OX40 ligand fusion protein delivered simultaneously with the BCG vaccine provides superior protection against murine Mycobacterium tuberculosis infection

Mycobacterium tuberculosis infection claims approximately 2 million lives per year, and improved efficacy of the BCG vaccine remains a World Health Organization priority. Successful vaccination against M. tuberculosis requires the induction and maintenance of T cells. Targeting molecules that promote T-cell survival may therefore provide an alternative strategy to classic adjuvants. We show that the interaction between T-cell-expressed OX40 and OX40L on antigen-presenting cells is critical for effective immunity to BCG. However, because OX40L is lost rapidly from antigen-presenting cells following BCG vaccination, maintenance of OX40-expressing vaccine-activated T cells may not be optimal. Delivering an OX40L:Ig fusion protein simultaneously with BCG provided superior immunity to intravenous and aerosol M. tuberculosis challenge even 6 months after vaccination, an effect that depends on natural killer 1.1(+) cells. Attenuated vaccines may therefore lack sufficient innate stimulation to maintain vaccine-specific T cells, which can be replaced by reagents binding inducible T-cell costimulators.     

Heterosubtypic T‐cell responses against avian influenza H5 haemagglutinin are frequently detected in individuals vaccinated against or previously infected with human subtypes of influenza

Background Cellula r immune responses play a critical role in providing help for the production of neutralizing antibodies to influenza virus, as well as producing anti‐viral cytokines and killing infected cells in the lung. Heterosubtypic T‐cell responses between different subtypes of influenza have been shown to exist in humans and to provide protection against morbidity and mortality associated with H5N1 infection in animal challenge models. Therefore, existing T‐cell responses induced by natural infection or vaccination in humans may provide some degree of protection from infection with H5N1 strains, or may attenuate the severity of disease. Objectives To investigate heterosubtypic T‐cell responses to avian influenza in humans. Methods T‐cell responses to an overlapping set of H5 HA peptides and inactivated viruses (H1N1, H3N2 and H5N1) were assessed using IFN‐γ and IL‐2 enzyme‐linked immunospot (ELISpot) assays in a cohort of adults either vaccinated against seasonal influenza in the last 3 years (n = 20) or previously infected (n = 40). Results T‐cell responses to all three subtypes of virus were found in both infected and vaccinated individuals by IFN‐γ and IL‐2 ELISpot assays. Approximately half of the participants from each group had a positive T‐cell response to the H5 HA peptides in the IFN‐γ or IL‐2 ELISpot assay. Conclusions Heterosubtypic T‐cell responses to H5 HA occur quite frequently in vaccinated and infected individuals. Further investigation of these responses and what role they may play upon challenge or vaccination against H5N1 may assist in vaccine design for avian influenza.     

Immune mechanisms of vaccine induced protection against chronic hepatitis C virus infection in chimpanzees

Hepatitis C virus(HCV) infection is characterized by a high propensity for development of life-long viral persistence. An estimated 170 million people suffer from chronic hepatitis caused by HCV. Currently,there is no approved prophylactic HCV vaccine available.With the near disappearance of the most relevant animal model for HCV,the chimpanzee,we review the progression that has been made regarding prophylactic vaccine development against HCV. We describe the results of the individual vaccine evaluation experiments in chimpanzees,in relation to what has been observed in humans. The results of the different studies indicate that partial protection against infection can be achieved,but a clear correlate of protection has thus far not yet been defined.     

Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses

The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus.     

Studies of the 1996-1997 inactivated influenza vaccine among children attending day care: immunologic response, protection against infection, and clinical effectiveness

A randomized, blinded, pilot study of influenza vaccine administered to children attending day care centers was conducted during the 1996-1997 winter. Vaccine efficacy in preventing serologically proven influenza virus infection was 0.45 (95% confidence limit [CL]: -0.02, 0.69) for influenza B and 0.31 (95% CL: -0.95, 0.73) for influenza A(H3N2). For both influenza A(H3N2) and B, children without preexisting hemagglutination inhibition (HI) antibody to these antigens had lower antibody responses to vaccine, were less likely to develop a serological response, and were more likely to develop serological evidence of influenza infection. Although there were no reductions in respiratory or febrile respiratory illnesses among all vaccinated children, there was a trend for reductions in such illnesses among vaccinated children with preexisting HI antibodies to influenza A(H3N2) and B. Therefore, immunologic priming in young children may be important for vaccine response and for protection against infection. Larger studies are needed in other influenza seasons to assess vaccine efficacy and clinical effectiveness.     

Difference in the protection against infection with different challenge strains of Salmonella enteritidis by killed vaccine.

Differences in protection against the challenge of different strains of formalin-killed cells obtained from Salmonella enteritidis were investigated. When strains 2547, 116M, 116-54, SR-98G, and 3775 were used as the challenge strain, protective effects were apparent in groups of mice immunized with formalin-killed cells from S. enteritidis strains (protective strains). Conversely, no protective effects were observed with the challenge of strains 2822, 3975, and IID-604 (nonprotective strains). Electrophoretic banding patterns of lipopolysaccharides in SDS-PAGE were similar between the LPS obtained from the various strains used in this study. Additionally, no differences in sensitivity to macrophage intracellular killing were observed between the protective and nonprotective strains. Phagocytic experiments by macrophages in vitro indicated that immune serum used as the opsonin promotes phagocytosis of various strains by macrophages as compared to using normal serum as the opsonin, but the rate of phagocytosis enhanced by immune serum is higher in protective strains than nonprotective strains. In studies of passive transfer of immune serum, it was found that mice passively immunized with immune serum could only protect against infection by challenging with protective strains with the exception of strain SR-98G. These results suggest that the protective effect observed with the challenge of protective strains may be due to macrophage phagocytosis enhanced by opsonization with immune serum.     

Dominant-negative mutants as antiviral agents: simultaneous infection with the cold-adapted live-virus vaccine for influenza A protects ferrets from disease produced by wild-type influenza A

The attenuated cold-adapted strain of influenza A virus that is a candidate live-virus vaccine suppressed clinical disease in ferrets when given simultaneously with a virulent epidemic strain of influenza A virus. The cold-adapted virus effectively prevented disease, even when the epidemic strain was of a different subtype than the attenuated virus. In this case, ferrets given a mixed inoculum produced antibody to both subtypes in the absence of clinical disease, indicating that both viruses are replicating in the respiratory tract. These findings suggest the possibility of the development of a novel class of antivirals for influenza, namely a live virus that is a dominant-negative attenuated mutant that interferes with the replication of epidemic strains of virus.     

Serum antibody as a marker of protection against natural rotavirus infection and disease

To determine whether naturally acquired serum IgA and IgG antibodies were associated with protection against rotavirus infection and illness, a cohort of 200 Mexican infants was monitored weekly for rotavirus excretion and diarrhea from birth to age 2 years. Serum samples collected during the first week after birth and every 4 months were tested for anti-rotavirus IgA and IgG. Children with an IgA titer >1:800 had a lower risk of rotavirus infection (adjusted relative risk [aRR], 0.21; P<.001) and diarrhea (aRR, 0. 16; P=.01) and were protected completely against moderate-to-severe diarrhea. However, children with an IgG titer >1:6400 were protected against rotavirus infection (aRR, 0.51; P<.001) but not against rotavirus diarrhea. Protective antibody titers were achieved after 2 consecutive symptomatic or asymptomatic rotavirus infections. These findings indicate that serum anti-rotavirus antibody, especially IgA, was a marker of protection against rotavirus infection and moderate-to-severe diarrhea.     

Immunity to influenza A virus infection in young children: a comparison of natural infection, live cold-adapted vaccine, and inactivated vaccine

Live attenuated, cold-adapted (ca) influenza A vaccines administered intranasally have been well characterized as safe and immunogenic, but comparative data on protective efficacy are required for further development. In this study, 59 young children were divided into the following four groups based on prior exposure to influenza A (H3N2) virus: natural infection, live ca vaccine given intranasally, inactivated vaccine given im, and no previous exposure. Virus challenge with homologous live ca vaccine occurred 12 months after vaccination or natural infection. Prior natural infection and live ca vaccine significantly reduced ca virus shedding after challenge compared with inactivated vaccine or no prior exposure to influenza A virus. Prechallenge nasal IgA, detected almost exclusively in subjects naturally infected or vaccinated with live ca virus, was associated with protection. Although inactivated vaccine failed to produce significant local IgA during the primary response, it seemed to prime for secondary local antibody responses after challenge with live ca virus.     

Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus

Development of an influenza vaccine that provides broadly cross-protective immunity has been a scientific challenge for more than half a century. This study presents an approach to overcome strain-specific protection by supplementing conventional vaccines with virus-like particles (VLPs) containing the conserved M2 protein (M2 VLPs) in the absence of adjuvants. We demonstrate that an inactivated influenza vaccine supplemented with M2 VLPs prevents disease symptoms without showing weight loss and confers complete cross protection against lethal challenge with heterologous influenza A viruses including the 2009 H1N1 pandemic virus as well as heterosubtypic H3N2 and H5N1 influenza viruses. Cross-protective immunity was long-lived, for more than 7 mo. Immune sera from mice immunized with M2 VLP supplemented vaccine transferred cross protection to naive mice. Dendritic and macrophage cells were found to be important for this cross protection mediated by immune sera. The results provide evidence that supplementation of seasonal influenza vaccines with M2 VLPs is a promising approach for overcoming the limitation of strain-specific protection by current vaccines and developing a universal influenza A vaccine.     

Effectiveness of oseltamivir treatment against influenza type A and type B infection in children

We investigated the effectiveness of oseltamivir treatment against influenza virus infection in children. We treated 131 patients (mean age, 5.8 +/- 3.6 years) with oseltamivir (4 mg/kg/day for 5 days) during the 2001-2002 epidemic. All of the patients had been diagnosed with influenza using a rapid diagnosis kit. When treatment was initiated within 48 hours of the onset of fever, 44% of the patients became afebrile (< 37.5 degrees C) within one day, and 86% of them recovered within two days. The average duration of fever after the initiation of oseltamivir treatment was 1.7 days. Oseltamivir was equally effective against both influenza type A and type B. No differences in the effectiveness of oseltamivir treatment were observed between young children (< 4 years of age) and school-aged children (> 6 years of age). No obvious side effects were observed.     

Alcohol,tobacco and coffee consumption and liver disease severity among individuals with Chronic Hepatitis B infection in North America

Introduction and objectivesThe prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described.Materials and methodsThe Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1–2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values.Results1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34–52). Median ALT was 33 U/L (IQR: 22–50), 37% had HBV DNA <10³ IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and ‘at-risk’ alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics.ConclusionsIn this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors.     

Differential T and B cell responses against Mycobacterium tuberculosis heparin-binding hemagglutinin adhesin in infected healthy individuals and patients with tuberculosis

Because only 10% of individuals infected with Mycobacterium tuberculosis will eventually develop disease, antigens that are recognized differently by the immune systems of infected healthy and diseased subjects may constitute potential vaccine candidates. Here, the heparin-binding hemagglutinin adhesin (HBHA) is identified as such an antigen. Lymphocytes from 60% of healthy infected individuals (n=25) produced interferon (IFN)-gamma after stimulation with HBHA, compared with only 4% of patients with active tuberculosis (n=24). In the responders, both CD4(+) and CD8(+) cells secreted HBHA-specific IFN-gamma, and the antigen was presented by both major histocompatibility complex class I and II molecules. In contrast to the reduced ability of patients with tuberculosis to produce HBHA-specific IFN-gamma, most of them (82%) produced anti-HBHA antibodies, compared with 36% of the infected healthy subjects. These observations indicate that HBHA is recognized differently by the immune systems of patients with tuberculosis and infected healthy individuals and might provide a marker for protection against tuberculosis.     

Short report: disease severity and outcome of melioidosis in HIV coinfected individuals

This study examined whether coinfection with HIV and Burkholderia pseudomallei leads to altered disease severity or outcome associated with melioidosis. Coinfection was detected in only 8 of 524 (1.5%) adults with melioidosis in northeast Thailand. Clinical presentation and acute outcome were similar in HIV-positive and HIV-negative patients.     

Exercise reduces the risk of chronic kidney disease in individuals with nonalcoholic fatty liver disease: A nationwide cohort study

AimsRecent studies of individuals with nonalcoholic fatty liver disease (NAFLD) have indicated benefits of exercise in improving outcomes. We investigated whether exercise reduces the risk of chronic kidney disease (CKD) in individuals with NAFLD.MethodsA total of 7275 participants from the Korea National Health and Nutrition Examination Survey (KNHANES) cohort, and 40,418 participants with NAFLD from the National Health Insurance Service (NHIS) cohort were included for the cross-sectional and longitudinal analyses, respectively. For the cross-sectional analysis, the primary outcome was prevalent CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m². For the longitudinal analysis, the primary outcome was incident CKD, defined as the occurrence of eGFR <60 mL/min/1.73m² or proteinuria (≥ trace) on two consecutive measurements during follow-up.ResultsIn the KNHANES cohort, prevalent CKD was observed in 229 (6.1%), 48 (2.6%), and 36 (2.1%) participants in the 0, 1-2, and ≥ 3 exercise sessions/week groups, respectively. The likelihood of prevalent CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted OR 0.49; 95% CI, 0.33-0.71; P < 0.001). During a median follow-up of 5.0 years in the NHIS cohort, incident CKD occurred in 1,047 (9.7/1,000 person-years), 188 (7.3/1,000 person-years), and 478 (7.4/1,000 person-years) participants in the 0, 1-2, and ≥ 3 sessions/week groups, respectively. The risk of incident CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted HR 0.85; 95% CI, 0.76-0.95; P = 0.004).ConclusionsExercise was significantly associated with a reduced risk of both prevalent and incident CKD in individuals with NAFLD.     

不同病期HIV-1感染者的病毒学和免疫学研究

目的了解不同疾病阶段艾滋病病毒Ⅰ型(HIV-1)感染者体内的病毒载量和免疫学变化,探讨其在疾病发展过程中的作用。方法应用核酸序列扩增技术(NASBA)、流式细胞仪和定量酶联免疫吸附试验(ELISA)检测20例正常人、38例HIV无症状感染者、24例HIV有症状感染者和21例艾滋病(AIDS)病人的外周血浆病毒载量、T淋巴细胞亚群和Th1/Th2细胞因子浓度,并结合临床情况进行分析。结果处于不同疾病阶段的HIV无症状感染者、HIV有症状感染者和AIDS病人的血浆病毒载量不同,3组之间有显著性差异(P<0.01),艾滋病组的病毒载量为HIV-RNA 6.04±0.28 log/ml,远远高于HIV无症状组的3.84±0.26 log/ml。3组的CD4 细胞、CD4/CD8比值及IL-2浓度不断下降且明显低于正常人群(P<0.01),Th2细胞因子IL-4和IL-10则明显高于正常人群,且各组之间均有显著性差异(P<0.01)。各因素的相关性分析显示:HIV-RNA与CD4 、CD4/CD8、IL-2,IL-2与IL-4、IL-10,IL-4与IFN-γ、CD4 细胞之间有高度直线负相关关系(P<0.001);HIV-RNA与IL-4、IL-10,CD4 与CD8 、CD4/CD8、IL-2,IL-2与IFN-γ,IL-4与IL-10之间有高度直线正相关关系(P<0.001)。结论不同病期的HIV-1感染者其病毒载量水平、免疫学状况有明显不同。当HIV-RNA升高,CD4 细胞、CD4/CD8比值下降和细胞因子由Th1型为主转变为以Th2型为主时,提示疾病处于进展中。因此,检测这些指标变化可为HIV的临床分期、判断预后和治疗提供依据。