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PubMed1987

Bovine cytotoxic T cell clones which recognize lymphoblasts infected with two antigenically different stocks of the protozoan parasite Theileria parva.

The Muguga and Marikebuni stocks of Theileria parva differ on the basis of cross-protection and in their schizont antigen profile determined with a panel of parasite-specific monoclonal antibodies. The phenotype and specificity of six cytotoxic T cell clones generated from an animal immunized against T. parva (Marikebuni) were investigated. All six clones had the BoT2+ BoT4- BoT8+ phenotype, were dependent on both specific antigen and T cell growth factor for proliferation and were restricted by determinants on class I major histocompatibility complex molecules. The clones killed target cells infected with either the Muguga or Marikebuni stocks of the parasite; the target cell lines tested included T cell clones which were infected in vitro with the two parasite stocks and subsequently recloned. The specificity of these cytotoxic T cell clones contrasts with that of T cell clones generated previously from animals immunized against T. parva (Muguga), in that the latter were specific for target cells infected with the Muguga stock of the parasite. Moreover, one of the clones generated against T. parva (Marikebuni) was restricted by the same major histocompatibility complex molecule as the Muguga-specific T cell clones. The difference in parasite strain-specificity between the two sets of clones appears to reflect the capacities of the two parasite stocks to cross-protect, since animals immunized against T. parva (Marikebuni) are protected against challenge with T. parva (Muguga) whereas a proportion of animals immunized with T. parva (Muguga) are susceptible to challenge with T. parva (Marikebuni). Another difference between the two sets of T cell clones was that those generated against T. parva (Marikebuni) only killed a proportion of cells of a given cell line in a 4-h cytotoxicity assay, whereas Muguga-specific T cells invariably kill the majority of cells. However, despite this partial killing, the clones markedly inhibited growth of parasitized cell lines when cultured with them for a period of 5 days.

Animals↗
PubMed1996

Synthetic recombinant influenza vaccine induces efficient long-term immunity and cross-strain protection.

Synthetic vaccines utilize specific antigenic epitopes in order to elicit a protective immune response. In this work we examined the immunogenicity of chimeric proteins expressing influenza epitopes and their ability, as single products or in various combinations, to protect mice from viral challenge. Oligonucleotides coding for three epitopes (HA91-108, NP55-69 and NP147-158) stimulating B cells, T helper cells and cytotoxic T lymphocytes (CTLs), respectively, were individually inserted into the flagellin gene of a Salmonella vaccine strain. Immunization of mice with the resultant hybrid flagella resulted in a specific humoral or cellular response. The protective efficacy of the chimeric flagella was evaluated by intranasal immunization of mice, without any adjuvant, and subsequent challenge with infectious virus. The construct containing the B-cell epitope by itself led to partial protection. However, the addition of the two T-cell epitopes augmented the protection in a significant manner. The protective immunity conferred by this combined vaccine, comprising the three epitopes, persisted for at least 7 months after the last boost, and was effective against several influenza A strains. Furthermore, this vaccine fully protected mice from a lethal challenge, and enhanced their recovery process. Our results indicate that stimulation of the different arms of the immune system is required for effective anti-influenza response, and demonstrate the applicability of such synthetic recombinant approach for preparing a broad spectrum influenza vaccine.

Amino Acid Sequence↗
PubMed2005

Cross-compartment protection by SOD1.

The absence of SOD1 in yeast has been found to result in inactivation of Lys4p. This [4Fe-4S]-containing dehydratase is in the pathway of biosynthesis of lysine, hence the oxygen-dependent lysine auxotrophy seen in this case. O(2)(-) is known to oxidize and thus destabilize the [Fe-4S] clusters of dehydratases; hence, this would make perfect sense were it not for the fact that SOD1 localizes to the cytosol and the intermembrane space of mitochondria, whereas Lys4p localizes to the mitochondrial matrix. How could SOD1 in one compartment protect against O(2)(-) attack in a different compartment? We suggest that the relatively high levels of O(2)(-) in the cytosol and intermembrane space of the SOD1 mutant may react with endogenous NO, forming HOONO that can diffuse into the mitochondrial matrix and there inactivate Lys4p and other [4Fe-4S]-containing dehydratases.

Amino Acids↗
PubMed2004

Superoxide inhibits 4Fe-4S cluster enzymes involved in amino acid biosynthesis. Cross-compartment protection by CuZn-superoxide dismutase.

Among the phenotypes of Saccharomyces cerevisiae mutants lacking CuZn-superoxide dismutase (Sod1p) is an aerobic lysine auxotrophy; in the current work we show an additional leaky auxotrophy for leucine. The lysine and leucine biosynthetic pathways each contain a 4Fe-4S cluster enzyme homologous to aconitase and likely to be superoxide-sensitive, homoaconitase (Lys4p) and isopropylmalate dehydratase (Leu1p), respectively. We present evidence that direct aerobic inactivation of these enzymes in sod1 Delta yeast results in the auxotrophies. Located in the cytosol and intermembrane space of the mitochondria, Sod1p likely provides direct protection of the cytosolic enzyme Leu1p. Surprisingly, Lys4p does not share a compartment with Sod1p but is located in the mitochondrial matrix. The activity of a second matrix protein, the tricarboxylic acid cycle enzyme aconitase, was similarly lowered in sod1 Delta mutants. We measured only slight changes in total mitochondrial iron and found no detectable difference in mitochondrial "free" (EPR-detectable) iron making it unlikely that a gross defect in mitochondrial iron metabolism is the cause of the decreased enzyme activities. Thus, we conclude that when Sod1p is absent a lysine auxotrophy is induced because Lys4p is inactivated in the matrix by superoxide that originates in the intermembrane space and diffuses across the inner membrane.

Amino Acids↗
PubMed1988

Oral immunization of rabbits with enterotoxigenic Escherichia coli protects against intraintestinal challenge.

The development of a successful oral vaccine against enterotoxigenic Escherichia coli depends upon the identification of appropriate protective antigens which can be delivered effectively to intestinal mucosa. We have determined in a modified RITARD model the relative protection against intraintestinal challenge afforded by oral immunization with live enterotoxigenic E. coli carrying different candidate antigens. Studies were done with both wild-type strains and genetically manipulated strains of enterotoxigenic E. coli (parent strain E1392/75 2A) which carried plasmids containing intact heat-labile toxin (LT) gene sequences or various mutations of the LT genes. Immunizations were done by orogastric tube inoculation on days 0, 7, and 14; challenges were done on day 33. Protection against diarrhea with a homologous challenge was found to be 84 to 100% (P less than 0.01). Protection against diarrhea with challenges in which specific antigens could be tested included the following: (i) O and H antigens (O6:H16), 87 to 100% protection with different E. coli strains with identical O and H antigens (P less than 0.01) but no protection against a heterologous challenge; (ii) LT or the B subunit of LT only, approximately 50% protection (P less than 0.02). These findings suggest that O antigens are highly protective in this model but afford only serotype-specific protection and that the B subunit (with or without the A subunit) affords less protection but confers cross-protection against heterologous strains producing LT. This model should be useful in further defining appropriate protective antigens for candidate enterotoxigenic E. coli vaccine strains.

Administration, Oral↗
PubMed2006

Prospects for cervical cancer prevention by human papillomavirus vaccination.

Recent clinical trials in young women have shown that subunit vaccines based on human papillomavirus (HPV) 16 and HPV18 L1 virus-like particles are approximately 100% effective in short-term prevention of persistent cervical infection and of cervical dysplasia by these major oncogenic types. These remarkable efficacy results, together with an excellent safety profile in thousands of vaccinated women, have led to the HPV prophylactic vaccine from one manufacturer having now been licensed for commercial use and the expectation that the vaccine from a second manufacturer will be approved in the near future. These vaccines seem to have great potential for reducing cervical cancer deaths and treatments to remove premalignant cervical lesions. However, before their public health effect can be fully estimated, several issues must be addressed. These include duration of protection, degree of cross-protection against nonvaccine types, efficacy in men, and vaccine availability to economically disadvantaged women.

Clinical Trials as Topic↗
PubMed2001

Heterosubtypic immunity against human influenza A viruses, including recently emerged avian H5 and H9 viruses, induced by FLU-ISCOM vaccine in mice requires both cytotoxic T-lymphocyte and macrophage function.

Induction of heterosubtypic immunity to influenza viral antigens is of paramount importance to the prevention of epidemics and potential pandemics. The 1997 incidence of avian influenza infections in humans in Hong Kong heightened the need for pandemic preparedness and a search for vaccines and vaccine delivery systems that can confer broad protection. In this report, we demonstrate that the delivery of H1N1 subtype influenza viral antigens as immunostimulating complexes (ISCOM) induces broad cross-protection in mice against challenge with various influenza virus subtypes, including the avian H9 and the H5 strains that were recently responsible for deaths in humans. The ISCOM delivery system induced high and long-lived serum antiviral antibodies and class I-restricted cytotoxic T-lymphocytes (CTL). Studies with perforin, IFN-gamma, and mu-chain gene knock-out mice demonstrated that the heterosubtypic protection required cross-reactive, functional cytotoxic T cells and nonhemagglutination inhibiting serum antibodies. Interferon-gamma, a major player in viral clearance by nonlytic mechanisms, did not appear to play a role in heterosubtypic immunity. Nonformulated H1N1 influenza antigens failed to induce significant CTL or long-lasting antibody responses or to protect mice against challenge with heterosubtypic viruses. Furthermore, while influenza virus infection induced a dominant nucleoprotein (NP)-specific CTL response in H2 mice, the ISCOM delivery system induced a dominant hemagglutinin-specific CTL response. Moreover, non-neutralizing but cross-reactive antibodies played a role in reducing viral titers by macrophages. These results suggest that exogenous delivery of influenza antigens as ISCOM can influence their antigen processing and presentation, their ability to induce/recall CTL specificities, and their capacity to mediate broad cross-protection against influenza virus variants.

Animals↗
PubMed1995

Immunogenicity and protective ability of corpuscular and soluble vaccines prepared from different Coxiella burnetii phase I strains.

BALB/c mice immunized intraperitoneally (ip) with killed purified Coxiella burnetii phase I corpuscular vaccines or trichloroacetic acid (TCA) extracts from phase I corpuscles (soluble vaccines) were protected against ip challenge with both homologous and heterologous C. burnetii phase I strains. Though the degree of protection, namely the inhibition of C. burnetii multiplication in the mouse spleen slightly varied, in general, corpuscular vaccines provided better protection than soluble ones. Cross-protection was accompanied by comparable levels of cell-mediated immune response as evaluated by lymphocyte transformation test (LTT). However, higher stimulation indices of LTT were obtained with homologous than with heterologous strains. The values of antibody response as determined by enzyme-linked immunosorbent assay (ELISA) were higher with homologous strains too. On average, both antibody-inducing and antibody-binding capabilities of the strains Priscilla and S were lower than those of the Nine Mile and Luga strains, except for values obtained with the antigens from homologous strains.

Animals↗
PubMed1993

Two successive outbreaks of SRSV-associated gastroenteritis in South Africa.

Two successive outbreaks of gastroenteritis in South Africa were investigated to identify the aetiological agents. Some patients were involved in both outbreaks. Enteropathogenic bacteria or parasites were not evident in either outbreak. Small round structured viruses (SRSVs) were demonstrated in both outbreaks by direct electron microscopy. SRSV UK3/Hawaii virus was identified by immune electron microscopy as the causative agent in the first outbreak. Using new recombinant Norwalk virus (rNV) immunoassays for antibodies and antigen, Norwalk virus was implicated in the second outbreak. Preexisting antibodies to Norwalk virus were not protective and there was no cross protection between Hawaii and Norwalk viruses. There was no anamnestic response to Norwalk virus following the SRSV UK3/Hawaii outbreak although those affected had preexisting antibodies to Norwalk virus. To our knowledge, this is the first definitive diagnosis of SRSV-associated gastroenteritis in South Africa.

Adult↗
PubMed2006

In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans.

BACKGROUND: Currently available vaccines against leptospirosis are of low efficacy, have an unacceptable side-effect profile, do not induce long-term protection, and provide no cross-protection against the different serovars of pathogenic leptospira. The current major focus in leptospirosis research is to discover conserved protective antigens that may elicit longer-term protection against a broad range of Leptospira. There is a need to screen vaccine candidate genes in the genome of Leptospira interrogans. RESULTS: Bioinformatics, comparative genomic hybridization (CGH) analysis and transcriptional analysis were used to identify vaccine candidates in the genome of L. interrogans serovar Lai strain #56601. Of a total of 4727 open reading frames (ORFs), 616 genes were predicted to encode surface-exposed proteins by P-CLASSIFIER combined with signal peptide prediction, alpha-helix transmembrane topology prediction, integral beta-barrel outer membrane protein and lipoprotein prediction, as well as by retaining the genes shared by the two sequenced L. interrogans genomes and by subtracting genes with human homologues. A DNA microarray of L. interrogans strain #56601 was constructed for CGH analysis and transcriptome analysis in vitro. Three hundred and seven differential genes were identified in ten pathogenic serovars by CGH; 1427 genes had high transcriptional levels (Cy3 signal > or = 342 and Cy5 signal > or = 363.5, respectively). There were 565 genes in the intersection between the set encoding surface-exposed proteins and the set of 307 differential genes. The number of genes in the intersection between this set of 565 and the set of 1427 highly transcriptionally active genes was 226. These 226 genes were thus identified as putative vaccine candidates. The proteins encoded by these genes are not only potentially surface-exposed in the bacterium, but also conserved in two sequenced L. interrogans. Moreover, these genes are conserved among ten epidemic serovars in China and have high transcriptional levels in vitro. CONCLUSION: Of the 4727 ORFs in the genome of L. interrogans, 226 genes were identified as vaccine candidates by bioinformatics, CGH and transcriptional analysis on the basis of the theory of reverse vaccinology. The proteins encoded by these genes might be useful as vaccine candidates as well as for diagnosis of leptospirosis.

Bacterial Outer Membrane Proteins↗
PubMed1986

Cell mediated immunity cross-reactions of mycobacteria: polymorphism of target bacterial antigens.

Swiss white mice were immunized with different mycobacteria and delayed type hypersensitivity (DTH) responses were studied by the foot-pad swelling technique of Gray and Jennings (1955). Extensive cross-reactions in DTH, outside the limits of Runyon's groups were observed. As a general trend slow growing mycobacteria showed greater cross-reactivity with slow growers than with rapid growers and vice versa. The implied cross-protective significance of DTH cross-reactions was further confirmed by demonstration of the ability of DTH cross-reacting sonicates to generate activated macrophages in M. avium immunized mice. An antiserum was raised against the earlier reported DTH eliciting antigen of M. tuberculosis H37Rv (DTH-H37Rv). The sero-reactivity of anti-DTH-H37Rv against the sonicates of different mycobacteria was studied with the objective of investigating the molecular basis of DTH cross-reactivity. Immunoprecipitation reactions of different mycobacterial sonicates with anti-DTH-H37Rv showed that the antigen was shared by all the mycobacteria tested irrespective of their cross-reactivity in a DTH response. All of the slow growers showed reactions of total identity with DTH-H37Rv. However with rapid growers DTH-H37Rv showed only a partial identity. From these data it was concluded that an antigen participating in DTH response is shared by all mycobacteria and that it is polymorphous, having genus specific and group specific (as slow and rapid grower groups) determinants.

Animals↗
PubMed2000

Hookworm burden reductions in BALB/c mice vaccinated with recombinant Ancylostoma secreted proteins (ASPs) from Ancylostoma duodenale, Ancylostoma caninum and Necator americanus.

Vaccination of mice with alum-precipitated recombinant Ancylostoma secreted protein-1 from the canine hookworm Ancylostoma caninum (Ac-ASP-1) results in protection against A. caninum larval challenge. Vaccine protection is manifested by host reductions in hookworm burden compared to control mice. The goal of this study was to determine whether ASP antigens cloned and expressed from different hookworm species will cross protect against A. caninum larval challenge. Cross-species protection against A. caninum challenge infections was observed with immunizations using recombinant ASP-1 from the human hookworms Ancylostoma duodenale and Necator americanus. However, the degree of protection was proportional to the extent of amino acid sequence homology between the ASP immunogen used for vaccination and the Ac-ASP-1 produced by the challenge larval strain. Vaccine protection was noted to decrease significantly as amino acid sequence homologies diverged 10% or more. It was also determined that Ac-ASP-2, a molecule cloned from A. caninum having 55% amino acid sequence homology to the C-terminus of Ac-ASP-1, did not elicit vaccine protection. These observations were partly reflected in the titer of antibodies that recognize Ac-ASP-1. The studies reported here will help to design immunogenic peptide vaccines based on the sequence divergence of hookworm ASPs.

Ancylostoma↗
PubMed1987

The roles of influenza virus haemagglutinin and nucleoprotein in protection: analysis using vaccinia virus recombinants.

Vaccinia virus recombinants expressing haemagglutinin (HA) or nucleoprotein (NP) from influenza virus A/PR/8/34 were used to investigate protective immunity in mice, with two protocols. Protection was assessed by mortality and morbidity rates and by lung virus titres after infection intranasally with A/PR/8/34. In the first protocol, mice immunized with vaccinia-HA recombinant virus and infected intranasally with A/PR/8/34 were almost totally protected, but mice immunized with vaccinia-NP virus were very poorly protected. In the second protocol, the recombinant viruses were used to stimulate in vitro T cells that are specific for HA and NP; both populations of T cells, when transferred to A/PR/8/34-infected mice, afforded good protection. The results indicate that an immune response specific for just HA provided protection that was almost indistinguishable from that provided by whole A/PR/8/34. On the other hand, immunization with vaccinia-NP provided poor protective immunity, despite the fact that transferred NP-specific T cells were very effective and vaccinia-NP immunization has previously been shown to stimulate cytotoxic T cells. These results demonstrate that a single viral antigen, delivered by live vaccinia virus, can provide effective protection, but that immunization for cross-protection against heterologous influenza virus remains elusive.

Animals↗
PubMed2000

A proposal for safety standards for human use of cholera toxin (or Escherichia coli heat-labile enterotoxin) derivatives as an adjuvant of nasal inactivated influenza vaccine.

Cholera toxin (CT) and Escherichia coli heat-labile toxin (LT) are not only the causative agents of diarrhea but are also strong mucosal adjuvants which enhance immune responses to mucosally coadministered bystander antigens. One of the most promising applications of these toxins would be as mucosal adjuvant of nasal influenza vaccine. In comparison to current inactivated vaccines, the nasal vaccine provides superior cross-protection by inducing production of cross-reacting anti-viral IgA antibodies in the respiratory tract even when the vaccine strain is different from the epidemic strain. On the use of the toxins as mucosal adjuvants in humans, toxicity and allergenicity of the toxins are problems which impinge on safety. To resolve these problems, various approaches have been attempted to produce less toxic and less allergenic CT (or LT) derivatives. We now propose the following standards for human use of safer CT (or LT) derivatives as an adjuvant of a nasal influenza vaccine. Thus, CT (or LT) derivatives can be administered intranasally together with a current inactivated influenza vaccine, provided they meet the following criteria. 1) A single dose of the derivatives, administered intranasally by spraying, should be around 100 Eg/adult in a volume of less than 0.5 ml. 2) CT (or LT) derivatives should retain the properties of the native CT (or LT), i. e., the ability to augment secretory IgA and serum IgG Ab responses to viral surface glycoproteins, when administered intranasally together with an inactivated influenza vaccine. 3) CT (or LT) derivatives should not induce IgE Ab responses to the vaccine, as well as to the CT (or LT) itself. 4) The CT (or LT) should be nontoxic; the toxicity of the derivatives, as determined by the Y-1 adrenal cell assay, should not exceed 1/100 EC(50) of the native CT (or 1/1000 ECi of the native CT). 5) CT (or LT) derivatives should not cause serious disease in guinea pigs when administered intranasally or intraperitoneally at the dose used in humans (around 100 Eg).

Adjuvants, Immunologic↗
PubMedDate not supplied

Study of protection by recombinant fowl poxvirus expressing C-terminal nucleocapsid protein of infectious bronchitis virus against challenge.

A stable recombinant fowl poxvirus (rFPV) expressing the C-terminal region (119 amino acids) of the nucleocapsid (N) protein of an infectious bronchitis virus (IBV) strain Ch3 was constructed by inserting the coding sequence within the thymidine kinase gene of fowl poxvirus (FPV) by homologous recombination. The N protein was expressed under control of the vaccinia virus promoter P7.5 in chicken embryo fibroblast cell cultures as seen in immunofluorescence assay and in rFPV-inoculated specific-pathogen-free (SPF) chickens by detecting antibodies with enzyme-linked immunosorbent assay (ELISA). A homologous IBV strain (Ch3) and two heterologous IBV strains (Ch5 and H4) were used to inoculate SPF chickens in a challenge to examine the protective efficacy of the rFPV. When the chickens were challenged with IBV Ch3 or Ch5, the control birds had respiratory signs of infections bronchitis, whereas all the vaccinated birds were clinically normal although low levels of the IBV infection were detected by a differential ELISA. In contrast, in the chickens challenged with IBV H4, all control birds and vaccinated birds suffered from the highly lethal IBV H4 infection. Our results suggest that the C-terminal 119 amino acid of the nucleocapsid expressed by FPV is a host-protective antigen and may induce cross-protective immunity against illness among some IBV strains.

Amino Acid Sequence↗
PubMed1991

Significance of flagella in colonization resistance of rabbits immunized with Campylobacter spp.

Cross-protection among different Lior and Penner serogroups of Campylobacter spp. was studied. Rabbits were orally immunized by gastric feeding with Campylobacter spp., and 27 to 30 days later, they were challenged with matched or unmatched serogroups by the removable intestinal tie adult rabbit diarrhea (RITARD) procedure. When immunized animals were challenged with different Lior serotypes, no protection against colonization was seen; however, when challenged with homologous Lior serogroups, protection was demonstrated. Immune animals were colonized for an average of 1 day or less versus at least 6 days for nonimmune animals. Rabbits challenged with matched Penner-unmatched Lior strains showed only marginal protection. Our study also demonstrated that flagella are important in initiating colonization and eliciting protective immunity. Campylobacter coli VC167B3, an isogenic, nonflagellated mutant, did not colonize rabbits regardless of the route of administration. Single feeding of the mutant strain did not protect the host, whereas three feedings, 48 h apart, resulted in complete protection against the flagellated parent strain. When mutant strain immunized rabbits were challenged with other strains of the same Lior serotype, marginal protection was obtained. Immunogold labeling indicated that there is one or more antigens on the cell surface of the nonflagellated mutant which reacts with a polyclonal antiserum from organisms of the same Lior serogroup. These data implicated the flagellum as the cross-strain protective component of the Lior antigen complex.

Animals↗