Vaccine Non-responders Research Articles

Baseline serum interleukin-6 to interleukin-2 ratio is associated with the response to seasonal trivalent influenza vaccine in solid organ transplant recipients

BackgroundThe analysis of pre- and post-vaccination B-cell-associated cytokines might be useful in predicting the immunogenicity of seasonal trivalent influenza vaccine (TIV) in solid organ transplant (SOT) recipients. MethodsWe performed a subanalysis of a clinical trial that compared the safety and efficacy of high-dose intradermal (ID) versus intramuscular (IM) TIV in SOT recipients. Serum levels of selected cytokines (interferon [IFN]-γ, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-12 and IL-21, and tumor necrosis factor [TNF]-α) were measured pre- and one month post-vaccination in 155 patients (with 84 and 71 receiving the ID and IM vaccines, respectively). Cytokine profiles were compared according to vaccine response (seroconversion [≥4-fold increase in hemagglutination inhibition antibody titers] to ≥1 influenza vaccine antigen). ResultsMean baseline IL-6 levels were higher (1.20 versus 0.65pg/mL; P-value=0.021) and IL-2 levels were lower (0.01 versus 0.50pg/mL; P-value=0.051) in patients achieving vaccine response. After adjusting for clinical variables, baseline IL-6/IL-2 ratio remained predictive of vaccine response (odds ratio per 10-unit increment: 1.06; 95% confidence interval: 1.02–1.10; P-value=0.002). Vaccination induced an increase in TNF-α (P-value <0.0001) and a decrease in IL-5 levels (P-value=0.0007). There were no significant differences in cytokine kinetics between vaccine responders and non-responders. Mean baseline TNF-α levels were higher in patients experiencing moderate-to-severe adverse events after vaccination (1.93 versus 1.72pg/mL; P-value=0.009). ConclusionsBaseline serum IL-6 and IL-2 levels, two cytokines that modulate the role of CD4+ T follicular helper cells and the terminal differentiation of B-cells, predict vaccine response in SOT recipients.

Incidence and Clinical Predictors of Nonresponse to Hepatitis B Vaccination among Patients Receiving Hemodialysis: Importance of Obesity.

The objectives of this study were to quantify the incidence of hepatitis B virus (HBV) vaccine nonresponse and identify clinical characteristics associated with vaccine nonresponse. A retrospective cohort study was conducted among patients undergoing hemodialysis (HD) receiving the HBV vaccine. Study inclusion criteria were age 18 years and older, receipt of HD treatment for ≥ 1 month, receipt of ≥ 1 dose of HBV vaccine, availability of anti-HB surface antibody (anti-HBs) laboratory values ≥ 2 weeks after last HBV vaccine, and prevaccine anti-HBs value <10 mIU/mL. Clinical data were abstracted from patients' medical records. The outcome of interest was vaccine nonresponse, defined as anti-HBs values <10 IU/mL. Multivariate regression was used to determine variables independently associated with vaccine nonresponse. Kaplan-Meier estimates were constructed for determining HBV vaccine response retention. Of the 119 patients evaluated, nonresponse was observed in 58%. Mean age at first vaccination for vaccine responders and nonresponders was 58.8 ± 16.5 and 65.9 ± 14.1 (P = 0.01), respectively. Variables independently associated with nonresponse were age 58 years and older (adjusted relative risk, 95% confidence interval 1.62, 1.06-2.46; P = 0.02) and body mass index ≥ 36.4 kg/m(2) (adjusted relative risk, 95% confidence interval 1.66, 1.34-2.07; P < 0.01). Among the 50 patients who achieved an initial vaccine response, 26% were not able to maintain vaccine response upon subsequent anti-HBs measurement. The probability of retaining vaccine response over time was significantly modified by body mass index ≥ 25 kg/m(2). The frequency of nonresponse to the HBV vaccine was high among patients undergoing HD. The clinical covariates most predictive of vaccine nonresponse were advanced age at the time of vaccination and excess body weight.

Safety and immunogenicity of double-dose versus standard-dose hepatitis B revaccination in non-responding adults with HIV-1 (ANRS HB04 B-BOOST): a multicentre, open-label, randomised controlled trial

Revaccination with double-dose hepatitis B vaccine has been recommended in HIV-infected patients who do not respond to standard vaccination, but has not yet been assessed. We aimed to compare the safety and immunogenicity of a reinforced hepatitis B revaccination protocol with the standard revaccination schedule in HIV-infected patients not responding to primary vaccination. We did this multicentre, open-label, randomised controlled trial, at 53 centres in France. HIV-infected adults (aged ≥18 years), with CD4 counts of 200 cells per μL or more and no response to a previous hepatitis B vaccination or a 20 μg booster dose, were randomly assigned (1:1), according to a computer-generated randomisation list with permuted blocks (block sizes of two to six), to receive either standard-dose (20 μg) or double-dose (40 μg) recombinant hepatitis B vaccine at weeks 0, 4, and 24. Randomisation was stratified by baseline CD4 count (200-349 vs ≥350 cells per μL). Patients and treating physicians were not masked to treatment allocation, but the randomisation list was concealed from the investigators who assigned participants to the vaccination groups. The primary endpoint was the proportion of responders, defined as patients with hepatitis B surface antibody (anti-HBs) titres of 10 mIU/mL or more, at week 28. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00670839. Between May 19, 2008, and May 8, 2011, 178 participants were randomly assigned to the standard-dose group (n=90) or the double-dose group (n=88), of whom 176 (98%) participants were included in the primary efficacy analysis. At week 28, we recorded a response in 60 patients (67%, 95% CI 57-77) in the standard-dose group versus 64 patients (74%, 63-82) in the double-dose group (p=0·334). Except for more frequent local reactions in the double-dose group than the standard-dose group (13 [15%] vs four [4%] patients; p=0·020), there was no difference in safety between groups. In adults with HIV-1 who have not responded to previous hepatitis B vaccination, double-dose revaccination did not achieve a higher response rate than did revaccination with standard single-dose regimen. However, the safety profile was similar between treatment groups. Our results should be assessed in future studies before double-dose vaccine can be considered for the standard of care of vaccine non-responders. French National Institute for Medical Research-French National Agency for Research on AIDS and Viral Hepatitis.

Hepatitis B revaccination in HIV-infected vaccine non-responders: is double dosing always necessary?

Limited data exist on hepatitis B revaccination strategies for HIV-infected individuals who do not develop immunity after the first vaccination series. A retrospective cohort study was conducted to assess the immunogenicity of the second series of hepatitis B vaccine given in standard dosing (SD) and double dosing (DD) strategies among Thai HIV-infected adults during the period from January 2006 to December 2014. Of the 120 eligible patients, 68 (57%) were men, median age was 38 years old, 87 (73%) received SD and 33 (27%) received DD revaccination. The demographic and clinical characteristics of SD and DD groups were comparable. The overall vaccine response rate was significantly higher in DD group than SD group (97% vs. 70%; p = 0.001). Independent factors associated with no response to hepatitis B revaccination were receipt of SD vaccine (adjusted odds ratio [aOR] 16.04; p = 0.009), age ≥ 40 years (aOR 3.66; p = 0.009) and CD4 cell count at the time of revaccination less than 450 cells/µL (aOR 2.96; p = 0.04). These findings suggest that DD hepatitis B revaccination series should be given in HIV-infected patients who were at least 40 years old or had CD4 counts less than 450 cells/µL after no response to the first vaccination series.

HIV infection Worsens Age-Associated Defects in Antibody Responses to Influenza Vaccine

Antibody responses to seasonal influenza vaccines are defective during older age and human immunodeficiency virus (HIV) infection. The effect of HIV on immune function in aging is relatively unknown. HIV-infected and HIV-uninfected young women (age, 19-54 years) and older women (age, >55 years) were evaluated for B-cell and T-cell responses before and 4 weeks after influenza vaccination. Frequencies of seroprotection pre-vaccination and vaccine responsiveness (≥4-fold increase in antibody titer) were lower in HIV-infected participants than in age-matched HIV-uninfected participants. A subgroup of vaccine nonresponders were compared to responders and found to have reduced frequencies of memory B cells and antigen-specific antibody-secreting cells after vaccination. Frequencies of peripheral T-follicular helper (pTfh) cells correlated with memory B-cell function and influenza A(H1N1) antibody titers. Serologic and immunologic deficits were most frequent in older HIV-infected participants. Underlying CD4(+) T-cell immune activation and inflammation correlated negatively with antibody titers and B-cell function, which was not enhanced by exogenous interleukin 21 supplementation in HIV-infected, older vaccine nonresponders. Immune activation associated with HIV infection and impaired pTfh function heighten deficiencies in antibody responses to influenza vaccine in older individuals. Strategies to reduce immune activation or augment pTfh function may enhance antibody responses in the aging HIV-infected population.

Investigation of immunity in sheep following footrot infection and vaccination

Ovine footrot is a major disease affecting sheep welfare and production. The anaerobic Gram-negative bacterium Dichelobacter nodosus is the essential transmitting agent. Monovalent or bivalent vaccines induce high levels of D. nodosus antibodies and are the basis of several successful footrot treatment, control and eradication programs. Due to the rapid rate of disease transmission within a flock, the presence of therapeutic vaccination non-responders has major implications for a control program. The aim of this study was to assess the immunological basis of a therapeutic vaccination non-response. Sheep (n=120) were infected with D. nodosus in an artificial pen challenge. Once disease had established, animals were vaccinated with a serogroup specific D. nodosus fimbrial vaccine. Based on the response to therapeutic vaccination, animals were allocated into one of three groups: (i) TVNR where disease persisted despite vaccination (ii) non-diseased, where disease never established and (iii) TVR, where disease was established but resolved with vaccination. Factors related to both the innate and adaptive immune pathways were assessed. These included antigen-specific serum antibodies, interferon-γ, interleukin-10, proliferation of lymphocyte subsets and phagocytic activity of leukocytes. There was no significant difference between the three groups of sheep for any of these parameters. All three groups of sheep produced antibody in excess of a previously published minimum antibody titre required for protection. Opsonising activity in sera from the three groups of sheep was also not significantly different and phagocytic cells from sheep from all three groups were able to destroy D. nodosus intracellularly. These findings show that the measured systemic adaptive and innate immune responses were unlikely to be the cause of a therapeutic vaccination non-response. They also show that the accepted minimum protective titre may be incorrect and may need further examination.

Association of HLA alleles with the responsiveness to hepatitis B virus vaccination in Korean infants

Hepatitis B virus (HBV) vaccination is the most effective means of countering HBV-related morbidity and mortality, and individuals who do not respond to vaccination (non-responders) are problematic. The aim of the present study was to investigate associations between HLA and responsiveness to HBV vaccine in Korean infants. A total of 944 healthy Korean infants 9–12 months old were enrolled, and HLA distribution was compared among subgroups in accordance with the response to HBV vaccination. The HLA distribution of the subjects was similar to known Korean population data and did not deviate from the HWE proportions. The alleles that showed positive associations with non-responsiveness (<10mIU/mL) or low antibody titer (<100mIU/mL) were HLA-A*33, B62, DRB1*04, and DRB1*07, while the alleles A*02 and DRB1*08 showed negative associations. Among these alleles, B62, DRB1*07 and DRB1*08(−) showed significant associations with a poor or decreased response to vaccination even after correction (OR=1.83, 1.99, 5.63; pc<0.05) and also showed dose effects. After stratification by other associated alleles at different loci, B62 and DRB1*07 were independently associated with non-responsiveness, but A*02(−) and DRB1*08(–) lost their individual associations. The combined association of A*02(–)–DRB1*08(–) and B62–DRB1*08(–) was significant (OR=25.2 and 24.5; pc<0.05). Although the hierarchy is not clear, we can assume the following: (i) B62 and DRB1*07 have independent effects, (ii) DRB1*08(–) has a very strong and synergic effect, and (iii) there is probability of a third factor controlling A*02(–) and DRB1*08(–) with an effect on non-responsiveness to HBV vaccination in Korean infants.

Microarray analysis reveals novel insights into immunity to H1N1/09 influenza vaccine in aviremic HIV infected children and adolescents in IMPAACT P1088 (VIR2P.1024)

Abstract HIV infected persons often exhibit poor responses to influenza vaccine despite effective HAART-mediated viral suppression. The goal of the present study was to identify gene expression profiles that characterize vaccine driven antibody responses in aviremic pediatric and adolescent HIV infected patients (4-25 yrs) given two doses of Novartis/H1N1 09 vaccine 21 days apart during the pandemic H1N1 influenza outbreak in 2009. Blood samples were collected in Paxgene tubes on days 0, 21, and 31 post-vaccination for microarray analysis. Supervised clustering analysis for contrasts between vaccine responders (R) and vaccine non-responders (NR) was performed and top pathways were ranked by Ingenuity Pathway analysis. Cutoffs for fold change (&amp;lt;-1.3, &amp;gt;1.3) and p value (0.05) were applied to assess the top upregulated and downregulated genes in pathways. Patients were segregated by age into 2 groups for analysis: 1) &amp;lt;12 yrs, n=16 and 2) ≥13 yrs, n=28. In group 1, R showed upregulation of genes related to cell growth and metabolism at both d0 and d21. At d21, B cell differentiation, cell survival and stress response pathways were also upregulated. In group 2, R showed upregulation of innate signaling pathways at d0, and at d21 showed reduced TNF and upregulation of genes involved in T helper differentiation and B cell signaling pathways. Our results reveal signatures of successful vaccine response in HIV infected subjects and may identify favorable targets for improved vaccine design.

Delayed-type hypersensitivity and hepatitis B vaccine responses, in vivo markers of cellular and humoral immune function, and the risk of AIDS or death

BackgroundDelayed-type hypersensitivity (DTH) test responsiveness is associated with HIV disease progression; however it is unknown whether other immune markers, such as hepatitis B virus (HBV) vaccine seroresponse, also predict HIV outcomes. MethodsEligible participants received HBV vaccine after HIV diagnosis, had non-anergic DTH testing at the time of last HBV vaccination, and available post-vaccine HBV antibody responses. The risk of progression to AIDS or death from the time of last HBV vaccination was evaluated. ResultsOf 369 eligible participants with non-anergic DTH responses, 148 (40%) were HBV vaccine responders. In a multivariate model adjusted for age, CD4 count, viral load, and number of vaccinations, HBV vaccine non-responders had an increased risk of progression to AIDS or death (HR 1.81; 95% CI, 1.03–3.19). ConclusionsHBV vaccine seroresponses were independent of DTH responses which suggest that non-response to HBV vaccine is not solely due to cell-mediated immune dysfunction in HIV-infected persons.

Hepatitis B vaccine response among infants born to hepatitis B surface antigen-positive women

PurposeAnnually, an estimated 25,000 infants are born to hepatitis B surface antigen (HBsAg)-positive women in the United States. Hepatitis B (HepB) vaccine and hepatitis B immune globulin (HBIG) are recommended at birth, followed by completion of vaccine series and post-vaccination serologic testing (PVST). In a large cohort of infants born to HBsAg-positive women, factors influencing vaccine response were evaluated. MethodsData were from HBsAg-negative infants born to HBsAg-positive women in the Enhanced Perinatal Hepatitis B Prevention Program (EPHBPP) from 2008 to 2013. Vaccine non-responders were defined as infants with antibody to hepatitis B surface antigen (anti-HBs) <10mIU/mL at PVST after receiving ≥3 vaccine doses. Multivariable analyses modeled statistically significant predictor variables associated with non-response. ResultsA total of 17,951 maternal-infant pairs were enrolled; 8654 HBsAg-negative infants born to HBsAg-positive mothers received ≥3 doses of vaccine with anti-HBs results. 8199 (94.7%) infants responded to a primary HepB series; 199 (94.8%) to a second series. Factors associated with anti-HBs <10mIU/mL included gestational age <37 weeks, vaccine birth dose >12h after birth, timing of final vaccine dose <6 months after birth, receipt of 3 vs. 4 vaccine doses, and PVST interval >6 months from final vaccine dose in bivariate analysis. PVST interval >6 months from final vaccine dose (OR=2.7, CI=2.0, 3.6) was significantly associated with anti-HBs <10mIU/mL; the proportion increased from 2% at 1–2 months to 21.6% at 15–16 months after the final dose. Receipt of a 4th dose improved the response rate (OR=0.5, CI=0.3, 0.8). ConclusionsNinety-five percent of a large cohort of uninfected infants born to HBsAg-positive mothers in the United States responded to primary HepB vaccine series. The proportion of infants with anti-HBs <10mIU/mL increased with longer interval between the final vaccine dose and PVST. Optimal timing of PVST is within 1–2 months of final vaccine dose to avoid unnecessary revaccination.

KLRG1 Impairs CD4+ T Cell Responses via p16ink4a and p27kip1 Pathways: Role in Hepatitis B Vaccine Failure in Individuals with Hepatitis C Virus Infection

Coinfection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. However, HBV vaccine responses in HCV-infected individuals are often blunted compared with uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in the regulation of CD4(+) T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was overexpressed on CD4(+) T cells from HCV-infected, HBV vaccine nonresponders compared with HBV vaccine responders. The capacity of CD4(+) T cells to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement in CD4(+) T cell proliferation and IL-2 production in HCV-infected, HBV vaccine nonresponders in response to TCR stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser(473)) and decreased the expression of cell cycle inhibitors p16(ink4a) and p27(kip1), which subsequently enhanced the expression of cyclin-dependent kinase 2 and cyclin E. These results suggest that the KLRG1 pathway impairs CD4(+) T cell responses to neoantigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative-signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.

Gene signatures related to B‐cell proliferation predict influenza vaccine‐induced antibody response

Vaccines are very effective at preventing infectious disease but not all recipients mount a protective immune response to vaccination. Recently, gene expression profiles of PBMC samples in vaccinated individuals have been used to predict the development of protective immunity. However, the magnitude of change in gene expression that separates vaccine responders and nonresponders is likely to be small and distributed across networks of genes, making the selection of predictive and biologically relevant genes difficult. Here we apply a new approach to predicting vaccine response based on coordinated upregulation of sets of biologically informative genes in postvaccination gene expression profiles. We found that enrichment of gene sets related to proliferation and immunoglobulin genes accurately segregated high responders to influenza vaccination from low responders and achieved a prediction accuracy of 88% in an independent clinical trial. Many of the genes in these gene sets would not have been identified using conventional, single-gene level approaches because of their subtle upregulation in vaccine responders. Our results demonstrate that gene set enrichment method can capture subtle transcriptional changes and may be a generally useful approach for developing and interpreting predictive models of the human immune response.

Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: Role in hepatitis B vaccine failure during hepatitis C infection

Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection.

Immunologic Pattern of Hepatitis B Infection among Exposed and Non-Exposed Babies in A PMTCT Program in Low Resource Setting: Does Every Exposed Newborn Require 200IU of Hepatitis B Immunoglobulin?

Background: Hepatitis B (HBV) is a vaccine-preventable infection. Vaccination programs instituted for virtual elimination of vertical and horizontal transmission are rarely evaluated. The prohibitive cost of HBV immunoprophylaxis (HBIG) engenders restrictive access in low-resource settings. Objective: Comparison of the immunologic pattern of HBV seromarkers and mother-to-child transmission (MTCT) rates among exposed and non-exposed babies who received either standard 200 iu or 100 iu HBIG in resource low settings. Method: This prospective pilot observational study involved a cohort of HBV-infected pregnant women and exposed babies and HBV-uninfected women-baby pairs as control at the Department of Obstetrics and Gynecology, UBTH, Nigeria. HBV seromarkers were detected using rapid, direct, third generation immunochromatographic test for qualitative monoclonal and polyclonal anti-HBsAg antibodies. Reactive samples were reanalyzed using LumiQuick HBV-5 panel test for visual detection of HBs-antigen, anti-HBs-antibodies, HBe-antigen, anti-HBe antibodies, anti- HBc(IgG/IgM) antibodies. Reactive samples were confirmed with ELISA. Exposed babies were “self-selected” into receiving either 200 IU or 100 IU HBIG within 12 hours of birth plus 3-dose course of HBV vaccine. Outcome measures were incidence of MTCT of HBV, pattern of immunologic response for HBV seromarkers and proportion of vaccine non-responders. Results and conclusion: The MTCT rate was 0.0% for all groups with no homogenous pattern of maternal to fetal transfer of HBV seromarkers. The overall rate of non-response to vaccination was high (8.0%) with exposed infants being poorer responders (17.1%) to vaccination p<0.01. We advocate introduction of HBIG as integral part of care into the NPI program and multicenter studies to evaluate our findings before policy change.

Revaccination with Fendrix® or HBVaxPro® results in better response rates than does revaccination with three doses of Engerix-B® in previous non-responders

Because non-response (<10IU/l anti-HBs) after revaccination for hepatitis B occurs frequently (50%), this study aimed to provide evidence for a more effective revaccination regimen by comparing four different revaccinations: (1) three revaccinations with Engerix-B® (n=201); (2) one revaccination with Engerix-B® (n=37); (3) one revaccination with HBVaxPro-40® (n=108); (4) one revaccination with Fendrix® (n=39). The level of anti-HBs antibodies was determined with the AXSYM-MEIA system (Abbott, Chicago, USA). Using linear and logistic regression, the efficacy (antibody response) after the four revaccinations was compared. Analyses were corrected for age, sex, primary titre and time lag between last revaccination and the titre measurement. The height of the primary titre independently predicted antibody response. Compared to the revaccination scheme using three Engerix-B® doses, revaccination with a single dose of HBVaxPro-40® or Fendrix® performed significantly better. The use of these highly potent vaccines should be considered when revaccinating hepatitis B vaccine non-responders.

Peripheral T follicular helper cells from H1N1/09 vaccine nonresponders fail to induce antigen-specific antibody production in vitro

Methods The study was conducted in cryopreserved cells of 16 HIVinfected, ART-treated individuals and 8 healthy donors (HD) who had been given a single dose of H1N1/09 influenza vaccine in 2009. Only 8 of the 16 patients and all HD had a flu-Ab response at 4 wks post vaccination. Vaccine responder (VR) and non responder (VNR) patients were equivalent in mean age, viral load, CD4 and CD8 T and B cells. B (CD20+) and TFH (CD3+ CD4+ CD45RA– CXCR5+) cells were purified by cell sorting on a FACS ARIA and co-cultured. IgG levels in culture supernatants were determined by ELISA. B and T cell phenotypic analysis was performed by multicolor flow cytometry. Differences between groups were analyzed by Student t-test or the 2-sample Wilcoxon rank-sum (Mann-Whitney) test.

Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine

AbstractThe generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5+ CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and CD4 T-cell loss are recognized features of HIV infection, in the present study, we investigated pTFH cells in 25 HIV-infected patients on antiretroviral therapy. pTFH frequency was equivalent in patients and healthy controls (HCs), and these cells displayed a central memory phenotype. Sixteen patients and 8 HCs in this group were given a single dose of H1N1/09 influenza vaccine during the 2009 H1N1 influenza outbreak. In the vaccine responders (n = 8) and HCs, pTFH cells underwent expansion with increased IL-21 and CXCL13 secretion in H1N1-stimulated PBMC culture supernatants at week 4 (T2). These changes were not seen in vaccine nonresponders (n = 8). In coculture experiments, sorted pTFH cells supported HIN1-stimulated IgG production by autologous B cells only in vaccine responders. At T2, frequencies of pTFH were correlated with memory B cells, serum H1N1 Ab titers, and Ag-induced IL-21 secretion. Characterization of pTFH cells may provide additional insight into cellular determinants of vaccine-induced Ab response, which may have relevance for vaccine design.

Host responses to live-attenuated Venezuelan equine encephalitis virus (TC-83)

Venezuelan equine encephalitis virus (VEEV) is a positive-strand RNA Alphavirus endemic in Central and South America, and the causative agent of fatal encephalitis in humans. In an effort to better understand the mechanisms of infection, including differences between people who produce a neutralizing antibody response to the vaccine and those who do not, we performed whole genome transcriptional analysis in human PBMCs exposed in vitro to the live-attenuated vaccine strain of VEEV, TC-83. We compared the molecular responses in cells from three groups of individuals: naïve; previously vaccinated individuals who developed a neutralizing antibody response to the vaccine (responders); and those who did not develop a neutralizing antibody response to the vaccine (nonresponders). Overall, the changes in gene expression were more intense for the naïve group after TC-83 challenge and least potent in the nonresponder group. The main canonical pathways revealed the involvement of interferon and interferon-induced pathways, as well as toll-like receptors TLR- and interleukin (IL)-12-related pathways. HLA class II genotype and suppression of transcript expression for TLR2, TLR4 and TLR8 in the nonresponder group may help explain the lack of vaccine response in this study group. Because TL3 and TLR7 transcripts were elevated in all study groups, these factors may be indicators of the infection and not the immunological state of the individuals. Biomarkers were identified that differentiate between the vaccine responder and the vaccine nonresponder groups. The identified biomarkers were contrasted against transcripts that were unique to the naïve population alone upon induction with TC-83. Biomarker analysis allowed for the discernment between the naïve (innate) responses; the responder (recall) responses; and the nonresponder (alternative) changes to gene transcription that were caused by infection with TC-83. The study also points to the existence of HLA haplotypes that may discriminate between vaccine low- and high-responder phenotypes.

Vitamin D Levels, Natural H1N1 Infection and Response to H1N1 Vaccine among HIV-Infected Individuals

BACKGROUND: Beyond its role in calcium homeostasis, vitamin D plays a critical role in immunological responses to pathogens. We evaluated the relationship between 25-OH vitamin D levels and susceptibility to natural H1N1 infection and H1N1 vaccine responses in HIV infected individuals. METHODS: This was a sub study of an H1N1 vaccine trial conducted at the University of Pennsylvania in 2009/10. We compared the 25-OH vitamin D levels among individuals with and without baseline evidence of prior H1N1 infection and between vaccine responders and non-responders. RESULTS: 120 participants enrolled in the trial, 71% male, 68% African American, median age 46 years. The majority had controlled HIV disease. At baseline, 86% had 25-OH vitamin D levels < 30 ng/ml and 54% had levels < 20 ng/ml. Thirty participants (25%) had evidence of prior H1N1 exposure. There was no difference in mean 25-OH vitamin D levels among patients with or without prior natural H1N1 infection (21 ng/ml vs 20 ng/ml, p=0.72). Among participants without previous H1N1 exposure, only 61% developed protective antibody titers following vaccination. 25-OH vitamin D levels were similar between vaccine responders (20 ng/ml) and non-responders (20 ng/ml) (p=0.83). CONCLUSION: Although 25-OH vitamin D deficiency was very common among HIV-infected individuals, it was not associated with natural susceptibility to H1N1 or to vaccine responses.

Efficacy of High-Dose Intra-dermal Hepatitis B Virus Vaccine in Previous Vaccination Non-responders with Chronic Liver Disease

Hepatitis B virus (HBV) vaccination is essential in chronic liver disease (CLD), because it can help prevent acute-on-chronic disease, which has potentially fatal complications. Unfortunately, this group has a significant proportion of HBV vaccination non-responders. A variety of intra-muscular (IM) vaccination methods have been used in an attempt to remedy this poor-response, but with limited success. Herein is reported the safety and efficacy of high-dose intra-dermal (ID) HBV vaccination in CLD individuals who had failed previous IM standard and boost-dosing regimens. Forty-eight CLD individuals, known HBcAb negative, who had failed both a three-dose schedule of 40 μg IM vaccination, and boost dosing of either 40 or 80 μg IM, were identified, of which 42 completed the vaccination course. Each received a 40 μg ID total dose (20 μg per arm) during their clinic visits until a response was documented or a maximum of three doses had been administered. HBsAb titer ≥ 10 mIU/ml was regarded as an immunologic response; the intention was to achieve an optimum response of ≥ 100 mIU/ml. Twenty-nine of forty-two (69%) individuals had an immunologic response, with 15 (51%) of the responders having the optimum response. No changes in serologic data occurred. No serious dermatologic reactions were observed. No differences between those who responded and those who did not were observed with regard to the presence of cirrhosis, diabetes mellitus, or chronic kidney disease. High-dose ID HBV vaccination of previous CLD non-responders to the standard IM regimen with boost dosing is both safe and efficacious, and should be considered for all such groups.