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PubMed2026

Safety, humoral and cellular immune responses to a pre-pandemic adjuvanted influenza A (H5N8) vaccine.

Highly pathogenic avian influenza (HPAI) A(H5) viruses can be transmitted from infected birds to various mammalian species, including humans. Avian influenza viruses (AIVs), members of the Orthomyxoviridae family, possess segmented RNA genomes prone to reassortment, favoring the emergence of novel genetic traits that may alter transmissibility, pathogenicity, and antigenicity. Although no sustained human-to-human transmission has been reported, the potential adaptation of these viruses poses a significant pandemic threat. This study aimed to evaluate the non-clinical safety, toxicity, and humoral immune responses induced by an adjuvanted H5 influenza vaccine in rats and rabbits, to support future clinical safety trials in humans. Male and female Wistar rats and New Zealand rabbits were observed for 14, 28, and 90&#xa0;days after receiving two intramuscular doses of the H5N8 vaccine (15&#xa0;&#x3bc;g HA/dose) formulated with the IB160 oil-in-water emulsion adjuvant. No systemic comorbidities, central nervous system alterations, or relevant clinical signs were observed. Hematological parameters remained within normal ranges, with total and differential leukocyte counts showing only minor fluctuations (<1% of total leukocytes). Mild biochemical variations in urea and hepatic transaminase levels were not correlated with histopathological alterations. The vaccine elicited a robust humoral response soon after immunization, with all groups reaching protective HAI-antibody titers. Although antibody levels declined over time, particularly in males, they remained significantly above baseline, indicating durable immunological memory. Furthermore, the vaccine induced a specific cellular immune response, confirmed by IL-2 and TNF production by antigen-specific T lymphocytes in splenic cell cultures after the booster dose. In conclusion, the H5N8 vaccine with the IB160 adjuvant was well tolerated locally and systemically, without compromising vital organ function. The safety and immunogenicity findings are consistent with expectations for adjuvanted influenza vaccines, demonstrating strong and durable humoral and cellular immune responses.

H5N8 influenza vaccine↗
PubMed2005

Antibodies and PMBC from EIAV infected carrier horses recognize gp45 and p26 synthetic peptides.

Equine infectious anemia virus (EIAV) is a lentivirus causing a persistent infection in horses characterized by recurrent febrile episodes and high levels of viremia associated with a novel antigenic strain of the virus. The virus contains two envelope glycoproteins, gp90 and gp45, and four internal proteins, p26, p15, p11 and p9. Considering that the most infected horses are able to restrict EIAV replication to very low levels and that gp45 and p26 contain highly conserved epitopes among lentiviruses, it would be necessary to identify those conserved epitopes stimulating cellular and humoral responses. The aims of this study were to determine if the synthetic peptides identified as gp45 (aa 523-547) and p26 (aa 318-346) representing two highly conserved and immunodominant regions of EIA virus are recognized by PBMC and antibodies to EIAV adult mixed-breed naturally infected carrier horses, and if these peptides are able to induce immune responses in mice. Antibodies from 100% of carrier horses, evaluated by ELISA, recognized both peptides; PBMC from 80% of carrier horses, evaluated by lymphoproliferation assay, recognized, at least, one peptide. Furthermore, immunization with 100 microg of each peptide elicited humoral and cellular responses in BALB/c mice, antibodies appeared at 48 or 63 days of immunization with gp45 or p26, respectively. Although the kinetics of gp45- and p26-specific antibody responses were similar, percentage of positivity was higher for gp45. The lymphoproliferation assay, evaluated by BrdU uptake, was higher in mice immunized with gp45 or p26 than in the control group (P<0.05). Based on our findings, we consider that both peptides could be included in an effective vaccine design to induce long-term immunological memory.

Amino Acid Sequence↗
PubMed1992

Efficacy and safety of a Haemophilus influenzae type b capsular polysaccharide-tetanus protein conjugate vaccine.

A polyribosylribitol phosphate (polysaccharide)-tetanus protein conjugate vaccine (PRP-T) against Haemophilus influenzae type b (Hib) was evaluated for safety and efficacy after vaccination of more than 100,000 infants. No major side effects were attributed to the vaccine. Immunogenicity studies showed an antibody response in 70% to 100% of infants after two doses, and in 98% to 100% of infants after three doses, within the first 6 months of life. Antibodies persisted in 90% of recipients, in whom significant anamnestic responses developed after a booster dose at 18 months of age. In comparison with other available Hib vaccines, PRP-T induces equal or higher mean titers after three doses. Although licensure of other vaccines interrupted controlled efficacy trials, up to that point five cases of Hib disease in those trials had occurred in placebo recipients, and no Hib disease has been reported in the more than 100,000 vaccinated infants who have received more than one dose of PRP-T. Thus PRP-T combined immunogenicity early in life with induction of immunologic memory.

Bacterial Vaccines↗
PubMedDate not supplied

Manson Lecture. Meningococcal meningitis in Africa.

This review covers the history of meningococcal meningitis in Africa since epidemics of the infection were first described around 100 years ago. It is possible that an epidemic strain of the meningococcus was introduced into West Africa from the Sudan by pilgrims returning from the Haj around the turn of the century. Since 1905 major epidemics of meningococcal meningitis have occurred in countries of the Sahel and sub-Sahel every few years, culminating in a massive epidemic in which nearly 200,000 cases were reported in 1996. Attempts to control epidemic meningococcal meningitis in Africa by vaccination with meningococcal polysaccharide vaccines have met with only modest success because epidemics can progress with great rapidity and vaccination is often started too late. This situation should be improved as a result of a recent initiative, the International Coordinating Group (ICG), which is contributing to better surveillance in countries at risk and ensuring that vaccine is available when needed. However, in the medium term, the best prospect for the control of meningococcal meningitis in Africa lies in the recent development of polysaccharide-protein conjugate vaccines which, unlike polysaccharide vaccines, are immunogenic in the very young, induce immunological memory and are likely to give long-lasting protection.

Africa↗
PubMed1997

Peripheral blood dendritic cells reinduce proliferation in in vitro aged T cell populations.

Dendritic cells (DC) are professional antigen presenting cells which are essential for the initiation of an immune response. Recently we demonstrated that DC, which had been propagated from the peripheral blood of healthy elderly people, were morphologically and functionally intact. It was the aim of the present study to analyze how DC from young and old healthy individuals could affect T cell responsiveness to antigen in an in vitro senescence model. Tetanus toxoid (TT)-specific T cell lines were derived from 3 young (< 30 years) and 3 old (> 65 years) individuals and were kept in long term culture. T cell proliferation in response to stimulation with antigen presented by either autologous peripheral blood mononuclear cells (PBMC) or DC was assessed at three different time points, once soon after the initiation of the cultures and twice after 20 to 30 population doublings at a stage when growth, was slow and programmed cell death imminent. Antigen presentation by DC enhanced T cell proliferation at each time point and reinduced proliferation in in vitro aged T cell populations which had stopped dividing. Terminal apoptosis was thus prevented. DC from old individuals were as effective as cells from young donors. Our results demonstrate that DC stimulate the clonal expansion and postpone the clonal elimination of antigen-specific T cell populations. As a consequence they may increase immunoreactivity, prolong immunological memory and be of particular importance for the maintenance of the T cell repertoire in old age.

Adult↗
PubMed2002

Brain-immune interactions in sleep.

This chapter discusses various levels of interactions between the brain and the immune system in sleep. Sleep-wake behavior and the architecture of sleep are influenced by microbial products and cytokines. On the other hand, sleep processes, and perhaps also specific sleep states, appear to promote the production and/or release of certain cytokines. The effects of immune factors such as endotoxin and cytokines on sleep reveal species specificity and usually strong dependence on parameters such as substance concentration, time relative to administration or infection with microbial products, and phase relation to sleep and/or the light-dark cycle. For instance, endotoxin increased SWS and EEG SWA in humans only at very low concentrations, whereas higher concentrations increased sleep stage 2 only, but not SWS. In animals, increases in NREM sleep and SWA were more consistent over a wide range of endotoxin doses. Also, administration of pro-inflammatory cytokines such as IL-6 and IFN-alpha in humans acutely disturbed sleep while in rats such cytokines enhanced SWS and sleep. Overall, the findings in humans indicate that strong nonspecific immune responses are acutely linked to an arousing effect. Although subjects feel subjectively tired, their sleep flattens. However, some observations indicate a delayed enhancing effect on sleep which could be related to the induction of secondary, perhaps T-cell-related factors. This would also fit with results in animals in which the T-cell-derived cytokine IL-2 enhanced sleep while cytokines with immunosuppressive functions like IL-4 and L-10 suppressed sleep. The most straightforward similarity in the cascade of events inducing sleep in both animals and humans is the enhancing effect of GHRH on SWS, and possibly the involvement of the pro-inflammatory cytokine systems of IL-1 beta and TNF-alpha. The precise mechanisms through which administered cytokines influence the central nervous system sleep processes are still unclear, although extensive research has identified the involvement of various molecular intermediates, neuropeptides, and neurotransmitters (cp. Fig. 5, Section III.B). Cytokines are not only released and found in peripheral blood mononuclear cells, but also in peripheral nerves and the brain (e.g., Hansen and Krueger, 1997; März et al., 1998). Cytokines are thereby able to influence the central nervous system sleep processes through different routes. In addition, neuronal and glial sources have been reported for various cytokines as well as for their soluble receptors (e.g., Kubota et al., 2001a). Links between the immune and endocrine systems represent a further important route through which cytokines influence sleep and, vice versa, sleep-associated processes, including variations in neurotransmitter and neuronal activity may influence cytokine levels. The ability of sleep to enhance the release and/or production of certain cytokines was also discussed. Most consistent results were found for IL-2, which may indicate a sleep-associated increase in activity of the specific immune system. Furthermore, in humans the primary response to antigens following viral challenge is enhanced by sleep. In animals results are less consistent and have focused on the secondary response. The sleep-associated modulation in cytokine levels may be mediated by endocrine parameters. Patterns of endocrine activity during sleep are probably essential for the enhancement of IL-2 and T-cell diurnal functions seen in humans: Whereas prolactin and GH release stimulate Th1-derived cytokines such as IL-2, cortisol which is decreased during the beginning of nocturnal sleep inhibits Th1-derived cytokines. The immunological function of neurotrophins, in particular NGF and BDNF, has received great interest. Effects of sleep and sleep deprivation on this cytokine family are particularly relevant in view of the effects these endogenous neurotrophins can have not only on specific immune functions and the development of immunological memories, but also on synaptic reorganization and neuronal memory formation.

Animals↗
PubMedDate not supplied

Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study.

BACKGROUND: Universal anti-hepatitis-B vaccination of infants and adolescents was implemented in Italy in 1991. We undertook a multicentre study in previously vaccinated individuals to assess the duration of immunity and need for booster, over 10 years after vaccination. METHODS: In 1212 children and 446 Italian Air Force recruits vaccinated as infants and adolescents, respectively, we measured the concentrations of antibodies to hepatitis-B surface antigen (anti-HBs) and the presence of antibodies to hepatitis-B core antigen (anti-HBc) at enrollment; postimmunisation values were not available. Individuals positive for anti-HBc were tested for hepatitis B surface antigen (HBsAg) and hepatitis B viral DNA. Individuals with anti-HBs concentrations at 10 IU/L or more were regarded as protected; those with antibody less than 10 IU/L were given a booster dose and retested 2 weeks later. Individuals showing postbooster anti-HBs concentrations of less than 10 IU/L were offered two additional vaccine doses and retested 1 month after the third dose. FINDINGS: Protective anti-HBs concentrations were retained in 779 (64%, 95% CI 61.6-67) children and 398 (89%, 86.4-92.1) recruits. We recorded antibody amounts of less than 10 IU/L in 433 children (36%, 33-38.4) and 48 (11%, 7.9-13.6) recruits. One child and four recruits were positive for anti-HBc, but negative for HBsAg and hepatitis B viral DNA. Antibody concentrations were higher in recruits than in children (geometric mean titre 234.8 IU/L vs 32.1 IU/L, p=0.0001). 332 (97%) of 342 children and 46 (96%) of 48 recruits who received a booster showed an anamnestic response, whereas ten (3%) children and two (4%) recruits remained negative for anti-HBs or had antibody concentrations of less than 10 IU/L. Prebooster and postbooster antibody titres were strongly correlated with each other in both groups. All individuals given two additional vaccine doses (eight children and two recruits) showed anti-HBs amounts of more than 10 IU/L at 1 month after vaccination. INTERPRETATION: Strong immunological memory persists more than 10 years after immunisation of infants and adolescents with a primary course of vaccination. Booster doses of vaccine do not seem necessary to ensure long-term protection.

Adult↗
PubMedDate not supplied

An enhanced role for the recirculating lymphocyte in the neonatal immune system.

Lymphocytes continually recirculate between the blood and the tissues via the lymph independent of antigen. A great deal is known regarding both the physiology and the molecular mechanisms responsible for the process in adults. However, relatively little is known regarding the development of the recirculating lymphocyte pool in very young animals or fetuses. We have directly measured the recirculation of lymphocyte subsets in antigen-inexperienced newborn animals, and found extensive recirculation of T cells through both intestinal and subcutaneous lymph nodes. Apparent selective migration of recirculating lymphocytes could be attributed to subset-specific migration of gammadelta-T cells through subcutaneous lymph nodes. This clearly demonstrates that the preference for gammadelta-T cells to recirculate through SCLN is lineage specific, and independent of the presence of antigen. Most surprising was the observation that the recirculating lymphocyte pool was proportionately larger in neonatal animals than in adults, which correlated with the histological appearance of newborn lymph nodes. This data strongly suggests that development of the recirculating lymphocyte pool is inversely correlated with antigen exposure, and decreases in size with age and the acquisition of immunological memory.

Animals↗
PubMed1978

Early ontogeny of germinal center formation in the chicken.

Germinal center formation was studied in the spleen of young chickens immunized in ovo and at the time of hatching. When immunization was performed on day 18 in ovo and on the day of hatching, the first germinal centers were observed at 4 days. This is markedly earlier than in unimmunized chickens, where the first germinal centers appear at the age of 10 days or later. Germinal center formation preceded significant antibody production. The possible role of germinal centers in the generation of immunological memory is discussed in the light of these and earlier observations.

Aging↗
PubMed2001

Comparative evaluation of the CD4+CD8+ and CD4+CD8- lymphocytes in the immune response to porcine rubulavirus.

The porcine immune system is unique in the expression of CD4+CD8+ (double-positive, DP) lymphocytes. These cells have been associated with immunological memory due to their gradual increase with age, the expression of memory phenotype and their ability to respond to recall viral antigen. This work analyzes the biological function of CD4+CD8- and CD4+CD8+ lymphocytes in the immune response to porcine rubulavirus (PRv). CD4+CD8- cells isolated from pigs 3 weeks after infection with porcine rubulavirus proliferated in response to homologous virus and generated lymphoblasts which were predominantly of the CD4+CD8+ phenotype, whereas stimulation with mitogen induced proliferation but did not switch the phenotype. CD4+CD8- lymphocytes isolated after 10 weeks of infection proliferated in response to phytohemagglutinin (PHA) but did not proliferate in response to homologous virus and did not change their phenotype, whereas CD4+CD8+ lymphocytes proliferated in response to PHA and to viral antigen. The cytokine profile of both lymphocyte populations showed the presence of IL-2 and IL-10 transcripts, quantitation demonstrated that CD4+CD8+ cells expressed mainly IL-10, whereas CD4+CD8- lymphocytes expressed primarily IL-2. Our results show that CD4+CD8- lymphocytes in the early phase of porcine rubulavirus infection can be converted to double-positive cells expressing IL-10 in an antigen-dependent manner, and that CD4+CD8- T-cells late in infection do not acquire CD8.

Animals↗
PubMed1997

Induction of oral tolerance in carp (Cyprinus carpio L.) after feeding protein antigens.

Induction of oral tolerance against ferritin, recombinant surface glycoprotein of viral haemorrhagic septicemia virus (KLG18) and ovalbumin (OVA) was studied in carp. Feeding of ferritin or KLG18 resulted in lower Ab titres compared to unprimed controls when animals were intramuscularly (i.m.) injected with protein 10 weeks later and sampled 21 days after this injection. After administration of OVA by different routes (oral, anal, i.m.) and i.m. injection with OVA + Freund's incomplete adjuvant 2 months later, only a few fish responded to OVA as measured by serum Ab titres. Responsiveness to OVA appeared to be carp strain dependent. When an isogenic carp strain was selected for an optimal response to i.m. injection with OVA, this carp strain did not develop oral tolerance after feeding. In contrast, 6 x feeding high doses of OVA on subsequent days, resulted in immunological memory formation. Oral tolerance can be induced in carp, but differences in tolerance induction may depend on the protein used. A possible role of genetic factors in the induction of oral tolerance in fish is discussed.

Administration, Oral↗
PubMed1998

Quantitative detection of porcine interferon-gamma in response to mitogen, superantigen and recall viral antigen.

Five monoclonal antibodies (mAbs) specific for porcine interferon-gamma (PoIFN-gamma) were isolated and utilized to develop a PoIFN-gamma sandwich ELISA. Specific reactivity of each mAb with E. coli derived recombinant PoIFN-gamma, but not with rPoIL-2 or rPolL-10, was confirmed in an indirect ELISA and in Western blots. Competitive ELISAs showed that mAbs P2A4 and P2C11 bound an epitope which was not recognized by mAbs P2G10, P1B7 or P2F6. The latter three mAbs were able to neutralize the ability of natural and recombinant PoIFN-gamma to induce the de novo expression of class II MHC antigens on porcine endothelial cells. To simplify the detection of biologically active porcine IFN-gamma, a sandwich ELISA was developed using the mAb P2G10 as a capture antibody and mAb P2C11 as the detecting reagent. The sensitivity of the assay for PolFN-gamma ranged from 1 to 50 ng/ml. Peripheral blood mononuclear cells (PBMC) from all pigs tested produced IFN-gamma when stimulated with either mitogen (PHA) or superantigen (SEB). In contrast, only PBMC obtained from pigs which had previously been vaccinated against PrV produced IFN-gamma in response to stimulation with this virus. Interestingly, cultures with the highest lymphoproliferative response did not necessarily have the highest level of IFN-gamma production.Furthermore, for recall viral antigen, the lymphoproliferative response decreased with time after immunization, whereas the IFN-gamma response increased. Thus, measurement of IFN-gamma production appears to be a good indicator of anti-viral immunological memory.

Animals↗
PubMed2001

Novel vaccine strategies to T-independent antigens.

T cell independent antigens do not require T cell help to induce an immune response, and are characterized by a lack of immunologic memory. These antigens can be divided into two classes, TI-1 or TI-2. TI-1 antigens, such as bacterial lipopolysaccharide, are potent B-cell mitogens, capable of non-specific, polyclonal activation of B cells. In contrast, TI-2 antigens can only activate mature B cells and consist of highly repetitive structures, such as capsular polysaccharides (CPS) from bacteria. Many vaccines currently in use consist of purified capsular polysaccharides from pathogenic bacteria such as Streptococcus pneumoniae and Neisseria meningitidis. These vaccines are efficacious in immune-competent adults, however, due to their TI-2 nature, are not effective in children <2 years of age. Converting polysaccharides into T cell dependent (TD) antigens, allows children, <2, to produce an effective immune response. This review focuses on various strategies used to convert the immune response to polysaccharide antigens from TI-2 to a TD response. Conjugate vaccines, anti-idiotypic antibodies, phage display library technology and DNA vaccines are discussed.

Animals↗
PubMed2000

Immunity to diphtheria and tetanus in England and Wales.

The immunity profile of the English and Welsh population to diphtheria and tetanus has been determined by measuring diphtheria and tetanus antitoxin levels for 3088 and 3142 sera, respectively. Time-resolved fluorimetric immunoassay - DELFIA was used to measure diphtheria antitoxin levels and an in-house, indirect ELISA to measure tetanus antitoxin levels. More than 80% of those aged between 2 and 20-24 years had protective diphtheria antitoxin levels of 0.01 IU/ml, or greater, and more than 80% of those aged between 4 and 35-39 years had protective tetanus antitoxin levels of 0.1 IU/ml, or greater. Only 29% and 53% of those aged 60 and over were protected against diphtheria and tetanus. Two increases of diphtheria antitoxin levels greater than 0.1 IU/ml and tetanus antitoxin levels greater than 1.0 IU/ml were apparent, starting at 4 and 14 years of age, which correspond with the policy of giving a diphtheria and tetanus toxoid booster on school entry and a tetanus plus low-dose diphtheria toxoid (recently introduced) booster to school leavers. This is the first comprehensive study of diphtheria and tetanus immunity in the English and Welsh population and shows that the accelerated schedule of immunisation, introduced in 1990, has effectively primed immunological memory against both these antigens and that boosting at school entry and at school leaving is effective in increasing levels of immunity.

Adolescent↗