Clinical Manifestations of an Outbreak of Monkeypox Virus in Captive Chimpanzees in Cameroon, 2016.

Monkeypox virus (MPXV) is a reemerging virus of global concern. An outbreak of clade I MPXV affected 20 captive chimpanzees in Cameroon in 2016. We describe the epidemiology, virology, phylogenetics, and clinical progression of this outbreak. Clinical signs included exanthema, facial swelling, perilaryngeal swelling, and eschar. Mpox can be lethal in captive chimpanzees, with death likely resulting from respiratory complications. We advise avoiding anesthesia in animals with respiratory signs to reduce the likelihood of death. This outbreak presented a risk to animal care staff. There is a need for increased awareness and a One Health approach to preparation for outbreaks in wildlife rescue centers in primate range states where MPXV occurs. Control measures should include quarantining affected animals, limiting human contacts, surveillance of humans and animals, use of personal protective equipment, and regular decontamination of enclosures.

Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry.

We have recently shown that the replication of rhinovirus, poliovirus and foot-and-mouth disease virus requires the co-translational N-myristoylation of viral proteins by human host cell N-myristoyltransferases (NMTs), and is inhibited by treatment with IMP-1088, an ultrapotent small molecule NMT inhibitor. Here, we examine the importance of N-myristoylation during vaccinia virus (VACV) infection in primate cells and demonstrate the anti-poxviral effects of IMP-1088. N-myristoylated proteins from VACV and the host were metabolically labelled with myristic acid alkyne during infection using quantitative chemical proteomics. We identified VACV proteins A16, G9 and L1 to be N-myristoylated. Treatment with NMT inhibitor IMP-1088 potently abrogated VACV infection, while VACV gene expression, DNA replication, morphogenesis and EV formation remained unaffected. Importantly, we observed that loss of N-myristoylation resulted in greatly reduced infectivity of assembled mature virus particles, characterized by significantly reduced host cell entry and a decline in membrane fusion activity of progeny virus. While the N-myristoylation of VACV entry proteins L1, A16 and G9 was inhibited by IMP-1088, mutational and genetic studies demonstrated that the N-myristoylation of L1 was the most critical for VACV entry. Given the significant genetic identity between VACV, monkeypox virus and variola virus L1 homologs, our data provides a basis for further investigating the role of N-myristoylation in poxviral infections as well as the potential of selective NMT inhibitors like IMP-1088 as broad-spectrum poxvirus inhibitors.

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.

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.¶.

Monkeypox in a Traveler Returning from Nigeria - Dallas, Texas, July 2021.

Monkeypox is a rare, sometimes life-threatening zoonotic infection that occurs in west and central Africa. It is caused by Monkeypox virus, an orthopoxvirus similar to Variola virus (the causative agent of smallpox) and Vaccinia virus (the live virus component of orthopoxvirus vaccines) and can spread to humans. After 39 years without detection of human disease in Nigeria, an outbreak involving 118 confirmed cases was identified during 2017-2018 (1); sporadic cases continue to occur. During September 2018-May 2021, six unrelated persons traveling from Nigeria received diagnoses of monkeypox in non-African countries: four in the United Kingdom and one each in Israel and Singapore. In July 2021, a man who traveled from Lagos, Nigeria, to Dallas, Texas, became the seventh traveler to a non-African country with diagnosed monkeypox. Among 194 monitored contacts, 144 (74%) were flight contacts. The patient received tecovirimat, an antiviral for treatment of orthopoxvirus infections, and his home required large-scale decontamination. Whole genome sequencing showed that the virus was consistent with a strain of Monkeypox virus known to circulate in Nigeria, but the specific source of the patient's infection was not identified. No epidemiologically linked cases were reported in Nigeria; no contact received postexposure prophylaxis (PEP) with the orthopoxvirus vaccine ACAM2000.

Rapid Diagnostic Testing for Response to the Monkeypox Outbreak - Laboratory Response Network, United States, May 17-June 30, 2022.

As part of public health preparedness for infectious disease threats, CDC collaborates with other U.S. public health officials to ensure that the Laboratory Response Network (LRN) has diagnostic tools to detect Orthopoxviruses, the genus that includes Variola virus, the causative agent of smallpox. LRN is a network of state and local public health, federal, U.S. Department of Defense (DOD), veterinary, food, and environmental testing laboratories. CDC developed, and the Food and Drug Administration (FDA) granted 510(k) clearance* for the Non-variola Orthopoxvirus Real-time PCR Primer and Probe Set (non-variola Orthopoxvirus [NVO] assay), a polymerase chain reaction (PCR) diagnostic test to detect NVO. On May 17, 2022, CDC was contacted by the Massachusetts Department of Public Health (DPH) regarding a suspected case of monkeypox, a disease caused by the Orthopoxvirus Monkeypox virus. Specimens were collected and tested by the Massachusetts DPH public health laboratory with LRN testing capability using the NVO assay. Nationwide, 68 LRN laboratories had capacity to test approximately 8,000 NVO tests per week during June. During May 17-June 30, LRN laboratories tested 2,009 specimens from suspected monkeypox cases. Among those, 730 (36.3%) specimens from 395 patients were positive for NVO. NVO-positive specimens from 159 persons were confirmed by CDC to be monkeypox; final characterization is pending for 236. Prompt identification of persons with infection allowed rapid response to the outbreak, including isolation and treatment of patients, administration of vaccines, and other public health action. To further facilitate access to testing and increase convenience for providers and patients by using existing provider-laboratory relationships, CDC and LRN are supporting five large commercial laboratories with a national footprint (Aegis Science, LabCorp, Mayo Clinic Laboratories, Quest Diagnostics, and Sonic Healthcare) to establish NVO testing capacity of 10,000 specimens per week per laboratory. On July 6, 2022, the first commercial laboratory began accepting specimens for NVO testing based on clinician orders.

Clinical and Epidemiological Findings from Enhanced Monkeypox Surveillance in Tshuapa Province, Democratic Republic of the Congo During 2011-2015.

BACKGROUND: Monkeypox is a poorly described emerging zoonosis endemic to Central and Western Africa. METHODS: Using surveillance data from Tshuapa Province, Democratic Republic of the Congo during 2011-2015, we evaluated differences in incidence, exposures, and clinical presentation of polymerase chain reaction-confirmed cases by sex and age. RESULTS: We report 1057 confirmed cases. The average annual incidence was 14.1 per 100 000 (95% confidence interval, 13.3-15.0). The incidence was higher in male patients (incidence rate ratio comparing males to females, 1.21; 95% confidence interval, 1.07-1.37), except among those 20-29 years old (0.70; .51-.95). Females aged 20-29 years also reported a high frequency of exposures (26.2%) to people with monkeypox-like symptoms.The highest incidence was among 10-19-year-old males, the cohort reporting the highest proportion of animal exposures (37.5%). The incidence was lower among those presumed to have received smallpox vaccination than among those presumed unvaccinated. No differences were observed by age group in lesion count or lesion severity score. CONCLUSIONS: Monkeypox incidence was twice that reported during 1980-1985, an increase possibly linked to declining immunity provided by smallpox vaccination. The high proportion of cases attributed to human exposures suggests changing exposure patterns. Cases were distributed across age and sex, suggesting frequent exposures that follow sociocultural norms.

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.

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.

Novel Poxvirus in Proliferative Lesions of Wild Rodents in East Central Texas, USA.

Northern pygmy mice from 2 localities in East Central Texas, USA, had proliferative epidermal lesions on the tail and feet. Electron microscopy of lesion tissue revealed poxvirus. Phylogenetic analyses indicated the virus differed 35% from its closest relatives, the Chordopoxvirinae. Future research is needed to determine whether this virus could affect human health.

Reemergence of Human Monkeypox in Nigeria, 2017.

In Nigeria, before 2017 the most recent case of human monkeypox had been reported in 1978. By mid-November 2017, a large outbreak caused by the West African clade resulted in 146 suspected cases and 42 laboratory-confirmed cases from 14 states. Although the source is unknown, multiple sources are suspected.

Novel Orthopoxvirus Infection in an Alaska Resident.

BACKGROUND.: Human infection by orthopoxviruses is being reported with increasing frequency, attributed in part to the cessation of smallpox vaccination and concomitant waning of population-level immunity. In July 2015, a female resident of interior Alaska presented to an urgent care clinic with a dermal lesion consistent with poxvirus infection. Laboratory testing of a virus isolated from the lesion confirmed infection by an Orthopoxvirus. METHODS.: The virus isolate was characterized by using electron microscopy and nucleic acid sequencing. An epidemiologic investigation that included patient interviews, contact tracing, and serum testing, as well as environmental and small-mammal sampling, was conducted to identify the infection source and possible additional cases. RESULTS.: Neither signs of active infection nor evidence of recent prior infection were observed in any of the 4 patient contacts identified. The patient's infection source was not definitively identified. Potential routes of exposure included imported fomites from Azerbaijan via the patient's cohabiting partner or wild small mammals in or around the patient's residence. Phylogenetic analyses demonstrated that the virus represents a distinct and previously undescribed genetic lineage of Orthopoxvirus, which is most closely related to the Old World orthopoxviruses. CONCLUSIONS.: Investigation findings point to infection of the patient after exposure in or near Fairbanks. This conclusion raises questions about the geographic origins (Old World vs North American) of the genus Orthopoxvirus. Clinicians should remain vigilant for signs of poxvirus infection and alert public health officials when cases are suspected.

Detection and Molecular Characterization of Zoonotic Poxviruses Circulating in the Amazon Region of Colombia, 2014.

During 2014, cutaneous lesions were reported in dairy cattle and farmworkers in the Amazon Region of western Colombia. Samples from 6 patients were analyzed by serologic and PCR testing, and results demonstrated the presence of vaccinia virus and pseudocowpox virus. These findings highlight the need for increased poxvirus surveillance in Colombia.

Characterization of Eptesipoxvirus, a novel poxvirus from a microchiropteran bat.

The genome of Eptesipoxvirus (EPTV) is the first poxvirus genome isolated from a microbat. The 176,688 nt sequence, which is believed to encompass the complete coding region of the virus, is 67% A+T and is predicted to encode 191 genes. 11 of these genes have no counterpart in GenBank and are therefore unique to EPTV. The presence of a distantly related ortholog of Vaccinia virus F5L in EPTV uncovered a link with fragmented F5L orthologs in Molluscum contagiosum virus/squirrelpox and clade II viruses. Consistent with the unique position of EPTV approximately mid-point between the orthopoxviruses and the clade II viruses, EPTV has 11 genes that are specific to the orthopoxviruses and 13 genes that are typical, if not exclusive, to the clade II poxviruses. This mosaic nature of EPTV blurs the distinction between the old description of the orthopoxvirus and clade II groups. Genome annotation and characterization failed to find any common virulence genes shared with the other poxvirus isolated from bat (pteropoxvirus); however, EPTV encodes 3 genes that may have been transferred to or from deerpox and squirrelpox viruses; 2 of these, a putative endothelin-like protein and a MHC class I-like protein are likely to have immunomodulatory roles.

Cervical spine immobilization may be of value following firearm injury to the head and neck.

BACKGROUND: Penetrating injuries to the head and neck may not be able to cause unstable fractures without concomitant spinal cord injury, rendering prehospital spinal immobilization (PHSI) ineffectual, and possibly harmful. However, this premise is based on reports including predominantly chest and abdominal injuries, which are unlikely to cause cervical spine (CS) injuries. METHODS: We performed a retrospective review of all patients presenting with a penetrating wound to the head or neck over a 4-year period at an urban, level 1 trauma center to determine if there was a benefit of PHSI. RESULTS: One hundred seventy-two patients were identified, of which 16 (9.3%) died prior to CS evaluation. Of 156 surviving patients, mechanism was gunshot wound (GSW) in 36 (28%) and stab wound (SW) in 120 (72%). Fifty-eight patients had PHSI placed (37%), and GSW patients' odds of having PHSI were greater than SW patients (OR 2.3; CI 1.08-4.9). Eight of 156 surviving patients eventually died (5.1%), and the odds of mortality were greater among those that had PHSI than those without (OR 5.54; CI 1.08-28.4). Six (3.8%; 5 GSW, 1 SW) patients had a CS fracture. Two GSW patients (5.6%) had unstable CS fractures with a normal neurological exam at initial evaluation. CONCLUSIONS: Of patients with a GSW to the head or neck that survived to be evaluated, 5.6% had unstable fractures without an initial neurologic deficit. PHSI may be appropriate in this population. Further studies are warranted prior to a determination that PHSI is unnecessary in penetrating head and neck injuries.

Novel poxvirus infection in 2 patients from the United States.

BACKGROUND: Some human poxvirus infections can be acquired through zoonotic transmission. We report a previously unknown poxvirus infection in 2 patients, 1 of whom was immunocompromised; both patients had known equine contact. METHODS: The patients were interviewed and clinical information was abstracted from the patients' medical files. Biopsies of the skin lesions were collected from both patients for histopathology, immunohistochemistry, and transmission electron microscopy analysis. Oral and skin swabs were collected from animals with frequent contact with the patients, and environmental sampling including rodent trapping was performed on the farm where the immunosuppressed patient was employed. "Pan-pox and high Guanine-cytosine" polymerase chain reaction assays were performed on patient, animal, and environmental isolates. Amplicon sequences of the viral DNA were used for agent identification and phylogenetic analysis. RESULTS: Specimens from both human cases revealed a novel poxvirus. The agent shares 88% similarity to viruses in the Parapoxvirus genus and 78% to those in the Molluscipoxvirus genus but is sufficiently divergent to resist classification as either. All animal and environmental specimens were negative for poxvirus and both patients had complete resolution of lesions. CONCLUSIONS: This report serves as a reminder that poxviruses should be considered in cutaneous human infections, especially in individuals with known barnyard exposures. The clinical course of the patients was similar to that of parapoxvirus infections, and the source of this virus is currently unknown but is presumed to be zoonotic. This report also demonstrates the importance of a comprehensive approach to diagnosis of human infections caused by previously unknown pathogens.

Variola virus-specific diagnostic assays: characterization, sensitivity, and specificity.

A public health response relies upon rapid and reliable confirmation of disease by diagnostic assays. Here, we detail the design and validation of two variola virus-specific real-time PCR assays, since previous assays cross-reacted with newly identified cowpox viruses. The assay specificity must continually be reassessed as other closely related viruses are identified.