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PubMed1985

Comparison of rat liver foci assay and strain A mouse lung tumor assay to detect carcinogens: a review.

A comparison was performed of the results reported in the literature of chemicals tested in the rat liver foci assay and/or in the strain A lung tumor assay to the results of the chemicals tested in long-term carcinogenicity bioassays. The rat liver foci assay was sensitive to 69% of 54 compounds found to be carcinogenic in long-term bioassays and the strain A lung tumor assay to 54% of 93 carcinogens. None of 10 compounds found to be noncarcinogenic in long-term bioassays were active in the rat liver foci assay, while 7 of 23 noncarcinogens (30%) were active in the lung tumor assay. Ten of the 17 carcinogens negative in the rat liver foci assay are believed to exhibit tumor-promoting activity; 3 are direct-acting alkylating agents (dimethylsulfate, epichlorohydrin, and beta-propiolactone); and the remaining 3 are azobenzene, 1,2-dibromoethane, and thioacetamide. Thirty-two of the 43 carcinogens negative in the lung tumor assay were active in either (1) the mouse liver only, (2) the rat and not in the mouse, or (3) in both the rat and mouse liver but not in other organs of the mouse. It is proposed that additional investigations be undertaken to further evaluate the rat liver foci assay and the strain A mouse lung tumor assay as short-term in vivo tests for the demonstration of the carcinogenic potential of genotoxic (mutagenic) chemicals and environmental samples of complex mixtures.

Adenoma↗
PubMed1988

Two-year carcinogenicity study on three aromatic epoxy resins applied cutaneously to CF1 mice.

The cutaneous and systemic carcinogenic potentials of pure and two technical diglycidyl ethers of bisphenol A, DGEBPA, EPON 828 and EPIKOTE 828, respectively, have been investigated in six groups each of 50 male and 50 female CF1 mice. Twice weekly over a period of 2 yr, 0.2 ml of a 1 or 10% (w/v) solution of one of the epoxy resins in acetone was applied to the dorsal skin. A group of 50 male and 50 female CF1 mice was similarly treated treated with 2% (w/v) beta-propiolactone in acetone (the positive control) while a group of 100 male and 100 female mice was treated with acetone alone (negative control). Survival of the CF1 mice to 2 yr was unaffected by cutaneous exposure to each epoxy resin. The compounds proved to be mildly irritant to murine skin, the response in males being greater than in females. There was a very low incidence of benign and malignant tumours of the skin and subcutis after exposure to any of these compounds. The number of systemic lymphoreticular/haematopoietic tumours was increased only in females treated with EPIKOTE 828 or DGEBPA. In male mice, treated with 10% EPON 828, there was a slight increase in the number of renal tumours. The incidence of other systemic tumours in either sex was not increased following cutaneous application of the purified or the two technical DGEBPA resins (1 to 10% in acetone). The significance of all these findings is fully discussed.

Administration, Topical↗
PubMedDate not supplied

The carcinogenic response in mice to the topical application of propane sultone to the skin.

The carcinogenic effects of limited and repeated skin applications of propane sultone were investigated in three strains of mice, CF1, C3H and CBah (a hairless strain). Propane sultone was shown to be carcinogenic when given as a single application of a 25% w/v solution in toluene and also following twice weekly application of a 2.5% w/v solution for up to 58 weeks. More limited exposure to 2.5% w/v solutions of propane sultone resulted in a few skin tumours, although the incidences were not statistically significant. Most neoplasms were papillomas or carcinomas, although a small number of mesenchymal tumours of dermal origin also developed. No skin neoplasms were found in any control mice. The skin application of propane sultone was associated with a statistically significant increase in the incidence of systematic neoplasia in CFl and C3H mice. The exposed CFl mice had a higher incidence of neoplasms of lymphoreticular and lung origin, while female C3H mice showed a higher incidence of mammary gland and uterine tumours. In mice exposed to beta-propiolactone as a positive control, neoplasms developed at the site of application but, there was no evidence of increased systemic neoplasis in contrast to the findings with ptopane sultone.

Animals↗
PubMed1991

Protection against murine potomac horse fever by an inactivated Ehrlichia risticii vaccine.

Ehrlichia risticii propagated in a murine macrophage cell line were freed from the host cell by hypotonic lysis of the infected cells. The cell-free ehrlichiae were inactivated with beta-propiolactone and combined or not combined with polymyxin-B. The vaccines were administered to mice with Quil-A (saponin) as an adjuvant twice at 2 to 3 week intervals and the mice were challenged with live E. risticii 2 to 3 weeks after the last vaccination. With or without the addition of polymyxin-B, the vaccine preparations protected mice from developing clinical signs and gross pathologic changes such as thymic atrophy, splenomegaly, and increase in whole intestinal weight. Mice vaccinated with or without polymyxin-B developed high titer IgG antibody against E. risticii before and after the challenge with live E. risticii. Spleen lymphocyte proliferative response assay at 11 days post challenge revealed that with polymyxin-B a higher lymphocyte proliferation occurred as compared with that of the mice which received polymyxin-B-free vaccine. Spleen lymphocytes of the placebo (polymyxin-B and Quil-A) pretreated/challenged mice showed no proliferative activity. Western blot analysis revealed that vaccinated mice reacted mainly with 110, 57 and 33 kDa antigen bands before and after challenge. The placebo (polymyxin-B and Quil-A)/challenged mice showed a very weak response to ehrlichial antigens at day 10 to 11 post challenge. Comparison with inactivated Renografin-purified E. risticii or 0.25% SDS-insoluble fraction of E. risticii with the inactivated host cell-free vaccine revealed no increased protection. These results indicate that inactivated host cell-free E. risticii can protect mice from murine Potomac horse fever. The presence of polymyxin-B appeared to be not harmful but rather beneficial for lymphocyte proliferation response upon challenge with live E. risticii.

Adjuvants, Immunologic↗
PubMed1994

Systemic vaccination with inactivated bovine virus diarrhoea virus protects against respiratory challenge.

Inactivated bovine virus diarrhoea virus, strain 11249nc, inoculated subcutaneously three times with Quil-A into calves protected against intranasal challenge with the same strain. Virus was isolated from nasopharyngeal swabs taken 4 to 8 days post challenge and blood taken 4 to 6 days post challenge from control calves but not from vaccinated calves. A second strain of virus, Ky1203nc, was selected on the basis of previously established data on its antigenicity and the amount of viral antigen produced by five cell cultures compared using an ELISA. Cultures of one cell line, MDBK, yielded a greater amount of viral antigen than the others. Strain Ky1203nc grown in MDBK cells was inactivated with beta-propiolactone, mixed with adjuvant and used as a vaccine inoculated into calves subcutaneously three times. All of 5 calves were protected against intranasal challenge with a heterologous strain. In contrast virus was isolated from nasopharyngeal swabs taken from 5 control calves and from the blood of 4 controls. All 5 control calves, but none of the vaccinates, had a leukopenia after challenge. We conclude that the selected strain and system of vaccine preparation provide an effective means of protecting calves against respiratory infection and that live vaccines are not required to protect against challenge via the respiratory tract.

Administration, Intranasal↗
PubMed1994

More than one component of the Newcastle disease virus particle is capable of interferon induction.

The interferon (IFN)-inducing capacities of intact NDV virions, beta-propiolactone-inactivated particles and several structural components were compared, using human PBML as the IFN producing cells. Intact and inactivated virions as well as the nucleocapsid fraction did not differ significantly in their IFN-inducing capacity. In contrast, genomic RNA as well as M protein fraction and envelopes induced IFN titres to a level of about 10% of those achieved with virions. NDV-induced IFN production could be blocked specifically by incubation with polyclonal anti-NDV-monoclonal antibodies (mAbs) and with two of three anti-HN-mAbs, but not with anti-NDV-mAbs directed against the F, M or NP protein. In addition, IFN induction by fixed MDBK cells, expressing NDV surface proteins after infection with NDV Ulster, was inhibited by one of two anti-F-mAbs. The results suggest that the induction of IFN synthesis in human PBML is a complex process involving not only the HN protein but also the uncleaved F protein precursor, a component of the M protein fraction and--once having entered the cell--the genomic RNA.

Animals↗
PubMed1990

Inactivation and stability of viral diagnostic reagents treated by gamma radiation.

The objective of this study was to apply the pertinent findings from gamma inactivation of virus infectivity to the production of high quality diagnostic reagents. A Gammacell 220 (Atomic Energy of Canada, Ltd., Ottawa, Canada) was used to subject 38 viruses grown in either susceptible tissue cultures or embryonated chicken eggs to various doses of gamma radiation from a cobalt-60 source. The radiation required to reduce viral infectivity was 0.42 to 3.7 megarads (Mrad). The effect of gamma treatment on the antigenic reactivity of reagents for the complement fixation (CF), hemagglutination (HA) and neuraminadase assays was determined. Influenza antigens inactivated with 1.7 Mrad displayed comparable potency, sensitivity, specificity and stability to those inactivated by standard procedures with beta-propiolactone (BPL). Significant inactivation of influenza N1 and B neuraminidase occurred with greater than 2.4 Mrad radiation at temperatures above 4 degrees C. All 38 viruses were inactivated, and CF or HA antigens were prepared successfully. Antigenic potency remained stable with all antigens for 3 years and with 83% after 5 years storage. Influenza HA antigens evaluated after 9 years of storage demonstrated 86% stability. Gamma radiation is safer than chemical inactivation procedures and is reliable and effective replacement for BPL in preparing diagnostic reagents.

Animals↗
PubMed2004

Inactivated SARS-CoV vaccine elicits high titers of spike protein-specific antibodies that block receptor binding and virus entry.

The only severe acute respiratory syndrome (SARS) vaccine currently being tested in clinical trial consists of inactivated severe acute respiratory syndrome-associate coronavirus (SARS-CoV). However, limited information is available about host immune responses induced by the inactivated SARS vaccine. In this study, we demonstrated that SARS-CoV inactivated by beta-propiolactone elicited high titers of antibodies in the immunized mice and rabbits that recognize the spike (S) protein, especially the receptor-binding domain (RBD) in the S1 region. The antisera from the immunized animals efficiently bound to the RBD and blocked binding of RBD to angiotensin-converting enzyme 2, the functional receptor on the susceptible cells for SARS-CoV. With a sensitive and quantitative single-cycle infection assay using pseudovirus bearing the SARS-CoV S protein, we demonstrated that mouse and rabbit antisera significantly inhibited S protein-mediated virus entry with mean 50% inhibitory titers of 1:7393 and 1:2060, respectively. These data suggest that the RBD of S protein is a major neutralization determinant in the inactivated SARS vaccine which can induce potent neutralizing antibodies to block SARS-CoV entry. However, caution should be taken in using the inactivated SARS-CoV as a vaccine since it may also cause harmful immune and/or inflammatory responses.

Angiotensin-Converting Enzyme 2↗
PubMed2004

In vitro inactivation of the rabies virus by ascorbic acid.

OBJECTIVE: The current recommended inactivating agent for the rabies virus, beta propiolactone (BPL) is very expensive and potentially carcinogenic. There is a need to evaluate alternative chemicals, which will inactivate the virus without affecting its antigenicity. In this study the effect of ascorbic acid on the infectivity of the rabies virus has been investigated. METHOD: Vero cell grown fixed rabies virus CVS strain was treated with 0.1 mg/ml, 0.5 mg/ml and 1mg/ml final concentrations of ascorbic acid and 5 microg/ml of copper sulfate and kept at 4 degrees C along with untreated virus material. Each aliquot was titrated after various intervals for viral infectivity using both mice inoculation and titration in vero cells. The antigenicity of the virus material was determined by antibody induction in mice and modified NIH tests in parallel with virus material inactivated with a 1:4000 concentration of BPL. RESULTS: An optimal concentration of 0.5 mg/ml of ascorbic acid and 5 microg/ml of copper sulfate completely inactivated the virus after 72 hours. The inactivated virus retained good antigenicity and potency value, which was comparable with using BPL. CONCLUSION: These findings suggest that ascorbic acid can be used as an inactivating agent for fixed rabies virus grown in cell culture particularly for the preparation of diagnostic reagents. Further studies are required to evaluate its effect on the cell associated virus, probable therapeutic potential and feasibility of replacing BPL in production of inactivated rabies vaccine.

Animals↗
PubMed2006

A strategy for selective, CD4+ T cell-independent activation of virus-specific memory B cells for limiting dilution analysis.

Complete characterization of the B cell response to infection or vaccination is dependent on accurate quantitation of the memory B cell (MBC) pool. An established method for measuring MBC frequencies is limiting dilution analysis based on in vitro stimulation of MBCs to divide and differentiate into antibody-secreting cells (ASCs). The presence of specific antibody then serves to identify cultures positive for precursor MBCs. The sensitivity of this approach is critically dependent on optimal in vitro MBC activation. To develop a limiting dilution assay (LDA) for measuring influenza-specific MBC frequencies, we evaluated strategies for the in vitro stimulation of influenza-specific MBCs. An ELISPOT assay to enumerate influenza-specific IgG ASCs was used as the readout for MBC activation. Culture of influenza-specific MBCs with influenza-infected splenocytes was effective for MBC activation, but T cell-associated factors were required for optimal LDA sensitivity and clonal expansion of activated MBCs. However, optimal influenza-specific MBC activation was T cell-independent when MBCs were simply cultured with beta-propiolactone (BPL)-inactivated influenza virus particles (BPL-flu). BPL-flu did not stimulate naïve B cells to produce influenza-specific IgG, demonstrating that only MBCs were activated. In addition, BPL-flu acted selectively and only activated influenza-specific MBCs, not MBCs of other specificities. Analysis of influenza-specific MBC frequencies in different anatomical locations in influenza-immune mice established that in vitro stimulation with BPL-flu provided the basis for a sensitive and reproducible LDA. Extending our studies to the herpes simplex virus (HSV) system, we demonstrated that HSV-specific MBCs cultured with BPL-inactivated HSV were selectively activated to IgG secretion in the absence of T cells. Our studies identify BPL-inactivated viral particles as a valuable tool for selective, T cell-independent activation of virus-specific MBCs in vitro. This strategy eliminates the influence of poorly defined T cell-associated factors on MBC frequency determinations.

Animals↗
PubMed2006

Frequencies of mutagen-induced coincident mitotic recombination at unlinked loci in Saccharomyces cerevisiae.

Frequencies of coincident genetic events were measured in strain D7 of Saccharomyces cerevisiae. This diploid strain permits the detection of mitotic gene conversion involving the trp5-12 and trp5-27 alleles, mitotic crossing-over and gene conversion leading to the expression of the ade2-40 and ade2-119 alleles as red and pink colonies, and reversion of the ilv1-92 allele. The three genes are on different chromosomes, and one might expect that coincident (simultaneous) genetic alterations at two loci would occur at frequencies predicted by those of the single alterations acting as independent events. Contrary to this expectation, we observed that ade2 recombinants induced by bleomycin, beta-propiolactone, and ultraviolet radiation occur more frequently among trp5 convertants than among total colonies. This excess among trp5 recombinants indicates that double recombinants are more common than expected for independent events. No similar enrichment was found among Ilv(+) revertants. The possibility of an artifact in which haploid yeasts that mimic mitotic recombinants are generated by a low frequency of cryptic meiosis has been excluded. Several hypotheses that can explain the elevated incidence of coincident mitotic recombination have been evaluated, but the cause remains uncertain. Most evidence suggests that the excess is ascribable to a subset of the population being in a recombination-prone state.

Alleles↗
PubMed2004

Vero-cell rabies vaccine produced using serum-free medium.

A new rabies vaccine was developed from Vero cells adhered to microcarriers, cultivated in a bioreactor in serum-free medium and infected with the PV/VERO-Paris rabies virus strain. The viral suspensions were concentrated by tangential filtration, purified by chromatography and inactivated with beta-propiolactone. In immunogenicity studies performed in mice immunized with three doses of the new vaccine (seven batches) and the commercial Verorab and HDCV, mean titers of neutralizing antibodies of 10.3-34.6, 6.54 and 9.36 IU/ml were found, respectively. The vaccine presented stability during 14 months at 2-8 degrees C, 30 days at 37 degrees C and 8 h at 45 degrees C. The use of serum-free medium facilitated the downstream process leading to residual cellular DNA values <22.8 pg per dose of vaccine in all produced batches. The effective immunogenicity induced in mice by this vaccine, the degree of purity of the product, the high antigen yield and the reduction of the cost of the product due to the virus production and purification processes, makes this technology very important for countries where rabies presents a great public health problem.

Animals↗
PubMed2005

Immunogenicity and protective efficacy in monkeys of purified inactivated Vero-cell SARS vaccine.

BACKGROUND: In 2003, severe acute respiratory syndrome (SARS) resulted in hundreds of infections and deaths globally. We aim to assess immunogenicity and protective efficacy of purified inactivated Vero-cell SARS vaccine in monkeys. METHODS: The cultures of SARS coronavirus (SARS-CoV) BJ-01 strain infected Vero cells were inactivated with beta-propiolactone. Sequential procedures, including ultrafiltration, gel filtration and ion exchange chromatography, were performed to obtain purified inactivated SARS vaccine. The purified SARS vaccine was analyzed with electron microscope, HPLC and Western blotting. We immunized three groups of cynomolgus macaques fascicularis with adjuvant-containing purified vaccine, purified vaccine and unpurified vaccine, respectively, and a fourth group served as a control. Antibody titers were measured by plaque reduction neutralization test. The vaccinated monkeys were challenged with SARS-CoV BJ-01 strain to observe protective efficacy. Additionally, three groups of rhesus monkeys were immunized with different doses of the purified inactivated SARS vaccine (0.5, 1 and 2mug/time/monkey) on days 0 and 7, and the monkeys were challenged with SARS-CoV GZ-01 strain. We assessed the safety of the SARS vaccine and observed whether the antibody dependent enhancement (ADE) occurred under low levels of neutralizing antibody in rhesus. FINDINGS: The purity of SARS vaccine was 97.6% by HPLC identification and reacted with convalescent sera of SARS patients. The purified SARS vaccine induced high levels of neutralizing antibodies and prevented the replication of SARS-CoV in monkeys. Under low levels of neutralizing antibody, no exacerbation of clinical symptoms was observed when the immunized monkeys were challenged with SARS-CoV. In this preliminary animal trial, no side effects were detected when monkeys were immunized with purified SARS vaccine either at normal or large doses. INTERPRETATION: The purified inactivated SARS vaccine could induce high levels of neutralizing antibody, and protect the monkeys from the challenge of SARS-CoV. The SARS vaccine prepared in the study appeared to be safe in monkeys.

Animals↗
PubMed2006

Intravaginal administration of an inactivated vaccine prevents lesions induced by caprine herpesvirus-1 in goats.

To evaluate the efficacy of mucosal vaccination with a beta-propiolactone inactivated caprine herpesvirus-1 (CpHV-1) vaccine, goats received vaginal administrations of two 7-day cycles at 2 weeks intervals. Seven days after the end of the second cycle, goats were challenged intravaginally with 4 ml of virulent BA.1 strain of CpHV-1. Vaccinated goats shed challenge virus for 8 days but, in comparison with control unvaccinated-challenged goats, were significantly protected from the classical clinical signs of genital lesions. Even without adjuvants, prolonged mucosal vaccination induced production of secretory IgA and provided significant clinical protection.

Administration, Intravaginal↗
PubMed2004

Influenza H5 virus escape mutants: immune protection and antibody production in mice.

Avian H5N1 influenza A viruses are considered to be of high pandemic potential as they are able to cross the avian-human species barrier and cause disease in humans. In the present study we assessed the impact of amino acid substitutions in the hemagglutinin (HA) of antigenic escape mutants of influenza A/Mallard/Pennsylvania/10218/84 (H5N2) (Mld/PA/84-MA) virus on the level of neutralizing antibodies and the ability to protect mice against challenge with the wild type H5 influenza virus. beta-Propiolactone-inactivated vaccines prepared from eight different H5 escape mutants could be separated into two groups based on levels of protection. One group of escape mutants [m46(7), m46(7)-24B9, m46(7)-55, and m46(7)-55-24B9] was characterized by providing high levels of protection (90.0-95.4% survival) to mice against subsequent challenge with 5 LD(50) of wild type Mld/PA/84-MA virus. The other group of escape mutants [m176/26, m55(2), m55(2)-24B9, and m24B9-176/26] provided moderate level of protection (57.1-66.6% survival) in mice. Analysis of the amino acid substitutions in the HA revealed that two amino acid changes in antigenic site B of the HA molecule (D(126)-->N and K(152)-->N) were associated for decreases in the levels of antibody and the immune protection afforded by vaccination with these H5 virus escape mutants. The phenotypic effects of mutations in HA gene of H5 virus may be of importance to appraise the extent and direction of H5 influenza viruses antigenic evolution.

Amino Acid Substitution↗
PubMed1987

Immunologic studies in subjects with a serum sickness-like illness after immunization with human diploid cell rabies vaccine.

Ten patients developing a serum sickness-like hypersensitivity reaction to human diploid cell rabies vaccine were studied and compared with control subjects matched for previous vaccination history and level of rabies virus-specific IgG response to immunization. The clinical reaction consisted of delayed onset, generalized urticaria, and angioedema, with some arthralgias. Skin biopsy specimens demonstrated a leukocytoclastic vasculitis. Individuals reacting to the vaccine possessed IgE antibodies to human diploid cell rabies vaccine, to mock vaccine lacking viral antigen, and to fetal calf serum (FCS), a vaccine trace contaminant. Increased levels of IgG antibodies to FCS, mock vaccine, and beta-propiolactone-modified FCS, and human serum albumin were also found. Such humoral responses to vaccine components other than rabies virus might be responsible for the hypersensitivity reactions developing after rabies vaccination.

Antibodies, Viral↗
PubMed1985

Early diagnosis of human Lassa fever by ELISA detection of antigen and antibody.

Sequential serum samples, beginning on the day of hospital admission, from three patients with Lassa fever were tested for the presence of Lassa-virus antigens and antibodies by means of an enzyme-linked immunosorbent assay. Lassa-virus antigens were detected in the first serum sample from each patient, thus providing an early definitive diagnosis. In contrast, seroconversion was not detectable by ELISA or indirect fluorescent antibody techniques until 3 days or more after admission. The antigen-detection ELISA has important advantages over conventional infectivity titrations; it takes only hours to carry out and can be accomplished safely, with beta-propiolactone-inactivated samples. Development of antibodies coincided with a decline in antigenaemia. All acute-phase Lassa-fever sera contained either antigen or IgM antibody, and most contained both, thus allowing early diagnosis with single serum samples. More extensive testing of these ELISA techniques is recommended in field hospitals where Lassa fever is endemic and rapid diagnostic tools are needed.

Antigens, Viral↗
PubMed2000

Comparison of IgG preparations by a turbidimetric assay of opsonizing capacity.

A convenient turbidimetric phagocytosis assay was applied for the functional comparison of various intravenous IgG preparations. Staphylococcus aureus (Oxford) was opsonized by the immunoglobulin samples in the presence of an IgG deficient serum as a source of complement. The opsonized bacteria were subjected to phagocytosis by neutrophil granulocytes isolated from healthy adults. The time course of phagocytosis was monitored by the decrease of light absorbance at 400 nm. Changes in light absorbance during a 15 min period of opsonophagocytosis (delta E(400)) were expressed as a percentage of delta E(400) obtained by a reference IgG preparation. The opsonizing effect of five commercially available i.v. IgG preparations was compared. Three different preparations containing whole, non-modified IgG molecules had a comparable opsonizing effect while a further one prepared by propiolacton modification displayed a reduced activity (52%) of the reference preparation, taken as 100%. A preparation consisting of IgG molecules without an Fc-region proved to be practically ineffective (8.7%).

Complement System Proteins↗