Vaccine-treated Group Research Articles

Lack of effects on male fertility from a quadrivalent HPV vaccine in Sprague‐Dawley rats

Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases in both men and women. A recently developed quadrivalent HPV vaccine, Gardasil, has been shown to be highly effective in the prevention of several HPV-mediated diseases. The objective of the present study was to evaluate the potential effects of the vaccine on male fertility including reproductive performance, sperm evaluations, and histology of the testes. In addition, anti-HPV antibodies were measured during the study. Group 1 (30 male rats) received the full human dose of vaccine (0.5 mL, ∼200-fold excess based on body weight) by intramuscular injection at 6 weeks, 3 weeks, and 3 days prior to cohabitation. Group 2 males received only 1 dose at 3 days prior to cohabitation. Additional groups (20 male rats each) were administered PBS or Merck Aluminum Adjuvant similarly to Group 1. Ten males in the vaccine-treated groups were bled for immunogenicity assays after each dose. Twenty males per group were mated to untreated female rats. Cesarean sections were performed on Gestation Day 15 or 16. Cohabited males were necropsied and sperm count and motility were evaluated. There were no unscheduled deaths during the study and no evidence of toxicity in vaccine-treated male rats. The vaccine induced a specific antibody response to the 4 HPV types after each injection. There were no effects on the cesarean-section parameters of females or reproductive parameters of the cohabited male rats, including histomorphology of testes and epididymis, sperm count, and sperm motility. These results demonstrate that this quadrivalent HPV vaccine had no detectable adverse effects on routine measures of male fertility in rats.

1-MT enhanced potency of dendritic cells pulsed with tumor cell lysate by downregulation of CD4 ~+ CD25~+ treg

Objective To determine whether 1-methyl-tryptophan (1-MT, an IDO inhibitor) might reduce CD4~+ CD25~+ Treg and improve the anti-tumor effects of dendritic cells pulsed with tumor cell lysate in the murine pancreas adenocarcinoma model. Methods Pan02 cell line was injected into syngeneic C57BL/6 mice. 1-MT was administered to pancreas adenocarcinoma mice and its effect on the prevalence of regulatory T cells (Treg) in tumor draining lymph nodes (TDLNs) and spleen was investigated. The prevalence of Treg in the TDLNs and tumor spleen (TS) was detected by using flow cytometry. The expression level of Foxp3 mRNA was detected in the spleen and TDLN by real-time PCR. To prepare the DC vaccine,dendritic cells were pulsed with tumor cell lysate. This DC vaccine, as a single agent or in combination with 1-MT, was administered to pancreas adenocarcinoma mice. The anti-tumor effects in different treatment were deter mined by regular observation of tumor development. Results There was statistically significant difference in the percentage of CD4~+ CD25~+ T lyraphocytessignificant between 1-MT-treated group [TDLNs (16.01 ± 2.21)% and TS (13. 11 ± 1. 93)%] than PBS control group [TDLNs (25. 00 ± 2. 16)% and TS (22.14 ±2.33)%] (P<0.05,P<0.01). In 1-MT-treated group,the Foxp3 expression was significantly lower in TDLN and TS than in control LN and spleen. Furthemore,in 1-MT + DC vaccine-treated group,the tumor growth rate was significantly slower than in groups of DC vaccine, 1-MT and PBS (the tumor volume was (789.0 ±111.0), (1768.0 ±251. 3), (1854.0 ±192. 1),(1899.0 ±201.2) mmJ at the 36th day af ter tumor challenge, respectively (P < 0. 01). Conclusion 1-MT can enhance anti-tumor effects of den dritic cells pulsed with tumor cell lysate by downregulating the expression of CD4~+ CD25~+ Treg. Key words: Pancreas adenocarcinoma; Dendritic cells; Vaccine

Ex Vivo Triggering of T-Cell-Mediated Immune Responses by Autologous Tumor Cell Vaccine in Oral Cancer Patients

We investigated immunomodulatory activity of autologous tumor cell vaccine from oral cancer patients ex vivo by lymphoproliferation assay and two color flow cytometry. Vaccine treatment lead to 10-fold higher proliferation of lymphocytes compared with the untreated controls. A significant increase in CD69+ and HLA-DR+ T-cells was observed in vaccine pulsed cultures compared with untreated (p<0.0001) controls. The frequency of IFN-γ and IL-2 expressing CD4+/CD8+T-cell subsets was significantly higher with a concomitant reduction in IL-4 and IL-10 expression in the vaccine-treated group (p<0.0001) compared with the untreated controls. Vaccine treatment further increased T-cell receptor Vβ3, Vβ5, and Vβ8 usage. It seems that the autologous tumor cell vaccine triggers T‐cell responses ex vivo, hence it may have a protective role in oral cancer patients.

Conformational HER-2/neu B-cell Epitope Peptide Vaccine Designed to Incorporate Two Native Disulfide Bonds Enhances Tumor Cell Binding and Antitumor Activities

Cancer vaccines designed to elicit an antibody response that target antigenic sites on a tumor antigen must closely mimic the three-dimensional structure of the corresponding region on the antigen. We have designed a complex immunogen derived from the extracellular domain of human HER-2/neu-(626-649) that represents a three-dimensional epitope. We have successfully introduced two disulfide bonds into this sequence, thereby recapitulating the natural disulfide pairings observed in the native protein. To evaluate the immunogenicity of the doubly cyclized disulfide-linked peptide versus the free uncyclized peptide we examined the induction of antibody responses in both inbred and outbred mice strains, with both constructs eliciting high titered antibodies. The disulfide-paired specific antibodies exhibited enhanced cross-reactivity to HER-2/neu expressed on BT-474 cell line as determined by flow cytometry. The antitumor activities of the disulfidepaired specific antibodies did not improve the in vitro growth inhibition of human breast cancer cells overexpressing HER-2, but showed superior antitumor responses in the context of ADCC and interferon-gamma induction. Inbred mice (FVB/n) vaccinated with the disulfide-paired epitope exhibited a statistically significant reduction in the development of exogenously administered tumors in vivo compared with mice receiving either the free uncyclized or the promiscuous T-cell epitope (MVF) control peptide (p = 0.001). This study demonstrates the feasibility and importance of designing conformational epitopes that mimic the tertiary structure of the native protein for eliciting biologically relevant anti-tumor antibodies. Such approaches are a prerequisite to the design of effective peptide vaccines.

Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome

Positive results of pilot studies of the effect of staphylococcus toxoid vaccine in patients with fibromyalgia and chronic fatigue syndrome were the incitement to the present, placebo-controlled study. It included 28 patients who fulfilled the criteria for both fibromyalgia and chronic fatigue syndrome. The effect of vaccination with a staphylococcus toxoid was compared with the effect of injections of sterile water. Psychometric assessment was made using 15 items from the comprehensive psychopathological rating scale (CPRS), Zung's self-rating depression scale and clinical global impressions (CGI). The visual analogue scale (VAS) was used to measure pain levels, and a hand-held electronic pressure algometer was used to measure pressure pain thresholds. Significant improvement was seen in seven of the 15 CPRS items in the vaccine group when pretreatment values were compared to post-treatment values. In CPRS ‘fatiguability’, there were significant intergroup differences, and in CPRS ‘pain’ intergroup differences bordered on significance. There was no significant improvement in CPRS items in the placebo group. Clinical global impressions showed significant improvement in the vaccine-treated group, and VAS did so in both groups. In a follow-up study of 23 patients, the vaccine treatment was continued for 2–6 years. Fifty percent were rehabilitated successfully and resumed half-time or full-time work. The results of this study support the authors' hypothesis that treatment with staphylococcus toxoid may be a fruitful strategy in patients with fibromyalgia and chronic fatigue syndrome.

Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection

Most individuals infected with HIV-1 show disease progression despite both cellular and humoral immune responses. We investigated whether immunisation of patients who had symptomless HIV-1 infection with an envelope subcomponent vaccine (MNrgp120) to augment immune response can slow progression of HIV-1 disease. In a randomised, double-blind, placebo-controlled trial, carried out in university infectious disease clinics and community infectious disease practices, we enrolled 573 HIV-infected patients with CD4 counts above 600 cells/microL (0.6 x 10(9)/L). Patients received 600 micrograms vaccine or placebo by intramuscular injection monthly for 6 months then every alternate month throughout the study. The primary endpoint was the rate of decline in CD4 count; secondary endpoints were HIV-1 RNA concentrations in plasma and minor clinical events associated with HIV. Analysis was by intention to treat. At baseline, the study participants had a mean CD4 count of 775 cells/microL (SD 172) and 89% of participants had detectable HIV RNA (> 200 copies/mL). These RNA-positive individuals had a median viral load of 9250 copies/mL (IQR 2670-26960). Analysis after 15 months of follow-up of the 568 subjects who had at least one CD4 count done after randomisation showed no difference between the 287 vaccine recipients and 281 placebo recipients in rate of decline of CD4 count (yearly decrease 53.8 [SE 7.6] vs 42.3 [7.6] cells/microL; ratio of mean gradients 1.27 [95% CI 0.63-2.55]) or in plasma HIV-1 RNA concentrations (p > or = 0.63). The study was designed with power to detect a vaccine-induced reduction in rate of decline in CD4 count of 60%; these results exclude with 95% confidence a reduction of 40% or more. More vaccine-treated patients than placebo recipients showed a 50% decrease in CD4 count (11 vs 5; relative risk 2.15 [95% CI 0.76-6.12], p = 0.13). The frequencies of HIV-related minor clinical events were similar in the two groups. Pain at the injection site was the only adverse event that occurred more frequently in vaccine-treated group. Postinfection immunisation of symptom-free HIV-infected patients with MNrgp120 vaccine did not alter HIV-1 disease progression as measured by immunological, virological, and clinical endpoints over a 15-month period.

Rhesus Rotavirus Candidate Vaccine

Live attenuated oral rhesus Rotavirus candidate vaccine (strain MMU 18006 [lot RRV-1]) was evaluated for immunogenicity, safety, and clinical protection in a double-blind, placebo-controlled trial involving 200 infants aged 2 to 5 months when vaccinated. Vaccine-induced fourfold or greater rise of Rotavirus antibodies was seen in 62% of the infants. Febrile reactions of short duration on days 3 and/or 4 after vaccination occurred in 26% of the vaccine recipients. The clinical follow-up covered two Rotavirus seasons, in which serotypes 1 and 4 were prevalent. There were 16 cases of confirmed Rotavirus diarrhea in the placebo-treated group and 10 in the vaccine-treated group; from this a vaccine protection rate of 38% was derived. Clinical severity of Rotavirus diarrhea was assessed by a score; 13 cases in the placebo-treated group and 5 in the vaccine-treated group were regarded as severe or moderately severe, giving a vaccine protection rate of 67%. The rhesus Rotavirus vaccine induces partial protection against heterotypic Rotavirus disease, but the level of protection achieved with the present vaccine dose in this age group appears to be insufficient for a general Rotavirus vaccination.

Swine Influenza Virus Vaccination in Patients with Multiple Sclerosis

A double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of inactivated influenza virus vaccines in patients with multiple sclerosis. The vaccine used contained 200 chick cell-agglutinating (CCA) units of influenza A/New Jersey/76 and 200 CCA units of influenza A/Victoria/75 whole viruses (Merrell-National Laboratories, Cincinnati, Ohio). The frequency of clinical relapses of multiple sclerosis was the same in the vaccine-treated (four of 33 patients) and placebo-treated (four of 33) groups. An untreated control group had a slightly higher rate of relapses (four of 22). Toxic reactions to the vaccine were not a significant problem. The efficacy of the vaccination as measured by titers of hemagglutination-inhibiting antibody was comparable to that reported for the general population. However, patients with preexisting antibody were less responsive to the vaccine than normal controls studied previously. The patients who did not respond to the vaccine tended to be older and more disabled. There were no changes in titers of antibody to rubeola or rubella virus after vaccination or in relation to change in clinical course. It is concluded that the vaccine is safe and effective in patients with multiple sclerosis.

BACTERIAL VACCINE AND INFECTIOUS ASTHMA.

A two-year double-blind control study to determine the effectiveness of bacterial-vaccine therapy was performed on 30 children with infectious asthma. The first year, from October to April, all the children received buffered saline injections weekly. Symptom cards were kept by the family during the two year study. The second year, the children were randomly divided into two groups, one receiving a bacterial vaccine, the other a placebo solution. A reduction in the incidence of wheezing, infection, and infectious episodes associated with wheezing was observed in a larger percentage of the placebo group than in the vaccine-treated group. The amount of antiasthmatic medication administered during the first and second years was equivalent.

STUDY OF THE VALUE OF BACTERIAL VACCINES IN THE TREATMENT OF BRONCHIAL ASTHMA ASSOCIATED WITH RESPIRATORY INFECTIONS

A controlled study of the value of bacterial vaccines in 118 infants and children subject to repeated episodes of asthma associated with respiratory infections is described. Both vaccine-treated and a control group, treated similarly except for omission of bacterial vaccines from hyposensitization therapy, were compared before and at the end of a 3½-year period. When the maximum dose of vaccine was administered every 28 days, no statistically significant differences were observed between the two groups with regard to the following criteria: 1) number of asthmatic episodes per year; 2) average number of days wheezing per year; 3) average number of days school missed per year during asthmatic episodes; 4) number of children with 100%, 50-100% or 0-50% reduction in number of asthma attacks per year. In the vaccine-treated group the type of vaccine used did not appear to influence the degree of improvement as reflected in number of asthmatic attacks per year in the last year of the study compared to the year preceding the study. The incidence of positive skin tests to stock bacterial vaccines and a commercially prepared vaccine was approximately the same in both groups.