Christina Dold

Ascaris and ascariasis.

Ascaris lumbricoides and Ascaris suum are widespread parasitic nematodes of humans and pigs respectively. Recent prevalence data suggests that approximately 1.2 billion people are infected. Adult worms exhibit an overdispersed frequency distribution in their hosts and individuals harbouring heavy burdens display associated morbidity. In this review, we describe the parasite, its distribution and measures undertaken to control infection.

Investigating the underlying mechanism of resistance to Ascaris infection.

The generative mechanism(s) of predisposition to Ascaris infection are currently unknown. While many factors play a role in interindividual infection intensity, much focus has been placed on the hosts immunological response to infection and the underlying genetics. The present review describes the research conducted that has examined various immunological parameters and genetic factors that may play a role in resistance to ascariasis. We also discuss the contribution that animal models have made to our understanding of resistance to the parasitic roundworm and their role in possible future work.

Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity

SUMMARY Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1‐ILCs) promote pro‐inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1‐ILCs. Experiments using parabiotic mice fed a high‐fat diet (HFD) showed differential trafficking of AT1‐ILCs, particularly in response to short‐ and long‐term HFD and diet restriction. At steady state, AT1‐ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1‐ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti‐inflammatory ATMs, and adoptive transfer of AT1‐ILCs exacerbated metabolic disorder. Diet‐induced obesity impaired AT1‐ILC killing ability. Our findings reveal a role for AT1‐ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease. Graphical Abstract Figure. No Caption available. HighlightsAT1‐ILCs are enriched in mouse and human adipose tissue and are predominantly tissue residentAT1‐ILCs kill adipose tissue macrophages (ATMs) and maintain ATM homeostasisSubsets of AT1‐ILCs infiltrate adipose tissue during the onset of obesityIn obesity, AT1‐ILCs are reduced and lose their ability to kill &NA; Boulenouar et al. define different subsets of type 1 innate lymphoid cells (AT1‐ILCs) in human and murine adipose tissues and show that at steady state, AT1‐ILCs kill adipose tissue macrophages (ATMs). In obesity, cytotoxicity is impaired. Interference with AT1‐ILC cytotoxicity impacted ATM homeostasis and systemic metabolism, pointing to its importance in homeostasis and disease.

A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial

Summary Objectives Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. Methods The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. Results MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetAonPorAoff compared to 51% in the strain 44/76 FetAoffPorAoff, demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. Conclusion This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

Genetic influence on the kinetics and associated pathology of the early stage (intestinal-hepatic) migration of Ascaris suum in mice.

The generative mechanism(s) of aggregation and predisposition to Ascaris lumbricoides and A. suum infections in their host population are currently unknown and difficult to elucidate in humans and pigs for ethical/logistical reasons. A recently developed, optimized murine model based on 2 inbred strains, putatively susceptible (C57BL/6j) and resistant (CBA/Ca) to infection, was exploited to elucidate further the basis of the contrasting parasite burdens, most evident at the pulmonary stage. We explored the kinetics of early infection, focusing on the composite lobes of the liver and lung, over the first 8 days in an effort to achieve a more detailed understanding of the larval dispersal over time and the point at which worm burdens diverge. Larval recoveries showed a heterogenous distribution among the lobes of the lungs, being higher in the right lung of both strains, and in the susceptible strain larvae accumulating preferentially in 2 (caudal and middle) of the 4 lobes. Total larval burdens in these 2 lobes were largely responsible for the higher worm burdens in the susceptible strain. While total lung larval recoveries significantly differed between mouse strains, a difference in liver larval burdens was not observed. However, an earlier intense inflammatory response coupled with more rapid tissue repair in the hepatic lobes was observed in CBA/Ca mice, in contrast to C57BL/6j mice, and it is possible that these processes are responsible for restricting onward pulmonary larval migration in the resistant genotype.

The capsular group B meningococcal vaccine, 4CMenB: clinical experience and potential efficacy

Introduction: Capsular group B meningococcal disease is a leading cause of childhood meningitis and septicaemia. Up to 10% of sufferers die, and sequelae remain in > 30% of survivors. A vaccine, four component meningococcal group B (4CMenB), designed with the aim to induce broad coverage against this highly variable bacterium, has been licensed in countries including in the European Union, Canada and Australia. Areas covered: Immunogenicity and safety data, published in peer-reviewed literature between 2004 and 2014, are presented in the context of the recent recommendation for the use of the vaccine in infants in the UK. Expert opinion: 4CMenB induces significant reactogenicity when administered with routine infant vaccines, in particular with respect to fever rates. Fevers can be somewhat reduced using paracetamol. The efficacy of the vaccine is unknown but has been extrapolated from effectiveness data obtained from use of one of its components in New Zealand, immunogenicity data from clinical trials and estimation of coverage from in vitro studies. These data suggest that the vaccine will prevent a proportion of invasive meningococcal disease cases in infants and young children. Implementation and well-planned post-marketing surveillance will address uncertainties over field effectiveness.

Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci

ABSTRACT MenB-4C is a meningococcal vaccine for the prevention of serogroup B disease. The vaccine contains factor H binding protein (FHbp) and three other antigens that can elicit serum bactericidal antibodies (SBA). For vaccine licensure, efficacy was inferred from the SBA responses against three antigen-specific indicator strains. The relation between those results and broad protection against circulating genetically diverse strains is not known. Twenty adults were immunized with two doses of MenB-4C given 1 to 2 months apart. SBA activity against 3 reference strains and 15 serogroup B test strains (6 from college outbreaks) was measured. Compared to the preimmunization titers, 70%, 95%, and 95% of subjects had ≥4-fold increases in the titers of anti-PorA P1.4, anti-NadA, and anti-FHbp antibodies against the reference strains, respectively. In contrast, only 25 to 45% of the subjects had ≥4-fold increases in responses to 10 of the 15 test strains, including 8 that expressed one to three of the antigens in the vaccine. At 1 month, the majority of subjects with <4-fold titer increases had serum titers of ≥1:4, which are considered sufficient for protection. However, the titers against four strains declined to <1:4 by 4 to 6 months in one-third to greater than 50% of the subjects tested. Clinically relevant isolates are often more resistant to SBA than the indicator strains used to measure antigen-specific SBA. A working model is that the percentage of subjects with titers of ≥1:4 at 1 month postimmunization correlates with short-term protection against that strain, whereas the percentage of subjects with ≥4-fold titer increases represents a more robust response. (The protocol used at the Oxford Vaccine Group has been registered at ClinicalTrials.gov under registration no. NCT02398396.)

Impact of Reducing Complement Inhibitor Binding on the Immunogenicity of Native Neisseria meningitidis Outer Membrane Vesicles.

Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMVlpxl1). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMVdis). Antibody responses elicited in mice with nOMVdis were compared to those elicited with nOMVlpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMVlpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMVlpxl1 or OMVdis) was versus PorA. Despite a considerable reduction of hfH binding to nOMVdis, and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMVlpxl1, in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMVdis and nOMVlpxl1–immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.

FetA Antibodies Induced by an Outer Membrane Vesicle Vaccine Derived from a Serogroup B Meningococcal Isolate with Constitutive FetA Expression

Invasive meningococcal disease causes over 3500 cases each year in Europe, with particularly high incidence among young children. Among serogroup B meningococci, which cause most of the cases, high diversity in the outer membrane proteins (OMPs) is observed in endemic situations; however, comprehensive molecular epidemiological data are available for the diversity and distribution of the OMPs PorA and FetA and these can be used to rationally design a vaccine with high coverage of the case isolates. The aim of this study was to determine whether outer membrane vesicles (OMVs) derived from an isolate with constitutive FetA expression (MenPF-1 vaccine) could be used to induce antibodies against both the PorA and FetA antigens. The immunogenicity of various dose levels and number of doses was evaluated in mice and rabbits, and IgG antibody responses tested against OMVs and recombinant PorA and FetA proteins. A panel of four isogenic mutants was generated and used to evaluate the relative ability of the vaccine to induce serum bactericidal activity (SBA) against FetA and PorA. Sera from mice were tested in SBA against the four target strains. Results demonstrated that the MenPF-1 OMVs were immunogenic against PorA and FetA in both animal models. Furthermore, the murine antibodies induced were bactericidal against isogenic mutant strains, suggesting that antibodies to both PorA and FetA were functional. The data presented indicate that the MenPF-1 vaccine is a suitable formulation for presenting PorA and FetA OMPs in order to induce bactericidal antibodies, and that proceeding to a Phase I clinical trial with this vaccine candidate is justified.

Larval Ascariasis: Impact, Significance, and Model Organisms

Abstract Larval ascariasis is much less well understood than adult worm infection. Part of the explanation for this is the difficulty in assessing the impact of larval infections in human subjects. In contrast, adult worms can be counted after post-chemotherapeutic expulsion or, additionally, eggs voided in host feces can be quantified as an indirect measure of infection intensity. Furthermore, respiratory and hepatic disease, which may be associated with transient passage of larvae through these organs, can be either non-specific or cryptic, making Ascaris-specific diagnosis through clinical signs of infection challenging. The influence of early infection on parasite establishment and host immunity is recognized as important but it remains challenging to unravel the complexities of the relationship. Both pigs as natural hosts of Ascaris suum and a range of abnormal hosts have been utilized to investigate larval migration. Few if any of these model systems have enabled clarification of the basis of variation in susceptibility and resistance to larval migration and accumulation in the liver and lungs. In this chapter, we document the literature on larval ascariasis with a particular emphasis on studies utilizing mice because mice are now developing as useful model systems for the study of early Ascaris infection, the migratory path and its duration being similar to that of pigs. We describe a mouse model of early Ascaris infection that mimics the extremes of the host phenotype displayed in the aggregated distribution of adult worms in human and pig populations, outline the existing evidence for the role of the liver in susceptibility to larval ascariasis and discuss future directions for the use of this model system.