Sufficiency of a single administration of filarial antigens adsorbed on polymeric lamellar substrate particles of poly (L-lactide) for immunization

A majority of antigens require repeated administration to ensure development of adequate humoral and cell mediated immune response. To minimize the number of administrations required, we investigated the utility of biodegradable polymeric lamellar substrate particles of poly (l-lactide) (PLSP) as adjuvant for filarial antigen preparations. PLSP was prepared and characterized and Brugia malayi adult worm extract (BmA) and its SDS-PAGE resolved 54-68 kDa fraction F6 were adsorbed on to PLSP. Swiss mice received a single injection of PLSP-F6, PLSP-BmA, FCA-F6, FCA-BmA and two doses of the plain antigens. Specific IgG, IgG1, IgG2a, IgG2b and IgE levels in serum, IFN-γ, TNF-α and nitric oxide (NO) release from cells of the immunized animals in response to antigen challenge were studied. The average size of PLSP particles was <10 μm and its % antigen adsorption efficacy was 60.4, 55.2 and 61.6 for BSA, BmA and F6, respectively. Single injection of PLSP-F6 or PLSP-BmA produced better immune responses compared to one injection of FCA-F6/BmA or two injections of plain F6 or BmA. Moreover, PLSP-F6 produced much better response than PLSP-BmA. These data demonstrate for the first time that PLSP is a superior immunoadjuvant for enhancing the immune response to filarial BmA and F6 molecules and obviates the need for multiple immunization injections.     

Scientific consultation on cell mediated immunity (CMI) in dengue and dengue vaccine development

Dengue is a re-emerging arboviral disease of great public health importance. Limited understanding of protective immune responses against dengue has hampered advancement of dengue vaccine candidates. Demonstrating an immunological correlate of protection has been limited to associating quantitative neutralizing antibody titers with clinical outcomes following infection. There have been a number of studies investigating the role of cell mediated immunity (CMI) in natural infections and these have demonstrated roles in both virus clearance and potentiating disease. Vaccine developers have extended the exploratory study of CMI in natural infection to the study of dengue vaccine recipients. Primary infections and monovalent vaccine administration generates dengue type-specific T-cell responses. Secondary infection, vaccination of flavivirus primed individuals, or administration of multivalent vaccine candidates results in broad, cross-reactive T-cell responses, similar to the broadening of antibody patterns. However, the precise function of CMI in protection or disease pathology remains ill-defined and, at present, there is no evidence to suggest that CMI can be utilized as a correlate of protection. Nonetheless, the study of CMI in natural infection and following vaccine administration should continue in an attempt to improve the understanding of dengue immunopathology, vaccine candidate immunogenicity, and potential correlates of protection.     

Detection of mesenteric ischemia by means of endoscopic visible light spectroscopy after luminal feeding

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Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women

Background

Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078, http://clinicaltrials.gov), assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741).

Methods

Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N = 65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N = 50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration.

Results

Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated.

Conclusion

A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.     

Human papillomavirus 16 L1-E7 chimeric virus like particles show prophylactic and therapeutic efficacy in murine model of cervical cancer

Cervical cancer is found to be associated with human papillomavirus (HPV) infection, with HPV16 being the most prevalent. An effective vaccine against HPV can thus, be instrumental in controlling cervical cancer. An ideal HPV vaccine should aim to generate both humoral immune response to prevent new infection as well as cell-mediated immunity to eliminate established infection. In this study, we have generated a potential preventive and therapeutic candidate vaccine against HPV16. We expressed and purified recombinant HPV16 L1(ΔN26)-E7(ΔC38) protein in E. coli which was assembled into chimeric virus like particles (CVLPs) in vitro. These CVLPs were able to induce neutralizing antibodies and trigger cell-mediated immune response, in murine model of cervical cancer, exhibiting antitumor efficacy. Hence, this study has aimed to provide a vaccine candidate possessing both, prophylactic and therapeutic efficacy against HPV16 associated cervical cancer.     

Generation of procoagulant activity by mononuclear phagocytes: optimisation of an in vitro assay

Leucocyte procoagulant activity (PCA) has previously been advocated as a useful measurement of cell-mediated immune reactivity. The assay is, however, susceptible to inter- and intra-experimental variation. This investigation identifies several factors which influence the stability and reproducibility of the test. Major factors which affect the recalcification time of plasma, include plasma lability, medium/buffer pH and both the nature and concentration of the indicator cells used in the assay. C. parvum-induced mouse peritoneal exudate cells have been used as a novel source of mononuclear phagocytes in the generation of PCA. Their sensitivity as indicator cells has been demonstrated by their responsiveness to stimulation by phytomitogen, endotoxin, and lymphokine (macrophage procoagulant-inducing factor). A simple test based on antigen-induced PCA of these cells, has provided an in vitro index of in vivo sensitisation to sheep red blood cells. Optimisation and standardisation of conditions detailed in this report for estimating PCA, renders the assay of value in monitoring lymphocyte and macrophage activation.     

Tricyclic response in obsessive compulsive disorder

Therapeutic responses to the tricyclic antidepressant clomipramine have been demonstrated in five double blind studies of patients with obsessive compulsive disorder. Biological alterations in patients with obsessive compulsive disorder resemble those of depressed patients for the dexamethasone suppression test, for some measures of sleep physiology, and in similar neuroendocrine responses to clonidine. Clomipramine's antiobsessional effect does not require high baseline depression ratings or biological abnormalities similar to those seen in depressives. Preliminary results suggest that in contrast to depressives, patients with obsessive compulsive disorder may respond to clomipramine but not to the tricyclic antidepressant desipramine.     

The effect of prenatal chlordane exposure on specific anti-influenza cell-mediated immunity

Previous studies in our laboratory have documented that in utero chlordane exposure caused a significant enhancement in the survival of the offspring to influenza A virus infection, and a depressed delayed type hypersensitivity (DTH) response to oxazolone. To correlate these 2 effects, we assayed influenza A virus-specific DTH response, and found that it was significantly decreased in chlordane-treated offspring. Virus-specific T-cell blastogenesis was also assayed in chlordane-treated animals. No significant differences due to the chlordane treatment were found in virus-specific T-cell blastogenesis, suggesting that the DTH depression did not result from a paucity of antigen-reactive T-cells. To determine whether enhanced survival was due, in part, to the effects of chlordane on virus replication, rather than on immunological alteration alone, the kinetics of influenza virus replication in the lungs of chlordane- and vehicle-treated animals were determined. In utero chlordane treatment caused no significant differences in in vivo virus replication. These data suggest that increased survival was due to a decrease in virus-specific DTH and its associated pathology.