Faculty Bibliography

The human immune response to eastern equine encephalitis virus (EEEV) infection is poorly characterized due to the rarity of infection. We examined the humoral and cellular immune response to EEEV acquired from an infected donor via liver transplantation. Both binding and highly neutralizing antibodies to EEEV as well as a robust EEEV-specific IgG memory B cell response were generated. Despite triple-drug immunosuppressive therapy, a virus-specific CD4+ T cell response, predominated by interferon-γ production, was generated. T cell epitopes on the E2 envelope protein were identified by interferon-γ ELISpot. Although these results are from a single person who acquired EEEV by a non-traditional mechanism, to our knowledge this work represents the first analysis of the human cellular immune response to EEEV.

During the 2014-2016 Ebola virus disease (EVD) outbreak, clinicians lacked a readily available resource cataloguing available medical countermeasures (MCMs) to treat EVD patients in West Africa and other regions. Some patients received investigational interventions under uncontrolled compassionate use protocols. Therefore, the Special Pathogens Research Network (SPRN) of the National Ebola Training and Education Center (NETEC) formed the MCMs Working Group (WG) with members from 10 Regional Ebola and other Special Pathogen Treatment Centers (RESPTC) and NETEC partners. The goal of the MCMs WG is to develop an evidence-informed, easily accessible, practical assessment of potential countermeasures for clinicians managing patients with selected highly hazardous communicable diseases. Pathogens were selected based on 1) ability to cause severe disease; 2) potential to cause large outbreaks; 3) paucity of currently available cleared MCMs; 4) occurrence of nosocomial spread to health care providers; and 5) transmissibility requiring specialized care in a biocontainment unit. After a standardized literature review is conducted, an assessment of potentially available countermeasures is performed by 2-4 subject matter experts, followed by peer review. Pathogens selected to date incluDe Marburg, Lassa, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Crimean Congo Hemorrhagic Fever (CCHF), Nipah, Variola (and Monkeypox) and South American Hemorrhagic Fever (Junin, Machupo, etc.) viruses. The list overlaps with the World Health Organization's list of ?Blueprint? priority diseases. Reviews on seven pathogens are in progress. In conclusion, the NETEC SPRN MCM WG was created to proviDe a preemptive compendium of systematic and clinically relevant summaries of available MCMs for selected pathogens based on pre-specified criteria. Challenges will incluDe updating current documents as new scientific evidence becomes available. Plans are in place for regular review and updates, with the most up-todate materials available on the NETEC website for open-source access

Invasive disease due to group B Streptococcus infection (Streptococcus agalactiae) results in a wide spectrum of clinical disease. In North America, serotypes Ia, Ib, II, III, and V are most frequently associated with invasive disease. Group B Streptococcus remains a continuing source of morbidity and mortality in high-risk populations, including pregnant women, neonates, and the elderly; an increasing incidence of invasive disease has been observed in nonpregnant adults. Group B Streptococcus remains the most common culture-confirmed neonatal bacterial infection in the United States and is a significant source of neonatal morbidity globally. Intrapartum antibiotic prophylaxis has reduced the incidence of early-onset neonatal disease without a notable impact on the incidence of late-onset neonatal disease. Penicillin G remains the mainstay of therapy, although reduced penicillin susceptibility has been observed in select isolates. Increased frequency of resistance to non-beta-lactam antibiotics, including clindamycin, erythromycin, and fluoroquinolones, has been observed, with some isolates demonstrating resistance to vancomycin. The development and implementation of strategies to identify hosts, treat judiciously with antimicrobials with the narrowest spectra, and prevent invasive disease, with vaccines, are essential to reduce the burden of group B Streptococcus disease.

Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be useful in infectious disease settings, including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical models, Mtb-infected PD-1^-/- mice mount exaggerated T_H1 responses that drive lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have been observed in patients with cancer, but in humans little is understood about Mtb-specific immune responses during checkpoint blockade-associated tuberculosis. Here, we report two more cases. We describe a patient who succumbed to disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel cell carcinoma who developed checkpoint blockade-associated tuberculosis and was successfully treated for the infection. After anti-PD-1 administration, interferon-γ-producing Mtb-specific CD4 T cells became more prevalent in the blood, and a tuberculoma developed a few months thereafter. Mtb-specific T_H17 cells, CD8 T cells, regulatory T cells, and antibody abundance did not change before the appearance of the granuloma. These results are consistent with the murine model data and suggest that boosting T_H1 function with PD-1 blockade may increase the risk or severity of tuberculosis in humans.

Background/UNASSIGNED:Clinical, virologic, and immunologic characteristics of Zika virus (ZIKV) infections in US patients are poorly defined. Methods/UNASSIGNED:US subjects with suspected ZIKV infection were enrolled. Clinical data and specimens were prospectively collected for ZIKV RNA detection and serologic and cellular assays. Confirmed ZIKV infection (cases) and ZIKV-negative (controls) subjects were compared. Dengue-experienced and dengue-naïve cases were also compared. Results/UNASSIGNED:= .046). In intracellular cytokine staining assays, the ZIKV proteins targeted most often by peripheral blood mononuclear cells from cases were structural proteins C and E for CD4+ T cells and nonstructural proteins NS3, NS5, and NS4B for CD8+ T cells. Conclusions/UNASSIGNED:ZIKV RNA detection was more frequent and prolonged in whole-blood specimens. Immunoglobulin G (IgG) and neutralizing antibodies, but not IgM, were influenced by prior dengue infection. Robust cellular responses to E and nonstructural proteins have potential vaccine development implications.

Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered.