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PubMed2002

Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte, Philippines: I. Assessment of 'resistance' versus 'susceptibility' to S. japonicum infection.

This study describes the categorical classification of 155 individuals living in an endemic village in Macanip, Leyte, Philippines as 'resistant' or 'susceptible' to Schistosoma japonicum infection using available exposure, infection and reinfection data collected from a 3-year water contact (WC) study. Epidemiological parameters including age, sex, and infection intensities in relation to observed reinfection patterns are also described. This classification was used in subsequent immunological studies described in two accompanying papers to identify protective immune mechanisms among resistant individuals induced by defined candidate vaccine molecules for S. japonicum. The study suggests that individuals who were most vulnerable to rapid reinfection were children belonging to the 5-14 age group. A drop in incidence at age group 15-19 and decreased intensity of infection starting at this age group and older (15+) suggests development of immunity. Controlling for the effect of the other variables, a multivariate analysis showed significant association for sex, in that females were more likely to be resistant. This implies that other than acquired immunity to infection, some age-dependent host factors may also play an important role in the overall changes of reinfection patterns seen in schistosomiasis japonica in this population.

Adolescent↗
PubMed1999

Immune correlates of protection against anthrax

Bacillus anthracis protective antigen (PA) has been produced from a recombinant B. subtilis and its efficacy, when combined with the Ribi adjuvant (MPL-TDW-CWS) or alhydrogel, has been compared with that of the licensed UK human vaccine, in guinea pigs challenged with aerosolized Ames strain spores. Recombinant PA combined with the Ribi adjuvant performed as well as PA from B. anthracis cultures in previous reports (Ivins & Welkos 1986; Ivins et al. 1990; Turnbull et al. 1991; Jones et al. 1996; McBride et al. 1998) giving protection in 100% of animals exposed to the highest challenge dose of the Ames strain of B. anthracis that can be administered practically (retained lung doses of approximately 106 spores). In attempts at identifying markers of protection in immunized individuals, rPA in combination with the Ribi adjuvant induced a marker IgG2 response in guinea pigs with no significant differences in IgG1 levels when compared with other vaccine formulations (McBride et al. 1998). In BALBc mice, rPA with the Ribi adjuvant induced a higher IgG2a response compared with rPA with anhydrogel and the human vaccine. To examine the role of anti-PA-specific antibodies in protection, guinea pig sera is being passively transferred into guinea pigs and SCID mice, followed by protection. Similarly, B- and T-lymphocytes from immunized BALB/c mice are being separately and passively transferred into SCID mice with subsequent challenge. The neutralizing ability of the PA-specific antibodies is being studied using an in vitro macrophage lysis assay.

Journal Article↗
PubMed2006

Immunogenicity of the rF1+rV vaccine for plague with identification of potential immune correlates.

The rF1+rV candidate sub-unit vaccine for plague, formulated by adsorption to alhydrogel, has been demonstrated to be immunogenic in the cynomolgus macaque in a clinically relevant dose-range (5-40 microg of each sub-unit) and regimen. Following two doses of vaccine, a specific IgG titre developed in a dose-related manner with predominance of the IgG1/IgG2 isotypes. Groups of macaques receiving only a single dose of vaccine at the 40 microg dose-level had a significantly reduced peak IgG response and faster decline to baseline. Serum collected at week 5 from 19 immunised animals competed with and displaced murine Mab7.3 from binding to the V antigen in vitro. By week 53 of the schedule, although absolute IgG titres had declined, 17/19 macaque sera tested contained competing antibody, indicating the durability of a functional immune response to rF1+rV in this species. Thirteen of these week 53 sera were passively transferred into groups of naive mice, and all conferred full or partial protection against subsequent challenge of the mice with plague. Generally, those sera which were most competitive with Mab 7.3 for binding to V antigen were fully protective by passive transfer, although one week-53 serum sample was fully protective by passive transfer but not active by competitive ELISA. The early development of protective immunity in macaques was also indicated from the protection conferred on naive mice by the passive transfer of immune macaque serum collected at 2-10 weeks of the immunisation schedule. Serum samples from representative macaques within this time period also inhibited the Yersinia-mediated cytotoxicity of J774 macrophages in a qualitative in vitro assay of type three secretion.

Animals↗
PubMed2003

Immune correlates of protection against influenza in the human challenge model.

Intranasal administration of laboratory passaged wild-type influenza viruses to adults induces a mild upper respiratory illness accompanied by nasopharyngeal shedding of virus. A second model has used inoculation of children with attenuated viruses as a surrogate for wild-type infection. Generally, results of studies of antiviral or vaccine approaches in the challenge model have been predictive of efficacy in the real world, but it is recognized that the model does not reproduce naturally acquired illness well and both viral shedding and symptoms in the challenge model are mostly restricted to the upper respiratory tract. Serum antibody plays a major role in protection in this model and it is difficult to infect adults who have serum HI titres of > 1:8. Among adults with lower levels of HI antibody, a variety of protective factors have been described, including nasal IgA and serum NI antibody, and CTL. In some challenge studies, subjects have been protected despite lack of a measurable immune response to vaccination. Because measurement of mucosal antibody has been difficult to standardize, there is not a level that can be considered a cut-off for susceptibility. Use of a consistent method for assessing mucosal IgA between studies may help to derive a target level for vaccination.

Adult↗
PubMed1984

Suppression of experimental allergic encephalomyelitis in Lewis rats treated with myelin basic protein-liposome complexes: clinical, histopathological, and cell-mediated immunity correlates.

Guinea pig myelin basic protein (MBP) was inserted into phosphatidylserine liposomes and Lewis rats were injected by the intracardiac (ic) route with 75 microgram doses of MBP-liposomes according to various schedules. After challenge with 75 microgram guinea pig MBP in complete Freund's adjuvant, the rats were followed for clinical signs, were tested for delayed hypersensitivity (DTH) and lymphocyte transformation (LT) to MBP. The animals were sacrificed 30 days after challenge and the central nervous system tissue was examined for histological modifications. Rats treated with two injections of MBP-liposomes, 7 days before and 7 days after challenge, showed the highest degree of protection from clinical manifestations. Histological lesions were not significantly reduced. DTH reactions to MBP were all positive, regardless of treatment. LT assays were positive overall in only 50% of the animals tested. The response to rat MBP was significantly lower than to guinea pig MBP, especially in the groups treated with MBP-liposomes. Adoptive transfer of spleen cells from MBP-liposome-treated donors reduced the clinical scores of actively induced EAE in syngeneic recipients by 40-50%. These results suggest that at least one mechanism responsible for antigen-specific protection in EAE by MBP-liposomes operates through active suppression transferable by spleen cells.

Animals↗
PubMed1995

Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs. Clinical and immune correlates.

OBJECTIVE: To determine the following: 1) whether dietary supplementation with fish oil will allow the discontinuation of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA); 2) the clinical efficacy of high-dose dietary omega 3 fatty acid fish oil supplementation in RA patients; and 3) the effect of fish oil supplements on the production of multiple cytokines in this population. METHODS: Sixty-six RA patients entered a double-blind, placebo-controlled, prospective study of fish oil supplementation while taking diclofenac (75 mg twice a day). Patients took either 130 mg/kg/day of omega 3 fatty acids or 9 capsules/day of corn oil. Placebo diclofenac was substituted at week 18 or 22, and fish oil supplements were continued for 8 weeks (to week 26 or 30). Serum levels of interleukin-1 beta (IL-1 beta), IL-2, IL-6, and IL-8 and tumor necrosis factor alpha were measured by enzyme-linked immunosorbent assay at baseline and during the study. RESULTS: In the group taking fish oil, there were significant decreases from baseline in the mean (+/- SEM) number of tender joints (5.3 +/- 0.835; P < 0.0001), duration of morning stiffness (-67.7 +/- 23.3 minutes; P = 0.008), physician's and patient's evaluation of global arthritis activity (-0.33 +/- 0.13; P = 0.017 and -0.38 +/- 0.17; P = 0.036, respectively), and physician's evaluation of pain (-0.38 +/- 0.12; P = 0.004). In patients taking corn oil, no clinical parameters improved from baseline. The decrease in the number of tender joints remained significant 8 weeks after discontinuing diclofenac in patients taking fish oil (-7.8 +/- 2.6; P = 0.011) and the decrease in the number of tender joints at this time was significant compared with that in patients receiving corn oil (P = 0.043). IL-1 beta decreased significantly from baseline through weeks 18 and 22 in patients consuming fish oil (-7.7 +/- 3.1; P = 0.026). CONCLUSION: Patients taking dietary supplements of fish oil exhibit improvements in clinical parameters of disease activity from baseline, including the number of tender joints, and these improvements are associated with significant decreases in levels of IL-1 beta from baseline. Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Primary dysthymia: a study of several psychosocial, endocrine and immune correlates.

The relationship between primary dysthymia (chronic, low grade depression) and indices of major and minor life stresses, uplifts and coping styles was examined. Additionally, circulating lymphocyte subsets were assessed in dysthymic patients to determine their relationship to stress/coping factors or plasma levels of cortisol, ACTH or norepinephrine. Primary dysthymia was found to be associated with increased minor stressors (daily hassles), reduced uplifts, as well as particular reliance on emotion-focused rather than problem-oriented coping strategies. Interestingly, among dysthymics, the early onset group exhibited a greater degree of hassles and greater emotion-focused coping compared to the late onset subgroup. Although hassles and coping styles were correlated with depressed mood, only coping styles predicted severity of depressed affect. It seems that although dysthymia is characterized by increased hassles and reduced uplifts, these variables do not distinguish between the severity of the depressive affect, whereas the coping styles employed in the face of the increased hassles and reduced uplifts are more closely aligned with depression severity. Dysthymia was associated with elevated levels of circulating natural killer (NK) cells. Since levels of plasma cortisol, ACTH or norepinephrine were not increased in the dysthymic subjects, it is likely that the elevated NK cell number was unrelated to these neuroendorcrine measures. In control subjects circulating NK cells were inversely related to the severity of hassles recently encountered, while in dysthymic patients stress and coping factors were unrelated to NK cell numbers. Thus, it appears that the altered NK cells in dysthymic patients were not related to the increased stress perception and altered coping which characterize these patients.

Adaptation, Psychological↗
PubMed1984

Lymphadenopathy-associated viral antibody in AIDS. Immune correlations and definition of a carrier state.

We investigated whether serologic evidence of lymphadenopathy-associated virus (LAV), an exogenous human T-cell lymphotropic and cytopathic retrovirus, correlated with the acquisition and transmission of the acquired immunodeficiency syndrome (AIDS). Serum from 17 of 25 patients with AIDS contained circulating IgG anti-LAV antibody (all of 5 adults with cancer and 6 of 12 adults and 6 of 8 children with opportunistic infections, with or without Kaposi's sarcoma). All of eight homosexual men with generalized lymphadenopathy or the AIDS-related complex and five homosexual men with AIDS prodromes who subsequently had AIDS were also seropositive. The anti-LAV antibody was not found in 99 of 100 healthy blood donors or in 23 patients with genetic immunodeficiencies, supporting the contention that LAV is unlikely to represent simply another opportunistic microorganism. An AIDS carrier state was indicated by the probable transfer of LAV from asymptomatic, immunologically competent mothers to their offspring. These data offer a basis for the hypotheses that LAV is a marker for AIDS, may be carried and transmitted in the absence of clinical findings or in vitro T-cell abnormalities, and is probably an etiologically important agent in AIDS and its prodromes.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Immune correlates of acute Mycobacterium tuberculosis infection in household contacts in Kampala, Uganda.

To determine immunologic and epidemiologic correlates of acute Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis cases, we performed a prospective, community-based cohort study of index cases and their household contacts in Kampala, Uganda. Contacts were evaluated for tuberculin skin test (TST) conversion over two years. Interferon-gamma expression was measured using a whole blood assay after stimulating with M. tuberculosis culture-filtrate. In 222 contacts with a TST less than 5 mm at baseline, the one-year rate of TST conversion was 27%. The TST conversion was associated with the infectiousness of the index case and proximity of contact. Interferon-gamma levels at baseline were greater among TST converters compared with those who did not convert. The risk of TST conversion increased four-fold as the baseline interferon-gamma increased 10-fold, but only in contacts with BCG vaccination. In household contacts of tuberculosis, interferon-gamma responses to non-specific mycobacterial antigens may be used to make an early diagnosis of tuberculosis infection, especially in resource-limited settings where bacille Calmette-Guérin vaccination is commonly used.

Acute Disease↗
PubMed2003

The use of correlates of immunity in European Union licensing of influenza vaccines.

Influenza vaccines are licensed in the European Union (EU) by means of the mutual recognition procedure, which includes a "fast track" variation for rapid approval of new vaccine strains. This "fast track" procedure involves an annual clinical trial and assessment of immunogenicity according to serological criteria published by the EU Committee for Proprietary Medicinal Products (CPMP). A survey of vaccine clinical trials in the elderly over the past four years has demonstrated that inter-laboratory differences in serology results can affect compliance with CPMP licensing criteria. Thus even well established immune correlates of influenza vaccine efficacy can be problematic. For the next generation of vaccines, however, where mucosal or cell-mediated immunity may contribute towards vaccine efficacy, the serological correlates may be inadequate.

Drug Approval↗
PubMed1996

Correlates of protective immunity against HIV-1 infection in immunized chimpanzees.

Several experimental vaccination strategies have been developed to prevent primary infection with human immunodeficiency virus (HIV), and as immunotherapeutics for infected individuals. Many of the putative vaccines have been tested in chimpanzees (p. troglodytes) to determine their safety, efficacy, and to delineate immune correlates of protection. To date, approximately 25 candidate vaccines representing active or passive strategies have been evaluated in chimpanzees, and efficacy has been based on protection against primary infection following intravenous or mucosal challenge with cell-free or cell-associated virus. Active immunization has been attempted with whole inactivated virus, envelope depleted viral preparation, vaccinia vector expressing gp 160 in combination with other viral gene products, and subunit vaccines containing recombinant gp 120 derived from different isolates. Polyclonal and monoclonal antibodies with neutralizing activity have been utilized for pre- and post-exposure passive immunization to block primary infection with HIV.

AIDS Vaccines↗
PubMed2001

Determining the immune mechanisms of protection from AIDS: correlates of immunity and the development of syngeneic macaques.

The AIDS pandemic is a global emergency and a preventive vaccine is urgently needed. CD4 and CD8 T-cell responses appear important in controlling human immunodeficiency virus (HIV)-1 in humans and simian immunodeficiency virus (SIV) in macaques. The utility of vaccines that induce high levels of SIV- or HIV-specific T cells has recently become clearer. Since T cells recognize virus-infected cells rather than free virus, T-cell-based vaccines only have the capacity to control infections (non-sterilizing immunity) and to prevent continuing or persisting infection. An HIV/SIV infection of macaques that is partially controlled by vaccine-induced T-cell responses permits a critical window of opportunity for the efficient generation and recruitment of additional T- and B-cell immune responses to the incoming viral inoculum. Although CD8-depletion experiments in macaques have defined the utility of CD8 T responses in control of SIV infections in macaques, direct evidence on the utility of either CD4 or CD8 T-cell responses in protective immunity to SIV following vaccination is lacking. The availability of genetically identical macaques would allow cell transfer studies and help define with more certainty the role of cellular immune responses in protection from AIDS. The review also focuses on the development of syngeneic macaques by twinning and cloning technologies.

AIDS Vaccines↗
PubMed2006

Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71.

We valuated specific cellular and humoral immune response of cases of enterovirus 71 (EV71) infection and correlated immune response with clinical outcome. After obtaining informed consent, we enrolled 30 EV71 cases including 7 cases with brainstem encephalitis plus pulmonary edema, 12 cases of CNS (CNS) involvement and 11 uncomplicated cases. We measured antibodies specific to EV71, lymphocyte proliferation response and EV71-stimulated cellular response of Th1/Th2 cytokines and chemokines. The 7 EV71 cases involving brainstem encephalitis plus pulmonary edema had a significantly lower phytohemagglutinin stimulation index than other cases (p = 0.04). After EV71 stimulation of peripheral mononuclear cells, there was a significant increase in cellular Th1 cytokine (gamma-interferon) and proinflammatroy cytokines. However, cases with pulmonary edema had significantly lower cellular gamma-interferon (p = 0.04), lower cellular IL-1beta (p = 0.04), lower cellular IL-6 (p = 0.04), lower cellular tumor necrosis factor-alpha response (p = 0.04), and lower cellular macrophage inflammatory protein-1alpha (p = 0.04) response compared with other cases. Their titers of EV71 neutralizing antibodies demonstrated no difference among cases. These results suggest lower EV71-specific cellular response may be associated with immunopathogenesis of EV71-related pulmonary edema.

Antibodies, Viral↗
PubMed2005

Identification of immune response correlates for protection against bovine tuberculosis.

Identification of an immune response correlate for protection against bovine tuberculosis would greatly facilitate the rational development of an effective vaccine. However, finding such a correlate has been a daunting task. Vaccination/challenge studies in cattle provide an ideal platform to compare induction of immune response parameters following vaccination and challenge, and assess the correlation of these parameters with protection. Protection against tuberculosis requires a Th 1-type cell-mediated immune response and induction of an antigen-specific interferon-gamma (IFN-gamma) response was the logical first choice in an investigation to identify an immune response correlate for protection. Calf vaccination studies showed that the subcutaneous injection of BCG vaccine induced significant protection against experimental challenge with Mycobacterium bovis. This protection was associated with strong whole blood IFN-gamma responses to bovine PPD 2-4 weeks after vaccination, but within the BCG-vaccinated groups, these responses were not correlated with protection. Use of a variety of vaccination strategies has shown that IFN-gamma responses in isolation were not necessarily associated with protection and concurrent IL-4 mRNA expression or antibody responses could also be induced. Collation of an immunological profile may be more informative than a study of individual cytokines. An indication of vaccine efficacy can be provided by the study of immune responses following challenge of the calves with M. bovis. IFN-gamma responses to ESAT-6, antibody responses following tuberculin skin testing and antigen-specific IL-4 mRNA expression all correlated with the severity of disease and indirectly provided an indication of protection. Future studies should be directed towards obtaining immunological profiles of calves following vaccination using techniques such as DNA microarray analysis, measurement of cytokine mRNA expression by real-time PCR, protein profiling by SELDI-TOF mass spectrometry as well as determining cytokine production by specific T cell sub-sets in individual protected animals.

Animals↗
PubMed2003

Generation of protective immunity by inactivated recombinant staphylococcal enterotoxin B vaccine in nonhuman primates and identification of correlates of immunity.

At this time there are no vaccines or therapeutics to protect against staphylococcal enterotoxin B (SEB) exposure. Here, we report vaccine efficacy of an attenuated SEB in a nonhuman primate model following lethal aerosol challenge and identify several biomarkers of protective immunity. Initial in vitro results indicated that the mutation of key amino acid residues in the major histocompatibility complex (MHC) class II binding sites of SEB produced a nontoxic form of SEB, which had little to no detectable binding to MHC class II molecules, and lacked T-cell stimulatory activities. When examined in a mouse model, we found that the attenuated SEB retained antigenic structures and elicited protective immune responses against wild-type SEB challenge. Subsequently, a vaccine regimen against SEB in a nonhuman primate model was partially optimized, and investigations of immune biomarkers as indicators of protection were performed. SEB-naïve rhesus monkeys were vaccinated two or three times with 5 or 20 microg of the attenuated SEB and challenged by aerosol with wild-type SEB toxin. Unlike exposure to the native toxin, the vaccine did not trigger the release of inflammatory cytokines (TNF alpha, IL6, or IFN gamma). All rhesus monkeys that developed anti-SEB serum titers > or = 10(4) and elicited high levels of neutralizing antibody survived the aerosol challenge. These findings suggest that the attenuated SEB is fully protective against aerosolized toxin when administered to unprimed subjects. Moreover, experiments presented in this study identified various biomarkers that showed substantial promise as correlates of immunity and surrogate endpoints for assessing in vivo biological responses in primates, and possibly in humans, to vaccines against SEs.

Animals↗
PubMed2024

Identification of autophagy-related genes as potential biomarkers correlated with immune infiltration in bipolar disorder: a bioinformatics analysis.

BACKGROUND: Bipolar disorder (BPD) is a kind of manic and depressive phase alternate episodes of serious mental illness, and it is correlated with well-documented cortical brain abnormalities. Emerging evidence supports that autophagy dysfunction in neuronal system contributes to pathophysiological changes in neurological disease. However, the role of autophagy in bipolar disorder has rarely been elucidated. This study aimed to identify the autophagy-related gene as a potential biomarker Correlated to immune infiltration in BPD. METHODS: The microarray dataset GSE23848 and autophagy-related genes (ARGs) were downloaded. Differentially expressed genes (DEGs) between normal and BPD samples were screened using the R software. Machine learning algorithms were performed to screen the significant candidate biomarker from autophagy-related differentially expressed genes (ARDEGs). The correlation between the screened ARDEGs and infiltrating immune cells was explored through correlation analysis. RESULTS: In this study, the autophagy pathway was abundantly enriched and activated in BPD, as indicated by Pathway enrichment analysis. We identified 16 ARDEGs in BPD compared to the normal group. A signature of 4 ARDEGs (ERN1, ATG3, CTSB, and EIF2AK3) was screened. ROC analysis showed that the above genes have good diagnostic performance. In addition, immune correlation analysis considered that the above four genes significantly correlated with immune cells in BPD. CONCLUSIONS: Autophagy - immune cell axis mediates pathophysiological changes in BPD. Four important ARDEGs are prospective to be potential biomarkers associated with immune infiltration in BPD and helpful for the prediction or diagnosis of BPD.

Bipolar Disorder↗