• The response of Vibrio- and Rhodobacter-related populations of the NW Mediterranean Sea to additions of dissolved organic matter, phages, or dilution.

      Weinbauer, Markus G; Christen, Richard; Höfle, Manfred G (2006-04-01)
      We investigated the growth response of the heterotrophic prokaryotic community focusing on Vibrio- and Rhodobacter-related populations (SRF3) to variation in the availability of dissolved organic matter (DOM), population density-dependent effects, and prokaryotic virus (phage) infection in coastal and offshore waters of the NW Mediterranean Sea. We tested the response of the prokaryotic community to three different DOM fractions prepared by ultrafiltration. One of the DOM fractions contained phages (<0.2 m), a second was virus-free (<100 kDa), and a third contained only low molecular weight (<1 kDa). The proportion of Vibrio and SRF3 populations as determined by fluorescent in situ hybridization in the community ranged from <1 to 6.2% and from 3.2 to 6.3%, respectively. Based on changes in cell numbers, growth rates ranged from 2.1 to 3.1 day(-1) for Vibrio and from 0.8 to 1.2 day(-1) for SRF3. Growth rates of Vibrio were similar or higher than those of the total prokaryotic community, whereas the ability of Vibrio to use high molecular weight (HMW) DOM and the responses to additions of phage-rich material were lower. Growth rates of SRF3 were lower than that of the community. Susceptibility to infection of SRF3 was sometimes lower than in the community, whereas the growth stimulation of HMW DOM was similar or lower. Reducing the cell concentrations of the prokaryotic community by dilution stimulated the overall growth of the community, including that of its constituent Vibrio and SRF3 populations, but the effect was smaller on the SRF3 and greater on Vibrio populations than for the total community. Comparisons with the community also revealed that life strategy traits of bacterial populations differed between coastal and offshore waters. Overall, our data suggest that Vibrio is an r-strategist or opportunistic population in the NW Mediterranean Sea, whereas SRF3 is a K-strategist or equilibrium population.
    • Responsiveness to Influenza Vaccination Correlates with NKG2C-Expression on NK Cells.

      Riese, Peggy; Trittel, Stephanie; Pathirana, Rishi D; Klawonn, Frank; Cox, Rebecca J; Guzmán, Carlos A; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-06-05)
      Influenza vaccination often results in a large percentage of low responders, especially in high-risk groups. As a first line of defense, natural killer (NK) cells play a crucial role in the fight against infections. However, their implication with regard to vaccine responsiveness is insufficiently assessed. Therefore, this study aimed at the validation of essential NK cell features potentially associated with differential vaccine responsiveness with a special focus on NKG2C- and/or CD57-expressing NK cells considered to harbor memory-like functions. To this end, 16 healthy volunteers were vaccinated with an adjuvanted pandemic influenza vaccine. Vaccine responders and low responders were classified according to their hemagglutination inhibition antibody titers. A majority of responders displayed enhanced frequencies of NKG2C-expressing NK cells 7- or 14-days post-vaccination as compared to low responders, whereas the expression of CD57 was not differentially modulated. The NK cell cytotoxic potential was found to be confined to CD56dimCD16+ NKG2C-expressing NK cells in the responders but not in the low responders, which was further confirmed by stochastic neighbor embedding analysis. The presented study is the first of its kind that ascribes CD56dimCD16+ NKG2C-expressing NK cells a crucial role in biasing adaptive immune responses upon influenza vaccination and suggests NKG2C as a potential biomarker in predicting pandemic influenza vaccine responsiveness.
    • Rheinheimera perlucida sp. nov., a marine bacterium of the Gammaproteobacteria isolated from surface water of the central Baltic Sea.

      Brettar, Ingrid; Christen, Richard; Höfle, Manfred G (2006-09-01)
      A bacterial isolate from the Baltic Sea, BA131(T), was characterized for its physiological and biochemical features, fatty acid profile, G+C content and phylogenetic position based on comparative 16S rRNA gene sequence analysis. The strain was isolated from surface water of the central Baltic Sea during the decay of a plankton bloom. Phylogenetic analyses of the 16S rRNA gene sequence revealed a clear affiliation with the Gammaproteobacteria, and showed closest phylogenetic relationships with the genera Alishewanella and Rheinheimera. The G+C content of the DNA of strain BA131(T) was 48.9 mol%. Cells were non-pigmented, Gram-negative, rod-shaped, motile by means of a single polar flagellum and catalase- and oxidase-positive. Growth was observed at salinities from 0 to 8 %, with an optimum at 1-3 %. Temperature for growth ranged from 4 to 37 degrees C, with an optimum around 25 degrees C. The fatty acids were dominated by 16 : 0 (17-18 %) and by unsaturated compounds (>61 % of the total): 16 : 1omega7c (24-33 %), 17 : 1omega8c (14-18 %) and 18 : 1omega7c (9-12 %). Based on the data presented, BA131(T) is proposed as the type strain of a novel species of the genus Rheinheimera, Rheinheimera perlucida sp. nov. The type strain is BA131(T) (=LMG 23581(T)=CIP 109200(T)).
    • Roads to advanced vaccines: influenza case study.

      Riese, Peggy; Guzmán, Carlos A; Helmholz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-09)
      Vaccines represent a cornerstone to ensure healthy lives and promote well-being for all at all ages. However, there are many diseases for which vaccines are not available, are relatively ineffective or need to be adapted periodically. Advances in microbial biotechnology will contribute to overcoming these roadblocks by laying the groundwork for improving and creating new approaches for developing better vaccines, as illustrated here in the case of influenza.
    • Rodents as pre-clinical models for predicting vaccine performance in humans.

      Riese, Peggy; Trittel, Stephanie; Schulze, Kai; Guzmán, Carlos A (2015-09)
      Vaccines represent a key building block for establishing a successful and sustainable control strategy against infectious diseases. Vaccine development often depends on the availability of correlates for protection and reliable animal models for the screening, selection and prioritization of potential vaccine candidates. This is performed according to their immunogenicity, efficacy and safety profiles in pre-clinical studies, which are also critical for identification of candidate antigens, selection of an optimal delivery system and design of appropriate vaccine formulations. Thus, pre-clinical studies in animal models are a prerequisite for addressing crucial issues and generating a solid pre-clinical package for the approval of clinical trials. This review addresses the strengths, limitations and perspectives of rodents as a vaccine development and pre-clinical validation tool.
    • Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17.

      Bugatti, Antonella; Marsico, Stefania; Mazzuca, Pietro; Schulze, Kai; Ebensen, Thomas; Giagulli, Cinzia; Peña, Esther; Badimón, Lina; Slevin, Mark; Caruso, Arnaldo; et al. (MDPI, 2020-03-16)
    • A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations.

      Bertoglio, Federico; Fühner, Viola; Ruschig, Maximilian; Heine, Philip Alexander; Abassi, Leila; Klünemann, Thomas; Rand, Ulfert; Meier, Doris; Langreder, Nora; Steinke, Stephan; et al. (Cell Press, 2021-07-07)
      The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcγR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19.
    • Seasonal dynamics of bacterial community structure and composition in cold and hot drinking water derived from surface water reservoirs.

      Henne, Karsten; Kahlisch, Leila; Höfle, Manfred G; Brettar, Ingrid; Dept of Vacciology, Helmholtz Centre for infection research, D-38124 Braunschweig, Germany (2014-02-14)
      In temperate regions, seasonal variability of environmental factors affects the bacterial community in source water and finished drinking water. Therefore, the bacterial core community and its seasonal variability in cold and the respective hot drinking water was investigated. The bacterial core community was studied by 16S rRNA-based SSCP fingerprint analyses and band sequencing of DNA and RNA extracts of cold and hot water (60 °C). The bacterial communities of cold and hot drinking water showed a highly different structure and phylogenetic composition both for RNA and DNA extracts. For cold drinking water substantial seasonal dynamics of the bacterial community was observed related to environmental factors such as temperature and precipitation affecting source and drinking water. Phylogenetic analyses of the cold water community indicated that the majority of phylotypes were very closely affiliated with those detected in former studies of the same drinking water supply system (DWSS) in the preceding 6 years, indicating a high stability over time. The hot water community was very stable over time and seasons and highly distinct from the cold water with respect to structure and composition. The hot water community displayed a lower diversity and its phylotypes were mostly affiliated with bacteria of high temperature habitats with high growth rates indicated by their high RNA content. The conversion of the cold to the hot water bacterial community is considered as occurring within a few hours by the following two processes, i) by decay of most of the cold water bacteria due to heating, and ii) rapid growth of the high temperature adapted bacteria present in the hot water (co-heated with the cold water in the same device) using the nutrients released from the decaying cold water bacteria. The high temperature adapted bacteria originated partially from low abundant but beforehand detected members of the cold water; additionally, the rare members ("seed bank ") of the cold water are considered as a source.
    • Self-Amplifying Pestivirus Replicon RNA Encoding Influenza Virus Nucleoprotein and Hemagglutinin Promote Humoral and Cellular Immune Responses in Pigs.

      Démoulins, Thomas; Ruggli, Nicolas; Gerber, Markus; Thomann-Harwood, Lisa J; Ebensen, Thomas; Schulze, Kai; Guzmán, Carlos A; McCullough, Kenneth C; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Frontiers, 2021-01-28)
      Self-amplifying replicon RNA (RepRNA) promotes expansion of mRNA templates encoding genes of interest through their replicative nature, thus providing increased antigen payloads. RepRNA derived from the non-cytopathogenic classical swine fever virus (CSFV) targets monocytes and dendritic cells (DCs), potentially promoting prolonged antigen expression in the DCs, contrasting with cytopathogenic RepRNA. We engineered pestivirus RepRNA constructs encoding influenza virus H5N1 (A/chicken/Yamaguchi/7/2004) nucleoprotein (Rep-NP) or hemagglutinin (Rep-HA). The inherent RNase-sensitivity of RepRNA had to be circumvented to ensure efficient delivery to DCs for intracellular release and RepRNA translation; we have reported how only particular synthetic delivery vehicle formulations are appropriate. The question remained concerning RepRNA packaged in virus replicon particles (VRPs); we have now compared an efficient polyethylenimine (PEI)-based formulation (polyplex) with VRP-delivery as well as naked RepRNA co-administered with the potent bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) adjuvant. All formulations contained a Rep-HA/Rep-NP mix, to assess the breadth of both humoral and cell-mediated defences against the influenza virus antigens. Assessment employed pigs for their close immunological relationship to humans, and as natural hosts for influenza virus. Animals receiving the VRPs, as well as PEI-delivered RepRNA, displayed strong humoral and cellular responses against both HA and NP, but with VRPs proving to be more efficacious. In contrast, naked RepRNA plus c-di-AMP could induce only low-level immune responses, in one out of five pigs. In conclusion, RepRNA encoding different influenza virus antigens are efficacious for inducing both humoral and cellular immune defences in pigs. Comparisons showed that packaging within VRP remains the most efficacious for delivery leading to induction of immune defences; however, this technology necessitates employment of expensive complementing cell cultures, and VRPs do not target human cells. Therefore, choosing the appropriate synthetic delivery vehicle still offers potential for rapid vaccine design, particularly in the context of the current coronavirus pandemic.
    • Self-Amplifying Replicon RNA Delivery to Dendritic Cells by Cationic Lipids

      Englezou, Pavlos C.; Sapet, Cedric; Démoulins, Thomas; Milona, Panagiota; Ebensen, Thomas; Schulze, Kai; Guzman, Carlos-Alberto; Poulhes, Florent; Zelphati, Olivier; Ruggli, Nicolas; et al.
    • Seropositivity for pathogens associated with chronic infections is a risk factor for all-cause mortality in the elderly: findings from the Memory and Morbidity in Augsburg Elderly (MEMO) Study.

      Zeeb, Marius; Kerrinnes, Tobias; Cicin-Sain, Luka; Guzman, Carlos A; Puppe, Wolfram; Schulz, Thomas F; Peters, Annette; Berger, Klaus; Castell, Stefanie; Karch, André; et al. (Springer, 2020-07-09)
      Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (Helicobacter pylori, Borrelia burgdorferi sensu lato, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for Helicobacter pylori (accelerated failure time (AFT) - 15.92, 95% CI - 29.96; - 1.88), cytomegalovirus (AFT - 22.81, 95% CI - 36.41; - 9.22) and Borrelia burgdorferi sensu lato (AFT - 25.25, 95% CI - 43.40; - 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection - 12.42 95% CI - 18.55; - 6.30). Our results suggest an effect of seropositivity for Helicobacter pylori, cytomegalovirus, and Borrelia burgdorferi sensu lato on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.
    • Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34 Cells.

      Theobald, Sebastian J; Khailaie, Sahamoddin; Meyer-Hermann, Michael; Volk, Valery; Olbrich, Henning; Danisch, Simon; Gerasch, Laura; Schneider, Andreas; Sinzger, Christian; Schaudien, Dirk; et al. (Frontiers, 2018-01-01)
      uman cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.
    • Simultaneous Extraction from Bacterioplankton of Total RNA and DNA Suitable for Quantitative Structure and Function Analyses

      Weinbauer, Markus G.; Fritz, Ingo; Wenderoth, Dirk F.; Höfle, Manfred G. (American Society for Microbiology, 2002-03)
    • An SopB-mediated immune escape mechanism of Salmonella enterica can be subverted to optimize the performance of live attenuated vaccine carrier strains.

      Link, Claudia; Ebensen, Thomas; Ständner, Lothar; Déjosez, Marion; Reinhard, Elena; Rharbaoui, Faiza; Guzmán, Carlos A; Department of Vaccinology, Division of Microbiology, GBF-German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany. (2006-07)
      Salmonellae have evolved several mechanisms to evade host clearance. Here, we describe the influence on bacterial immune escape of the effector protein SopB, which is translocated into the cytosol through a type III secretion system. Wild-type bacteria, as well as the sseC and aroA attenuated mutants exerted a stronger cytotoxic effect on dendritic cells (DC) than their SopB-deficient derivatives. Cells infected with the double sseC sopB, phoP sopB and aroA sopB mutants also exhibited higher expression of MHC, CD80, CD86 and CD54 molecules, and showed a stronger capacity to process and present an I-E(d)-restricted epitope from the influenza hemagglutinin (HA) to CD4+ cells from TCR-HA transgenic mice in vitro. The incorporation of an additional mutation into the sopB locus of the attenuated sseC, phoP and aroA mutants resulted in the stimulation of improved humoral and cellular immune responses following oral vaccination. The obtained results define a new potential immune escape strategy of this important pathogen, and also demonstrate that this mechanism can be subverted to optimize the immune responses elicited using Salmonella as a live vaccine carrier.
    • Stable expression of pertussis toxin in Bordetella bronchiseptica under the control of a tightly regulated promoter.

      Suarez, A; Staendner, L H; Rohde, Manfred; Piatti, G; Timmis, K N; Guzmán, C A (1997-01)
    • The STING activator c-di-AMP exerts superior adjuvant properties than the formulation poly(I:C)/CpG after subcutaneous vaccination with soluble protein antigen or DEC-205-mediated antigen targeting to dendritic cells.

      Volckmar, Julia; Knop, Laura; Stegemann-Koniszewski, Sabine; Schulze, Kai; Ebensen, Thomas; Guzmán, Carlos A; Bruder, Dunja; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2019-08-14)
      Vaccination is the most efficient strategy to protect from infectious diseases and the induction of a protective immune response not only depends on the nature of the antigen, but is also influenced by the vaccination strategy and the co-administration of adjuvants. Therefore, the precise monitoring of adjuvant candidates and their immune modulatory properties is a crucial step in vaccine development. Here, one central aspect is the induction of appropriate humoral and cellular effector mechanisms. In our study we performed a direct comparison of two promising candidates in adjuvant development, the STING activator bis-(3,5)-cyclic dimeric adenosine monophosphate (c-di-AMP) and the Toll-like receptor ligand formulation poly(I:C)/CpG. These were evaluated in C57BL/6 mice using the model antigen ovalbumin (OVA) in subcutaneous vaccination with soluble protein as well as in a dendritic cell (DC) targeting approach (αDEC-OVA). Strikingly, c-di-AMP as compared to poly(I:C)/CpG resulted in significantly higher antigen-specific IgG antibody levels when used in immunization with soluble OVA as well as in antigen targeting to DC. In vaccination with soluble OVA, c-di-AMP induced a significantly stronger CTL, Th1 and IFNγ-producing CD8+ memory T cell response than poly(I:C)/CpG. The response was CTL and Th1 cell dominated, a profile shared by both adjuvants. In the context of targeting OVA to DC, c-di-AMP induced significantly increased Th1 and Th2 cell responses as compared to poly(I:C)/CpG. Interestingly, the Th1 response dominated the overall T cell response only when c-di-AMP was used, indicating a distinct modulatory property of c-di-AMP when the DC targeting immunization approach was exploited. Taken together, we describe superior properties of c-di-AMP as compared to poly(I:C)/CpG in subcutaneous vaccination with soluble antigen as well as antigen targeting to DC. This indicates exceptionally effective adjuvant properties for c-di-AMP and provides compelling evidence of its potential for further adjuvant development, especially also when using DC targeting approaches.
    • Structural and functional characterization of human Iba proteins.

      Schulze, Jörg O; Quedenau, Claudia; Roske, Yvette; Adam, Thomas; Schüler, Herwig; Behlke, Joachim; Turnbull, Andrew P; Sievert, Volker; Scheich, Christoph; Mueller, Uwe; et al. (2008-09)
      Iba2 is a homolog of ionized calcium-binding adapter molecule 1 (Iba1), a 17-kDa protein that binds and cross-links filamentous actin (F-actin) and localizes to membrane ruffles and phagocytic cups. Here, we present the crystal structure of human Iba2 and its homodimerization properties, F-actin cross-linking activity, cellular localization and recruitment upon bacterial invasion in comparison with Iba1. The Iba2 structure comprises two central EF-hand motifs lacking bound Ca2+. Iba2 crystallized as a homodimer stabilized by a disulfide bridge and zinc ions. Analytical ultracentrifugation revealed a different mode of dimerization under reducing conditions that was independent of Ca2+. Furthermore, no binding of Ca2+ up to 0.1 mM was detected by equilibrium dialysis. Correspondingly, Iba EF-hand motifs lack residues essential for strong Ca2+ coordination. Sedimentation experiments and microscopy detected pronounced, indistinguishable F-actin binding and cross-linking activity of Iba1 and Iba2 with induction of F-actin bundles. Fluorescent Iba fusion proteins were expressed in HeLa cells and co-localized with F-actin. Iba1 was recruited into cellular projections to a larger extent than Iba2. Additionally, we studied Iba recruitment in a Shigella invasion model that induces cytoskeletal rearrangements. Both proteins were recruited into the bacterial invasion zone and Iba1 was again concentrated slightly higher in the cellular extensions.
    • A study of Chitosan and c-di-GMP as mucosal adjuvants for intranasal influenza H5N1 vaccine.

      Svindland, Signe C; Pedersen, Gabriel K; Pathirana, Rishi D; Bredholt, Geir; Nøstbakken, Jane K; Jul-Larsen, Åsne; Guzmán, Carlos A; Montomoli, Emanuele; Lapini, Giulia; Piccirella, Simona; et al. (2013-11)
      Highly pathogenic avian influenza A/H5N1 virus remains a potential pandemic threat, and it is essential to continue vaccine development against this subtype. A local mucosal immune response in the upper respiratory tract may stop influenza transmission. It is therefore important to develop effective intranasal pandemic influenza vaccines that induce mucosal immunity at the site of viral entry.
    • Superior immunogenicity of HCV envelope glycoproteins when adjuvanted with cyclic-di-AMP, a STING activator or archaeosomes.

      Landi, A; Law, J; Hockman, D; Logan, M; Crawford, K; Chen, C; Kundu, J; Ebensen, T; Guzman, C A; Deschatelets, L; et al. (2017-12-15)
      Three decades after the discovery, hepatitis C virus (HCV) is still the leading cause of liver transplantation and poses a major threat to global health. In spite of recent advances in the development of direct acting antivirals, there is still a need for a prophylactic vaccine to limit the virus spread and protect at-risk populations, especially in developing countries, where the cost of the new treatments may severely limit access. The use of recombinant HCV glycoproteins E1E2 (rE1E2) in combination with the MF59, an oil-in-water emulsion-based adjuvant, has previously been shown to reduce the rate of chronicity in chimpanzees and to induce production of cross-neutralizing antibodies and cellular immune responses in human volunteers. To further improve neutralizing antibody responses in recipients along with robust T cell responses, we have explored the immunogenicity of different adjuvants when formulated with the HCV rE1E2 vaccine in mice. Our data show that cyclic di-adenosine monophosphate (c-di-AMP) and archaeosomes elicit strong neutralizing antibodies similar to those elicited using aluminum hydroxide/monophosphoryl lipid A (Alum/monophos. /MPLA) and MF59. However, both c-di-AMP and archaeosomes induced a more robust cellular immune response, which was confirmed by the detection of vaccine-specific poly-functional CD4+ T cells. We conclude that these adjuvants may substantially boost the immunogenicity of our E1E2 vaccine. In addition, our data also indicates that use of a partial or exclusive intranasal immunization regimen may also be feasible using c-di-AMP as adjuvant.