Experience and Challenges from Clinical Trials with Malaria Vaccines in Africa.

Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available.African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need.However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained

T-cell and serological responses to Erp, an exported Mycobacterium tuberculosis protein, in tuberculosis patients and healthy individuals

<p>Abstract</p> <p>Background</p> <p>The identification of antigens able to differentiate tuberculosis (TB) disease from TB infection would be valuable. Cellular and humoral immune responses to Erp (Exported repetitive protein) – a recently identified <it>M. tuberculosis </it>protein – have not yet been investigated in humans and may contribute to this aim.</p> <p>Methods</p> <p>We analyzed the cellular and humoral immune responses to Erp, ESAT-6, Ag85B and PPD in TB patients, in BCG⁺individuals without infection, BCG⁺individuals with latent TB infection (LTBI) and BCG^-controls. We used lymphoproliferation, ELISpot IFN-γ, cytokine production assays and detection of specific human antibodies against recombinant <it>M. tuberculosis </it>proteins.</p> <p>Results</p> <p>We included 22 TB patients, 9 BCG⁺individuals without TB infection, 7 LTBI and 7 BCG^-controls. Erp-specific T cell counts were higher in LTBI than in the other groups. Erp-specific T cell counts were higher in LTBI subjects than TB patients (median positive frequency of 211 SFC/10⁶PBMC (range 118–2000) for LTBI subjects compared to 80 SFC/10⁶PBMC (range 50–191), p = 0.019); responses to PPD and ESAT-6 antigens did not differ between these groups. IFN-γ secretion after Erp stimulation differed between TB patients and LTBI subjects (p = 0.02). Moreover, LTBI subjects but not TB patients or healthy subjects produced IgG3 against Erp.</p> <p>Conclusion</p> <p>The frequencies of IFN-γ-producing specific T cells, the IFN-γ secretion and the production of IgG3 after Erp stimulation are higher in LTBI subjects than in TB patients, whereas PPD and ESAT-6 are not.</p

Understanding Human-Plasmodium falciparum Immune Interactions Uncovers the Immunological Role of Worms

BACKGROUND: Former studies have pointed to a monocyte-dependent effect of antibodies in protection against malaria and thereby to cytophilic antibodies IgG1 and IgG3, which trigger monocyte receptors. Field investigations have further documented that a switch from non-cytophilic to cytophilic classes of antimalarial antibodies was associated with protection. The hypothesis that the non-cytophilic isotype imbalance could be related to concomittant helminthic infections was supported by several interventions and case-control studies. METHODS AND FINDINGS: We investigated here the hypothesis that the delayed acquisition of immunity to malaria could be related to a worm-induced Th2 drive on antimalarial immune responses. IgG1 to IgG4 responses against 6 different parasite-derived antigens were analyzed in sera from 203 Senegalese children, half carrying intestinal worms, presenting 421 clinical malaria attacks over 51 months. Results show a significant correlation between the occurrence of malaria attacks, worm carriage (particularly that of hookworms) and a decrease in cytophilic IgG1 and IgG3 responses and an increase in non-cytophilic IgG4 response to the merozoite stage protein 3 (MSP3) vaccine candidate. CONCLUSION: The results confirm the association with protection of anti-MSP3 cytophilic responses, confirm in one additional setting that worms increase malaria morbidity and show a Th2 worm-driven pattern of anti-malarial immune responses. They document why large anthelminthic mass treatments may be worth being assessed as malaria control policies

Innate Immune Response to Rift Valley Fever Virus in Goats

Rift Valley fever (RVF), a re-emerging mosquito-borne disease of ruminants and man, was endemic in Africa but spread to Saudi Arabia and Yemen, meaning it could spread even further. Little is known about innate and cell-mediated immunity to RVF virus (RVFV) in ruminants, which is knowledge required for adequate vaccine trials. We therefore studied these aspects in experimentally infected goats. We also compared RVFV grown in an insect cell-line and that grown in a mammalian cell-line for differences in the course of infection. Goats developed viremia one day post infection (DPI), which lasted three to four days and some goats had transient fever coinciding with peak viremia. Up to 4% of peripheral blood mononuclear cells (PBMCs) were positive for RVFV. Monocytes and dendritic cells in PBMCs declined possibly from being directly infected with virus as suggested by in vitro exposure. Infected goats produced serum IFN-γ, IL-12 and other proinflammatory cytokines but not IFN-α. Despite the lack of IFN-α, innate immunity via the IL-12 to IFN-γ circuit possibly contributed to early protection against RVFV since neutralising antibodies were detected after viremia had cleared. The course of infection with insect cell-derived RVFV (IN-RVFV) appeared to be different from mammalian cell-derived RVFV (MAM-RVFV), with the former attaining peak viremia faster, inducing fever and profoundly affecting specific immune cell subpopulations. This indicated possible differences in infections of ruminants acquired from mosquito bites relative to those due to contact with infectious material from other animals. These differences need to be considered when testing RVF vaccines in laboratory settings

Are Algae Relevant to the Detritus-Based Food Web in Tank-Bromeliads?

We assessed the occurrence of algae in five species of tank-bromeliads found in contrasting environmental sites in a Neotropical, primary rainforest around the Nouragues Research Station, French Guiana. The distributions of both algal abundance and biomass were examined based on physical parameters, the morphological characteristics of bromeliad species and with regard to the structure of other aquatic microbial communities held in the tanks. Algae were retrieved in all of the bromeliad species with mean densities ranging from ∼102 to 104 cells/mL. Their biomass was positively correlated to light exposure and bacterial biomass. Algae represented a tiny component of the detrital food web in shaded bromeliads but accounted for up to 30 percent of the living microbial carbon in the tanks of Catopsis berteroniana, located in a highly exposed area. Thus, while nutrient supplies are believed to originate from wind-borne particles and trapped insects (i.e., allochtonous organic matter), our results indicate that primary producers (i.e., autochtonous organic matter) are present in this insectivorous bromeliad. Using a 24-h incubation of size-fractionated and manipulated samples from this plant, we evaluated the impact of mosquito foraging on algae, other microorganisms and rotifers. The prey assemblages were greatly altered by the predation of mosquito larvae. Grazing losses indicated that the dominant algal taxon, Bumilleriopsis sp., like protozoa and rotifers, is a significant part of the diet of mosquito larvae. We conclude that algae are a relevant functional community of the aquatic food web in C. berteroniana and might form the basis of a complementary non-detrital food web

Silencing of the Violaxanthin De-Epoxidase Gene in the Diatom Phaeodactylum tricornutum Reduces Diatoxanthin Synthesis and Non-Photochemical Quenching

Diatoms are a major group of primary producers ubiquitous in all aquatic ecosystems. To protect themselves from photooxidative damage in a fluctuating light climate potentially punctuated with regular excess light exposures, diatoms have developed several photoprotective mechanisms. The xanthophyll cycle (XC) dependent non-photochemical chlorophyll fluorescence quenching (NPQ) is one of the most important photoprotective processes that rapidly regulate photosynthesis in diatoms. NPQ depends on the conversion of diadinoxanthin (DD) into diatoxanthin (DT) by the violaxanthin de-epoxidase (VDE), also called DD de-epoxidase (DDE). To study the role of DDE in controlling NPQ, we generated transformants of P. tricornutum in which the gene (Vde/Dde) encoding for DDE was silenced. RNA interference was induced by genetic transformation of the cells with plasmids containing either short (198 bp) or long (523 bp) antisense (AS) fragments or, alternatively, with a plasmid mediating the expression of a self-complementary hairpin-like construct (inverted repeat, IR). The silencing approaches generated diatom transformants with a phenotype clearly distinguishable from wildtype (WT) cells, i.e. a lower degree as well as slower kinetics of both DD de-epoxidation and NPQ induction. Real-time PCR based quantification of Dde transcripts revealed differences in transcript levels between AS transformants and WT cells but also between AS and IR transformants, suggesting the possible presence of two different gene silencing mediating mechanisms. This was confirmed by the differential effect of the light intensity on the respective silencing efficiency of both types of transformants. The characterization of the transformants strengthened some of the specific features of the XC and NPQ and confirmed the most recent mechanistic model of the DT/NPQ relationship in diatoms

Differential antibody responses to Plasmodium falciparum merozoite proteins in Malawian children with severe malaria

Cerebral malaria (CM) and severe malarial anemia (SMA) are 2 major causes of death in African children infected with Plasmodium falciparum. We investigated levels of naturally acquired antibody to conserved and variable regions of merozoite surface protein (MSP)-1 and MSP-2, apical membrane antigen (AMA)-1, and rhoptry-associated protein 1 in plasma samples from 126 children admitted to the hospital with CM, 59 with SMA, and 84 with uncomplicated malaria (UM) in Malawi. Children with SMA were distinguished by very low levels of immunoglobulin (Ig) G to the conserved C-terminus of MSP-1 and MSP-2 and to full-length AMA-1. Conversely, children with CM had significantly higher levels of IgG to the conserved regions of all antigens examined than did children with UM (for MSP-1 and AMA-1, P&lt; .005; for MSP-2, P&lt; .05) or SMA (for MSP-1 and MSP-2, P&lt;.001; for AMA-1, P&lt; .005). These distinct IgG patterns might reflect differences in age, exposure to P. falciparum, and/or genetic factors affecting immune responses

Letter. Late cretaceous seasonal ocean variability from the arctic

The modern Arctic Ocean is regarded as barometer of global change and amplifier of global warming1 and therefore records of past Arctic change are of a premium for palaeoclimate reconstruction. Little is known of the state of the Arctic Ocean in the greenhouse period of the late Cretaceous, yet records from such times may yield important clues to its future behaviour given current global warming trends. Here we present the first seasonally resolved sedimentary record from the Cretaceous from the Alpha Ridge of the Arctic Ocean. This “paleo-sediment trap” provides new insights into the workings of the Cretaceous marine biological carbon pump. Seasonal primary production was dominated by diatom algae but was not related to upwelling as previously hypothesised. Rather, production occurred within a stratified water column, involving specially adapted species in blooms resembling those of the modern North Pacific Subtropical Gyre, or those indicated for the Mediterranean sapropels. With increased CO2 levels and warming currently driving increased stratification in the global ocean, this style of production that is adapted to stratification may become more widespread. Our evidence for seasonal diatom production and flux testify to an ice-free summer, but thin accumulations of terrigenous sediment within the diatom ooze are consistent with the presence of intermittent sea ice in the winter, supporting a wide body of evidence for low temperatures in the Late Cretaceous Arctic Ocean, rather than recent suggestions of a 15 °C mean annual temperature at this time