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Immune response to secondary immunization with live or inactivated VZV vaccine in elderly adults.

Healthy varicella zoster virus (VZV) immune subjects > 55 years old, were immunized with 4,000 PFU of Oka strain VZV live vaccine or a similar amount of heat-inactivated vaccine. A subset of each group was also immunized with tetanus toxoid (TT) 3 months before receiving the VZV vaccine. The live and inactivated VZV vaccine groups had similar ages, sex distribution, and previous immunity to VZV. The live and inactivated VZV vaccines elicited similar increases in the frequency in blood of VZV-specific T cells, in vitro interferon-gamma production, and serum antibody levels both 3 and 12 months after immunization. Individuals with the highest responder cell frequency (RCF) at entry had the highest postimmunization RCF following either vaccine. There was no correlation at entry between the RCF to TT or RCF to VZV. There was a weak (P = 0.05) correlation in the incremental response to TT and VZV among individuals who responded to both vaccines. Entry variables that did not correlate with the response included percent of T cells or the CD45R0 (memory) T cell subset in blood, serum antibody levels, or amount of interferon-gamma production. The results indicate that the inactivated vaccine is safe for VZV-immune subjects and boosts their antibody and T-cell responses as effectively as the live vaccine for at least 1 year following immunization.

Aged↗

Mediation of cytotoxic immune responses against human tumor-associated antigens by allogeneic immune RNA.

Allogeneic immune RNA (I-RNA), extracted from the peripheral blood lymphocytes of patients putatively cured of cancer, mediated cytotoxic immune reactions that apparently were directed specifically against human tumor-associated antigens. I-RNA was extracted from the peripheral blood lymphocytes of patients with various types of cancer. Patients selected had not been previously sensitized to HL-A or other normal transplantation antigens or to blood group antigens. Normal human peripheral blood lymphocytes were incubated with these allogeneic I-RNA preparations and tested for cytotoxicity against human target cells in vitro. Allogeneic I-RNA mediated cytotoxic immune reactions only against tumor target cells of the same histologic type as the I-RNA donor. I-RNA's extracted from peripheral blood lymphocytes of melanoma patients mediated cytotoxic immune reactions only against melanoma cells. Similarly, only I-RNA's extracted from the lymphocytes of patients with colon cancer mediated cytotoxic immune reactions against colon carcinoma cells, and only I-RNA's from the lymphocytes of breast cancer patients mediated immune reactions against breast cancer target cells. Allogeneic I-RNA extracted from peripheral blood lymphocytes of cancer patients possibly mediated specific cytotoxic immune reactions that were directed against common tumor-associated antigens shared by human tumors of similar histologic type.

Antigens, Neoplasm↗

Long-term persistence of protective immunity in cynomolgus monkeys immunized with a recombinant vaccinia virus expressing the human T cell leukaemia virus type I envelope gene.

To develop effective vaccines against infection with human T cell leukaemia virus type I (HTLV-I), we constructed a recombinant vaccinia virus (WR-SFB5env) synthesizing the HTLV-I envelope (Env) gp46 protein under the control of a strong promoter, termed the ATI hybrid promoter. WR-SFB5env expressed a large quantity of gp46. In cynomolgus monkeys (Macaca fascicularis) immunized with WR-SFB5env, anti-HTLV-I Env antibody, including neutralizing antibody, was induced and remained at a high level until 136 weeks (2-6 years) post-infection (p.i.). These immunized monkeys had HTLV-I Env-specific cytotoxic T lymphocyte activity. At 136 weeks p.i., the immunized monkeys were challenged with an HTLV-I-producing cynomolgus T lymphocyte cell line. Neither HTLV-I antigen nor HTLV-I proviruses were detected in peripheral blood mononuclear cells, lymph nodes or spleens of the WR-SFB5env-immunized monkeys, in contrast to non-immunized control monkeys. These results indicate that a single immunization with WR-SFB5env induced prolonged humoral and cellular immune responses to HTLV-I and protected the monkeys against virus challenge.

Animals↗

Intradermal immunization with a bovine herpesvirus-1 DNA vaccine induces protective immunity in cattle.

Although intramuscular (i.m.) injection of DNA encoding glycoprotein D (gD) of bovine herpesvirus-1 (BHV-1) induces immune responses in cattle, this route of delivery is inefficient. Here we assessed three parameters that may enhance the efficacy of a gD DNA vaccine in cattle. First, the immune response generated by i.m. injected plasmid expressing a secreted form of gD (tgD) was determined and found to be very similar in magnitude to the response induced by gD-expressing plasmid. Secondly, gD- and tgD-expressing plasmids were administered by intradermal (i.d.) immunization, which resulted in a superior immune response to the secreted form, but no improvement in the response to the membrane-associated form. However, the form of gD used for immunization did not influence the immunoglobulin subtype, the ratio of antigen-specific IgG1 to IgG2 being approximately 4:1. Finally, the effect of promoter strength was assessed by replacing the Rous sarcoma virus (RSV) promoter, which was used in the original experiments, with the human cytomegalovirus immediate early promoter and first intron A (HCMV/IA). Although upon transfection in vitro the HCMV/IA promoter appeared to be stronger than the RSV promoter, there was only a 2-fold higher antibody response in vivo upon i.d. injection of cattle. Protection against virus challenge was obtained in the calves immunized i.d. with tgD-encoding plasmid, as shown by a significant reduction in weight loss, virus excretion, temperature response and clinical disease. No significant protection was observed in the animals vaccinated i.d. with the gD-expressing plasmid, which correlates with the lower level of immunity pre-challenge.

Animals↗

The comparison of cell-mediated immunity induced by immunization with porin, viable cells and killed cells of Salmonella typhimurium.

A marked level of cell-mediated immunity (CMI) to Salmonella typhimurium-infection in mice, as determined by acquired resistance, delayed-type hypersensitivity, interleukin-2 production and interferon-gamma production, was induced by immunization with porin or viable cells but not with killed cells of S. typhimurium LT2. When the up-regulation of immune system to each immunogen was studied by comparing increases of Ia-bearing macrophages, the immunization with porin or viable cells, but not killed cells, could stimulate the immune system for more than 14 days. Interleukin-1 (IL-1) production of macrophages to each immunogen was also examined; the result showed that immunization with porin or viable cells could induce a notable level of IL-1 production, while killed cells could not. However, when the abilities to induce these immune responses were compared between UV-killed and heat-killed cells, UV-killed cells were superior to heat-killed cells. These results suggested that the ineffectiveness of immunogen that lacked CMI-inducing ability might be ascribed to the denaturation of antigen and the insufficient inductions of Ia-bearing macrophages and IL-1 production.

Animals↗

The nontoxic CTA1-DD adjuvant enhances protective immunity against Helicobacter pylori infection following mucosal immunization.

Safe and efficacious adjuvants are much needed to facilitate the development of mucosal vaccines. Here, we have asked whether our nontoxic vaccine adjuvant, CTA1-DD, can enhance protective immunity against Helicobacter pylori infection. Intranasal immunizations with H. pylori lysate together with CTA1-DD-adjuvant induced significant protection in C57Bl/6 mice, almost as strong as similar immunizations using cholera toxin (CT)-adjuvant. Protection remained strong even at 8 weeks postchallenge and the bacterial colonization was reduced by 20-fold compared to lysate-immunized controls. Although CTA1-DD was designed to bind to B cells, microMT mice developed significant, but lower, level of protection following immunization. Intranasal immunizations with CT adjuvant in C57Bl/6 mice resulted in the development of severe postimmunization gastritis at 2 and 8 weeks postchallenge, whereas the degree of gastritis was substantially lower in the CTA1-DD-immunized mice. Protection induced by both CTA1-DD- and CT adjuvant was associated with a strong local infiltration of CD4(+) T cells in the gastric mucosa, and recall responses to specific Ag elicited substantial IFN-gamma production, indicating Th1-dominance. These findings clearly demonstrate that CTA1-DD adjuvant is a promising candidate to be further exploited in the development of a mucosal vaccine against H. pylori infection.

Adjuvants, Immunologic↗

Special feature for the Olympics: effects of exercise on the immune system: effects of exercise on the immune system in the elderly population.

Immunosenescence is characterized by impaired cellular immune function concomitant with increased inflammatory activity. Immune dysfunction is associated with increased mortality risk in elderly people. An important part of human ageing is characterized by a decline in the ability of individuals to adapt to environmental stress. Exercise has been suggested as a prototype for studying the effects of stress factors on the cellular immune system. Studies of interactions between an acute bout of exercise and immune function may be a useful and an ethically acceptable tool to investigate cell trafficking, immune mobilization/deficiency and the acute phase response during physical stress situations in relation to human ageing. Elderly humans have a preserved ability to recruit T lymphocytes and NK cells in response to an acute bout of exercise. Physical exercise training programs do not result in major restoration of the senescent immune system in humans. However, highly conditioned elderly humans seem to have a relatively better preserved immune system, although it is not possible to conclude if this is linked to training or other lifestyle-related factors.

Adolescent↗

Immune complex deposition in adult male Sprague-Dawley rats chronically immunized with GnRH.

PROBLEM: This study was undertaken to evaluate whether the anti-GnRH antibodies and immune complexes (IC) generated by immunization with GnRH-TT cause cellular damage within the animal. METHOD OF STUDY: Chronic immunization of rats with GnRH-TT injected i.m. was followed by tissue/organ analysis for immune complex deposition by immunofluorescence microscopy. Two groups were studied: (1) those immunized throughout the experiment until their ultimate demise, and (2) those given a chance to recover from the effects of chronic immunization before final analysis. RESULTS: GnRH-TT was effective in stopping spermatogenesis, which resumed after withdrawal of the immunogen. Most tissues from chronically immunized animals were not significantly different than controls, however the kidneys of treated animals exhibited a higher accumulation of IC. Despite increased IC deposition, pathologic effects were not detected at the cellular level. CONCLUSIONS: GnRH-TT is an effective immunocontraceptive although the accumulation of glomerular IC represents a potential deleterious side effect.

Animals↗

The impact of immunization record aggregation on up-to-date rates--implications for immunization registries in rural areas.

Problems with poorly documented immunization records may be especially important in rural areas. To evaluate the potential impact of a regional registry in a rural region, this study quantified the change in documented immunization rates for nine primary care sites in rural Colorado resulting from the addition of public health department immunization clinic records. Manual chart reviews of immunization data were conducted at both private primary care and public health department sites in two geographic areas in rural Colorado. Data from private primary care sites were matched to data from the public health department sites. Immunization up-to-date (UTD) rates at each primary care site were then recalculated for 12- and 24-month-olds after including data from public health department sites. Of 1,533 children, 469 (31 percent) were given immunizations at both a private primary care and a public health department site. The UTD rate (3:2:3:2) of 12-month-olds using only data from primary care sites ranged from 32 to 79 percent. Including the public health department data increased the rates by 0 to 26 percent (mean = 11 percent) for 12-month-old children. The UTD rate of 24-month-olds (4:3:1:3 and any Hib on/after 12 months) ranged from 6 to 54 percent at the primary care sites. These rates increased by 6 to 21 percent (mean = 12 percent) when public health department data were added. This "virtual" registry combining primary care and public health department data increased calculated immunization rates at primary care sites substantially, with a range of 0 to 26 percent.

Colorado↗

Immunization of BALB/c mice with killed Neospora caninum tachyzoite antigen induces a type 2 immune response and exacerbates encephalitis and neurological disease.

BALB/c mice were immunized subcutaneously with soluble Neospora caninum tachyzoite antigen (NSO) entrapped in nonionic surfactant vesicles (NISVs) or administered with Freund's complete adjuvant (FCA). Following virulent parasite challenge, groups of mice immunized with NSO and either NISVs or FCA had clinical neurological disease and increased numbers of brain lesions compared to groups of mice inoculated with FCA, NISVs, or phosphate-buffered saline (PBS) alone. Increased numbers of brain lesions were statistically significant only between mice immunized with NISV-NSO and NISV- or PBS-treated mice. Following parasite challenge, brain inflammatory infiltrates in all experimental and control groups of mice were relatively similar and consisted of compact infiltrates of macrophages admixed with various numbers of lymphoid cells. Increased brain lesions in NSO-immunized mice were associated with increased antigen-specific interleukin 4 (IL-4) secretion and increased IL-4:gamma interferon secretion ratios from splenocytes in vitro and increased antigen-specific immunoglobulin G1 (IgG1):IgG2a ratios in vivo. Thus, immunization with whole killed N. caninum antigen and either liposoidal or Freund's adjuvant induced a type 2 immune response that was associated with worsened disease. The present studies emphasize the need to identify specific N. caninum antigens or other delivery systems that will elicit protective immune responses to neosporosis.

Animals↗

Passive immunization with milk produced from an immunized cow prevents oral recolonization by Streptococcus mutans.

Cell surface protein antigen (PAc) and water-insoluble glucan-synthesizing enzyme (GTF-I) produced by cariogenic Streptococcus mutans are two major factors implicated in the colonization of the human oral cavity by this bacterium. We examined the effect of bovine milk, produced after immunization with a fusion protein of functional domains of these proteins, on the recolonization of S. mutans. To prepare immune milk, a pregnant Holstein cow was immunized with the fusion protein PAcA-GB, a fusion of the saliva-binding alanine-rich region (PAcA) of PAc and the glucan-binding (GB) domain of GTF-I. After eight adult subjects received cetylpyridinium chloride (CPC) treatment, one subgroup (n = 4) rinsed their mouths with immune milk and a control group (n = 4) rinsed with nonimmune milk. S. mutans levels in saliva and dental plaque decreased after CPC treatment in both groups. Mouth rinsing with immune milk significantly inhibited recolonization of S. mutans in saliva and plaque. On the other hand, the numbers of S. mutans cells in saliva and plaque in the control group increased immediately after the CPC treatment and surpassed the baseline level 42 and 28 days, respectively, after the CPC treatment. The ratios of S. mutans to total streptococci in saliva and plaque in the group that received immune milk were lower than those in the control group. These results suggest that milk produced from immunized cow may be useful for controlling S. mutans in the human oral cavity.

Adult↗

Immunization with R mutants of Salmonella minnesota. II. Comparison of the protective effect of immunization with lipid A and the Re mutant.

The protective effect of active immunization with Salmonella minnesota Re bacilli or lipid A was assessed in the granulocytopenic rabbit model. Animals were immunized with Re bacilli, lipid A, or Pseudomonas aeruginosa as a nonspecific immunogen. After colonization with one of three enterobacterial strains (two Escherichia coli, one Enterobacter aerogenes), the immunized rabbits as well as controls given saline injections were made leukopenic with nitrogen mustard and monitored for fever, bacteremia, and death. Survival rates were significantly greater in Re-immunized animals than in saline controls or P. aeruginosa-immunized animals. Immunization with lipid A afforded no protection. In addition, rabbits immunized with Re mutant bacilli developed bacteremia less frequently than the others, indicating that antibody to Re may inhibit invasion of the intestinal mucosa as well as protect after bacteremia has developed.

Animals↗

Local (immunoglobulin A) immune response by the intestine to cholera toxin and its partial suppression with combined systemic and intra-intestinal immunization.

Chronically isolated Thiry-Vella (T-V) ileal loops in rabbits were used to study the local and systemic immune response to purified cholera toxin (CT). Immunization consisted of intraloop (i.l.), subcutaneous (s.c.), or combined i.l. and s.c. inoculation of CT. Fluid from the loops and sera were tested for neutralization of CT by the blueing test and for relative content of isotype-specific (immunoglobulins A [IgA] and G [IgG]) anti-CT. To demonstrate protection against CT, fluid production by the chronic T-V loops was measured after challenge with CT; an "acute" loop prepared from adjacent intestine at the time of challenge was also tested in some animals. The highest neutralizing titers in loop fluids were found in animals receiving i.l. or i.l. and s.c. inoculations, whereas titers in sera were highest in rabbits receiving s.c. or i.l. and s.c. inoculations. IgA anti-CT in fluids became greatest after i.l. inoculation alone and was lowest in s.c. animals. Combined s.c. and i.l. immunization was accompanied by reduced content of IgA anti-CT in fluids as compared with that obtained with i.l. inoculation alone. This finding strongly suggested a suppressive effect on local immunization by s.c. inoculation. While this suppression may have been due to a direct (toxigenic) effect of CT on lymphocytes, an immunogenic mechanism, probably mediated through suppressor T cells, is favored. Little IgG anti-CT was detected in any loop fluids, but high levels were found in sera after two s.c. inoculations or four i.l. inoculations. Neutralization titers for the fluid specimens showed much better correlation with IgA anti-CT values than with IgG anti-CT values. The chronic and acute T-V loops showed protection against fluid production after exposure to CT in systemically and locally immunized animals. However, IgG anti-CT usually appeared in both loops; leakage of serum antibodies because of surgical manipulation was felt, therefore, to invalidate these protection results as a demonstration of local immunity. In challenge studies in undisturbed chronic loops, only local immunization alone was found to result in definite protection.

Animals↗

Effect of parenteral immunization on the intestinal immune response to Salmonella typhi Ty21a.

The effects of parenteral administration of a killed typhoid vaccine on the intestinal immune response to live orally administered Salmonella typhi Ty21a in human subjects was evaluated. Priming with parenteral vaccination neither enhanced nor suppressed the subsequent specific serum and intestinal immunoglobulin A (IgA) immune responses to a booster course of live oral vaccine. Neither a single oral dose of live vaccine nor a single dose of parenteral vaccine had any measurable booster effect on the observed primary intestinal IgA response to the live oral vaccine. Two booster doses of subcutaneously administered killed typhoid vaccine did result in a significant increase in the specific intestinal IgA antibody in those subjects primed with the oral live vaccine. This response was comparable in magnitude to the primary intestinal response. No evidence of this response could be found in serum IgA, although nonsignificant rises in serum IgG were evident. Previous parenteral priming had no effect on secondary immune responses to a live oral vaccine in humans. Serum immune responses were generally found to be of little value as indicators of local intestinal immunity. This study confirmed that parenteral vaccination was only able to induce an intestinal immune response following priming with live, orally administered organisms and that multiple parenteral booster doses were necessary to induce a measurable effect on intestinal immune responses.

Adolescent↗

Adoptive transfer of immunity to oral challenge with virulent salmonellae in innately susceptible BALB/c mice requires both immune serum and T cells.

The mechanisms of immunity to salmonellae conferred by immunization with live vaccines were studied by adoptive transfer using the mouse-virulent strain Salmonella typhimurium C5 and innately susceptible BALB/c (ltys) mice. This organism cannot establish a sublethal infection in naive BALB/c mice. Animals immunized 2 to 3 months earlier with the S. typhimurium SL3261 aroA live vaccine were used as donors of serum, spleen cells, and mesenteric lymph node cells for naive recipients which were challenged orally with the virulent C5 strain. Simultaneous transfer of both immune serum and immune cells was necessary for protection. Simultaneously depleting the donors of CD4+ and CD8+ T cells by administration of antisera in vivo prior to cell harvesting showed that T cells were necessary for protection. The results demonstrate that both antibody and T cells are required for recall of immunity to oral challenge with virulent salmonellae in innately susceptible mice and suggest that the ability to elicit opsonizing antibody in addition to cell-mediated immunity is important for optimal protection induced by salmonella vaccines.

Animals↗

Comparison of immune responses of mice immunized with five different Mycobacterium bovis BCG vaccine strains.

Among the various parameters which may contribute to Mycobacterium bovis BCG vaccination efficiency, the choice of the vaccine strain may play an important role. In the present study, we therefore compared the immunogenicity of five different BCG strains that are commonly used for BCG vaccine production (Glaxo 1077, Japanese 172, Pasteur 1173P2, Prague, and Russian strains). The comparison of the growth capacity of these BCG strains in BALB/c and C3H mice demonstrated that a great difference exists between the capacity of various BCG strains to multiply and persist in target organs. A much lower recovery of BCG could be shown in mice immunized with Prague and Japanese BCG strains. T-cell responses of BCG-immunized mice were also examined by analyzing T-cell proliferative responses, cytokine production, delayed-type hypersensitivity responses, and cytotoxic activity. All these assays demonstrated that BCG immunization induced strong CD4+ T-cell responses, mostly of the Th1 type, as demonstrated by interleukin-2 and gamma interferon production. These studies also demonstrated that there are differences between BCG strains in stimulating these T-cell responses. A lack of induction of cytotoxic activity was observed following immunization with the Japanese strain. Lower anti-purified protein derivative antibody responses were also observed after intravenous or oral immunization with this BCG strain. Finally, the protective activity of these BCG strains was tested by measuring the capacity of immunized mice to eliminate recombinant Pasteur and Japanese BCG strains which expressed beta-galactosidase. The results of these experiments clearly demonstrated that the Prague and Japanese strains were unable to protect mice against a second mycobacterial challenge whereas mice immunized with the Glaxo, Pasteur, or Russian strain eliminated the recombinant BCG very efficiently. Altogether, the results of the present study strongly support the view that there are considerable differences in the immunogenicity of various BCG vaccine strains and that these differences may play a major role in BCG vaccination efficiency.

Animals↗

Oral immunization with PspA elicits protective humoral immunity against Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a major respiratory mucosal pathogen affecting infants and children. Although a polysaccharide-based vaccine has been useful in adult populations, it does not elicit protective immunity in infants and young children. Pneumococcal surface protein A (PspA) is a highly immunogenic surface protein produced by all strains of Streptococcus pneumoniae. Previous studies have shown that systemic immunization of mice with PspA can elicit protective immunity against fatal pneumococcal infection. In this study, we demonstrated that oral immunization with PspA could elicit protective immune responses against pneumococcal infection. When mice were orally immunized with PspA alone, low levels of PspA-specific immunoglobulin G (IgG) responses were induced in serum; none was induced in secretion. On the other hand, when PspA was given orally with the mucosal adjuvant cholera toxin (CT), significant levels of IgG and IgA anti-PspA responses were induced in serum. The major IgG subclass was IgG1, followed by IgG2b, a profile of antibody response supported by Th2-type cells. In addition, all mice orally immunized with PspA and CT were protected from the lethal challenge with capsular serotype 3 S. pneumoniae A66. These results suggested that an oral PspA vaccine may be a useful means of preventing pneumococcal disease.

Adjuvants, Immunologic↗

Rectal and intranasal immunizations with recombinant urease induce distinct local and serum immune responses in mice and protect against Helicobacter pylori infection.

To determine the optimal inductive sites for immunization against Helicobacter pylori infection, the protective efficacy of recombinant urease (rUre) was assessed for mice given the vaccine by either the oral (p.o.), intranasal (i.n.), or rectal route. When mice were immunized with rUre (25 microg p.o. or rectally or 10 microg i.n.) plus heat-labile toxin from Escherichia coli as the mucosal adjuvant, all routes afforded protection against challenge with H. pylori, as indicated by a significant reduction in gastric urease activity (P < 0.0005) compared to that of sham-immunized controls. Quantitative H. pylori culture of stomach tissue demonstrated a >97% reduction in bacterial burden in mice immunized by all routes (P < 0.05). Induction of antiurease immunoglobulin A (IgA) levels in gastric luminal secretions after p.o. immunization was greater than after i.n. administration (means, 6.0 and 1.02 ng/ml, respectively) and was dependent upon challenge with H. pylori. However, immunization by the rectal route resulted in the generation of the highest levels of gastric antiurease IgA (mean, 40. 89 ng/ml), which was detectable prior to challenge with H. pylori. Immunohistochemical staining of stomach tissue for cells secreting urease-specific antibody and CD4(+) T cells showed levels of recruitment to be dependent upon challenge with H. pylori and equivalent for all routes. These results identify both the rectum and nasal passages as suitable inductive sites for urease immunization.

Administration, Intranasal↗