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Biomedical subjects

D I Bernstein

Publications and source records attributed to D I Bernstein.

At least 37 records · Page 2Linked to original sources
PubMed2000

Preconception immunization with a cytomegalovirus (CMV) glycoprotein vaccine improves pregnancy outcome in a guinea pig model of congenital CMV infection.

The guinea pig (gp) model of congenital cytomegalovirus (CMV) infection was used to evaluate a gpCMV glycoprotein vaccine. Hartley guinea pigs were immunized 3 times with 50 microg of lectin column-purified glycoproteins prepared from gpCMV-infected or -uninfected tissue culture. Immunization with the gpCMV vaccine produced seroconversion in all animals. Animals then were placed with gpCMV-seronegative male animals and were challenged late in pregnancy with virulent salivary gland-passaged gpCMV. Immunization with gpCMV glycoproteins significantly improved pregnancy outcome, with 54 of 63 pups live-born in immunized animals, compared with 21 of 48 in the controls (P<.001). In addition, virus was isolated from 24 of 54 live-born pups born to immunized mothers, compared with 16 of 20 live-born pups born to controls, indicating that immunization significantly reduced in utero transmission in surviving animals (P<.01).

Animals↗
PubMed2000

Herpes simplex virus DNA vaccine efficacy: effect of glycoprotein D plasmid constructs.

The impact of vaccination with plasmid DNA encoding full-length glycoprotein D (gD) from herpes simplex virus (HSV) type 2 (gD2), secreted gD2, or cytosolic gD2 was evaluated in mice and guinea pigs. Immunization with plasmids encoding full-length gD2 or secreted gD2 produced high antibody levels, whereas immunization with DNA encoding cytosolic gD2 resulted in significantly lower antibody titers in both species (P<.001). Vaccination with DNA encoding full-length or secreted gD2 significantly reduced acute disease in mice and guinea pigs (both P<.001) and subsequent recurrent disease in guinea pigs (P<.05). In guinea pigs, immunization with DNA encoding cytosolic gD2 did not protect from acute or recurrent disease, whereas in mice it did protect, but not as well as DNA encoding full-length or secreted gD2. None of the vaccines resulted in improved virus clearance from the inoculation site, and none significantly reduced recurrent disease when used as a therapeutic vaccine in HSV-2-infected guinea pigs.

Animals↗
PubMed2000

Effect of route of vaccination with vaccinia virus expressing HSV-2 glycoprotein D on protection from genital HSV-2 infection.

To evaluate the effects of the route of vaccination on protection against genital HSV infection guinea pigs were vaccinated twice with vaccinia recombinants expressing HSV-2 glycoprotein D or controls by intradermal, intranasal or intravaginal inoculation. Following HSV-2 intravaginal challenge, immunization by all 3 routes reduced vaginal HSV shedding and acute genital disease. The intravaginal vaccination, however, most effectively reduced primary and recurrent HSV disease. Vaccinia and HSV antibody titers were similar in all vaccinia gD immunized groups while the lymphoproliferative response was highest in the intradermal group. In a smaller follow-up experiment we demonstrated that intrarectal immunization with vaccinia gD could also induce antibody and T cell responses.

Administration, Intranasal↗
PubMed2000

Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine.

OBJECTIVE: To determine the safety, immunogenicity, and efficacy of revaccination of children with live attenuated influenza vaccine. STUDY DESIGN: A 2-year multicenter, double-blind, placebo-controlled, efficacy field trial of live attenuated, cold-adapted trivalent influenza vaccine administered by nasal spray to children. This report summarizes year 2 results, a year in which the epidemic strain of influenza A/Sydney was not well matched to the vaccine strains. Each year, vaccine strains were antigenically equivalent to the contemporary inactivated influenza vaccine. In year 2, a single intranasal revaccination was administered. Active surveillance for influenza was conducted during the influenza season by means of viral cultures. Influenza cases were defined as illnesses with wild-type influenza virus isolated from respiratory secretions. RESULTS: In year 2, 1358 (85%) children, 26 to 85 months of age, returned for revaccination. The intranasal vaccine was easily accepted, well tolerated, and immunogenic. Revaccination resulted in 82% to 100% of the vaccinated children in a subset studied for immunogenicity being seropositive as compared with 26% to 65% of placebo recipients, depending on the influenza strain tested. No serious adverse events were associated with the vaccine. In addition to the strains in the vaccine, antibody was induced to the variant strain A/Sydney/H3N2. In year 2, influenza A/Sydney/H3N2, a variant not contained in the vaccine, caused 66 of 70 cases of influenza A; nonetheless, intranasal vaccine was 86% efficacious in preventing A/Sydney influenza. Eight cases of lower respiratory tract disease were associated with A/Sydney influenza; all cases were in the placebo group. CONCLUSIONS: This live attenuated, cold-adapted influenza vaccine was safe, immunogenic, and efficacious against influenza A/H3N2 (including a variant, A/Sydney, not contained in the vaccine) and influenza B. The characteristics of this vaccine make it suitable for routine use in children to prevent influenza.

Administration, Intranasal↗
PubMed2000

Cyclic HPMPC is safe and effective against systemic guinea pig cytomegalovirus infection in immune compromised animals.

Cidofovir (HPMPC) is licensed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS but its use is limited by nephrotoxicity. We evaluated the safety and efficacy of 1-[((s)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne dihydrate (CHPMPC) the cyclic congener of cidofovir. Treatment was well tolerated both in normal guinea pigs and in animals immune compromised with cyclophosphamide. Further, blood chemistry analysis showed no adverse effects of CHPMPC treatment on kidney or liver function. In efficacy studies in immune compromised guinea pigs challenged with a virulent salivary gland passaged guinea pig CMV, CHPMPC treatment significantly reduced mortality resulting from disseminated virus infection. Quantitative culture showed that treatment also significantly reduced virus replication in the liver and spleen, but not the lungs of infected animals. The efficacy of CHPMPC combined with its improved safety profile appear to make it an attractive alternative to cidofovir for the treatment of herpesvirus infections. Further evaluation is warranted.

Animals↗
PubMed2000

Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations.

Our understanding of the pathogenesis of acyclovir (ACV)-resistant herpes simplex virus (HSV) is limited, especially with regard to reactivation and recurrent disease. To further explore the pathogenesis of ACV-resistant HSV-2 viruses, we used the guinea pig model of genital HSV-2 infection to evaluate several ACV-resistant isolates of both thymidine kinase (Tk)-altered and Tk-deficient phenotypes obtained from HIV-infected patients. Two plaque-purified workpools from each isolate were initially evaluated. Each produced acute disease and at least one clinical recurrence. The two strains that produced the most severe primary disease and most recurrences, one Tk-deficient virus and one Tk-altered virus, were further evaluated and shown to produce acute and recurrent genital disease similar to that seen with wild-type viruses. Furthermore, the reactivated virus producing recurrent lesions could be a pure population with minimal Tk activity. Finally, we showed that topical foscarnet treatment could alter disease and vaginal virus replication following vaginal inoculation with these two ACV-resistant strains. Using the guinea pig model of genital HSV-2 infection, we found that recurrent disease following infection with markedly Tk-deficient viruses was more common than expected, especially in select isolates. Furthermore, this model should be useful in evaluating potential new therapies for ACV-resistant HSV strains.

Acyclovir↗
PubMed2000

Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma.

BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

Administration, Inhalation↗
PubMed2000

Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine.

The authors conducted a 2-year, multicenter, double-blind, placebo-controlled efficacy field trial of live, attenuated, cold-adapted, trivalent influenza vaccine administered by nasal spray to children 15-71 months old. Overall, vaccine was 92% efficacious at preventing culture-confirmed infection by influenza A/H3N2 and influenza B. Because influenza A/H1N1 did not cause disease during the years in which this study was conducted, the authors sought to determine vaccine efficacy and correlates of immune protection against experimental challenge with 107 TCID50 of attenuated H1N1 (vaccine strain) by intranasal spray. Prechallenge assessments included serum hemaglutination-inhibiting (HAI) antibody and nasal wash IgA antibody to H1N1. Vaccine was 83% efficacious (95% confidence interval, 60%-93%) at preventing shedding of H1N1 virus after challenge. Any serum HAI antibody or any nasal wash IgA antibody was correlated with significant protection from H1N1 infection as indicated by vaccine-virus shedding, and high efficacy against H1N1 challenge was demonstrated.

Administration, Intranasal↗
PubMed2000

Immunogenicity evaluation of DNA vaccines that target guinea pig cytomegalovirus proteins glycoprotein B and UL83.

Vaccines are needed for control of congenital human cytomegalovirus (HCMV) infection. Although the species-specificity of cytomegaloviruses precludes preclinical evaluation of HCMV vaccines in animal models, the guinea pig cytomegalovirus (GPCMV), which causes disease in utero, is a relevant model for the study of vaccines against congenital infection. We investigated whether DNA vaccines that target two GPCMV proteins, glycoprotein B (gB) and UL83 (pp65), are capable of eliciting immune responses in vivo. After cloning each gene into an expression vector, DNA was delivered by intramuscular inoculation and by pneumatic epidermal delivery. In Swiss-Webster mice, anti-gB titers were significantly higher after epidermal delivery. After epidermal inoculation in guinea pigs, all gB-immunized animals (n = 6) had antibody responses comparable to those induced by natural infection. Viral neutralization titers ranged from 1:64 to greater than 1:128. A GPCMV UL83 DNA vaccine also elicited an antibody response in all immunized guinea pigs (n = 6) after epidermal administration. Immunoprecipitation and Western blot assays confirmed that immune sera were immunoreactive with virion-associated UL83 and gB proteins. We conclude that DNA vaccines against GPCMV structural proteins are immunogenic, and warrant further investigation in the guinea pig model of congenital CMV infection.

Animals↗
PubMed2000

Diminution of the anti-polyribosylribitol phosphate response to a combined diphtheria-tetanus-acellular pertussis/Haemophilus influenzae type b vaccine by concurrent inactivated poliovirus vaccination.

BACKGROUND: Prelicensure studies of Haemophilus influenzae type b vaccines (Hib) and diphtheria-tetanus-acellular pertussis vaccines (DTaP) were evaluated with concurrent oral poliovirus vaccine (OPV). However, inactivated poliovirus vaccine (IPV) is now recommended. A trial was conducted in which infants received a DTaP and Hib vaccine, separately (+) or combined (/), with either all OPV, all IPV or sequential IPV-OPV for the primary series of vaccinations. METHODS: In this protocol 567 infants were equally randomized to receive one of the following: Reference Arm A, DTaP + Hib + OPV; Treatment Arm B, DTaP/Hib + OPV; Treatment Arm C, DTaP/Hib + IPV at 2 and 4 months and OPV at 6 months; or Treatment Arm D, DTaP/Hib + IPV. antibodies against all administered antigens were measured at 7 months of age. Children with an antibody response to Hib (anti-polyribosylribitol phosphate (anti-PRP) <0.15 microg/ml had an antibody titer repeated after the toddler booster immunization. RESULTS: A significant diminution in the anti-PRP response was observed at 7 months of age in children given two or three doses of IPV concurrently with DTaP/Hib, compared with the groups given OPV. The geometric mean concentration of anti-PRP, percentage of children with > or = 0.15 microg/ml and percentage of children with > or = 1.0 microg/ ml, respectively, were: A, 4.4, 98%, 81%; B, 3.2, 94%, 78%; C, 1.3, 86%, 58% and D, 1.2, 84%, 53%. CONCLUSION: In this trial concurrent IPV appeared to interfere with the anti-PRP response to DTaP/Hib vaccine, suggesting that introduction of new vaccines may require evaluation of immune responses to all concurrently administered vaccines.

Adhesins, Bacterial↗
PubMed2000

Dendrimers, a new class of candidate topical microbicides with activity against herpes simplex virus infection.

Dendrimers are large highly branched macromolecules synthesized from a polyfunctional core. They have shown a variety of biological properties, including, in some instances, antiviral activity. In this study, five dendrimers were evaluated for in vitro activity against herpes simplex virus (HSV) types 1 and 2 by cytopathic effect (CPE) inhibition and plaque reduction (PR) assay in human foreskin fibroblast cells. All of the compounds were active against both virus types in the CPE inhibition assay, in which drug was added to the cells prior to the addition of virus. Antiviral activity was reduced or lost in the PR assays, in which the cells were incubated with the virus before the drug was added. The prophylactic efficacy suggested that the dendrimers might have potential as topical microbicides, products intended to be applied to the vaginal or rectal mucosa to protect against sexually transmitted infections. Three dendrimers were evaluated for this application against genital HSV infection in mice. Two of the compounds, BRI-2999 and BRI-6741, significantly reduced infection rates when 15 microl of a 100-mg/ml solution was administered immediately prior to intravaginal challenge, and the most effective compound, BRI-2999, provided significant protection even when applied 30 min before challenge. This is the first report of microbicidal activity by dendrimers in vivo.

Administration, Topical↗
PubMed2000

Attitudes regarding vaccinations of STDs and other diseases.

The purpose of this study was to examine, among 2 groups of individuals with different risk profiles, the similarity of their attitudes towards vaccines for sexually transmitted diseases (STDs) and non-STDs. Subjects were recruited from an undergraduate psychology class at an urban university (n=518) or were participants in genital herpes vaccine trials (n=87). The participants were asked to complete a questionnaire regarding their attitudes about vaccines for selected diseases. The results of this study revealed that, in general, both groups supported vaccination for most diseases. There were differences, however, between groups regarding 3 diseases: measles, genital warts, and chlamydia. The vaccine trial participants were more likely to accept vaccines for measles and the college students were more likely to accept vaccines for chlamydia and genital warts. The results of this study suggest that negative attitudes regarding vaccination to control STDs may not be a significant barrier to use.

Adolescent↗
PubMed1999

Immunity induced by DNA immunization with herpes simplex virus type 2 glycoproteins B and C.

The complete sequence of herpes simplex virus type 2 (HSV-2) glycoproteins B and C (gB & gC) were cloned into plasmid expression vectors and evaluated in murine and guinea pig genital HSV-2 models. Balb/c mice were immunized with either pgB-2 or pgC-2 plasmids intramuscularly (IM) or intradermally (ID). The vaccines induced HSV-2-specific neutralizing and ELISA IgG antibody, but little or no enhancement of viral clearance from the vagina was detected following intravaginal challenge. Immunization of guinea pigs with pgB-2 or pgC-2 induced ELISA IgG antibody; however, antibody titers were approximately one log(10) unit lower than that seen in HSV-2 convalescent sera. IM immunization of guinea pigs with either plasmid also did not decrease vaginal viral shedding following vaginal challenge, but the severity of the acute disease and the subsequent number of recurrent lesion days were reduced in animals immunized with pgB-2. Lastly, IM immunization of latently infected guinea pigs with a combined gB-2 and gC-2 plasmid vaccine significantly reduced the number of subsequent HSV-2 recurrences. DNA vectors expressing gB-2 or gC-2 were both immunogenic, although the gB-2 plasmid induced higher titers of antibody and significantly reduced primary and recurrent herpetic disease in the guinea pig model. These results also suggest that immunotherapy with plasmid expression vectors may be effective against recurrent genital HSV-2 disease.

Animals↗
PubMed1999

Efficacy of live, attenuated, human rotavirus vaccine 89-12 in infants: a randomised placebo-controlled trial.

BACKGROUND: Rotavirus is the most common cause of severe, dehydrating diarrhoea in infants worldwide. We assessed the safety, immunogenicity, and efficacy of a live, oral human rotavirus vaccine, 89-12, in US children in a randomised, placebo-controlled, double-blind multicentre trial. METHODS: 215 healthy infants were enrolled, of whom 213 were given two doses of 89-12 (containing 1x10(5) plaque-forming units) or placebo, and 213 were followed up through one rotavirus season. The frequency of side-effects was compared for 7 days after each dose of vaccine. Immune responses to rotavirus were assessed by serum and stool IgA, and by serum 89-12 neutralising titres. The primary outcome variable (protection from rotavirus disease) was evaluated by comparing the frequencies of rotavirus gastroenteritis in an intention-to-treat analysis. FINDINGS: Adverse reactions were mild. Low-grade fever (> or = 38.1 degrees C) after the first dose was the only side-effect significantly more common in the vaccine group than in the placebo group (21 [19%] vs 5 [5%], p=0.001). An immune response to vaccine was detected in 94.4% of vaccinees. Rotavirus disease occurred in 18 of 107 placebo recipients and two of 108 vaccine recipients (vaccine efficacy 89.0% [95% CI 65.4-94.5]). Ten infants in the placebo group but none in the vaccine group were presented for medical care. INTERPRETATION: The 89-12 rotavirus vaccine was safe and immunogenic and provided a high degree of protection against rotavirus disease. Further investigations of this vaccine are needed to confirm these findings in other settings.

Administration, Oral↗
PubMed1999

Effects of DNA immunization formulated with bupivacaine in murine and guinea pig models of genital herpes simplex virus infection.

The immunogenicity and efficacy of a herpes simplex virus type 2 glycoprotein D (gD2) DNA vaccine formulated with bupivacaine was evaluated using murine and guinea pig models of genital herpes. Animals received three doses of 100 microg of gD2 plasmid or control plasmid intramuscularly prior to intravaginal challenge with HSV-2. Immunization induced HSV ELISA and neutralizing antibody in serum and ELISA antibody in the vaginal secretions of all animals evaluated. Following intravaginal HSV-2 challenge, vaginal viral replication was reduced in both models with peak reductions of greater than 99%. Immunization also decreased the number of animals developing any clinical disease (p < 0.001) and the severity of the acute disease (total lesion score 6.4 versus 0.6 in guinea pigs, p < 0.001). Further recurrent lesion days were reduced from 14.5 to 4.9 days in immunized guinea pigs (p < 0.001). DNA immunization with gD2 + bupivacaine was effective in reducing clinical disease and viral replication in both guinea pigs and mice.

Animals↗
PubMed1999

Herpes simplex virus vaccines.

Herpes simplex virus (HSV) infections are common and produce not only a primary infection, but also latent and recurrent infections. Therefore, the goals of a HSV vaccine are different from other vaccines. In this review, the goals of both prophylactic and therapeutic HSV vaccines are discussed and related to the immunobiology of acute and recurrent HSV infections. Next, the vaccine strategies that have been and are being evaluated for control of HSV disease are described. Current approaches take advantage of many of the modern methodologies for vaccine development. Thus, as we await final evaluations of subunit HSV glycoprotein vaccines, early phase I trails are evaluating newer vaccine approaches including DNA-based vaccines and replication-impaired viruses. The definitive HSV vaccine may await increased knowledge of the optimal viral antigen(s) and routes to induce genital tract immunity.

Animals↗
PubMed1999

Current diagnostic methods for diisocyanate induced occupational asthma.

BACKGROUND: Diisocyanates are among the most frequent causes of occupational asthma in industrialized countries. Early diagnosis of diisocyanate asthma followed by prompt termination of chemical exposure can prevent chronic morbidity due to persistent asthma. The accurate diagnosis of diisocyanate asthma requires a systematic approach that combines information obtained from the occupational history, immunologic tests and physiologic studies. METHODS: The advantages, limitations and validity of various methods and diagnostic guidelines utilized in the evaluation of diisocyanate asthma are reviewed. RESULTS: Recommended methods for evaluation of diisocyanates asthma are similar to approaches for other causative agents. Serologic assays of specific IgE are specific but insensitive diagnostic markers of diisocyanate asthma. If possible, workers should be evaluated, while at work, in order to demonstrate work-related changes in lung function associated with diisocyanate exposures. Specific bronchoprovocation challenge testing with diisocyanates, is reserved for situations where the diagnosis cannot be confirmed at work. Such tests can be performed safely but should be conducted exclusively at specialized centers by experienced personnel. CONCLUSIONS: Published diagnostic guidelines for occupational asthma are directly applicable to the evaluation of diisocyanate asthma.

Asthma↗