Factors Possibly Associated with Emerging Zoonotic Vaccinia Virus in a Farming Community, Colombia.

In 2014, vaccinia virus (VACV) infections were identified among farmworkers in Caquetá Department, Colombia; additional cases were identified in Cundinamarca Department in 2015. VACV, an orthopoxvirus (OPXV) used in the smallpox vaccine, has caused sporadic bovine and human outbreaks in countries such as Brazil and India. In response to the emergence of this disease in Colombia, we surveyed and collected blood from 134 farmworkers and household members from 56 farms in Cundinamarca Department. We tested serum samples for OPXV antibodies and correlated risk factors with seropositivity by using multivariate analyses. Fifty-two percent of farmworkers had OPXV antibodies; this percentage decreased to 31% when we excluded persons who would have been eligible for smallpox vaccination. The major risk factors for seropositivity were municipality, age, smallpox vaccination scar, duration of time working on a farm, and animals having vaccinia-like lesions. This investigation provides evidence for possible emergence of VACV as a zoonosis in South America.

Novel Treatment of a Vaccinia Virus Infection from an Occupational Needlestick - San Diego, California, 2019.

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*,†) (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.

Strengthening of Surveillance during Monkeypox Outbreak, Republic of the Congo, 2017.

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.

Emergence of Monkeypox - West and Central Africa, 1970-2017.

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.

Potential Confounding of Diagnosis of Rabies in Patients with Recent Receipt of Intravenous Immune Globulin.

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.