In recent years, the emergence of several highly pathogenic zoonotic diseases in humans has led to a renewed emphasis on the interconnectedness of human, animal, and environmental health, otherwise ...known as One Health. For example, Hendra virus (HeV), a zoonotic paramyxovirus, was discovered in 1994, and since then, infections have occurred in 7 humans, each of whom had a strong epidemiologic link to similarly affected horses. As a consequence of these outbreaks, eradication of bat populations was discussed, despite their crucial environmental roles in pollination and reduction of the insect population. We describe the development and evaluation of a vaccine for horses with the potential for breaking the chain of HeV transmission from bats to horses to humans, thereby protecting horse, human, and environmental health. The HeV vaccine for horses is a key example of a One Health approach to the control of human disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It has recently been recognised that vaccine adjuvants play a critical role in directing the nature of a vaccine induced effector response. In the present study, several adjuvants were evaluated for ...their ability to protect sheep after field vaccination with the larval-specific Haemonchus contortus antigen, HcsL3. Using a suboptimal antigen dose, aluminium adjuvant was shown to reduce the cumulative faecal egg counts (cFEC) and worm burden by 23% and 25% respectively, in agreement with a previous study. The addition of Quil A to the aluminium-adjuvanted vaccine brought cFEC back to control levels. Vaccination with the adjuvant DEAE-dextran almost doubled the protection compared to the aluminium-adjuvanted vaccine resulting in 40% and 41% reduction in cFEC and worm counts compared to controls. Examination of skin responses following i.d. injection of exsheathed L3, revealed that cFEC was negatively correlated with wheal size and tissue eosinophils for the DEAE-dextran and aluminium-adjuvanted groups respectively. These studies have for the first time shown the potential of DEAE-dextran adjuvant for helminth vaccines, and discovered significant cellular correlates of vaccine-induced protection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Aluminium adjuvants are potent enhancers of immune responses. Despite being a component in most human and animal vaccines, their specific mode of action remains elusive. We have used a sheep ...lymphatic cannulation model to directly measure the trafficking of soluble and particulate antigen in real-time from the site of injection. Aluminium adjuvant does not alter the kinetics of antigen flow from the site of injection; however it does reduce the amount of soluble antigen entering into afferent lymph. Large numbers of neutrophils, but not DCs, were recruited into the lymph in both saline and aluminium-injected sites and were predominantly responsible for the early uptake of particulate antigen into the lymphatic. Aluminium adjuvant did not significantly increase neutrophil uptake but markedly increased the subsequent uptake of particulate antigen by DCs from 48 to 72 h after antigen injection. Thus, the adjuvanticity of aluminium does not correlate with slow antigen release or increased cell recruitment, but with retention of antigen at the site of injection, and increased uptake of particulate antigen by mature migratory DCs after 24 h.
Liposomal vaccine formulations incorporating stimulants that target innate immune receptors have been shown to significantly increase vaccine immunity. Following vaccination, innate cell populations ...respond to immune stimuli, phagocytose and process Ag, and migrate from the injection site, via the afferent lymphatic vessels, into the local lymph node. In this study, the signals received in the periphery promote and sculpt the adaptive immune response. Effector lymphocytes then leave the lymph node via the efferent lymphatic vessel to perform their systemic function. We have directly cannulated the ovine lymphatic vessels to detail the in vivo innate and adaptive immune responses occurring in the local draining lymphatic network following vaccination with a liposome-based delivery system incorporating CpG. We show that CpG induces the rapid recruitment of neutrophils, enhances dendritic cell-associated Ag transport, and influences the maturation of innate cells entering the afferent lymph. This translated into an extended period of lymph node shutdown, the induction of IFN-γ-positive T cells, and enhanced production of Ag-specific Abs. Taken together, the results of this study quantify the real-time in vivo kinetics of the immune response in a large animal model after vaccination of a dose comparable to that administered to humans. This study details enhancement of numerous immune mechanisms that provide an explanation for the immunogenic function of CpG when employed as an adjuvant within vaccines.
Vaccine adjuvants stimulate the innate immune system and determine the outcome of the immune response induced. A better understanding of their action is therefore crucial to the development of new ...and safer vaccines. Monophosphoryl lipid A (MPL), a ‘detoxified’ version of lipolysaccharide, is a promising new adjuvant component in human vaccines. The present study uses an ovine lymphatic cannulation model to study cell recruitment and antigen transport from the injection site into the afferent lymph, and how this is modulated by co‐injection with MPL. Compared with saline, MPL injections caused only minor variations in lymph flow and no difference in cell number migrating into the lymph. MPL did, however, cause a significantly increased recruitment of neutrophils and monocytes, but not dendritic cells (DC) into the lymph for the first 12 h. Soluble ovalbumin (OVA) antigen flowed freely into the lymph over a 24‐h period and was slightly reduced at 6–9 h in the MPL‐injected sites. OVA‐coated fluorescent 1‐μ beads were initially transported predominantly by neutrophils and, from 24 to 72 h, by DC. MPL induced an increased and more sustained transport of beads by neutrophils and monocytes although it did not increase the phagocytic capacity of these cells. In contrast to aluminium adjuvant, MPL did not increase bead transport by DC at the later time point. These studies provide important new insights in the in vivo action of different adjuvants and the initial events that set up an immune response after vaccination.
Highlights • Liposomal poly(I:C) increases neutrophil recruitment and antigen uptake by DCs. • Liposomal poly(I:C) induces a unique pattern of migratory DC maturation. • Monocytes up-regulate ...anti-viral genes but do not mature in response to poly(I:C). • Innate gene expression profiles of sorted cell populations after local vaccination. • The in vivo real time immune response to liposome-based adjuvant delivery system.
Summary
Vaccine formulations incorporating innate immune stimulants are highly immunogenic; however, the biological signals that originate in the peripheral tissues at the site of injection and are ...transmitted to the local lymph node to induce immunity remain unclear. By directly cannulating the ovine afferent lymphatic vessels, we have previously shown that it takes 72 hr for mature antigen‐loaded dendritic cells and monocytes to appear within afferent lymph following injection of a liposomal formulation containing the Toll‐like receptor ligand CpG. In this present study, we characterize the global transcriptional signatures at this time‐point in ovine afferent lymph cells as they migrate from the injection site into the lymphatics following vaccination with a liposome antigen formulation incorporating CpG. We show that at 72 hr post vaccination, liposomes alone induce no changes in gene expression and inflammatory profiles within afferent lymph; however, the incorporation of CpG drives interferon, antiviral and cytotoxic gene programmes. This study also measures the expression of key genes within individual cell types in afferent lymph. Antiviral gene signatures are most prominent in lymphocytes, which may play a significant and unexpected role in sustaining the immune response to vaccination at the site of injection. These findings provide a comprehensive analysis of the in vivo immunological pathways that connect the injection site with the local draining lymph node following vaccination.
Highlights ► Antigen is transported first by neutrophils and monocytes, then by dendritic cells. ► There is little antigen trafficking via afferent lymph with oil-based formulations. ► ...Poly(I:C)-containing liposomes-in oil form ectopic lymphoid tissues.
The ESAT-6 antigen from Mycobacterium tuberculosis is a dominant target for cell-mediated immunity in the early phase of tuberculosis (TB) in TB patients as well as in various animal models. The ...purpose of our study was to evaluate the potential of ESAT-6 in an experimental TB vaccine. We started out using dimethyl dioctadecylammonium bromide (DDA), an adjuvant which has been demonstrated to be efficient for the induction of cellular immune responses and has been used successfully before as a delivery system for TB vaccines. Here we demonstrate that, whereas immune responses to both short-term-culture filtrate and Ag85B are efficiently induced with DDA, this adjuvant was inefficient for the induction of immune responses to ESAT-6. Therefore, we investigated the modulatory effect of monophosphoryl lipid A (MPL), an immunomodulator which in different combinations has demonstrated strong adjuvant activity for both cellular and humoral immune responses. We show in the present study that vaccination with ESAT-6 delivered in a combination of MPL and DDA elicited a strong ESAT-6-specific T-cell response and protective immunity comparable to that achieved with Mycobacterium bovis BCG.
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