Intratumoral hemorrhage in vestibular schwannomas after stereotactic radiosurgery.

OBJECTIVE: Vestibular schwannomas (VSs) are benign tumors of the cerebellopontine angle that are typically managed with stereotactic radiosurgery (SRS). Intratumoral hemorrhage (ITH) of VSs is a rare occurrence that results in worsening vestibular and new cranial nerve deficits. Few reports have described the management and outcomes of this entity after SRS. To further delineate the incidence and impact of this event, the authors performed a retrospective review of their VS SRS patients at a single center. METHODS: Between 1987 and 2022, 2058 patients with VSs underwent Gamma Knife radiosurgery (GKRS) at the University of Pittsburgh Medical Center. The authors performed a review of the prospectively maintained VS database at their center to identify patients with ITH. The presentation, management, and clinical and imaging outcomes of the patients are reported. RESULTS: A total of 1902 VS patients had sufficient clinical and imaging follow-up data. Five Koos grade III (n = 1) and IV (n = 4) VS patients developed ITH after GKRS, resulting in a cumulative incidence rate of 0.26%. The age at presentation ranged from 62 to 79 years, and 3 patients were male. The time from VS diagnosis to GKRS ranged from 1 to 13 months, and the time from GKRS to ITH ranged from 2 to 130 months. Three patients had bleeding risk factors. One patient required urgent surgical intervention due to the ITH volume, while the other 4 patients were initially observed. Three patients remained stable and required no delayed intervention; 1 patient required delayed resection because of symptom progression and hemorrhagic expansion. Histopathological analysis revealed multiple fragments of S-100-positive cells, hemorrhage, and hemosiderin-laden macrophages. At last follow-up, 4 patients had clinically improved and 1 patient remained stable. CONCLUSIONS: ITH after VS radiosurgery is a rare phenomenon with a cumulative incidence rate of 0.26% in this series. Patient-tailored management in the form of observation or resection is based on patient presentation, acuity, and ITH size.

Superiority of craniotomy over supportive care for octogenarians and nonagenarians in operable acute traumatic subdural hematoma.

OBJECTIVE: Neurosurgical evacuation in elderly trauma patients is controversial. We analyzed impact of craniotomy for acute subdural hematoma on survival in octogenarians and nonagenarians. Methods The study population included all patients aged ≥ 80 years who presented with acute traumatic SDHs 09/01/15 - 01/01/20, with radiography indicating operative eligibility (i.e. MLS >5 mm and/or overall thickness >10 mm). Of 1054 TBIs aged ≥ 80 years, 104 (9.87%) were surgically indicated. Of these, 35 received craniotomy and 69 received supportive measures due to family/patient wishes or surgeon's professional decision. We analyzed these data using a Poisson regression adjusted for influence of covariates. RESULTS: Of 35 craniotomies, 21 (60.00%) were deceased at 2 years of follow-up, compared to 48 (69.57%) deceased of 69 non-surgical patients. No significant demographic differences existed between these groups, other than age (craniotomy patients were younger; median age 84 vs 86; p < 0.001). In outcomes, the craniotomy cohort survived longer and in higher proportions (p = 0.028; Gehan-Breslow-Wilcoxon). When adjusting for covariates, this effect became more pronounced: craniotomy patients died at 41.1% the rate of non-surgical ones. Of all the covariates, only initial GCS significantly impacted the protective effect of craniotomy. In a logarithmic relationship, each point on initial GCS was associated with less benefit from surgery. We also found that patients with GCS< 3 were overall less likely to benefit from surgery. Our conclusions are limited by the impact of patient/surgeon choice on whether or not to operate. It is possible healthier subjects elected for craniotomies. We have attempted to correct for this by including comorbidities as covariates in our regression analyses. CONCLUSIONS: Our results indicate a surgical benefit for this elderly cohort, consistent with prior findings of benefit in the setting of severe traumatic aSDH. Patients with worse neurologic impairment, i.e. low GCS, had the greatest survival benefit from surgical intervention.

Refocusing the Immune Response to Selected Epitopes on a Zika Virus Protein Antigen by Nanopatterning.

Infections with Zika virus (ZIKV) are linked to the development of severe central nervous system disorders, but the need for a ZIKV vaccine remains unmet. Although the design of vaccines that elicit antibodies targeting domain III (DIII) of the ZIKV envelope (E) protein as an antigen is an attractive strategy, poorly neutralizing or cross-reactive antibodies that target the E protein may lead to antibody-dependent enhancement of disease. It is therefore decided to use the previously reported nanopatterning technique, which combines the site-specific incorporation of non-canonical amino acids with site-specific functionalization of the protein with polyethylene glycol (PEG), to shield selected epitopes on DIII. Two different nanopatterned DIII variants are designed and characterized and demonstrate that epitope shielding with PEG completely inhibits the binding of epitope-specific antibodies in vitro. Furthermore, immunization with multivalent nanopatterned DIII antigens results in the refocusing of the antibody response toward the exposed epitopes on the protein surface and away from potentially enhancing epitopes. This ability to redirect the antibody response toward targeted regions of the DIII protein should be useful for the design of effective and safe ZIKV vaccines.

Successful management of an intraluminal superior sagittal sinus meningioma causing elevated intracranial pressure using gamma knife radiosurgery in subacute setting: A case report.

BACKGROUND: Gamma Knife stereotactic radiosurgery (GKRS) facilitates precisely focused radiation to an intracranial target while minimizing substantial off-target radiation in the surrounding normal tissue. Meningiomas attached to or invading the superior sagittal sinus may result in sinus occlusion and are often impossible to completely resect safely. The authors describe successful management of a patient with a meningioma located completely inside the posterior aspect of the superior sagittal sinus. CASE DESCRIPTION: A 46-year-old woman presented to the emergency department with progressive generalized headaches accompanied by worsening vision. The patient underwent a diagnostic brain magnetic resonance imaging which showed a solitary a 7 × 6 × 10 mm homogeneously contrast-enhancing lesion within the lumen of the posterior aspect of superior sagittal sinus without ventricular enlargement or peritumoral edema. The lesion was thought to be a meningioma radiographically. To evaluate the suspected increased intracranial pressure, a lumbar puncture was subsequently performed and demonstrated an opening pressure of 30 cm H2O. After drainage of 40 cc of CSF, the spinal closing pressure was 9 cm H2O. After failure of conservative management with acetazolamide, and determination of surgical inoperability due to the critical intraluminal location of the mass lesion, the patient underwent Gamma Knife radiosurgery. The 0.36 cc tumor was treated as an outpatient in the Perfexion® model Gamma Knife with a highly conformal and selective plan that enclosed the 3D geometry of the tumor with a minimal margin tumor dose of 14 gy at the 50% isodose. Three months after GKRS, the patient reported continued reduction in the frequency and severity of both her headaches and her visual disturbance. Ophthalmological consultation noted progressive resolution of her optic disc edema confirmed by formal optical coherence tomography. The patient is now 3 years out from GKRS with complete resolution of headache symptoms along with persistent reduction in tumor size (3 × 1 × 4 mm) on serial period imaging and resolution of papilledema. CONCLUSION: Tumors located in such critical anatomic regions, as in our patient, should be considered for primary GKRS when the risks of biopsy or removal are too high. GKRS was able to provide great radiographic and clinical result in an intricately located meningioma.

Cervical intramedullary spinal cavernoma in setting of unresolved myelopathy: A case report.

BACKGROUND: Spinal cavernous malformations are rare, accounting for approximately 5-12% of all spinal cord vascular lesions. Fortunately, improvements in imaging technologies have made it easier to establish the diagnosis of intramedullary spinal cavernomas (ISCs). CASE DESCRIPTION: Here, we report the case of a 63-year-old male with an >11-year history of left-sided radiculopathy, ataxia, and quadriparesis. Initially, radiographic findings were interpreted as consistent with spondylotic myelopathy with cord signal changes from the C3-C7 levels. The patient underwent a C3-C7 laminectomy/foraminotomy with instrumentation. It was only after several symptomatic recurrences and repeated magnetic resonance images (MRI) that the diagnosis of a ventrally-located intramedullary lesion, concerning for a cavernoma, at the level C6 was established. CONCLUSION: Early and repeated enhanced MR studies may be required to correctly establish the diagnosis and determine the optimal surgical management of ISCs.

A cross-reactive mouse monoclonal antibody against rhinovirus mediates phagocytosis in vitro.

Rhinoviruses (RVs) are the main cause of the common cold worldwide. To date, more than 160 types of the virus have been recognized, categorized into three major species - A, B, and C. There are currently no approved vaccines available to prevent infection with RVs. To elicit antibodies against conserved regions located on capsid proteins of RV A viruses, mice were sequentially vaccinated with DNA plasmids encoding capsid proteins of different RV A types. After a final boost with whole virus, antibody-expressing hybridomas were generated. After isotyping, 11 monoclonal antibodies (mAbs) expressing an IgG subtype Fc-domain were selected for further expansion and purification. Three mAbs showed cross-reactivity against multiple strains of RV A viruses by ELISA, including strains A1A, A1B, A15, A16 and A49. Other mAbs had strain-specific binding patterns, with the majority of mAbs showing reactivity to RV-A15, the strain used for the final vaccination. We found that the RV-A15-specific mAbs, but not the cross-reactive mAbs, had neutralizing activity against RV-A15. An antibody dependent cellular phagocytosis (ADCP) assay revealed substantial ADCP activity for one of the cross-reactive mAbs. Epitope mapping of the neutralizing mAbs via escape mutant virus generation revealed a shared binding epitope on VP1 of RV-A15 for several neutralizing mAbs. The epitope of the ADCP-active, non-neutralizing mAb was determined by microarray analysis of peptides generated from the VP1 capsid protein. VP1-specific, cross-reactive antibodies, especially those with ADCP activity, could contribute to protection against RV infections.

Neutralizing Monoclonal Antibodies against the Gn and the Gc of the Andes Virus Glycoprotein Spike Complex Protect from Virus Challenge in a Preclinical Hamster Model.

Hantaviruses are the etiological agent of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The latter is associated with case fatality rates ranging from 30% to 50%. HCPS cases are rare, with approximately 300 recorded annually in the Americas. Recently, an HCPS outbreak of unprecedented size has been occurring in and around Epuyén, in the southwestern Argentinian state of Chubut. Since November of 2018, at least 29 cases have been laboratory confirmed, and human-to-human transmission is suspected. Despite posing a significant threat to public health, no treatment or vaccine is available for hantaviral disease. Here, we describe an effort to identify, characterize, and develop neutralizing and protective antibodies against the glycoprotein complex (Gn and Gc) of Andes virus (ANDV), the causative agent of the Epuyén outbreak. Using murine hybridoma technology, we generated 19 distinct monoclonal antibodies (MAbs) against ANDV GnGc. When tested for neutralization against a recombinant vesicular stomatitis virus expressing the Andes glycoprotein (GP) (VSV-ANDV), 12 MAbs showed potent neutralization and 8 showed activity in an antibody-dependent cellular cytotoxicity reporter assay. Escape mutant analysis revealed that neutralizing MAbs targeted both the Gn and the Gc. Four MAbs that bound different epitopes were selected for preclinical studies and were found to be 100% protective against lethality in a Syrian hamster model of ANDV infection. These data suggest the existence of a wide array of neutralizing antibody epitopes on hantavirus GnGc with unique properties and mechanisms of action.IMPORTANCE Infections with New World hantaviruses are associated with high case fatality rates, and no specific vaccine or treatment options exist. Furthermore, the biology of the hantaviral GnGc complex, its antigenicity, and its fusion machinery are poorly understood. Protective monoclonal antibodies against GnGc have the potential to be developed into therapeutics against hantaviral disease and are also great tools to elucidate the biology of the glycoprotein complex.

Monoclonal Antibodies with Neutralizing Activity and Fc-Effector Functions against the Machupo Virus Glycoprotein.

Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever (BHF), is a New World arenavirus that was first isolated in Bolivia from a human spleen in 1963. Due to the lack of a specific vaccine or therapy, this virus is considered a major risk to public health and is classified as a category A priority pathogen by the U.S. National Institutes of Health. In this study, we used DNA vaccination against the MACV glycoprotein precursor complex (GPC) and murine hybridoma technology to generate 25 mouse monoclonal antibodies (MAbs) against the GPC of MACV. Out of 25 MAbs, five were found to have potent neutralization activity in vitro against a recombinant vesicular stomatitis virus expressing MACV GPC (VSV-MACV) as well as against authentic MACV. Furthermore, the five neutralizing MAbs exhibited strong antibody-dependent cellular cytotoxicity (ADCC) activity in a reporter assay. When tested in vivo using VSV-MACV in a Stat2-/- mouse model, three MAbs significantly lowered viral loads in the spleen. Our work provides valuable insights into epitopes targeted by neutralizing antibodies that could be potent targets for vaccines and therapeutics and shed light on the importance of effector functions in immunity against MACV.IMPORTANCE MACV infections are a significant public health concern and lead to high case fatality rates. No specific treatment or vaccine for MACV infections exist. However, cases of Junin virus infection, a related virus, can be treated with convalescent-phase serum. This indicates that a MAb-based therapy for MACV could be effective. Here, we describe several MAbs that neutralize MACV and could be used for this purpose.

Antibodies Elicited by an NS1-Based Vaccine Protect Mice against Zika Virus.

Zika virus is a mosquito-borne flavivirus which can cause severe disease in humans, including microcephaly and other congenital malformations in newborns and Guillain-Barré syndrome in adults. There are currently no approved prophylactics or therapeutics for Zika virus; the development of a safe and effective vaccine is an urgent priority. Preclinical studies suggest that the envelope glycoprotein can elicit potently neutralizing antibodies. However, such antibodies are implicated in the phenomenon of antibody-dependent enhancement of disease. We have previously shown that monoclonal antibodies targeting the Zika virus nonstructural NS1 protein are protective without inducing antibody-dependent enhancement of disease. Here, we investigated whether the NS1 protein itself is a viable vaccine target. Wild-type mice were vaccinated with an NS1-expressing DNA plasmid followed by two adjuvanted protein boosters, which elicited high antibody titers. Passive transfer of the immune sera was able to significantly protect STAT2 knockout mice against lethal challenge by Zika virus. In addition, long-lasting NS1-specific IgG responses were detected in serum samples from patients in either the acute or the convalescent phase of Zika virus infection. These NS1-specific antibodies were able to functionally engage Fcγ receptors. In contrast, envelope-specific antibodies did not activate Fc-mediated effector functions on infected cells. Our data suggest that the Zika virus NS1 protein, which is expressed on infected cells, is critical for Fc-dependent cell-mediated immunity. The present study demonstrates that the Zika virus NS1 protein is highly immunogenic and can elicit protective antibodies, underscoring its potential for an effective Zika virus vaccine.IMPORTANCE Zika virus is a global public health threat that causes microcephaly and congenital malformations in newborns and Guillain-Barré syndrome in adults. Currently, no vaccines or treatments are available. While antibodies targeting the envelope glycoprotein can neutralize virus, they carry the risk of antibody-dependent enhancement of disease (ADE). In contrast, antibodies generated against the NS1 protein can be protective without eliciting ADE. The present study demonstrates the effectiveness of an NS1-based vaccine in eliciting high titers of protective antibodies against Zika virus disease in a mouse model. Sera generated by this vaccine can elicit Fc-mediated effector functions against Zika virus-infected cells. Lastly, we provide human data suggesting that the antibody response against the Zika virus NS1 protein is long-lasting and functionally active. Overall, our work will inform the development of a safe and effective Zika virus vaccine.

Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy.

Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts. ZIKV-infected human placental tissues also showed increased replication in the presence of DENV antibodies, which was reversed by FcγR blocking antibodies. Furthermore, ZIKV-mediated fetal pathogenesis was enhanced in mice in the presence of a DENV-reactive monoclonal antibody, but not in the presence of the LALA variant, indicating a dependence on FcγR engagement. Our data suggest a possible mechanism for the recent increase in severe pregnancy outcomes after ZIKV infection in DENV-endemic areas.

Human antibodies targeting Zika virus NS1 provide protection against disease in a mouse model.

Zika virus is a mosquito-borne flavivirus closely related to dengue virus that can cause severe disease in humans, including microcephaly in newborns and Guillain-Barré syndrome in adults. Specific treatments and vaccines for Zika virus are not currently available. Here, we isolate and characterize four monoclonal antibodies (mAbs) from an infected patient that target the non-structural protein NS1. We show that while these antibodies are non-neutralizing, NS1-specific mAbs can engage FcγR without inducing antibody dependent enhancement (ADE) of infection in vitro. Moreover, we demonstrate that mAb AA12 has protective efficacy against lethal challenges of African and Asian lineage strains of Zika virus in Stat2-/- mice. Protection is Fc-dependent, as a mutated antibody unable to activate known Fc effector functions or complement is not protective in vivo. This study highlights the importance of the ZIKV NS1 protein as a potential vaccine antigen.

Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses.

Arenaviruses pose a major public health threat and cause numerous infections in humans each year. Although most viruses belonging to this family do not cause disease in humans, some arenaviruses, such as Lassa virus and Machupo virus, are the etiological agents of lethal hemorrhagic fevers. The absence of a currently licensed vaccine and the highly pathogenic nature of these viruses both make the necessity of developing viable vaccines and therapeutics all the more urgent. Arenaviruses have a single glycoprotein on the surface of virions, the glycoprotein complex (GPC), and this protein can be used as a target for vaccine development. Here, we describe immunization strategies to generate monoclonal antibodies (MAbs) that cross-react between the glycoprotein complexes of both Old World and New World arenaviruses. Several monoclonal antibodies isolated from immunized mice were highly cross-reactive, binding a range of Old World arenavirus glycoproteins, including that of Lassa virus. One such monoclonal antibody, KL-AV-2A1, bound to GPCs of both New World and Old World viruses, including Lassa and Machupo viruses. These cross-reactive antibodies bound to epitopes present on the glycoprotein 2 subunit of the glycoprotein complex, which is relatively conserved among arenaviruses. Monoclonal antibodies binding to these epitopes, however, did not inhibit viral entry as they failed to neutralize a replication-competent vesicular stomatitis virus pseudotyped with the Lassa virus glycoprotein complex in vitro In addition, no protection from virus challenge was observed in in vivo mouse models. Even so, these monoclonal antibodies might still prove to be useful in the development of clinical and diagnostic assays.IMPORTANCE Several viruses in the Arenaviridae family infect humans and cause severe hemorrhagic fevers which lead to high case fatality rates. Due to their pathogenicity and geographic tropisms, these viruses remain very understudied. As a result, an effective vaccine or therapy is urgently needed. Here, we describe efforts to produce cross-reactive monoclonal antibodies that bind to both New and Old World arenaviruses. All of our MAbs seem to be nonneutralizing and nonprotective and target subunit 2 of the glycoprotein. Due to the lack of reagents such as recombinant glycoproteins and antibodies for rapid detection assays, our MAbs could be beneficial as analytic and diagnostic tools.

Tick-Borne Encephalitis Virus Vaccine-Induced Human Antibodies Mediate Negligible Enhancement of Zika Virus Infection InVitro and in a Mouse Model.

Recent reports in the scientific literature have suggested that anti-dengue virus (DENV) and anti-West Nile virus (WNV) immunity exacerbates Zika virus (ZIKV) pathogenesis in vitro and in vivo in mouse models. Large populations of immune individuals exist for a related flavivirus (tick-borne encephalitis virus [TBEV]), due to large-scale vaccination campaigns and endemic circulation throughout most of northern Europe and the southern Russian Federation. As a result, the question of whether anti-TBEV immunity can affect Zika virus pathogenesis is a pertinent one. For this study, we obtained 50 serum samples from individuals vaccinated with the TBEV vaccine FSME-IMMUN (Central European/Neudörfl strain) and evaluated their enhancement capacity in vitro using K562 human myeloid cells expressing CD32 and in vivo using a mouse model of ZIKV pathogenesis. Among the 50 TBEV vaccinee samples evaluated, 29 had detectable reactivity against ZIKV envelope (E) protein by enzyme-linked immunosorbent assay (ELISA), and 36 showed enhancement of ZIKV infection in vitro. A pool of the most highly reacting and enhanced samples resulted in no significant change in the morbidity/mortality of ZIKV disease in immunocompromised Stat2-/- mice. Our results suggest that humoral immunity against TBEV is unlikely to enhance Zika virus pathogenesis in humans. No clinical reports indicating that TBEV vaccinees experiencing enhanced ZIKV disease have been published so far, and though the epidemiological data are sparse, our findings suggest that there is little reason for concern. This study also displays a clear relationship between the phylogenetic distance between two flaviviruses and their capacity for pathogenic enhancement. IMPORTANCE The relationship between serial infections of two different serotypes of dengue virus and more severe disease courses is well-documented in the literature, driven by so-called antibody-dependent enhancement (ADE). Recently, studies have shown the possibility of ADE in cells exposed to anti-DENV human plasma and then infected with ZIKV and also in mouse models of ZIKV pathogenesis after passive transfer of anti-DENV human plasma. In this study, we evaluated the extent to which this phenomenon occurs using sera from individuals immunized against tick-borne encephalitis virus (TBEV). This is highly relevant, since large proportions of the European population are vaccinated against TBEV or otherwise seropositive.

Novel Cross-Reactive Monoclonal Antibodies against Ebolavirus Glycoproteins Show Protection in a Murine Challenge Model.

Out of an estimated 31,100 cases since their discovery in 1976, ebolaviruses have caused approximately 13,000 deaths. The vast majority (∼11,000) of these occurred during the 2013-2016 West African epidemic. Three out of five species in the genus are known to cause Ebola Virus Disease in humans. Several monoclonal antibodies against the ebolavirus glycoprotein are currently in development as therapeutics. However, there is still a paucity of monoclonal antibodies that can cross-react between the glycoproteins of different ebolavirus species, and the mechanism of these monoclonal antibody therapeutics is still not understood in detail. Here, we generated a panel of eight murine monoclonal antibodies (MAbs) utilizing a prime-boost vaccination regimen with a Zaire ebolavirus glycoprotein expression plasmid followed by infection with a vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein. We tested the binding breadth of the resulting monoclonal antibodies using a set of recombinant surface glycoproteins from Reston, Taï Forest, Bundibugyo, Zaire, Sudan, and Marburg viruses and found two antibodies that showed pan-ebolavirus binding. An in vivo Stat2-/- mouse model was utilized to test the ability of these MAbs to protect from infection with a vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein. Several of our antibodies, including the broadly binding ones, protected mice from mortality despite lacking neutralization capability in vitro, suggesting their protection may be mediated by Fc-FcR interactions. Indeed, three antibodies displayed cellular phagocytosis and/or antibody-dependent cell-mediated cytotoxicity in vitro Our antibodies, specifically the two identified cross-reactive monoclonal antibodies (KL-2E5 and KL-2H7), might add to the understanding of anti-ebolavirus humoral immunity.IMPORTANCE This study describes the generation of a panel of novel anti-ebolavirus glycoprotein monoclonal antibodies, including two antibodies with broad cross-reactivity to all known ebolavirus species. The antibodies were raised using a heterologous DNA-viral vector prime-boost regimen, resulting in a high proportion of cross-reactive antibodies (25%). Similar vaccination regimens have been used successfully to induce broad protection against influenza viruses in humans, and our limited data indicate that this might be a useful strategy for filovirus vaccines as well. Several of our antibodies showed protective efficacy when tested in a novel murine challenge model and may be developed into future therapeutics.

Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity.

Zika virus (ZIKV) is spreading rapidly into regions around the world where other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), are endemic. Antibody-dependent enhancement has been implicated in more severe forms of flavivirus disease, but whether this also applies to ZIKV infection is unclear. Using convalescent plasma from DENV- and WNV-infected individuals, we found substantial enhancement of ZIKV infection in vitro that was mediated through immunoglobulin G engagement of Fcγ receptors. Administration of DENV- or WNV-convalescent plasma into ZIKV-susceptible mice resulted in increased morbidity-including fever, viremia, and viral loads in spinal cord and testes-and increased mortality. Antibody-dependent enhancement may explain the severe disease manifestations associated with recent ZIKV outbreaks and highlights the need to exert great caution when designing flavivirus vaccines.

Cross-Reactive and Cross-Neutralizing Activity of Human Mumps Antibodies Against a Novel Mumps Virus From Bats.

To evaluate the antigenic relationship between bat mumps virus (BMV) and the JL5 vaccine strain of mumps virus (MuVJL5), we rescued a chimeric virus bearing the F and HN glycoproteins of BMV in the background of a recombinant JL5 genome (rMuVJL5). Cross-reactivity and cross-neutralization between this chimeric recombinant MuV bearing the F and HN glycoproteins of BMV (rMuVJL5-F/HNBMV) virus and rMuVJL5 were demonstrated using hyperimmune mouse serum samples and a curated panel of human serum. All mouse and human serum samples that were able to neutralize rMuVJL5 infection had cross-neutralizing activity against rMuVJL5-F/HNBMV. Our data suggest that persons who have neutralizing antibodies against MuV might be protected from infection by BMV.

ISG15 deficiency and increased viral resistance in humans but not mice.

ISG15 is an interferon (IFN)-α/ß-induced ubiquitin-like protein. It exists as a free molecule, intracellularly and extracellularly, and conjugated to target proteins. Studies in mice have demonstrated a role for Isg15 in antiviral immunity. By contrast, human ISG15 was shown to have critical immune functions, but not in antiviral immunity. Namely, free extracellular ISG15 is crucial in IFN-γ-dependent antimycobacterial immunity, while free intracellular ISG15 is crucial for USP18-mediated downregulation of IFN-α/ß signalling. Here we describe ISG15-deficient patients who display no enhanced susceptibility to viruses in vivo, in stark contrast to Isg15-deficient mice. Furthermore, fibroblasts derived from ISG15-deficient patients display enhanced antiviral protection, and expression of ISG15 attenuates viral resistance to WT control levels. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans, a mechanism not operating in mice.