The immunology of human babesiosis is poorly investigated. We present a comprehensive investigation of a 75-year-old man with B-cell deficiency who experienced 3 episodes of babesiosis over a 6-year period. Slowly evolving clinical immunity was observed, as evidenced by milder clinical symptoms and lower peak parasite burden after each subsequent babesiosis episode. The patient exhibited several striking immunologic findings. First, the patient had exceptionally high Babesia microti-specific antibodies despite very few circulating B cells, which predominantly coexpressed CD27 (memory marker) and CD95 (death receptor). Second, we demonstrated the presence of long-lasting NK cells and expansion of T memory stem cells. Third, levels of the IP-10 cytokine directly correlated with parasite burden. These results raise fundamental questions on the priming, maintenance, and location of a B-cell population that produces high antibody levels in the face of severe B-cell deficiency. Our results should invoke interest among researchers to study the immunology and pathogenesis of human babesiosis.

In April 2014, a kidney transplant recipient in the United States experienced headache, diplopia, and confusion, followed by neurologic decline and death. An investigation to evaluate the possibility of donor-derived infection determined that 3 patients had received 4 organs (kidney, liver, heart/kidney) from the same donor. The liver recipient experienced tremor and gait instability; the heart/kidney and contralateral kidney recipients were hospitalized with encephalitis. None experienced gastrointestinal symptoms. Encephalitozoon cuniculi was detected by tissue PCR in the central nervous system of the deceased kidney recipient and in renal allograft tissue from both kidney recipients. Urine PCR was positive for E. cuniculi in the 2 surviving recipients. Donor serum was positive for E. cuniculi antibodies. E. cuniculi was transmitted to 3 recipients from 1 donor. This rare presentation of disseminated disease resulted in diagnostic delays. Clinicians should 'consider donor-derived microsporidial infection in organ recipients with unexplained encephalitis, even when gastrointestinal manifestations are absent.

Background. UpToDate is an online clinical decision support resource that is used extensively by clinicians around the world. Digital surveillance techniques have shown promise to aid with the detection and monitoring of infectious disease outbreaks. We sought to determine whether UpToDate searches for Middle East respiratory syndrome (MERS) could be used to detect and monitor MERS outbreaks in Saudi Arabia.Methods. We analyzed daily searches related to MERS in Jeddah and Riyadh, Saudi Arabia during 3 outbreaks in these cities in 2014 and 2015 and compared them with reported cases during the same periods. We also compared UpToDate MERS searches in the affected cities to those in a composite of 4 negative control cities for the 2 outbreaks in 2014.Results. UpToDate MERS searches during all 3 MERS outbreaks in Saudi Arabia showed a correlation to reported cases. In addition, UpToDate MERS search volume in Jeddah and Riyadh during the outbreak periods in 2014 was significantly higher than the concurrent search volume in the 4 negative control cities. In contrast, during the baseline periods, there was no difference between UpToDate searches for MERS in the affected cities compared with the negative control cities.Conclusions. UpToDate search activity seems to be useful for detecting and monitoring outbreaks of MERS in Saudi Arabia.

Community-acquired pneumonia is a commonly diagnosed illness in which no causative organism is identified in half the cases. Application of molecular diagnostic techniques has the potential to lead to more targeted therapy in the face of increasing antibiotic resistance.

The development and implementation of highly active antiretroviral therapy (HAART) for the treatment of the human immunodeficiency virus has revolutionised the care of patients with this disease. Despite the positive impact that antiretroviral therapy has had on the lives of individuals with HIV infection, the adverse effects, potential long-term toxicities, complexity of regimens, development of drug resistance and cost have made decisions about when to initiate HAART difficult. The benefits and risks of antiretroviral therapy vary considerably among patients at different stages of disease, mainly as a result of the irreversible destruction of the immune system that occurs as HIV infection progresses.In acute HIV infection, the primary aim of treatment is preservation and reconstitution of HIV-specific immune function. In symptomatic or late-stage disease, the goal is control of viral replication with resulting improvement in non-HIV-specific immunity, which leads to decreased morbidity and increased survival. The most controversial decision involves when to start therapy in persons with asymptomatic chronic HIV, where the benefits are less well established and may be outweighed by the drawbacks, depending on the individual patient.In all patients, the advantages and disadvantages must be considered carefully, and the readiness and ability of the individual to adhere to a complex multidrug regimen needs to be assessed before the initiation of therapy.

Infections with rare pathogens are being recognized with increasing frequency in severely immunocompromised patients. As a result of these patients' underlying compromised defenses and susceptibility to atypical organisms, tissue biopsies from patients within this population may demonstrate nonclassical histopathological findings. Here, we describe an unusual granulomatous reaction to gram-positive cocci in the skin of a 52-year-old man undergoing salvage chemotherapy for acute myeloid leukemia. The patient presented with a papular eruption on the arms, trunk, and face and fever; concomitant blood cultures were positive for Rothia mucilaginosa and Streptococcus salivarius. Histologic evaluation revealed a granulomatous dermatitis associated with numerous small, round, predominantly intracellular bacteria. Classically, cutaneous infiltrates associated with coccoid bacterial infections are suppurative and not granulomatous. The intracellular organisms stained positive for Gram, periodic acid-Schiff, and Grocott methenamine silver stains, suggestive of R. mucilaginosa. Rothia mucilaginosa, a component of the oral flora, was first reported as a human pathogen in 1978. Although the majority of cases in the literature have described R. mucilaginosa bacteremia, other reported manifestations include meningitis, endocarditis, pneumonia, osteomyelitis, and peritonitis. To our knowledge, however, only 1 prior report has described a cutaneous manifestation of R. mucilaginosa septicemia, which occurred in a patient with neutropenia. This is the second reported case of an infectious granulomatous dermatitis associated with R. mucilaginosa bacteremia and raises awareness of this unusual histopathological presentation in the setting of a bacterial infection affecting the skin.

The development of a prophylactic HIV-1 vaccine is a global health priority. It has proven extraordinarily challenging, however, to develop immunogens that elicit broadly reactive HIV-1-specific neutralizing antibodies. As a result, most HIV-1 vaccine candidates in development focus on generating virus-specific cellular immune responses. Both plasmid DNA vaccines and recombinant live vectors have been shown to elicit cellular immune responses, and vaccine candidates based on these technologies are now being evaluated for safety, immunogenicity, and efficacy in advanced phase clinical trials. This review examines the progress and prospects of these vaccine strategies.

ABSTRACT Recombinant adenovirus serotype 5 (rAd5) vector-based vaccines are currently being developed for both human immunodeficiency virus type 1 and other pathogens. The potential limitations associated with rAd5 vectors, however, have led to the construction of novel rAd vectors derived from rare Ad serotypes. Several rare serotype rAd vectors have already been described, but a detailed comparison of multiple rAd vectors from subgroups B and D has not previously been reported. Such a comparison is critical for selecting optimal rAd vectors for advancement into clinical trials. Here we describe the construction of three novel rAd vector systems from Ad26, Ad48, and Ad50. We report comparative seroprevalence and immunogenicity studies involving rAd11, rAd35, and rAd50 vectors from subgroup B; rAd26, rAd48, and rAd49 vectors from subgroup D; and rAd5 vectors from subgroup C. All six rAd vectors from subgroups B and D exhibited low seroprevalence in a cohort of 200 individuals from sub-Saharan Africa, and they elicited Gag-specific cellular immune responses in mice both with and without preexisting anti-Ad5 immunity. The rAd vectors from subgroup D were also evaluated using rhesus monkeys and were shown to be immunogenic after a single injection. The rAd26 vectors proved the most immunogenic among the rare serotype rAd vectors studied, although all rare serotype rAd vectors were still less potent than rAd5 vectors in the absence of anti-Ad5 immunity. These studies substantially expand the portfolio of rare serotype rAd vectors that may prove useful as vaccine vectors for the developing world.

ABSTRACT The high prevalence of preexisting immunity to adenovirus serotype 5 (Ad5) in human populations has led to the development of recombinant adenovirus (rAd) vectors derived from rare Ad serotypes as vaccine candidates for human immunodeficiency virus type 1 and other pathogens. Vaccine vectors have been constructed from Ad subgroup B, including rAd11 and rAd35, as well as from Ad subgroup D, including rAd49. However, the optimal combination of vectors for heterologous rAd prime-boost vaccine regimens and the extent of cross-reactive vector-specific neutralizing antibodies (NAbs) remain poorly defined. We have shown previously that the closely related vectors rAd11 and rAd35 elicited low levels of cross-reactive NAbs. Here we show that these cross-reactive NAbs correlated with substantial sequence homology in the hexon hypervariable regions (HVRs) and suppressed the immunogenicity of heterologous rAd prime-boost regimens. In contrast, vectors with lower hexon HVR homology, such as rAd35 and rAd49, did not elicit detectable cross-reactive vector-specific NAbs. Consistent with these findings, rAd35-rAd49 vaccine regimens proved more immunogenic than both rAd35-rAd5 and rAd35-rAd11 regimens in mice with anti-Ad5 immunity. These data suggest that optimal heterologous rAd prime-boost regimens should include two vectors that are both rare in human populations to circumvent preexisting antivector immunity as well as sufficiently immunologically distinct to avoid cross-reactive antivector immunity.

ABSTRACT We assessed neutralizing antibody titers to adenovirus serotype 5 (Ad5) and six rare adenovirus serotypes, serotypes 11, 35, 50, 26, 48, and 49, in pediatric populations in sub-Saharan Africa. We observed a clear age dependence of Ad5-specific neutralizing antibody titers. These data will help to guide the development of Ad vector-based vaccines for human immunodeficiency virus type 1 and other pathogens.

Adenoviral Recombinant vectors based on type 5 (rAd5) show great promise as vaccine carrier. However, neutralizing activity against Ad5 is prevalent and high titered among human populations and significantly dampens Ad5-based vaccine modalities. The generation of alternative adenoviral vectors with low sero-prevalence thus receives much research interest. We have previously published that several members of human subgroup D adenoviruses display low sero-prevalence in Europe and here we demonstrate that one such member, i.e. Ad49, is immunologically distinct from Ad5. We next set out to construct a plasmid system that allows formation of replication incompetent adenovirus serotype 49 vaccine vectors (rAd49) and demonstrate that rAd49 can be successfully propagated to high titers on existing E1-complementing cell lines such as PER.C6®. Using a rAd49 vector carrying the luciferase marker gene sero-prevalence studies were performed demonstrating that rAd49 has low sero-prevalence and neutralizing antibody titers worldwide. Also, we have initiated rAd49 vector receptor usage suggesting that rAd49 utilizes hCD46 as a cellular receptor. Next, we assessed the immunogenicity of the rAd49 vector and show that a rAd49.SIVGag vaccine induces strong anti-SIVGag CD8+T-lymphocytes in naive mice albeit approximately 1.5-fold less compared to a rAd5.SIVGag vaccine. However, in mice with high anti-Ad5 immunity the anti- SIVGag response was not statistically significant suppressed using the rAd49.SIVGag vaccine whereas the rAd5.SIVGag vaccine was severely blunted. Finally, rAd35.SIVGag prime-rAd49.SIVGag boost experiments in mice carrying high-level anti-Ad5 neutralizing activity demonstrated that the rAd49 based vaccine is not hampered by neither rAd5 nor rAd35 neutralizing activity. These data demonstrate the potential of a replication deficient human D-group adenoviral vector as stand-alone vaccine carrier or in prime-boost settings with other rare human adenoviral vectors.

tailor-made viral vector Adenovirus 5 (Ad5) causes mild respiratory tract infections in humans but its main claim to fame is as a potential vaccine vector for key diseases such as HIV/AIDS and malaria. Its potential clinical utility is, however, hampered by the fact that about half of the population in developed countries and 90% in Africa have been exposed to Ad5 before and have built up immunity. A team based at Harvard Medical School and the Dutch biotechnology company Crucell has devised a way of circumventing this problem by replacing parts of an Ad5 viral capsid protein with those from a related virus, the much rarer Ad48 adenovirus. The strategy was effective in tests in mice and monkeys; if the work can be repeated in humans then modified Ad5 will be a strong candidate as a vector for vaccines and also for delivering gene therapy.

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease that occurs in patients with defects in cell-mediated immunity, including those with AIDS and lymphoproliferative disorders. It is caused by reactivation of JC virus (JCV), which infects 70% to 90% of the population by adulthood, but remains latent in normal hosts. Once reactivated, JCV infects oligodendrocytes and astrocytes, with resultant cell lysis, leading to focal areas of demyelination and necrosis in cerebral white matter causing focal neurologic deficits and characteristic findings on MRI. Polymerase chain reaction for the detection of JCV is a sensitive and specific test, replacing brain biopsy as the initial diagnostic test in the appropriate clinical setting. Historically, the prognosis of progressive multifocal leukoencephalopathy is poor, with most patients dying within 6 months of diagnosis. Antiviral medications targeted against JCV have shown little success. However, with the use of highly active antiretroviral therapy, survival of AIDS patients with progressive multifocal leukoencephalopathy has improved.