scholarly journals Immunogenicity of a Live Recombinant Salmonellaenterica Serovar Typhimurium Vaccine Expressing pspA in Neonates and Infant Mice Born from Naïve and Immunized Mothers

2010 ◽  
Vol 17 (3) ◽  
pp. 363-371 ◽  
Author(s):  
Huoying Shi ◽  
Shifeng Wang ◽  
Kenneth L. Roland ◽  
Bronwyn M. Gunn ◽  
Roy Curtiss
Keyword(s):  
Immune Responses ◽  
Oral Delivery ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Maternal Antibodies ◽  
Interleukin 4 ◽  
Lymphoid Tissues ◽  
Adult Mice ◽  
Serovar Typhimurium ◽  
Vectored Vaccine

ABSTRACTWe are developing aSalmonellavectored vaccine to prevent infant pneumonia and other diseases caused byStreptococcus pneumoniae. One prerequisite for achieving this goal is to construct and evaluate new recombinant attenuatedSalmonellavaccine (RASV) strains suitable for use in neonates and infants.Salmonella entericaserovar Typhimurium strain χ9558(pYA4088) specifies delivery of the pneumococcal protective antigen PspA and can protect adult mice from challenge withS. pneumoniae. This strain is completely safe for oral delivery to day-old and infant mice. Here we assess the colonizing ability, immunogenicity, and protective efficacy of χ9558(pYA4088) in neonatal mice. Colonization was assessed in mice 0, 2, 4, or 7 days of age after oral inoculation. In the presence of maternal antibodies, the colonization of lymphoid tissues was delayed, but the immune responses were enhanced in mice born to immunized mothers. Both oral and intranasal routes were used to assess immunogenicity. All orally or intranasally immunized neonatal and infant mice born to either immunized or naïve mothers developed PspA-specific mucosal and systemic immune responses. Mice born to immunized mothers produced higher titers of PspA-specific antibodies in the blood and mucosa and greater numbers of PspA-specific interleukin-4 (IL-4)-secreting cells than mice born to naïve mothers. More importantly, mice born to immune mothers showed a significant increase in protection againstS. pneumoniaechallenge. These results suggest that strain χ9558(pYA4088) can circumvent some of the limitations of the immature immune system in neonatal and infant mice, generating enhanced protective immune responses in the presence of maternal antibodies.

scholarly journals Induction of Specific T-Cell Responses, Opsonizing Antibodies, and Protection against Plasmodium chabaudi adami Infection in Mice Vaccinated with Genomic Expression Libraries Expressed in Targeted and Secretory DNA Vectors

2003 ◽  
Vol 71 (8) ◽  
pp. 4506-4515 ◽  
Author(s):  
A. Rainczuk ◽  
T. Scorza ◽  
P. M. Smooker ◽  
T. W. Spithill
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Genomic Library ◽  
Protective Efficacy ◽  
T Cell Responses ◽  
Interleukin 4 ◽  
Plasmodium Chabaudi ◽  
Lethal Challenge ◽  
Cell Responses ◽  
Expression Libraries

ABSTRACT It has been proposed that a multivalent malaria vaccine is necessary to mimic the naturally acquired resistance to this disease observed in humans. A major experimental challenge is to identify the optimal components to be used in such a multivalent vaccine. Expression library immunization (ELI) is a method for screening genomes of a pathogen to identify novel combinations of vaccine sequences. Here we describe immune responses associated with, and the protective efficacy of, genomic Plasmodium chabaudi adami DS expression libraries constructed in VR1020 (secretory), monocyte chemotactic protein-3 (chemoattractant), and cytotoxic T lymphocyte antigen 4 (lymph node-targeting) DNA vaccine vectors. With splenocytes from vaccinated mice, specific T-cell responses, as well as gamma interferon and interleukin-4 production, were observed after stimulation with P. chabaudi adami-infected erythrocytes, demonstrating the specificity of genomic library vaccination for two of the three libraries constructed. Sera obtained from mice vaccinated with genomic libraries promoted the opsonization of P. chabaudi adami-infected erythrocytes by murine macrophages in vitro, further demonstrating the induction of malaria-specific immune responses following ELI. Over three vaccine trials using biolistic delivery of the three libraries, protection after lethal challenge with P. chabaudi adami DS ranged from 33 to 50%. These results show that protective epitopes or antigens are expressed within the libraries and that ELI induces responses specific to P. chabaudi adami malaria. This study further demonstrates that ELI is a suitable approach for screening the malaria genome to identify the components of multivalent vaccines.

scholarly journals Signaling via Interleukin-4 Receptor α Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice

2001 ◽  
Vol 69 (1) ◽  
pp. 228-236 ◽  
Author(s):  
Adrian P. Mountford ◽  
Karen G. Hogg ◽  
Patricia S. Coulson ◽  
Frank Brombacher
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Interleukin 4 ◽  
Lymphoid Tissues ◽  
Partial Protection ◽  
Exposure Site ◽  
Ifn Γ ◽  
Α Chain ◽  
Interleukin 4 Receptor ◽  
Effector Response

ABSTRACT Although protective immunity in C57BL/6 mice induced by a single dose of the radiation-attenuated schistosome vaccine is believed to be mediated by Th1-type immune responses, we here report that in BALB/c mice protection can also depend upon signaling via the interleukin-4 (IL-4) receptor which conventionally governs the development of Th2-type immune responses. We show that in BALB/c mice deficient for the IL-4 receptor α chain (IL-4Rα−/−), which are unresponsive to IL-4 and IL-13, vaccine-induced protection is abrogated compared with that in wild-type (WT) mice. In vaccinated IL-4Rα−/− mice, IL-12p40 production by cells from the skin exposure site was elevated, although gamma interferon (IFN-γ) production in draining lymphoid tissues was similar in WT and IL-4Rα−/− mice. Nevertheless, the effector response in IL-4Rα−/− mice was Th1 biased with elevated IFN-γ in the lungs and higher immunoglobulin G2a (IgG2a) and IgG2b titers but negligible quantities of Th2-associated IgG1 and IgE. Interestingly, levels of IL-4 were equivalent in WT and IL-4Rα−/−mice, indicating that Th2 responses were not dependent upon signaling by IL-4 or IL-13. No differences in the phenotype and composition of the pulmonary effector mechanism that might explain the failure to induce protection in IL-4Rα−/− mice were detected. However, passive transfer of partial protection to naive IL-4Rα−/− mice, using serum from vaccinated WT mice, indicates that Th2-associated antibodies such as IgG1 have a role in parasite elimination in BALB/c strain mice and that signaling via IL-4R can be an important factor in the generation of protection.

scholarly journals The EtpA Exoprotein of Enterotoxigenic Escherichia coli Promotes Intestinal Colonization and Is a Protective Antigen in an Experimental Model of Murine Infection

2008 ◽  
Vol 76 (5) ◽  
pp. 2106-2112 ◽  
Author(s):  
Koushik Roy ◽  
David Hamilton ◽  
Kenneth P. Allen ◽  
Mildred P. Randolph ◽  
James M. Fleckenstein
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Vaccine Development ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Enterotoxigenic Escherichia Coli ◽  
Deletion Mutants ◽  
Diverse Group ◽  
Intestinal Colonization

ABSTRACT The enterotoxigenic Escherichia coli (ETEC) strains are major causes of morbidity and mortality due to diarrheal illness in developing countries. At present, there is no broadly protective vaccine for this diverse group of pathogens. The EtpA protein, identified in ETEC H10407 in a recent search for candidate immunogens, is a large glycosylated exoprotein secreted via two-partner secretion (TPS). Similar to structurally related molecules, EtpA functions in vitro as an adhesin. The studies reported here use a recently developed murine model of ETEC intestinal colonization to examine the immunogenicity and protective efficacy of EtpA. We report that mice repeatedly exposed to ETEC are protected from subsequent colonization and that they mount immune responses to both EtpA and its presumed two-partner secretion transporter (EtpB) during the course of experimental infection. Furthermore, isogenic etpA deletion mutants were impaired in the colonization of mice, and intranasal immunization of mice with recombinant EtpA conferred protection against ETEC H10407 in this model. Together, these data suggest that EtpA is required for optimal colonization of the intestine, findings paralleling those of previous in vitro studies demonstrating its role in adherence. EtpA and other TPS proteins may be viable targets for ETEC vaccine development.

scholarly journals Reduced Protective Efficacy of a Blood-Stage Malaria Vaccine by Concurrent Nematode Infection

2006 ◽  
Vol 74 (4) ◽  
pp. 2138-2144 ◽  
Author(s):  
Zhong Su ◽  
Mariela Segura ◽  
Mary M. Stevenson
Keyword(s):  
Immune Responses ◽  
Malaria Vaccine ◽  
Transforming Growth Factor ◽  
Protective Efficacy ◽  
Nematode Infection ◽  
Blood Stage ◽  
Interleukin 4 ◽  
Spleen Cells ◽  
The Impact

ABSTRACT Helminth infections, which are prevalent in areas where malaria is endemic, have been shown to modulate immune responses to unrelated pathogens and have been implicated in poor efficacy of malaria vaccines in humans. We established a murine coinfection model involving blood-stage Plasmodium chabaudi AS malaria and a gastrointestinal nematode, Heligmosomoides polygyrus, to investigate the impact of nematode infection on the protective efficacy of a malaria vaccine. C57BL/6 mice immunized with crude blood-stage P. chabaudi AS antigen in TiterMax adjuvant developed strong protection against malaria challenge. The same immunization protocol failed to induce strong protection in H. polygyrus-infected mice. Immunized nematode-infected mice produced significantly lower levels of malaria-specific antibody than nematode-free mice produced. In response to nematode and malarial antigens, spleen cells from immunized nematode-infected mice produced significantly lower levels of gamma interferon but more interleukin-4 (IL-4), IL-13, and IL-10 in vitro than spleen cells from immunized nematode-free mice produced. Furthermore, H. polygyrus infection also induced a strong transforming growth factor β1 response in vivo and in vitro. Deworming treatment of H. polygyrus-infected mice before antimalarial immunization, but not deworming treatment after antimalarial immunization, restored the protective immunity to malaria challenge. These results demonstrate that concurrent nematode infection strongly modulates immune responses induced by an experimental malaria vaccine and consequently suppresses the protective efficacy of the vaccine against malaria challenge.

scholarly journals An M2 Rather than a TH2 Response Contributes to Better Protection against Latency Reactivation following Ocular Infection of Naive Mice with a Recombinant Herpes Simplex Virus 1 Expressing Murine Interleukin-4

2018 ◽  
Vol 92 (10) ◽  
Author(s):  
Dhong Hyun Lee ◽  
Homayon Ghiasi
Keyword(s):  
Immune Responses ◽  
Protective Efficacy ◽  
Parental Virus ◽  
Interleukin 4 ◽  
Trigeminal Ganglia ◽  
Herpes Simplex Virus 1 ◽  
Corneal Scarring ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTWe found previously that altering macrophage polarization toward M2 responses by injection of colony-stimulating factor 1 (CSF-1) was more effective in reducing both primary and latent infections in mice ocularly infected with herpes simplex virus 1 (HSV-1) than M1 polarization by gamma interferon (IFN-γ) injection. Cytokines can coordinately regulate macrophage and T helper (TH) responses, with interleukin-4 (IL-4) inducing type 2 TH(TH2) as well as M2 responses and IFN-γ inducing TH1 as well as M1 responses. We have now differentiated the contributions of these immune compartments to protection against latency reactivation and corneal scarring by comparing the effects of infection with recombinant HSV-1 in which the latency-associated transcript (LAT) gene was replaced with either theIL-4(HSV-IL-4) orIFN-γ(HSV-IFN-γ) gene using infection with the parental (LAT-negative) virus as a control. Analysis of peritoneal macrophagesin vitroestablished that the replacement ofLATwith theIL-4orIFN-γgene did not affect virus infectivity and promoted polarization appropriately. Protection against corneal scarring was significantly higher in mice ocularly infected with HSV-IL-4 than in those infected with HSV-IFN-γ or parental virus. Levels of primary virus replication in the eyes and trigeminal ganglia (TG) were similar in the three groups of mice, but the numbers of gC+cells were lower on day 5 postinfection in the eyes of HSV-IL-4-infected mice than in those infected with HSV-IFN-γ or parental virus. Latency and explant reactivation were lower in both HSV-IL-4- and HSV-IFN-γ-infected mice than in those infected with parental virus, with the lowest level of latency being associated with HSV-IL-4 infection. Higher latency correlated with higher levels of CD8, PD-1, and IFN-γ mRNA, while reduced latency and T-cell exhaustion correlated with lower gC+expression in the TG. Depletion of macrophages increased the levels of latency in all ocularly infected mice compared with their undepleted counterparts, with macrophage depletion increasing latency in the HSV-IL-4 group greater than 3,000-fold. Our results suggest that shifting the innate macrophage immune responses toward M2, rather than M1, responses in HSV-1 infection would improve protection against establishment of latency, reactivation, and eye disease.IMPORTANCEOcular HSV-1 infections are among the most frequent serious viral eye infections in the United States and a major cause of virus-induced blindness. As establishment of a latent infection in the trigeminal ganglia results in recurrent infection and is associated with corneal scarring, prevention of latency reactivation is a major therapeutic goal. It is well established that absence of latency-associated transcripts (LATs) reduces latency reactivation. Here we demonstrate that recombinant HSV-1 expressing IL-4 (an inducer of TH2/M2 responses) or IFN-γ (an inducer of TH1/M1 responses) in place of LAT further reduced latency, with HSV-IL-4 showing the highest overall protective efficacy. In naive mice, this higher protective efficacy was mediated by innate rather than adaptive immune responses. Although both M1 and M2 macrophage responses were protective, shifting macrophages toward an M2 response through expression of IL-4 was more effective in curtailing ocular HSV-1 latency reactivation.

scholarly journals Oral and Nasal DNA Vaccines Delivered by Attenuated Salmonella enterica Serovar Typhimurium Induce a Protective Immune Response against Infectious Bronchitis in Chickens

2011 ◽  
Vol 18 (7) ◽  
pp. 1041-1045 ◽  
Author(s):  
Hongmei Jiao ◽  
Zhiming Pan ◽  
Yuelan Yin ◽  
Shizhong Geng ◽  
Lin Sun ◽  
...  
Keyword(s):  
Immune Responses ◽  
Salmonella Enterica ◽  
Dna Vaccines ◽  
Protective Efficacy ◽  
Nasal Administration ◽  
N Gene ◽  
Content Type ◽  
Infectious Bronchitis ◽  
Mucosal Vaccination ◽  
Serovar Typhimurium

ABSTRACTSeveral studies have reported that intramuscular injection of DNA vaccines against infectious bronchitis virus (IBV) induces protective immune responses. In the present study, we developed oral and nasal DNA vaccines that carried the S1 gene and N gene of IBV delivered by attenuatedSalmonella entericaserovar Typhimurium strains SL/pV-S1 and SL/pV-N, respectively. The safety and stability of recombinantSalmonellavaccine were evaluated. Following oral and nasal administration to chickens, the serum and mucosal samples were collected and antibodies against IBV were measured. Chickens were then challenged with IBV strain M41 by the nasal-ocular route 3 weeks after boosting. The results showed that oral and nasal immunization with coadministered SL/pV-S1 and SL/pV-N elicited significant IBV-specific humoral and mucosal immune responses and conferred protective efficacy against IBV challenge higher than that in chickens immunized only with SL/pV-S1. The current study shows that novel DNA vaccines delivered by attenuatedS.Typhimurium may be promising candidates for the prevention of infectious bronchitis (IB).These vaccines are efficacious, easily produced economically, and able to be delivered orally and nasally rather than injected. Coadministration of SL/pV-S1 and SL/pV-N may represent an effective mucosal vaccination regimen.

scholarly journals Type 2 immunity induced by bladder extracellular matrix enhances corneal wound healing

2021 ◽  
Vol 7 (16) ◽  
pp. eabe2635
Author(s):  
Xiaokun Wang ◽  
Liam Chung ◽  
Joshua Hooks ◽  
David R. Maestas ◽  
Andriana Lebid ◽  
...  
Keyword(s):  
Wound Healing ◽  
Immune Responses ◽  
Smooth Muscle Actin ◽  
Treated Group ◽  
Interleukin 4 ◽  
Impaired Wound Healing ◽  
Urinary Bladder Matrix ◽  
Incomplete Healing ◽  
Haze Formation

The avascular nature of cornea tissue limits its regenerative potential, which may lead to incomplete healing and formation of scars when damaged. Here, we applied micro- and ultrafine porcine urinary bladder matrix (UBM) particulate to promote type 2 immune responses in cornea wounds. Results demonstrated that UBM particulate substantially reduced corneal haze formation as compared to the saline-treated group. Flow cytometry and gene expression analysis showed that UBM particulate suppressed the differentiation of corneal stromal cells into α-smooth muscle actin–positive (αSMA+) myofibroblasts. UBM treatments up-regulated interleukin-4 (IL-4) produced primarily by eosinophils in the wounded corneas and CD4+ T cells in draining lymph nodes, suggesting a cross-talk between local and peripheral immunity. Gata1−/− mice lacking eosinophils did not respond to UBM treatment and had impaired wound healing. In summary, stimulating type 2 immune responses in the wounded cornea can promote proregenerative environments that lead to improved wound healing for vision restoration.

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

scholarly journals Immunogenicity and protective efficacy of enterotoxigenic Escherichia coli (ETEC) total RNA against ETEC challenge in a mouse model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mandi Liu ◽  
Yue Zhang ◽  
Di Zhang ◽  
Yun Bai ◽  
Guomei Liu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Mouse Model ◽  
Immune Responses ◽  
Protective Efficacy ◽  
Enterotoxigenic Escherichia Coli ◽  
Economic Losses ◽  
Th2 Response ◽  
Total Rna ◽  
Etec Infection

AbstractEnterotoxigenic Escherichia coli (ETEC), an essential cause of post-weaning diarrhea (PWD) in piglets, leads to significant economic losses to the pig industry. The present study aims to identify the role of ETEC total RNA in eliciting immune responses to protect animals against ETEC infection. The results showed that the total RNA isolated from pig-derived ETEC K88ac strain effectively stimulated the IL-1β secretion of porcine intestinal epithelial cells (IPEC-J2). The mouse model immunized with ETEC total RNA via intramuscular injection (IM) or oral route (OR) was used to evaluate the protective efficiency of the ETEC total RNA. The results suggested that 70 μg ETEC total RNA administered by either route significantly promoted the production of the serum IL-1β and K88ac specific immunoglobulins (IgG, IgM, and IgA). Besides, the ETEC RNA administration augmented strong mucosal immunity by elevating K88ac specific IgA level in the intestinal fluid. Intramuscularly administered RNA induced a Th1/Th2 shift toward a Th2 response, while the orally administered RNA did not. The ETEC total RNA efficiently protected the animals against the ETEC challenge either by itself or as an adjuvant. The histology characterization of the small intestines also suggested the ETEC RNA administration protected the small intestinal structure against the ETEC infection. Particularly of note was that the immunity level and protective efficacy caused by ETEC RNA were dose-dependent. These findings will help understand the role of bacterial RNA in eliciting immune responses, and benefit the development of RNA-based vaccines or adjuvants.

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