Evidence of Mpox Virus Infection Among Persons Without Characteristic Lesions or Rash Presenting for First Dose of JYNNEOS Vaccine-District of Columbia, August 2022.

We assessed mpox virus prevalence in blood, pharyngeal, and rectal specimens among persons without characteristic rash presenting for JYNNEOS vaccine. Our data indicate that the utility of risk-based screening for mpox in persons without skin lesions or rash via pharyngeal swabs, rectal swabs, and/or blood is likely limited.

High-Contact Object and Surface Contamination in a Household of Persons with Monkeypox Virus Infection - Utah, June 2022.

In May 2022, the Salt Lake County Health Department reported two real-time polymerase chain reaction (PCR)-confirmed travel-associated cases of monkeypox to the Utah Department of Health and Human Services (UDHHS). The two persons with monkeypox (patients A and B) lived together without other housemates. Both persons experienced prodromal symptoms (e.g., fatigue and body aches). Eight days after symptom onset, patient A experienced penile lesions; lesions spread to the lips, hands, legs, chest, and scalp by day 10. Patient B experienced prodromal symptoms 8 days after illness onset of patient A; patient B experienced a lesion on the foot which spread to the leg and finger by day 11. Although both patients had lesions in multiple anatomic areas, the overall number of lesions was small, and lesions varied in presentation from "pimple-like" or ulcerated, to characteristically well-circumscribed and centrally umbilicated. Both patients had mild illness. The time from symptom onset to resolution was approximately 30 days for patient A and approximately 22 days for patient B.

Monkeypox Case Investigation - Cook County Jail, Chicago, Illinois, July-August 2022.

Knowledge about monkeypox transmission risk in congregate settings is limited. In July 2022, the Chicago Department of Public Health (CDPH) confirmed a case of monkeypox in a person detained in Cook County Jail (CCJ) in Chicago, Illinois. This case was the first identified in a correctional setting in the United States and reported to CDC during the 2022 multinational monkeypox outbreak. CDPH collaborated with CCJ, the Illinois Department of Public Health (IDPH), and CDC to evaluate transmission risk within the facility. Fifty-seven residents were classified as having intermediate-risk exposures to the patient with monkeypox during the 7-day interval between the patient's symptom onset and his isolation. (Intermediate-risk exposure was defined as potentially being within 6 ft of the patient with monkeypox for a total of ≥3 hours cumulatively, without wearing a surgical mask or respirator, or potentially having contact between their own intact skin or clothing and the skin lesions or body fluids from the patient or with materials that were in contact with the patient's skin lesions or body fluids.) No secondary cases were identified among a subset of 62% of these potentially exposed residents who received symptom monitoring, serologic testing, or both. Thirteen residents accepted postexposure prophylaxis (PEP), with higher acceptance among those who were offered counseling individually or in small groups than among those who were offered PEP together in a large group. Monkeypox virus (MPXV) DNA, but no viable virus, was detected on one surface in a dormitory where the patient had been housed with other residents before he was isolated. Although monkeypox transmission might be limited in similar congregate settings in the absence of higher-risk exposures, congregate facilities should maintain recommended infection control practices in response to monkeypox cases, including placing the person with monkeypox in medical isolation and promptly and thoroughly cleaning and disinfecting spaces where the person has spent time. In addition, officials should provide information to residents and staff members about monkeypox symptoms and transmission modes, facilitate confidential monkeypox risk and symptom disclosure and prompt medical evaluation for symptoms that are reported, and provide PEP counseling in a private setting.

A cocktail of human monoclonal antibodies broadly neutralizes North American rabies virus variants as a promising candidate for rabies post-exposure prophylaxis.

Human rabies remains a globally significant public health problem. Replacement of polyclonal anti-rabies immunoglobulin (RIG), a passive component of rabies post-exposure prophylaxis (PEP), with a monoclonal antibody (MAb), would eliminate the cost and availability constraints associated with RIG. Our team has developed and licensed a human monoclonal antibody RAB1 (Rabishield©), as the replacement for RIG where canine rabies is enzootic. However, for the highly diverse rabies viruses of North America, a cocktail containing two or more MAbs targeting different antigenic sites of the rabies glycoprotein should be included to ensure neutralization of all variants of the virus. In this study, two MAb cocktails, R172 (RAB1-RAB2) and R173 (RAB1-CR57), were identified and evaluated against a broad range of rabies variants from North America. R173 was found to be the most potent cocktail, as it neutralized all the tested North American RABV isolates and demonstrated broad coverage of isolates from both terrestrial and bat species. R173 could be a promising candidate as an alternative or replacement for RIG PEP in North America.

Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model.

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [Cmax]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.

Use of partial N-gene sequences as a tool to monitor progress on rabies control and elimination efforts in Ethiopia.

Ethiopia is one of the African countries most affected by rabies. A coarse catalog of rabies viruses (RABV) was created as a benchmark to assess the impact of control and elimination activities. We evaluated a 726 bp amplicon at the end of the N-gene to infer viral lineages in circulation using maximum likelihood and Bayesian methods for phylogenetic reconstruction. We sequenced 228 brain samples from wild and domestic animals collected in five Ethiopian regions during 2010-2017. Results identified co-circulating RABV lineages that are causing recurrent spillover infections into wildlife and domestic animals. We found no evidence of importation of RABVs from other African countries or vaccine-induced cases in the area studied. A divergent RABV lineage might be involved in an independent rabies cycle in jackals. This investigation provides a feasible approach to assess rabies control and elimination efforts in resource-limited countries.

Laboratory Infection of Novel Akhmeta Virus in CAST/EiJ Mice.

Akhmeta virus is a zoonotic Orthopoxvirus first identified in 2013 in the country of Georgia. Subsequent ecological investigations in Georgia have found evidence that this virus is widespread in its geographic distribution within the country and in its host-range, with rodents likely involved in its circulation in the wild. Yet, little is known about the pathogenicity of this virus in rodents. We conducted the first laboratory infection of Akhmeta virus in CAST/EiJ Mus musculus to further characterize this novel virus. We found a dose-dependent effect on mortality and weight loss (p < 0.05). Anti-orthopoxvirus antibodies were detected in the second- and third-highest dose groups (5 × 104 pfu and 3 × 102 pfu) at euthanasia by day 10, and day 14 post-infection, respectively. Anti-orthopoxvirus antibodies were not detected in the highest dose group (3 × 106 pfu), which were euthanized at day 7 post-infection and had high viral load in tissues, suggesting they succumbed to disease prior to mounting an effective immune response. In order of highest burden, viable virus was detected in the nostril, lung, tail, liver and spleen. All individuals tested in the highest dose groups were DNAemic. Akhmeta virus was highly pathogenic in CAST/EiJ Mus musculus, causing 100% mortality when ≥3 × 102 pfu was administered.

Pharmacokinetic Profiles of Gabapentin after Oral and Subcutaneous Administration in Black-tailed Prairie Dogs (Cynomys ludovicianus).

In veterinary and human medicine, gabapentin (a chemical analog of γ-aminobutyric acid) is commonly prescribed to treat postoperative and chronic neuropathic pain. This study explored the pharmacokinetics of oral and subcutaneous administration of gabapentin at high (80 mg/kg) and low (30 mg/kg) doses as a potential analgesic in black-tailed prairie dogs (Cynomys ludovicianus; n = 24). The doses (30 and 80 mg/kg) and half maximal effective concentration (1.4 to 16.7 ng/mL) for this study were extrapolated from pharmacokinetic efficacy studies in rats, rabbits, and cats. Gabapentin in plasma was measured by using an immunoassay, and data were evaluated using noncompartmental analysis. The peak plasma concentrations (mean ±1 SD) were 42.6 ±14.8 and 115.5 ±15.2 ng/mL, respectively, after 30 and 80 mg/kg SC and 14.5 ±3.5 and 20.7 ±6.1 ng/mL after the low and high oral dosages, respectively. All peak plasma concentrations of gabapentin occurred within 5 h of administration. Disappearance half-lives for the low and high oral doses were 7.4 ± 6.0 h and 5.0 ± 0.8 h, respectively. The results of this study demonstrate that oral administration of gabapentin at low (30 mg/kg) doses likely would achieve and maintain plasma concentrations at half maximum effective concentration for 12 h, making it a viable option for an every 12-h treatment.

Inactivated Rabies Virus-Vectored Immunocontraceptive Vaccine in a Thermo-Responsive Hydrogel Induces High and Persistent Antibodies against Rabies, but Insufficient Antibodies against Gonadotropin-Releasing Hormone for Contraception.

Rabies is preventable through vaccination, but the need to mount annual canine vaccination campaigns presents major challenges in rabies control and prevention. The development of a rabies vaccine that ensures lifelong immunity and animal population management in one dose could be extremely advantageous. A nonsurgical alternative to spay/neuter is a high priority for animal welfare, but irreversible infertility in one dose has not been achieved. Towards this goal, we developed a rabies virus-vectored immunocontraceptive vaccine ERA-2GnRH, which protected against rabies virus challenge and induced >80% infertility in mice after three doses in a live, liquid-vaccine formulation (Wu et al., 2014). To improve safety and use, we formulated an inactivated vaccine in a thermo-responsive chitosan hydrogel for one-dose delivery and studied the immune responses in mice. The hydrogel did not cause any injection site reactions, and the killed ERA-2GnRH vaccine induced high and persistent rabies virus neutralizing antibodies (rVNA) in mice. The rVNA in the hydrogel group reached an average of 327.40 IU/mL, more than 200 times higher than the liquid vaccine alone. The Gonadotropin-releasing hormone (GnRH) antibodies were also present and lasted longer in the hydrogel group, but did not prevent fertility in mice, reflecting a possible threshold level of GnRH antibodies for contraception. In conclusion, the hydrogel facilitated a high and long-lasting immunity, and ERA-2GnRH is a promising dual vaccine candidate. Future studies will focus on rabies protection in target species and improving the anti-GnRH response.