Cementing links between industry and the university.
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Biotechnology↗
Biomedical subjects
R Jennings
Publications and source records attributed to R Jennings.
Adjuvants and delivery systems for viral vaccines--mechanisms and potential.
Of the vaccines against viral diseases of man currently available, several are less than satisfactory, and the present surge of interest in improving such vaccines, and in developing new vaccines against viral diseases as yet unchallenged, has led to major developments in three areas. The capacity to identify the nature and form of antigenic epitopes in proteins allows the specific design of molecular entities to promote relevant and protective immune responses. Such entities, although ideal in terms of specificity and purity, may not achieve their goals through failure to reach relevant cells of the immune system due to simple dilution, elimination by host enzymes or lack of specific targeting. Concomitant with the above there has been development of a plethora of adjuvants aimed at enhancing immune responses to these 'new' immunogens, paralleled by an almost equally rapid increase in understanding the complex nature of the immune response, particularly with respect to antigen processing, the nature and role of cytokines and the importance of T-cell subsets in infection. These developments allow exploration of matching the properties and mechanistic action of a given adjuvant to a defined immune response. Adjuvants can be grouped according to their physical characteristics and mode of action. They include particulate adjuvants, oil and emulsifier-based adjuvants, those providing controlled antigen delivery, adjuvants based on specific targeting of antigen, and gel-type adjuvants. They may act non-specifically in promoting an immune response to an antigen through depot formation, or very specifically as in a "delivery system" where an antigen is linked to a cellular protein, targeted to a specific cell receptor. As adjuvant technology develops it is becoming increasingly clear that these differing approaches may be combined, and an adjuvant/delivery system designed, to provide slow release of a targeted antigen. The role of adjuvants in modern viral vaccine technology and their influence on the immune system are the subject of this review.
Adjuvants, Immunologic↗
Humoral response to HSV-1 subunit vaccines--a statistical analysis.
Following primary infection with HSV, the virus becomes latent in the local sensory ganglia for the lifetime of the host. In some cases, periodic reactivation may occur due to various stimuli and cause a recrudescent lesion at or near the initial site of infection. As yet there is no suitable vaccine to prevent its spread within the human population. We investigated the potential of a large number of commercial and experimental adjuvant preparations to enhance the immunogenicity of an HSV-1 glycoprotein subunit vaccine. Evaluation was based on toxicity, total antibody titre, neutralizing antibody production and protection against lethal challenge. All adjuvants tested increased the titre of antigen specific total and neutralizing lg when compared to subunit vaccine alone, although functional neutralising antibody was only detected in some cases. Following challenge, a broad range of protective responses was noted but no correlation between antibody levels and protection was observed. The results emphasize the requirement of adjuvants when using subunit preparations as vaccine formulations and demonstrate that the magnitude and effectiveness of the induced immune response varies greatly with the choice of adjuvant.
Adjuvants, Immunologic↗
Changes in the immune system during and after spaceflight.
The results of immunological analyses before, during and after spaceflight, have established the fact that spaceflight can result in a blunting of the immune mechanisms of human crew members and animal test species. There is some evidence that the immune function changes in short-term flights resemble those occurring after acute stress, while the changes during long-term flights resemble those caused by chronic stress. In addition, this blunting of the immune function occurs concomitant with a relative increase in potentially infectious microorganisms in the space cabin environment. This combination of events results in an increased probability of inflight infectious events. The realization of this probability has been shown to be partially negated by the judicious use of a preflight health stabilization program and other operational countermeasures. The continuation of these countermeasures, as well as microbial and immunological monitoring, are recommended for continued spaceflight safety.
Acute Disease↗
Large scale comparison of adjuvant effects on immunogenicity and protection in a herpes simplex virus type 1 vaccination model.
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Adjuvants, Immunologic↗
A genetically inactivated herpes simplex virus type 2 (HSV-2) vaccine provides effective protection against primary and recurrent HSV-2 disease.
A glycoprotein H (gH)-deleted herpes simplex virus type 2 (HSV-2) was evaluated as a vaccine for the prevention of HSV-induced disease. This virus, which we term a DISC (disabled infectious single cycle) virus, can only complete one replication cycle in normal cells and should thus be safe yet still able to stimulate broad humoral and cell-mediated antiviral immune responses. A gH-deleted HSV-2 virus that has been tested as a vaccine in the guinea pig model of recurrent HSV-2 infection was constructed. Animals vaccinated with DISC HSV-2 showed complete protection against primary HSV-2-induced disease, even when challenged 6 months after vaccination. In addition, the animals were almost completely protected against recurrent disease. Even at low vaccination doses, there was a high degree of protection against primary disease. A reduction in recurrent disease symptoms was also observed following therapeutic vaccination of animals already infected with wild type HSV-2.
Animals↗
Induction of IL-2 and IFN-gamma in BALB/c mice immunised with subunit influenza A vaccine in combination with whole cell or acellular DTP vaccine.
Splenocytes from mice immunised with two doses of subunit influenza A/Beijing/353/89 vaccine mixed with whole cell DTP (wDTP), acellular DTP (aDTP) or PBS were collected 7 and 10 days after the second immunisation, and re-stimulated with subunit influenza vaccine or live virus in vitro. Interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were assayed in supernates from these cultures by an ELISA procedure. Splenocytes from mice given subunit influenza vaccine in wDTP produced greater than two-fold and greater than five-fold responses of IL-2 and IFN-gamma, respectively, compared with splenocytes from mice immunised with subunit vaccine alone. In contrast, the response of splenocytes from mice immunised with subunit vaccine in saline or aDTP was similar, significantly less than for vaccine in wDTP (p < 0.01) and only slightly greater than for controls (p < 0.05). The production of IL-2 and IFN-gamma by these spleen cells was not significantly different on days 7 and 10 post-immunisation. Previous reports have shown that wDTP and aDTP enhance the serum antibody response of mice to influenza vaccine, but wDTP enhanced the response 100-fold greater than aDTP, and induced greater IgG2a and IgG2b subclass antibody responses; this last result indicates a cell-mediated immune response to vaccine. The present studies confirm these earlier findings; furthermore, as the IL-2 and IFN-gamma responses of splenocytes are associated with Th-1 subset T-lymphocyte response, the findings indicate a cytotoxic T-cell response to immunisation. The results indicate that influenza vaccine combined with wDTP induced a cell-mediated response in mice, which could confer a more solid immunity to challenge virus infection.
Adjuvants, Immunologic↗
Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid.
Tumor necrosis factor alpha (TNF-alpha) may play a central role in the disease pathogenesis which occurs as a consequence of chlamydial infection. To investigate the importance of TNF-alpha gene promoter polymorphisms and TNF-alpha levels in tear fluid in scarring trachoma, a large matched-pair case-control study was performed in The Gambia. The -308A allele was present in a higher proportion of patients (28.4%) than controls (18.4%), with an increasing association for homozygotes (chi2 for trend, P = 0.032; allele frequency, 0.163 in patients and 0.099 in controls; chi2, P = 0.025). For the -238A allele, the association was similar but not significant. The disease association was highly significant when the number of either -308A or -238A sites in an individual was considered (P = 0.003). TNF-alpha promoter alleles are tightly linked to some HLA class I and II alleles, but multivariate analysis confirmed that the disease associations were independent of HLA, although a class I allele, A*6802, is also associated with disease. TNF-alpha was more frequently detected in tear samples from patients (27.6%) than from controls (15.9%), increasingly so for higher levels of detectable TNF-alpha (P = 0.015). Among patients, detectable TNF-alpha in tears was highly associated with the presence of ocular chlamydial infection (P < 0.001). The results indicate that TNF-alpha plays a major role in the tissue damage and scarring which occurs as a consequence of Chlamydia trachomatis infection.
Adolescent↗
Laparoscopic surgery in weightlessness.
BACKGROUND: Performing a surgical procedure in weightlessness has been shown not to be any more difficult than in a 1g environment if the requirements for the restraint of the patient, operator, and surgical hardware are observed. The feasibility of performing a laparoscopic surgical procedure in weightlessness, however, has been questionable. Concerns have included the impaired visualization from the lack of gravitational retraction of the bowel and from floating debris such as blood. METHODS: In this project, laparoscopic surgery was performed on a porcine animal model in the weightlessness of parabolic flight. RESULTS: Visualization was unaffected due to the tethering of the bowel by the elastic mesentery and the strong tendency for debris and blood to adhere to the abdominal wall due to surface tension forces. CONCLUSIONS: There are advantages to performing a laparoscopic instead of an open surgical procedure in a weightless environment. These will become important as the laparoscopic support hardware is miniaturized from its present form, as laparoscopic technology becomes more advanced, and as more surgically capable crew medical officers are present in future long-duration space-exploration missions.
Abdomen↗
Induction of a protective immune response by mucosal vaccination with a DISC HSV-1 vaccine.
The vaccine potential of a genetically disabled Herpes Simplex Virus Type 1 virus (DISC HSV-1) was investigated in the guinea pig model of intravaginal (i.vag.) HSV-2 infection. Three mucosal vaccination routes, i.vag., intranasal (i.n.) and oral, were compared for their ability to protect guinea pigs from challenge with wild-type HSV-2. Each was effective, particularly the i.n. route, which almost completely abolished primary disease. This was accompanied by significantly lower challenge virus titres in vaginal swabs collected from the vaccinated animals. In all cases, vaccination with the inactivated virus preparation provided substantially less protection from disease than the live DISC HSV-1 by the equivalent route. Antibody levels in serum and vaginal washes were measured both after vaccination and challenge by ELISA and neutralization tests. The highest titres were observed following administration of the DISC HSV-1 vaccine by the i.n. route. Significant increases in IgA and IgG in vaginal wash fluids were also found in these vaccinated animals.
Administration, Intranasal↗
Immune responses in mice induced by HSV-1 glycoproteins presented with ISCOMs or NISV delivery systems.
The purpose of this study was to evaluate the immunogenicity of a herpes simplex virus type I (HSV-1) antigen preparation, obtained following zwitterionic detergent treatment of virus, and incorporation of the antigens into either immunostimulating complexes (ISCOMs) or non-ionic surfactant vesicles (NISV) delivery systems. Using Balb/c mice the ISCOM and NISV HSV-1 vaccines were assayed for their capacity to induce and enhance both the humoral and cellular immune responses, and to elicit protection against both homologous and heterologous virus challenge. The serum from animals vaccinated with either the NISV or the ISCOM HSV-1 antigen preparation, were found to contain high levels of total IgG and IgG1 and IgG2a subclass antibodies. In addition, both preparations were found to induce high neutralizing (NT) antibody levels following a two immunization protocol and to provide some protection against homologous and heterologous HSV challenge infection. Lymphoproliferative responses were observed in cultures of splenocytes from mice immunized with both HSV-1 NISV vaccine and HSV-1 ISCOMs vaccine, following various antigenic stimuli in vitro. In general, these were most marked in animals immunized with the HSV-1 NISV preparation, and particularly so when the splenocytes were stimulated in vitro with live HSV-1. Both the NISV and ISCOM HSV-1 vaccines were found to have induced interleukin 2, interleukin 10 and interferon-gamma in spleen cell culture supernatants, although again, the highest responses in general were observed in supernatant fluids from spleen cell cultures from animals immunized with the HSV-1 NISV preparation. These results suggest that a wide range of immune activity can be elicited by HSV-1 antigens presented to the immune system of mice in these formulations.
Animals↗
Immunogenicity of influenza and HSV-1 mixed antigen ISCOMs in mice.
Immunostimulating complexes (ISCOMs) were prepared with mixtures of antigens from influenza A virus (A/PR/8/34 or A/Sichuan/2/87) and herpes simplex virus type 1 (HSV-1), and were characterised by enzyme linked immunosorbent assay (ELISA) and electron microscopy using double-labelling immunogold techniques employing monoclonal antibodies to influenza or HSV-1 glycoproteins. The immunogenicity of the mixed antigen ISCOMs was evaluated in mice, following administration by the subcutaneous route, by measuring the total and subclass IgG antibody responses. Protection of these animals against challenge with live influenza A/Sichuan virus or live HSV-1, was compared with that induced by immunization with aqueous mixed antigen preparations. It was found that relatively high humoral responses to both influenza and HSV antigens, and increased levels of protection to both influenza and HSV viruses were elicited in mice receiving the mixed antigen ISCOM preparation compared to those observed in animals receiving the mixed aqueous subunit preparation. The findings also indicate that antigens from more than one virus can be used in an ISCOM formulation to produce immunity and protection.
Animals↗
Immune response and protection against influenza A infection in mice immunised with subunit influenza A vaccine in combination with whole cell or acellular DTP vaccine.
Following the demonstration of the strong adjuvant effect of whole-cell DTP vaccine (wDTP) on the immune responses to influenza subunit vaccine, studies were undertaken to identify the component of wDTP responsible for the adjuvant effect, and to determine if acellular DTP (aDTP) vaccine was as effective since it is less reactogenic and likely to replace wDTP for primary or secondary immunisation. In addition, wDTP and aDTP were directly compared in a dose-response study. Experiments in mice indicated that the adjuvant effect of wDTP resided in the LPS component of B. pertussis, since purified LPS enhanced the IgG antibody response, the IgG subclass response and protection to the same level as wDTP. An adjuvant effect was detected using aDTP, but was statistically less pronounced than wDTP by a factor of some 100-fold. These results suggest that immunisation against influenza in infants and young children can be achieved combining small amounts of influenza antigen with wDTP or LPS, and to a lesser extent by combining vaccine with aDTP. However, these results were obtained in mice and should be confirmed in man since species vary considerably in response to adjuvant.
Adjuvants, Immunologic↗
Immune response of mice to immunization with subunit influenza A vaccine in DTP vaccine.
Experiments were carried out to examine the initial feasibility of immunizing infants and children with inactivated influenza virus vaccine combined with diphtheria-tetanus-pertussis (DTP) vaccine. Groups of mice were immunized with saline vaccine or vaccine mixed with DTP: three doses of vaccine were given 3 weeks apart, and the antibody response and resistance to challenge infection were tested 3 weeks after the 1st and 3rd immunizations. The results showed that the antibody response and immunity to challenge virus infection were significantly greater for mice given vaccine in DTP than for mice given saline vaccine alone. Comparison of the response to graded doses of vaccine in saline or DTP indicated that vaccine in DTP was > 250-fold more effective in inducing serum antibody and protection than saline vaccine alone. The enhancing activity of DTP was significant for the alum component alone; however, most of the adjuvant effect was from the antigen components of the DTP vaccine. The results suggest that immunization against influenza in infants and young children could be achieved by combining small amounts of influenza antigen with DTP vaccines; however, the present results have been obtained in mice, and, since the responses to vaccines and adjuvants vary from species to species, the present results cannot be used to indicate similar results in human volunteers. The results indicate the potential value of an immunization procedure which should be tested in volunteers and which could provide a simple strategy for the immunization of at-risk infants and children against influenza.
Adjuvants, Immunologic↗
Comparative antibody responses and protection in mice immunised by oral or parenteral routes with influenza virus subunit antigens in aqueous form or incorporated into ISCOMs.
The total and subclass antibody responses of mice and protection of these animals against live influenza A/Sichuan/2/87 virus challenge infection were determined after immunisation with homologous A/Sichuan/87 aqueous or ISCOM-formulated surface glycoprotein subunit antigens administered by either the oral or intramuscular routes. The results show that the greatest systemic and local antibody responses were elicited in mice immunised with A/Sichuan ISCOMs by the intramuscular route; protection against homologous virus challenge was also effective in these animals, particularly after two doses of the vaccine. However, relatively high immune responses and protection were also elicited by the A/Sichuan/87 ISCOM vaccine administered orally. Immunisation of mice by the intramuscular route resulted in levels of serum IgG2a subclass antibody significantly greater than those induced by the same preparation given by the oral route, or by the aqueous A/Sichuan/87 subunit antigen preparation administered by either route. The findings indicate that the ISCOM delivery system can be used for immunisation by the oral route, although in mice, under the conditions used, this strategy compares unfavourably with the intramuscular route in terms of both local and systemic immune responses and protection against homologous challenge virus infection.
Administration, Oral↗
Psychosocial correlates and sequelae of electroencephalographic sleep in healthy elders.
This research examines longitudinal data on psychosocial status and polysomnographic sleep collected annually from 57 healthy, community-residing elders aged 61-89. Cluster analysis of variables reflecting sleep continuity and architecture at the baseline assessment was used to identify three groups of elders: those whose sleep was either (a) superior to all remaining respondents across a variety of measures, (b) marred only by significantly reduced sleep efficiency relative to other respondents, or (c) poorer than all other respondents in multiple areas. Cross-validation procedures suggested that the three-group cluster solution was stable and replicable over persons and over time. Subsequent multivariate analyses indicated that recent life events, as well as psychosocial stability and support variables at baseline, distinguished between the sleep pattern groups. Moreover, sleep pattern group membership itself predicted subjects' subsequent sleep characteristics and psychosocial status at follow-up. Implications of these results for conceptualizing psychosocial factors that affect, and are ultimately affected by, sleep disturbances in late life are discussed.
Aged↗
Protective vaccination against primary and recurrent disease caused by herpes simplex virus (HSV) type 2 using a genetically disabled HSV-1.
The vaccine potential of a mutant herpes simplex virus (HSV) type 1, with a deletion in the glycoprotein H (gH) gene, was evaluated. The virus requires a gH-expressing cell line for multi-cycle growth but can complete a single cycle of infection in noncomplementing cells. Such viruses, termed DISC (disabled infectious single cycle) viruses, should be safe, yet still able to stimulate humoral and cell-mediated responses against a broad range of virus antigens in vaccinated hosts. Prophylactic vaccination of guinea pigs with DISC HSV-1, by ear scarification or direct infection of the vaginal mucosa, afforded a high degree of protection against HSV-2-induced primary genital disease and reduced significantly the frequency of subsequent disease recurrence. There was also a trend toward reduced recurrence following therapeutic vaccination of animals already infected with HSV-2. DISC HSV vaccination, therefore, offers an effective route for control of HSV disease.
Animals↗
IgG subclass response and protection against challenge following immunisation of mice with various influenza A vaccines.
The serum total IgG and IgG subclass and nasal wash IgA and IgG antibody responses of mice to influenza virus A/Hong Kong/68 (H3N2) subunit preparations administered parenterally as a single dose, incorporated either in immune stimulatory compounds (ISCOMs) or liposomes with Freund's Complete Adjuvant, or as an aqueous material, as well as to live, infectious virus were measured by ELISA at 10 days and 3, 5, 7 and 22 weeks after immunisation. The protection of the upper and lower respiratory tracts provided by these preparations against homologous and heterologous challenge infection was assessed. Of the four variously-presented subunit preparations, influenza subunit ISCOMs induced relatively high and persisting levels of each of the different IgG subclasses, particularly IgG2a, throughout the study, and most nearly approached those observed after intranasal infection of mice with infectious virus. Furthermore, nasal wash IgA and IgG antibody levels, particularly at 5 or 7 weeks after immunisation, were also significantly greater in mice given the subunit ISCOM preparation than those induced by other subunit preparations with adjuvant or subunits given alone, and provided protection of both the upper and lower respiratory tracts against challenge as similar to that elicited by infectious virus.
Animals↗