Alginate-coated chitosan microparticles encapsulating an oral plasmid-cured live Salmonella enterica serovar Gallinarum vaccine cause a higher expression of interferon-gamma in chickens compared to the parenteral live vaccine.

Salmonella enterica serovar Gallinarum causes a disease in chickens known as fowl typhoid. Interferon-gamma (IFN-γ) has been shown to be crucial in eliminating salmonellosis infection because of its strong association with T-cell responses. This study was undertaken to compare the expression of IFN-γ in chickens generated by different vaccine formulations. Eighty one-day-old Lohmann layer chicks were divided into four groups of 20 birds each for the experiment. This comprised an unvaccinated negative control group (NEG), a group vaccinated with the live 9R vaccine by the injection route (SC), a group vaccinated with alginate-coated chitosan microparticles encapsulating live plasmid-cured S. Gallinarum strain 9 (PC) by the oral route, and a group vaccinated with a weak attenuated live S. Gallinarum strain 9 encapsulated in alginate-coated chitosan microparticles (VM) given orally. Vaccinations were done at 10 and 14 weeks of age followed by challenge at 16 weeks of age. IgG was measured using ELISA. qRT-PCR was used to compare the mRNA fold expression of IFN-γ in the PC, VM and SC groups using the unvaccinated/unchallenged group as the control. There were significant differences in the IgG levels between each vaccinated group and the unvaccinated group (P < 0.05) after booster vaccination and post-challenge. There was 100% protection of the birds in SC and VM groups, 80% protection in PC group and 0% protection in the NEG group. Using 2-ΔΔCT calculation, IFN-γ was more highly expressed in the PC group than in the SC group or VM group. In conclusion, the IFN-γ was more highly expressed in the PC group (though not significantly higher) compared to the SC and VM groups and this could be attributed to the alginate-coated chitosan microparticles which acted as an adjuvant.

Typhoid vaccines: WHO position paper, March 2018 - Recommendations.

This article presented the World Health Organization's (WHO) recommendations on the use of Typhoid vaccines excerpted from the Typhoid vaccines: WHO position paper - March 2018 published in the Weekly Epidemiological Record (World Health Organization, 2018) [1]. This position paper replaces the 2008 WHO position paper on typhoid vaccines (WHO, 2008) [2]. It re-emphasizes the importance of vaccination to control typhoid fever and presents the WHO recommendations on the use of a new generation of typhoid conjugate vaccines. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/October/presentations_background_docs/en/.

Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines.

All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4ß7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4ß7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/ß signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.

Development of a synthetic Vi polysaccharide vaccine for typhoid fever.

Typhoid fever remains a serious public health problem with a high impact on toddlers and young children. Vaccines against the Vi capsular polysaccharide are efficacious against typhoid fever demonstrating that antibodies against Vi confer protection. The currently licensed Vi typhoid vaccines have however limited efficacy and are manufactured by a complex process from wild-type bacteria. Due to these inherent issues with the current vaccines, an alternative vaccine based on an O-acetylated high molecular weight (HMW) polygalacturonic acid (GelSite-OAc™) was generated. The HMW polygalacturonic acid shares the same backbone as the Vi polysaccharide of Salmonella Typhi. The GelSite-OAc™ has a high molecular weight (>1 × 106 Da) and a high degree of O-acetylation (DOAc) (>5 µmole/mg), both exceeding the potency specifications of the current Vi vaccine. Studies in Balb/c mice demonstrated that GelSite-OAc™ was highly immunogenic, inducing a strong antigen-specific antibody response in a DOAc- and dose-dependent manner which was comparable to or higher than those induced by the licensed Vi vaccine. Importantly, the GelSite-OAc™ was shown to be fully protective in mice against lethal challenge with Salmonella Typhi. Furthermore, the GelSite-OAc™ demonstrated a boosting effect or memory response, exhibiting a >2-fold increase in antibody levels upon the second immunization with either GelSite-OAc™ or the Vi vaccine. This novel boosting effect is unique among polysaccharide antigens and potentially makes GelSite-OAc™ effective in people under 2 years old. Together these results suggest that the GelSite-OAc™ could be a highly effective vaccine against Salmonella Typhi.

Adjuvant potential of low dose all-trans retinoic acid during oral typhoid vaccination in Zambian men.

There is an urgent need to identify ways of enhancing the mucosal immune response to oral vaccines. Rotavirus vaccine protection is much lower in Africa and Asia than in industrialized countries, and no oral vaccine has efficacy approaching the best systemic vaccines. All-trans retinoic acid (ATRA) up-regulates expression of α4ß7 integrin and CCR9 on lymphocytes in laboratory animals, increasing their gut tropism. The aim of this study was to establish the feasibility of using ATRA as an oral adjuvant for oral typhoid vaccination. In order to establish that standard doses of oral ATRA can achieve serum concentrations greater than 10 nmol/l, we measured ATRA, 9-cis and 13-cis retinoic acid in serum of 14 male volunteers before and 3 h after 10 mg ATRA. We then evaluated the effect of 10 mg ATRA given 1 h before, and for 7 days following, oral typhoid vaccine in eight men, and in 24 men given various control interventions. We measured immunoglobulin (Ig)A directed against lipopolysaccharide (LPS)and protein preparations of vaccine antigens in whole gut lavage fluid (WGLF) and both IgA and IgG in serum, 1 day prior to vaccination and on day 14. Median [interquartile range (IQR)] C(max) was 26·2 (11·7-39·5) nmol/l, with no evidence of cumulation over 8 days. No adverse events were observed. Specific IgA responses to LPS (P = 0·02) and protein (P = 0·04) were enhanced in WGLF, but no effect was seen on IgA or IgG in serum. ATRA was well absorbed, well tolerated and may be a promising candidate oral adjuvant.

Effect of a mixture of micronutrients, but not of bovine colostrum concentrate, on immune function parameters in healthy volunteers: a randomized placebo-controlled study.

BACKGROUND: Supplementation of nutritional deficiencies helps to improve immune function and resistance to infections in malnourished subjects. However, the suggested benefits of dietary supplementation for immune function in healthy well nourished subjects is less clear. Among the food constituents frequently associated with beneficial effects on immune function are micronutrients such as vitamin C, vitamin E, beta-carotene and zinc, and colostrum. This study was designed to investigate the effects these ingredients on immune function markers in healthy volunteers. METHODS: In a double-blind, randomized, parallel, 2*2, placebo-controlled intervention study one hundred thirty-eight healthy volunteers aged 40-80 y (average 57 +/- 10 y) received one of the following treatments: (1) bovine colostrum concentrate 1.2 g/d (equivalent to approximately 500 mg/d immunoglobulins), (2) micronutrient mix of 288 mg vitamin E, 375 mg vitamin C, 12 mg beta-carotene and 15 mg zinc/day, (3) combination of colostrum and micronutrient mix, or (4) placebo. Several immune function parameters were assessed after 6 and 10 weeks. Data were analyzed by analysis of variance. Groups were combined to test micronutrient treatment versus no micronutrient treatment, and colostrum treatment versus no colostrum treatment. RESULTS: Overall, consumption of the micronutrient mix significantly enhanced delayed-type hypersensitivity (DTH) responses (p < 0.05). Adjusted covariance analysis showed a positive association between DTH and age. Separate analysis of younger and older age groups indicated that it was the older population that benefited from micronutrient consumption. The other immune function parameters including responses to systemic tetanus and oral typhoid vaccination, phagocytosis, oxidative burst, lymphocyte proliferation and lymphocyte subset distribution were neither affected by the consumption of micronutrients nor by the consumption of bovine colostrum concentrate. CONCLUSION: Consumption of bovine colostrum had no effect on any of the immune parameters assessed. The micronutrient mix enhanced cellular immunity as measured by DTH, with an increased effect by incremental age, but did not affect any of the other immune parameters measured. Although correlations between decreased DTH and enhanced risk of certain infection have been reported, it remains unclear whether and enhanced DTH response actually improves immune defense. The present data suggests that improvement of immune parameters in a population with a generally good immune and nutritional status is limited and that improvement of immune function in this population may be difficult.

Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.

OBJECTIVES: Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans. METHODS: Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial N(G)-monomethyl-l-arginine (l-NMMA) and bradykinin, respectively. The effects of supplementation with l-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion. RESULTS: Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and l-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with l-arginine had no effect. CONCLUSION: Inflammation causes widespread endothelial dysfunction, reduces vascular NO bioavailability and increases oxidative stress. These actions are partially reversible with local anti-oxidants. These findings suggest a role for reactive oxygen species in inflammation-induced endothelial dysfunction.

[A chemical typhoid vaccine containing a surface-antigen complex including the K-antigen]. / Khimicheskaia briushnotifoznaia vaktsina, soderzhashchaia kompleks poverkhnostnykh antigenov, vkliuchaiushchii K-antigen.

A new chemical typhoid vaccine containing the complex of surface Vi- and K-antigens has been obtained and experimentally studied. The vaccine has been found to possess high immunogenic and antigenic potency. Typhoid complex vaccine containing K-antigen stimulates the development of anti-infection and postvaccinal complex.

[Experimental justification for combined subcutaneous immunization against cholera and typhoid fever]. / Eksperimental'noe obosnovanie assotsiirovannoi podkozhnoi immunizatsii protiv kholery i briushnogo tifa.

The article presents materials on experiments substantiating the method for the subcutaneous administration of chemical adsorbed typhoid vaccine by means of a jet-injector and the possibility of using this preparation in combination with cholerogen toxoid.

[Reactogenicity and immunological effectiveness study of a complex paratyphoid B antigen]. / Izuchenie reaktogennosti i immunologicheskoi éffektivnosti kompleksnogo paratifoznogo B antigena.

Reactogenic property and immunological efficacy of the paratyphoid preparation containing a complex of O-, K- and H-antigens obtained by single-stage antigens extraction were studied in a limited group of volunteers (22 persons). The antigen gave no untoward reactions and proved to be safe when given orally in doses of 25 to 150 mg. Paratyphoid B antigen was characterized by a marked immunization activity and stimulated formation of specific paratyphoid O-, K- and H-agglutinins and antibodies of the IgA,- IgG,- and IgM-classes.

Fever: reciprocal shift in brain sodium to calcium ratio as the set-point temperature rises.

A bacterial pyrogen acts on the brain by disturbing the natural balance between two essential cations in the cerebral region involved in thermoregulation. After typhoid vaccine is administered to the unanesthetized cat, (45)Ca(2+) efflux into the third cerebral ventricle increases while (22)Na(+) is retained in hypothalamic tissue at the same time that the set-point temperature begins to rise. The subsequent rates of (22)Na(+) and (45)Ca(2+) efflux parallel the course of the bacterial fever but in a reciprocal fashion. This supports the theory that a change in the set-point temperature is determined by an alteration in the inherent ratio of Na(+) to Ca(2+) ions in the hypothalamus.