Undetectable Titers Research Articles

Occurrence of specific humoral non-responsiveness to swine antigens following administration of GalT-KO bone marrow to baboons

Hematopoietic chimerism induces transplantation tolerance across allogeneic and xenogeneic barriers, but has been difficult to achieve in the pig-to-primate model. We have now utilized swine with knockout of the gene coding for alpha-1,3-galactosyltransferase (GalT-KO pigs) as bone marrow donors in an attempt to achieve chimerism and tolerance by avoiding the effects of natural antibodies to Gal determinants on pig hematopoietic cells. Baboons (n = 4; Baboons 1 to 4 = B156, B158, B167, and B175, respectively) were splenectomized and conditioned with TBI (150 cGy), thymic irradiation (700 cGy), T cell depletion with rabbit anti-thymocyte globulin (rATG) and rat anti-primate CD2 (LoCD2b), and received FK506 and supportive therapy for 28 days. All animals received GalT-KO bone marrow (1 to 2 x 10(9) cells/kg) in two fractions on days 0 and 2, and were thereafter monitored for the presence of pig cells by flow cytometry, for porcine progenitor cells by PCR of BM colony-forming units, and for cellular reactivity to pig cells by mixed lymphocyte reaction (MLR). In vitro antibody formation to LoCD2b and rATG was tested by ELISA; antibody reactivity to GalT-KO pig cells was tested by flow cytometry and cytotoxicity assays. Additionally, Baboons 3 and 4 received orthotopic kidney transplants on days 17 and 2, respectively, to test the potential impact of the protocol on renal transplantation. None of the animals showed detectable pig cells by flow cytometry for more than 12 h post-BM infusion. However, porcine progenitor cell engraftment, as evidenced by pig-derived colony forming units in the BM, as well as peripheral microchimerism in the thymus, lymph node, and peripheral blood was detected by PCR in baboons 1 and 2 for at least 28 days post-transplant. ELISA results confirmed humoral immunocompetence at time of transplantation as antibody titers to rat (LoCD2b) and rabbit (ATG) increased within 2 weeks. However, no induced antibodies to GalT-KO pig cells or increased donor specific cytotoxicity was detectable by flow cytometry. In contrast, baboons 3 and 4 developed serum antibodies to pig cells as well as to rat and rabbit immunoglobulin by day 14. Retrospective analysis revealed that although all four baboons possessed low levels of antibody-mediated cytotoxicity to GalT-KO cells prior to transplantation, the two baboons (3 and 4) that became sensitized to pig cells (and rejected pig kidneys) had relatively high pre-transplantation titers of anti-non-Gal IgG detectable by flow cytometry, whereas baboons 1 and 2 had undetectable titers. Engraftment and specific non-responsiveness to pig cells has been achieved in two of four baboons following GalT-KO pig-to-baboon BMT. Engraftment correlated with absence of preformed anti-non-Gal IgG serum antibodies. These results are encouraging with regard to the possibility of achieving transplantation tolerance across this xenogeneic barrier.

Effect of Revaccination Using Different Schemes among Adults with Low or Undetectable Anti-HBs Titers after Hepatitis B Virus Vaccination

Our objective was to investigate the effect of various reimmunization schemes for hepatitis B in adults with low or undetectable anti-HBs titers. Over 2 years, 10 μg of Saccharomyces cerevisiae-recombinant hepatitis B virus (HBV) vaccine (synthesized in China) was used in at least one standardized scheme to immunize 2,310 healthy male and nonpregnant female adults. Of these, 240 subjects tested negative for hepatitis B markers. These 240 subjects were equally divided into 4 groups. The first group, designated Engerix-40, was revaccinated with 40 μg Engerix-B; the second, Engerix-20, was revaccinated with 20 μg Engerix-B; the third, Chinese-20, was revaccinated with 20 μg Chinese-made yeast-recombinant vaccine; and the last group, Chinese-10, was revaccinated with 10 μg Chinese-made yeast-recombinant vaccine. Blood samples were collected before and 1, 2, 8, and 12 months after the first injection. The anti-HBs-positive conversion rates of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than that of the Chinese-10 group (P < 0.01). Over time, the anti-HBs conversion rate increased in all groups, but values were significantly different from those for the other groups only in the Chinese-10 group (P < 0.001). The anti-HBs geometric mean titers (GMTs) of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than in the Chinese-10 group (P < 0.05). Increased doses raise and maintain anti-HBs titers in subjects with low or undetectable titers after HBV vaccination.

Detection of mumps virus‐specific memory B cells by transfer of peripheral blood mononuclear cells into immune‐deficient mice

Waning immunity to mumps after one or two doses of the measles, mumps and rubella (MMR) vaccine has been described. Using a human peripheral blood lymphocyte (PBL)-severe combined immunodeficiency (SCID) mouse model, MMR vaccine recipients with undetectable and high antibody titres against mumps were compared for the presence of circulating mumps-specific memory B cells. Peripheral blood mononuclear cells (PBMC) from six donors (three subjects with undetectable and three with high antibody titres against mumps) were injected into the spleens of non-obese diabetic (NOD)-SCID mice (three mice per subject). Mice were pretreated with TMbeta1 and total body irradiation to improve engraftment. In vivo production of human antibodies against mumps was evaluated in mouse plasma on days 7, 10 and 13 with a commercial enzyme-linked immunosorbent assay (ELISA), functional reduction neutralization test. Three donors had mumps antibody titres below the detection limit (titre < 230) and three had high antibody titres (range 5700-7300). None of the mice injected with PBMC from subjects with undetectable antibody titres showed detectable human antibody titres, despite the presence of cell-mediated immunity in two of the three donors. Seven out of nine mice injected with PBMC from subjects with high antibody titres acquired detectable antibody titres for mumps in their plasma. PBMC from vaccinees without detectable serum antibodies against mumps virus were unable to induce secretion of anti-mumps antibodies in the blood of recipient mice, whereas PBMC from vaccinees with high antibody titres were able to do so. This observation suggests that the frequency of mumps-specific memory B cells is very low in vaccinees with undetectable antibody titres. These individuals may therefore be at risk of developing mumps disease upon encounter with wild-type virus.

Rituximab in der Behandlung der erworbenen Hämophilie A bei einem Patienten mit Polymyalgia rheumatica

SummaryAcquired hemophilia A is a rare but potentially life-threatening bleeding disorder. It is caused by the development of autoantibodies directed against coagulation factor VIII in adults or elderly patients, who do not have a personal or family history of bleeding. Case: A man (age: 76 years) on prednisone and leflunomide for polymyalgia rheumatica developed spontaneous severe haematomas. The patient was diagnosed with acquired factor VIII deficiency (FVIII activity 1.2%, FVIII inhibitor 31.7 BU). Due to the active bleeding diathesis, treatment was administered with activated prothrombin complex concentrates (FEIBA®, Baxter). Immunosuppressive treatment with a combination of oral prednisone (1 mg/kg daily) and cyclophosphamide (1,5 mg/kg daily) was administered to reduce the FVIII inhibitor. However, after two weeks of treatment, FVIII was only 3% and no clinical improvement was observed. Treatment with the anti CD20 monoclonal antibody rituximab intravenously at 375 mg/m2 once weekly for four consecutive weeks was started. The patient showed rapid clinical improvement following rituximab treatment. He achieved a complete remission defined as return to normal FVIII activity and undetectable FVIII inhibitor titer. After a follow-up of six months no relapse occurred. Conclusion: Rituximab appears an effective and well-tolerated treatment for patients with acquired haemophilia.

Protective immunity against viral nervous necrosis (VNN) in brown-marbled grouper ( Epinephelus fuscogutattus) following vaccination with inactivated betanodavirus

Viral nervous necrosis (VNN) caused by betanodaviruses has been recently implicated in serious mortalities of groupers in the grow-out culture system. A safe and effective vaccine against this disease is urgently needed. This study demonstrates that a single intramuscular vaccination with formalin-inactivated Philippine strain of piscine betanodavirus (genotype: redspotted grouper nervous necrosis virus; RGNNV) induces potent immune responses and substantial protective immunity against an intramuscular challenge with the homologous virus in brown-marbled grouper, Epinephelus fuscogutattus, a highly susceptible marine fish species to VNN. Seroneutralization assay conducted on sera of vaccinated fish revealed the occurrence of substantial neutralizing-antibody titers from Days 15 (mean titer 1:800) to 190 (1:400) with the highest titer observed at Day 60 post-vaccination (1:5120). When vaccinated fish were challenged with the homologous virus at Days 15, 30 and 75 post-vaccination, significantly higher survival rates were obtained in these fish compared with their corresponding controls (L-15 injected fish). Abrogation of virus multiplication in all vaccinated survivors was indicated by undetectable virus titers in the brains and kidneys paralleled by significantly high levels of neutralizing antibodies in the sera of these fish. Consecutively, replicates of vaccinated fish that survived betanodavirus challenge at Days 15 and 75 post-vaccination were maintained in flow-through aquaria and rechallenged with the homologous virus 3 and 5 months later, respectively. A significant drop in neutralizing-antibody titers of 3 and 8 folds, respectively, were observed in the sera of Days 15 and 75 post-vaccinated fish assayed before the virus rechallenge. Interestingly, reversion in the levels of neutralizing antibodies to significantly high levels (8–15 folds) were noted in these fish after the virus rechallenge. Taken together, our current data clearly demonstrate that a single administration of the inactivated Philippine strain of betanodavirus vaccine can effectively mount a specific anamnestic response and concomitant long-term protection against VNN in grouper at the grow-out culture system.

Lack of Association between Retrospectively Collected Pharmacy Refill Data and Electronic Drug Monitoring of Antiretroviral Adherence

Antiretroviral medication refill adherence has not been compared directly to electronic drug monitoring (EDM) in any identifiable published study. We retrospectively studied adults with undetectable HIV titers on highly active antiretroviral therapy. We used Pearson correlation coefficients and receiver operating characteristic curves to relate the two adherence measures, and we used the Wilcoxon rank-sum test to assess the relation between adherence and viral load. In sixty-five subjects, the majority of whom were African American and male with median age of 44 years, pharmacy refill adherence was difficult to collect retrospectively, was not significantly correlated with EDM adherence, and was not significantly related to viral load. Ninety-day supply pharmacy refill adherence correctly classified 95% EDM adherence maximally at 94 days between refills, and the measure was most sensitive for non-adherence at <90 days. Reassessment of the relation between pharmacy refill data and EDM would be warranted when pharmacy refill data is collected as soon as feasible from sources with complete data capture.

Immunogenicity of the Tetravalent Protein-Conjugated Meningococcal Vaccine in Recipients of Related and Unrelated Allogeneic Hematopoietic Cell Transplants (HCT)

Following the successful introduction of the highly immunogenic protein-conjugated Haemophilus influenza and pneumococcal vaccines, Neisseria meningitidis has become the most common cause of bacterial meningitis in the US. Each year, invasive disease (meningitis, sepsis, pneumonia) due to this organism occurs in approximately 500, 000 persons world-wide, including 1400–2800 in the US. Despite rapid institution of appropriate antibiotics, 10%–14% of affected patients die and significant morbidity occurs in up to 20% of survivors. In 2005, the quadrivalent (A, C, Y, W-135) protein conjugated polysaccharide vaccine (MCV4) was approved in the US and recommended for children 11–12 years of age, previously unimmunized adolescents entering college, military recruits, patients with acquired or functional asplenia, and all travelers to hyperendemic or epidemic areas such as sub-Sahara Africa. Improved disease-free survival following HCT has resulted in an increasing number of survivors entering college and traveling abroad. Due to the lack of information on the immunogenicity of this vaccine in transplant survivors, we assessed the responses of 41 patients immunized with MCV4 following an HLA matched related (n=16), mis-matched related (n=2) or unrelated (n=23) HCT. The median age at HCT and at vaccination was 14 years and 18 years, respectively. Patients were transplanted for acute or chronic leukemia (n=28), immunodeficiency disease (n=4), hemoglobinopathy (n=4), HLH (n=1), NHL (n=1), MDS or aplastic anemia (n=3). Fifty percent of patients received an unmodified HCT and four patients were splenectomized prior to vaccination. MCV4 was administered at a median (range) of 3.2 (0.7–12.5) years following transplant. Ninety percent of patients had undetectable titers to all 4 serotypes prior to immunization. Antibody responses were measured by ELISA. Positive response was defined as > 4 ug/ml (serotype A), >5 ug/ml (serotype C), >4 ug/ml (serotype Y), and >3 ug/ml for serotype W-135. Sixty-one percent of patients developed an antibody response to 31 vaccine serotypes, although only 13 developed positive titers to all 4 serotypes. Response to serotypes A, C, Y, and W-135 was observed in 20, 13, 18, and 13 patients, respectively. Responses were significantly poorer in recipients of an unrelated HCT. Of the 7 non-responders who received a second MCV4, 3 of 4 evaluated patients developed titers to all 4 serotypes. This data suggests that although HCT recipients respond to MCV4, the response is sub-optimal, that pre and post vaccine titers should be assessed to ensure adequate protection, and that a booster immunization should be explored in this patient population.

Relationship ofPneumocystisAntibody Response to Severity of Chronic Obstructive Pulmonary Disease

Pneumocystis colonization has been associated with severity of chronic obstructive pulmonary disease (COPD). The relationship of Pneumocystis antibody status to COPD severity has not been investigated, but antibody levels might relate to both colonization susceptibility and COPD progression. We investigated anti-Pneumocystis antibody titers and airway obstruction in a cohort of patients with COPD. Undetectable anti-Pneumocystis antibody titer was an independent predictor of more-severe airway obstruction, although use of inhaled corticosteroids is a possible confounder of this effect.

Long-term protection of hepatitis B vaccine 18 years after vaccination

This is the third evaluation study of the hepatitis B virus (HBV) vaccination program, initiated in 1989 in Saudi Arabia. This study sought to assess the efficacy and long-term protection of the hepatitis B vaccine among Saudi adolescents. School students between the ages of 16 and 18 years were randomly chosen from high endemic (Aseer), intermediate endemic (Madinah), and low endemic (Al-Qaseem) areas of the country. Hepatitis B surface antigen (HBsAg), hepatitis B core IgG antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs) were measured using standard techniques. A total of 1355 students (689 males and 666 females) were selected randomly from the three areas. No cases of positive HBsAg or anti-HBc were detected among the study population. Five hundred and ten students (38%) showed protective anti-HBs titers (>/= 10mIU/ml), while 528 (39%) students had undetectable anti-HBs titers (<1 mIU/ml). This study shows the excellent efficacy of the HBV vaccination program in Saudi Arabia 18 years after its launch. Based on this study and others, a booster dose for the adult population appears to be unnecessary.

Pathogenicity and Vaccine Efficacy of Different Clades of Asian H5N1 Avian Influenza A Viruses in Domestic Ducks

Waterfowl represent the natural reservoir of all subtypes of influenza A viruses, including H5N1. Ducks are especially considered major contributors to the spread of H5N1 influenza A viruses because they exhibit diversity in morbidity and mortality. Therefore, as a preventive strategy against endemic as well as pandemic influenza, it is important to reduce the spread of H5N1 influenza A viruses in duck populations. Here, we describe the pathogenicity of dominant clades (clades 1 and 2) of H5N1 influenza A viruses circulating in birds in Asia. Four representatives of dominant clades of the viruses cause symptomatic infection but lead to different profiles of lethality in domestic ducks. We also demonstrate the efficacy, cross-protectiveness, and immunogenicity of three different inactivated oil emulsion whole-virus H5 influenza vaccines (derived by implementing reverse genetics) to the viruses in domestic ducks. A single dose of the vaccines containing 1 mug of hemagglutinin protein provides complete protection against a lethal A/Duck/Laos/25/06 (H5N1) influenza virus challenge, with no evidence of morbidity, mortality, or shedding of the challenge virus. Moreover, two of the three vaccines achieved complete cross-clade or cross-subclade protection against the heterologous avian influenza virus challenge. Interestingly, the vaccines induce low or undetectable titers of hemagglutination inhibition (HI), cross-HI, and/or virus neutralization antibodies. The mechanism of complete protection in the absence of detectable antibody responses remains an open question.

Biomarkers for early diagnosis of Alzheimer disease: 'ALZheimer ASsociated gene'--a new blood biomarker?

Simple, non-invasive tests for an early detection of degenerative dementia by use of biomarkers are urgently required. However, up to the present, no validated extracerebral diagnostic markers (plasma/serum, platelets, urine, connective tissue) for the early diagnosis of Alzheimer disease (AD) are available. In disease stages with evident cognitive disturbances, the clinical diagnosis of probable AD is made with around 90% accuracy using modern clinical, neuropsychological and imaging methods. Diagnostic sensitivity and specificity even in early disease stages are improved by CSF markers, in particular combined tau and amyloid β peptides (Aβ) and plasma markers (e.g. Aβ-42/Aβ-40 ratio). Recently, a novel gene/protein – ALZAS (ALZheimer ASsociated protein) – with a 79 amino acid sequence, containing the amyloid β-42 fragment (Aβ-42), the amyloid precursor protein (APP) transmembrane signal and a 12 amino acid C-terminal, not present in any other known APP alleles, has been discovered on chromosome 21 within the APP region. Reverse transcriptase-PCR revealed the expression of the transcript of this protein in the cortex and hippocampal regions as well as in lymphocytes of human AD patients. The expression of ALZAS is mirrored by a specific autoimmune response in AD patients, directed against the ct-12 end of the ALZAS-peptide but not against the Aβ-sequence. ELISA studies of plasma dectected highest titres of ALZAS in patients with mild cognitive impairment (presymptomatic AD), but only moderately increased titres in autopsy-confirmed AD, whereas low or undetectable ct-12 titres were found in cognitively intact age-matched subjects and young controls. The antigen, ALZAS protein, was detected in plasma in later clinical stages of AD. It is suggested that ALZAS represents an indicator in a dynamic equilibrium between both peripheral and brain degenerative changes in AD and may become a useful ‘non-invasive’ diagnostic marker via a simple blood test.

T Lymphocytes Contribute to Antiviral Immunity and Pathogenesis in Experimental Human Metapneumovirus Infection

Human metapneumovirus (hMPV), a member of the family Paramyxoviridae, is a leading cause of lower respiratory tract infections in children, the elderly, and immunocompromised patients. Virus- and host-specific mechanisms of pathogenesis and immune protection are not fully understood. By an intranasal inoculation model, we show that hMPV-infected BALB/c mice developed clinical disease, including airway obstruction and hyperresponsiveness (AHR), along with histopathologic evidence of lung inflammation and viral replication. hMPV infection protected mice against subsequent viral challenge, as demonstrated by undetectable viral titers, lack of body weight loss, and a significant reduction in the level of lung inflammation. No cross-protection with other paramyxoviruses, such as respiratory syncytial virus, was observed. T-lymphocyte depletion studies showed that CD4(+) and CD8(+) T cells cooperate synergistically in hMPV eradication during primary infection, but CD4(+) more than CD8(+) T cells also enhanced clinical disease and lung pathology. Concurrent depletion of CD4(+) and CD8(+) T cells completely blocked airway obstruction as well as AHR. Despite impaired generation of neutralizing anti-hMPV antibodies in the absence of CD4(+) T cells, mice had undetectable viral replication after hMPV challenge and were protected from clinical disease, suggesting that protection can be provided by an intact CD8(+) T-cell compartment. Whether these findings have implications for naturally acquired human infections remains to be determined.

Early Childhood Infection by Human Herpesvirus 8 in Zambia and the Role of Human Immunodeficiency Virus Type 1 Coinfection in a Highly Endemic Area

Kaposi's sarcoma occurs at high incidence among Zambian adults and children, but there is a paucity of data on human herpesvirus 8 (HHV-8) incidence and routes of infection, especially in children. Between 1998 and 2004, the authors conducted a prospective study of viral transmission in a cohort of 684 children in Lusaka, Zambia, to estimate the annual incidence of HHV-8 from birth through 48 months of age. Maternal and pediatric human immunodeficiency virus type 1 (HIV-1) infection status was also determined. The results, based on 1,532 child-years of follow-up, showed that HHV-8 seroconversion occurs early in life. The incidence rate of HHV-8 seroconversion was 13.8 infections per 100 child-years by 48 months of age. HIV-1-infected children were at substantially higher risk for HHV-8 seroconversion (adjusted hazard ratio = 4.60, 95% confidence interval: 2.93, 7.22). Maternal HIV-1 and HHV-8 infection status were not independently associated with risk of HHV-8 seroconversion in the child. HHV-8 antibody titers in children followed at all consecutive time points revealed sero-reversion of HHV-8 antibodies, with undetectable titers in some children at one or more time points after seroconversion. These results demonstrate that cross-sectional serologic screening probably underestimates true HHV-8 seroprevalence in young Zambian children because of fluctuations in detectable antibody titers.

HLA and response to booster hepatitis B vaccination in anti-HBs-seronegative adolescents who had received primary infantile vaccination

To explore contemporarily genetic and non-genetic determinants of long-term immunological memory to hepatitis B (HB) vaccination, we conducted a case–control study nested in an adolescent cohort of booster recipients who had received primary infantile HB vaccination but with residual anti-HBs titers <10 mIU/mL at 15–18 years of age. High-resolution phenotypes of human leukocyte antigen (HLA)-A, -B, and -DRB1 loci were determined by sequence-specific oligonucleotide probe hybridization. After controlling for pre-booster anti-HBs levels, the absences of HLA- A*02 and - DRB1*08, simply expressed as A*02 − and - DRB1*08 −, and the presence of B*15 were significantly associated with elevated risks of non-response (post-booster anti-HBs titers < 10 mIU/mL) to booster vaccination. The adjusted odds ratios (ORs) were 3.85 (CI, 1.82–8.33), 4.55 (CI, 1.23–16.67), 3.59 (CI, 1.40–9.17), respectively. There was multiplicative synergism between A*02 and B*15 on the risk of non-response to booster vaccination. The multivariate-adjusted ORs for A*02 −/ B*15, A*02 −/ B*15 −, A*02/ B*15, and A*02/ B*15 − haplotypes were 20.39 ( p = 0.0003), 3.29 ( p = 0.007), 1.32 ( p > 0.05), and 1.0, respectively. Recent cigarette smoking and/or betel-quid chewing was associated with a 12-fold risk of non-response to booster vaccination. Further comparisons between responders and adolescents who had undetectable post-booster anti-HBs titers (<0.1 mIU/mL) demonstrated similar results. Our results indicated that response to booster HB vaccination as well as long-term immunological responses to HB vaccination are closely related with host genetic factors, and probably modified by recent substance use.

Herd immunity to Newcastle disease virus in poultry by vaccination

Newcastle disease is an economically important disease of poultry for which vaccination is applied as a preventive measure in many countries. Nevertheless, outbreaks have been reported in vaccinated populations. This suggests that either the vaccination coverage level is too low or that vaccination does not provide perfect immunity, allowing the virus to spread in partially vaccinated populations. Here we study the requirements of an epidemiologically effective vaccination program against Newcastle disease in poultry, based on data from experimental transmission studies. The transmission studies indicate that vaccinated birds with low or undetectable antibody titres may be protected against disease and mortality but that infection and transmission may still occur. In fact, our quantitative analyses show that Newcastle disease virus is highly transmissible in poultry with low antibody titres. As a consequence, herd immunity can only be achieved if a high proportion of birds (>85%) have a high antibody titre (log2 haemagglutination inhibition titre ≥3) after vaccination. We discuss the implications for the control of Newcastle disease in poultry by vaccination.

SUSTAINED IMMUNOLOGIC AND VIROLOGIC EFFICACY AFTER FOUR YEARS OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY IN HUMAN IMMUNODEFICIENCY VIRUS INFECTED CHILDREN IN THAILAND

We report the long-term efficacy of highly active antiretroviral therapy (HAART) in 107 antiretroviral-naive human immunodeficiency virus (HIV)-infected Thai children. In an intention-to-treat analysis, 70% of the children had undetectable HIV RNA titers after 192 weeks of HAART. The mean CD4 cell percentage increased from 5.3% to 26.6%. HAART is effective for HIV-infected children in this resource-poor setting despite initiation of treatment in the advanced stage of disease.

Modifications of the PSAP region of the matrix protein lead to attenuation of vesicular stomatitis virus in vitro and in vivo

The matrix (M) protein of vesicular stomatitis virus (VSV) is a multi-functional protein involved in virus assembly, budding and pathogenesis. The (24)PPPY(27) late (L) domain of the M protein plays a key role in virus budding, whereas amino acids downstream of the PPPY motif contribute to host protein shut-off and pathogenesis. Using a panel of (37)PSAP(40) recombinant viruses, it has been demonstrated previously that the PSAP region of M does not possess L-domain activity similar to that of PPPY in BHK-21 cells. This study reports the unanticipated finding that these PSAP recombinants were attenuated in cell culture and in mice compared with control viruses. Indeed, PSAP recombinant viruses exhibited a small-plaque phenotype, reduced CPE, reduced levels of activated caspase-3, enhanced production of IFN-beta and reduced titres in the lungs and brains of infected mice. In particular, recombinant virus M6PY>A4-R34E was the most severely attenuated, exhibiting little or no CPE in cell culture and undetectable titres in the lungs and brains of infected mice. These findings indicate an important role for the PSAP region (aa 33-44) of the M protein in the pathology of VSV infection and may have implications for the development of VSV as a vaccine and/or oncolytic vector.

Short-term response to a booster dose of hepatitis B vaccine in anti-HBs negative adolescents who had received primary vaccination 16 years ago

We conducted a revaccination study to investigate the short-term response to booster hepatitis B (HB) vaccination in seronegative adolescents who had received primary infantile HB vaccination. A booster dose of recombinant HB vaccine was administered to 395 adolescents 15-18 years of age whose serum titers of antibody against hepatitis B surface antigen (HBsAg) (anti-HBs) were <10 mIU/mL. Seventy-seven percent of the booster recipients converted to anti-HBs seropositivity (postbooster titers> or =10 mIU/mL). As compared with adolescents who had undetectable prebooster anti-HBs titers (<0.1 mIU/mL), the seropositive rates and geometric mean titers (GMTs) of 2-month and 1-year postbooster were significantly higher for those of prebooster titers of 0.1-0.9 and 1.0-9.9 mIU/mL (all p<0.0001). Postbooster titers declined significantly more rapidly for those with undetectable prebooster anti-HBs titers than for those with prebooster titers of 0.1-0.9 and 1.0-9.9 mIU/mL. Our observations indicate that a booster dose of HB vaccine maybe unable to induce sufficient immunological response in adolescents who had undetectable residual anti-HBs titers.

Ethnicity, substance use, and response to booster hepatitis B vaccination in anti-HBs-seronegative adolescents who had received primary infantile vaccination

In this revaccination study, we explored the determinants of response to booster hepatitis B (HB) vaccination in anti-HBs-seronegative adolescents who had received primary HB vaccination 15-18 years before. After controlling for prebooster anti-HBs levels, cigarette smoking, betel-quid chewing, alcohol drinking, and indigenous ethnicity were significantly associated with elevated risks of non-response to booster HB vaccination. The adjusted odds ratios (aORs) were 3.21 (CI: 1.33-7.84), 8.78 (CI: 2.03-37.94), 2.64 (CI: 1.15-6.02), and 2.46 (CI: 1.28-4.72), respectively. Among adolescents with undetectable prebooster anti-HBs titers, only indigenous ethnicity significantly associated with elevated risk, with an adjusted OR of 2.57 (CI: 1.20-5.54), of non-response to booster HB vaccination. On the contrary, the influences of cigarette smoking, betel-quid chewing, and alcohol drinking were restricted to adolescents with prebooster anti-HBs titers of 0.1-9.9mIU/mL. The corresponding multivariate-adjusted ORs were 5.70, 17.41, and 3.72, respectively. Adolescents who smoked cigarettes and chewed betel-quid were at highest risk of non-response (aOR, 25.3; CI: 2.97-215.7). A booster dose of HB vaccine may be insufficient to induce immunological response in healthy adolescents who had undetectable prebooster anti-HBs titers or who were of Malay-Polynesian ethnicity. Responses to booster vaccination are probably modified by recent cigarette smoking and/or betel-quid chewing.

Sustained Viral Response to Pegylated Interferon α-2b and Ribavirin in Chronic Hepatitis C Refractory to Prior Treatment

Hepatitis C virus (HCV) infection refractory to previous therapy is common. Treatment of patients with refractory disease is difficult and less studied. Pegylated interferon alpha-2b plus ribavirin is used for treatment of HCV patients naïve to therapy. We conducted a randomized study for refractory HCV patients using a high- vs. a low-dose pegylated interferon alpha-2b and ribavirin protocol. Our aim was (1) to determine the efficacy of pegylated interferon alpha-2b plus ribavirin to eradicate HCV in previously treated individuals and (2) to compare a low-dose to a high-dose regimen. One hundred fifty-two patients were initiated in the study, 112 (74%) were male and 40 (26%) female. Nineteen percent of patients obtained a sustained viral response (SVR) in the high-dose arm. Prior relapsers had the highest SVR rates: 50% in non-genotype 1 and 34% in genotype 1. The odds of achieving a SVR were six times higher in previous relapsers. The rate of SVR in genotype 1 patients who were nonresponders to prior therapy was only 8%. All patients who achieved a SVR had no detectable virus at week 24. However, only half of those who had undetectable viral titers at week 24 achieved a SVR. In conclusion, retreatment of patients with refractory hepatitis C infection with interferon alpha-2b and ribavirin combination therapy is well tolerated and gives modest response rates. The most important factor in predicting response to therapy is the manner of response to previous treatment. The likelihood of response to treatment can be predicted from the viral titers at 24 weeks.