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In this report, Ebola virus was cultured from aqueous humor 14 weeks after disease onset and 9 weeks after resolution of viremia, a finding that indicates the potential for delayed clearance of the virus from immune-privileged sites. The current outbreak of EVD is believed to have begun in December 2013. 1 As of April 26, 2015, a total of 26,312 cases of EVD (including 10,899 deaths) had been reported in six countries in West Africa (i.e., Sierra Leone, Liberia, Guinea, Mali, Nigeria, and Senegal), the United States, the United Kingdom, and Spain. 2 The outbreak has also resulted in the largest number of EVD survivors in history. Among survivors of EVD, late complications that include ocular disease can develop during convalescence. 3 , 4 However, few systematic studies have been conducted on post-EVD sequelae, so the incidence and clinical manifestations of . . .

Immunologic memory promotes faster and more-efficient responses after re-exposure to pathogens. Ahmed and colleagues characterize a subset of human B cells that arise after vaccination against or exposure to influenza or Ebola virus and contribute to the memory cell pool. Antigen-specific B cells bifurcate into antibody-secreting cells (ASCs) and memory B cells (MBCs) after infection or vaccination. ASCs (plasmablasts) have been extensively studied in humans, but less is known about B cells that become activated but do not differentiate into plasmablasts. Here we have defined the phenotype and transcriptional program of a subset of antigen-specific B cells, which we have called 'activated B cells' (ABCs), that were distinct from ASCs and were committed to the MBC lineage. We detected ABCs in humans after infection with Ebola virus or influenza virus and also after vaccination. By simultaneously analyzing antigen-specific ASCs and ABCs in human blood after vaccination against influenza virus, we investigated the clonal overlap and extent of somatic hypermutation (SHM) in the ASC (effector) and ABC (memory) lineages. Longitudinal tracking of vaccination-induced hemagglutinin (HA)-specific clones revealed no overall increase in SHM over time, which suggested that repeated annual immunization might have limitations in enhancing the quality of influenza-virus-specific antibody.

Since the beginning of the current Ebola epidemic, several patients with Ebola virus disease have been cared for in the United States and Europe. In this report, the clinical course and care of these 27 patients are described. The Ebola virus disease (EVD) epidemic in West Africa had resulted in more than 28,600 reported cases and more than 11,300 deaths through December 2015; mortality reported for patients with EVD cared for in Ebola treatment units in West Africa has ranged from 37 to 74%. 1 – 5 The provision of clinical care to patients with EVD in Ebola treatment units in West Africa has involved the need to balance many challenges, such as overwhelming numbers of severely ill patients, limited medical and nonmedical supplies, insufficient numbers of caregivers and resources, and hot and humid working conditions that limit the time . . .

Significance In 2014, Ebola virus became a household term. The ongoing outbreak in West Africa is the largest Ebola virus outbreak ever recorded, with over 20,000 cases and over 8,000 deaths to date. Very little is known about the human cellular immune response to Ebola virus infection, and this lack of knowledge has hindered development of effective therapies and vaccines. In this study, we characterize the human immune response to Ebola virus infection in four patients. We define the kinetics of T- and B-cell activation, and determine which viral proteins are targets of the Ebola virus-specific T-cell response in humans. Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10–50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1–2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients’ discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus.

We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.

Significance Vaccination is the most effective means of attaining protection against influenza viruses. However, the constantly evolving nature of influenza viruses enables them to escape preexisting immune surveillance, and thus thwarts public health efforts to control influenza annual epidemics and occasional pandemics. One solution is to elicit antibodies directed against highly conserved epitopes, such as those within the stem region of influenza HA, the principal target of virus-neutralizing antibody responses. This study shows that annual influenza vaccines induce antibody responses that are largely directed against the highly variable HA head region. In contrast, heterologous immunization with HA derived from influenza strains that are currently not circulating in humans (e.g. H5N1) can substantially increase HA stem-specific responses.

Treatment of Ebola virus disease is a tremendous challenge for both the patient and the care team. In this report, two patients with EVD were evacuated from Liberia and successfully treated with fluid and electrolyte support and other therapies at Emory University Hospital. The largest outbreak of EVD in history began in December 2013 in Guinea, a country in West Africa. 1 By late March, Liberia had reported seven cases. By the end of May, the epidemic had spread to Sierra Leone. As of November 5, 2014, a total of 13,042 cases of EVD (including 4818 deaths) had been reported in six countries in West Africa (Guinea, Sierra Leone, Liberia, Mali, Nigeria, and Senegal), the United States, and Spain. 2 EVD causes a nonspecific febrile illness associated with myalgia, with progression to gastrointestinal symptoms (abdominal pain, nausea, vomiting, and diarrhea). In the second week of . . .

High-consequence infectious diseases (HCIDs) are acute human infectious diseases with high illness and case-fatality rates, few or no available effective treatment or prevention options, and the ability to spread in the community and within healthcare settings. Those characteristics lead to significant risks to patients and their close contacts, healthcare workers, laboratory personnel, and communities exposed to an outbreak. We describe aspects of healthcare system preparedness for and response to HCIDs, including the role of high-level isolation units, ensuring safe clinical laboratory capabilities and waste management, increasing availability of medical countermeasures, coordinating with stakeholders and systems of care, and communicating with the public. Finally, we discuss priority areas for further investment in HCID preparedness, care, and research. Effective and equitably disseminated medical countermeasures for HCIDs are urgently needed.

Identifying molecular predictors of effective vaccination is an important clinical and technical goal. Pulendran and colleagues use a systems biology approach to study human responses to vaccination against influenza and determine the correlates of immunogenicity. Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.