Potent neutralization of Rift Valley fever virus by human monoclonal antibodies through fusion inhibition.

Rift Valley fever virus (RVFV), an emerging arboviral and zoonotic bunyavirus, causes severe disease in livestock and humans. Here, we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of immune individuals following natural infection in Kenya or immunization with MP-12 vaccine. The B cell responses of individuals who were vaccinated or naturally infected recognized similar epitopes on both Gc and Gn proteins. The Gn-specific mAbs and two mAbs that do not recognize either monomeric Gc or Gn alone but recognized the hetero-oligomer glycoprotein complex (Gc+Gn) when Gc and Gn were coexpressed exhibited potent neutralizing activities in vitro, while Gc-specific mAbs exhibited relatively lower neutralizing capacity. The two Gc+Gn-specific mAbs and the Gn domain A-specific mAbs inhibited RVFV fusion to cells, suggesting that mAbs can inhibit the exposure of the fusion loop in Gc, a class II fusion protein, and thus prevent fusion by an indirect mechanism without direct fusion loop contact. Competition-binding analysis with coexpressed Gc/Gn and mutagenesis library screening indicated that these mAbs recognize four major antigenic sites, with two sites of vulnerability for neutralization on Gn. In experimental models of infection in mice, representative mAbs recognizing three of the antigenic sites reduced morbidity and mortality when used at a low dose in both prophylactic and therapeutic settings. This study identifies multiple candidate mAbs that may be suitable for use in humans against RVFV infection and highlights fusion inhibition against bunyaviruses as a potential contributor to potent antibody-mediated neutralization.

Traumatic Rupture of Cystic Left Retroperitoneal Mass: An Atypical Presentation of Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Though the presentation is diverse, patients typically have a history of "B" symptoms and lymphadenopathy in areas such as the neck, mediastinum, or abdomen. However, a growing body of evidence suggests DLBCL can present as a cystic mass in diverse tissues. We present the case of a large cystic left retroperitoneal mass of unknown origin in a patient subsequently diagnosed with DLBCL. The diagnosis was obtained via percutaneous biopsy of the cystic mass in preparation for surgical excision. Upon diagnosis, surgical intervention was aborted, and the patient was started on chemotherapy treatment. However, four weeks into her treatment, she slipped and fell while in the bathroom and presented to the emergency department in shock with a computed tomography (CT) scan suggestive of splenic rupture. She underwent emergent splenectomy and resection of the cystic mass. She was discharged on postoperative day 7 and is currently continuing with outpatient chemotherapy. The presentation of DLBCL is notoriously diverse, however, this patient represents a unique presentation that adds to a growing body of literature suggesting DLBCL can present as a cystic mass. Pathological diagnosis should be obtained in all patients with cystic lesions of unknown origin before any surgical intervention to avoid unnecessary surgery and provide an optimal management plan.

Incidental Discovery of Nonrotation in a Patient With Nonspecific Abdominal Pain: A Surgical Diagnostic Dilemma.

Intestinal nonrotation is a subtype of malrotation occurring when the midgut fails to rotate before returning to the peritoneal cavity between weeks 8-10 of development. Though sometimes presenting as volvulus during the neonatal period, a subset of patients remains asymptomatic and are identified incidentally as adults. When patients with intestinal nonrotation present with abdominal symptoms, there exists a diagnostic dilemma for the treating surgeon. We present the case of a patient who presented with acute abdominal pain and vomiting, with radiographic findings of intestinal nonrotation and no other acute pathology. Symptoms spontaneously resolved with conservative management for likely etiology of viral gastroenteritis. At the one-month follow-up, the patient had no residual or recurrent symptoms, with no further interventions planned.

Isolation of a Potently Neutralizing and Protective Human Monoclonal Antibody Targeting Yellow Fever Virus.

Yellow fever virus (YFV) causes sporadic outbreaks of infection in South America and sub-Saharan Africa. While live-attenuated yellow fever virus vaccines based on three substrains of 17D are considered some of the most effective vaccines in use, problems with production and distribution have created large populations of unvaccinated, vulnerable individuals in areas of endemicity. To date, specific antiviral therapeutics have not been licensed for human use against YFV or any other related flavivirus. Recent advances in monoclonal antibody (mAb) technology have allowed the identification of numerous candidate therapeutics targeting highly pathogenic viruses, including many flaviviruses. Here, we sought to identify a highly neutralizing antibody targeting the YFV envelope (E) protein as a therapeutic candidate. We used human B cell hybridoma technology to isolate mAbs from circulating memory B cells from human YFV vaccine recipients. These antibodies bound to recombinant YFV E protein and recognized at least five major antigenic sites on E. Two mAbs (designated YFV-136 and YFV-121) recognized a shared antigenic site and neutralized the YFV-17D vaccine strain in vitro. YFV-136 also potently inhibited infection by multiple wild-type YFV strains, in part, at a postattachment step in the virus replication cycle. YFV-136 showed therapeutic protection in two animal models of YFV challenge, including hamsters and immunocompromised mice engrafted with human hepatocytes. These studies define features of the antigenic landscape of the YFV E protein recognized by the human B cell response and identify a therapeutic antibody candidate that inhibits infection and disease caused by highly virulent strains of YFV. IMPORTANCE Yellow fever virus (YFV) is a mosquito-borne virus that occasionally causes outbreaks of severe infection and disease in South America and sub-Saharan Africa. There are very effective live-attenuated (weakened) yellow fever virus vaccines, but recent problems with their production and distribution have left many people in affected areas vulnerable. Here, we sought to isolate an antibody targeting the surface of the virus for possible use in the future as a biologic drug to prevent or treat YFV infection. We isolated naturally occurring antibodies from individuals who had received a YFV vaccine. We created antibodies and tested them. We found that the antibody with the most powerful antiviral activity was a beneficial treatment in two different small-animal models of human infection. These studies identified features of the virus that are recognized by the human immune system and generated a therapeutic antibody candidate that inhibits infection caused by highly virulent strains of YFV.