Crimean-Congo hemorrhagic fever virus (CCHFV) is an important tick-borne human pathogen endemic throughout Asia, Africa and Europe. CCHFV is also an emerging virus, with recent outbreaks in Western Europe. CCHFV can infect a large number of wild and domesticated mammalian species and some avian species, however the virus does not cause severe disease in these animals, but can produce viremia. In humans, CCHFV infection can lead to a severe, life-threating disease characterized by hemodynamic instability, hepatic injury and neurological disorders, with a worldwide lethality rate of ~20–30%. The pathogenic mechanisms of CCHF are poorly understood, largely due to the dearth of animal models. However, several important animal models have been recently described, including novel murine models and a non-human primate model. In this review, we examine the current knowledge of CCHF-mediated pathogenesis and describe how animal models are helping elucidate the molecular and cellular determinants of disease. This information should serve as a reference for those interested in CCHFV animal models and their utility for evaluation of medical countermeasures (MCMs) and in the study of pathogenesis.

Traditional pathogenesis studies of alphaviruses involves monitoring survival, viremia, and pathogen dissemination via serial necropsies; however, molecular imaging shifts this paradigm and provides a dynamic assessment of pathogen infection. Positron emission tomography (PET) with PET tracers targeted to study neuroinflammation (N,N-diethyl-2-[4-phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide, [¹⁸F]DPA-714), apoptosis (caspase-3 substrate, [¹⁸F]CP-18), hypoxia (fluormisonidazole, [¹⁸F]FMISO), blood–brain barrier (BBB) integrity ([¹⁸F]albumin), and metabolism (fluorodeoxyglucose, [¹⁸F]FDG) was performed on C3H/HeN mice infected intranasally with 7000 plaque-forming units (PFU) of Venezuelan equine encephalitis virus (VEEV) TC-83. The main findings are as follows: (1) whole-brain [¹⁸F]DPA-714 and [¹⁸F]CP-18 uptake increased three-fold demonstrating, neuroinflammation and apoptosis, respectively; (2) [¹⁸F]albumin uptake increased by 25% across the brain demonstrating an altered BBB; (3) [¹⁸F]FMISO uptake increased by 50% across the whole brain indicating hypoxic regions; (4) whole-brain [¹⁸F]FDG uptake was unaffected; (5) [¹⁸F]DPA-714 uptake in (a) cortex, thalamus, striatum, hypothalamus, and hippocampus increased through day seven and decreased by day 10 post exposure, (b) olfactory bulb increased at day three, peaked day seven, and decreased day 10, and (c) brain stem and cerebellum increased through day 10. In conclusion, intranasal exposure of C3H/HeN mice to VEEV TC-83 results in both time-dependent and regional increases in brain inflammation, apoptosis, and hypoxia, as well as modest decreases in BBB integrity; however, it has no effect on brain glucose metabolism.

: The Rift Valley fever virus (RVFV) MP-12 vaccine is a promising human and veterinary vaccine. Although the vaccine elicited neutralizing antibody (nAb) in human volunteers, the minimal antibody titer that is needed to afford protection is unknown. Therefore, this study was conducted to determine the minimal nAb titer elicited by the RVFV MP-12 vaccine in human volunteers that protected mice against lethal RVFV challenge as a surrogate assessment of the protective efficacy of the vaccine. Among volunteers who were vaccinated with the MP-12 vaccine during a phase II trial, sera with antibody titers of 1:20 collected 5 years post-vaccination (PV), 1:40 titer collected 2 years PV, and 1:80 titer collected 1 year PV was passively transferred to groups of BALB/c mice. Blood samples were obtained 1 day after passive transfer to determine the RVFV neutralizing nAb titer before challenge with pathogenic RVFV (strain ZH501). Our results indicated that 1 day after passive transfer of the immune sera, an approximate 4-fold reduction in circulating nAb titers was detected in the mice. The presence of RVFV nAb titers in the range of 1:5 to 1:20 were generally protective (75–100% survival). These results suggested that circulating titers of 1:5 or higher offer a high degree of protection by MP-12-elicited antibody in human volunteers. Also, the findings highlighted the value of using the BALB/c mouse RVFV challenge model as a surrogate for evaluating the protective nAb responses elicited by MP-12 and possible use for evaluating the efficacy of other RVFV vaccine candidates.

The emergence of SARS-CoV-2 variants complicates efforts to control the COVID-19 pandemic. Increasing genomic surveillance of SARS-CoV-2 is imperative for early detection of emerging variants, to trace the movement of variants, and to monitor effectiveness of countermeasures. Additionally, determining the amount of viable virus present in clinical samples is helpful to better understand the impact these variants have on viral shedding. In this study, we analyzed nasal swab samples collected between March 2020 and early November 2021 from a cohort of United States (U.S.) military personnel and healthcare system beneficiaries stationed worldwide as a part of the Defense Health Agency's (DHA) Global Emerging Infections Surveillance (GEIS) program. SARS-CoV-2 quantitative real time reverse-transcription PCR (qRT-PCR) positive samples were characterized by next-generation sequencing and a subset was analyzed for isolation and quantification of viable virus. Not surprisingly, we found that the Delta variant is the predominant strain circulating among U.S. military personnel beginning in July 2021 and primarily represents cases of vaccine breakthrough infections (VBIs). Among VBIs, we found a 50-fold increase in viable virus in nasal swab samples from Delta variant cases when compared to cases involving other variants. Notably, we found a 40-fold increase in viable virus in nasal swab samples from VBIs involving Delta as compared to unvaccinated personnel infected with other variants prior to the availability of approved vaccines. This study provides important insight about the genomic and virological characterization of SARS-CoV-2 isolates from a unique study population with a global presence.