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Background: Infections with Plasmodium ovale are widely distributed but rarely investigated, and the resulting burden of disease has been underestimated. Plasmodium ovale curtisi Duffy binding protein domain region II (PocDBP-RII) is an essential ligand for reticulocyte recognition and host cell invasion by P. ovale curtisi. However, the genomic variation, antigenicity and immunogenicity of PocDBP-RII remain major knowledge gaps. Methods: A total of 93 P. ovale curtisi samples were collected from migrant workers who returned to China from 17 countries in Africa between 2012 and 2016. The genetic polymorphism, natural selection and copy number variation (CNV) were investigated by sequencing and real-time PCR. The antigenicity and immunogenicity of the recombinant PocDBP-RII (rPocDBP-RII) protein were further examined, and the humoral and cellular responses of immunized mice were assessed using protein microarrays and flow cytometry. Results: Efficiently expressed and purified rPocDBP-RII (39 kDa) was successfully used as an antigen for immunization in mice. The haplotype diversity (Hd) of PocDBP-RII gene was 0.105, and the nucleotide diversity index (π) was 0.00011. No increased copy number was found among the collected isolates of P. ovale curtisi. Furthermore, rPocDBP-RII induced persistent antigen-specific antibody production with a serum IgG antibody titer of 1: 16,000. IFN-γ-producing T cells, rather than IL-10-producing cells, were activated in response to the stimulation of rPocDBP-RII. Compared to PBS-immunized mice (negative control), there was a higher percentage of CD4+CD44highCD62L− T cells (effector memory T cells) and CD8+CD44highCD62L+ T cells (central memory T cells) in rPocDBP-RII‑immunized mice. Conclusions: PocDBP-RII sequences were highly conserved in clinical isolates of P. ovale curtisi. rPocDBP-RII protein could mediate protective blood-stage immunity through IFN-γ-producing CD4+ and CD8+ T cells and memory T cells, in addition to inducing specific antibodies. Our results suggested that rPocDBP-RII protein has potential as a vaccine candidate to provide assessment and guidance for malaria control and elimination activities. [ABSTRACT FROM AUTHOR]

Simple Summary: Ticks affect the health of humans and animals. In tropical African countries, cattle are threatened by ticks and the diseases they transmit, making necessary a tick control to avoid endangering the production of this industry. In this review, different vaccine candidates and different approaches are proposed as an environmentally friendly control alternative that can be included in the strategies of these countries to prevent tick-borne diseases their consequences. Ticks are worldwide ectoparasites to humans and animals, and are associated with numerous health and economic effects. Threatening over 80% of the global cattle population, tick and tick-borne diseases (TTBDs) particularly constrain livestock production in the East, Central and Southern Africa. This, therefore, makes their control critical to the sustainability of the animal industry in the region. Since ticks are developing resistance against acaricides, anti-tick vaccines (ATVs) have been proposed as an environmentally friendly control alternative. Whereas they have been used in Latin America and Australia to reduce tick populations, pathogenic infections and number of acaricide treatments, commercially registered ATVs have not been adopted in tropical Africa for tick control. This is majorly due to their limited protection against economically important tick species of Africa and lack of research. Recent advances in various omics technologies and reverse vaccinology have enabled the identification of many candidate anti-tick antigens (ATAs), and are likely to usher in the next generation of vaccines, for which Africa should prepare to embrace. Herein, we highlight some scientific principles and approaches that have been used to identify ATAs, outline characteristics of a desirable ATA for vaccine design and propose the need for African governments to investment in ATV research to develop vaccines relevant to local tick species (personalized vaccines). We have also discussed the prospect of incorporating anti-tick vaccines into the integrated TTBDs control strategies in the sub-Saharan Africa, citing the case of Uganda. [ABSTRACT FROM AUTHOR]

Yellow fever, a mosquito-borne flavivirus infection, is an important public health problem in Africa and Latin America. A Yellow Fever vaccine (YFV) was developed and tested in a study in India. This was a Phase I, open-label, randomized, controlled study where healthy adults received SII YFV intramuscularly (SII YFV IM), SII YFV subcutaneously (SII YFV SC) or STAMARIL® (Sanofi-Pasteur) in 1:1:1 ratio. They were followed for solicited reactions for 10 days and unsolicited events for 28 days and serious adverse events for 3 months. YF-neutralizing antibodies were measured at baseline and on Days 10, 14, 28. A total of 60 adults were enrolled in the study. The proportion of participants with solicited reactions was 10%, 40%, and 25% in SII YFV SC, SII YFV IM, and STAMARIL® arms, respectively. No causally related unsolicited events or any serious adverse event was reported. After vaccination, the seroconversion was 94.44%, 100%, and 100%, in the three arms respectively. The post-vaccination geometric mean titers were similar in the study arms. The new YFV was found safe and immunogenic by IM as well as SC routes. The vaccine can be tested in further phases of clinical studies. [ABSTRACT FROM AUTHOR]

Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. In Plasmodium falciparum malaria, the var multigene family encoding for the major blood-stage antigen PfEMP1 has evolved enormous genetic diversity through ectopic recombination and mutation. With 50-60 var genes per genome, it is unclear whether immune selection can act as a dominant force in structuring var repertoires of local populations. The combinatorial complexity of the var system remains beyond the reach of existing strain theory and previous evidence for non-random structure cannot demonstrate immune selection without comparison with neutral models. We develop two neutral models that encompass malaria epidemiology but exclude competitive interactions between parasites. These models, combined with networks of genetic similarity, reveal non-neutral strain structure in both simulated systems and an extensively sampled population in Ghana. The unique population structure we identify underlies the large transmission reservoir characteristic of highly endemic regions in Africa. [ABSTRACT FROM AUTHOR]

Background: Large genome-wide association (GWA) studies of European ancestry individuals have identified multiple genetic variants influencing iron status. Studies on the generalizability of these associations to African ancestry populations have been limited. These studies are important given interethnic differences in iron status and the disproportionate burden of iron deficiency among African ancestry populations. Methods: We tested the associations of 20 previously identified iron status-associated single nucleotide polymorphisms (SNPs) in 628 Kenyans, 609 Tanzanians, 608 South Africans and 228 African Americans. In each study, we examined the associations present between 20 SNPs with ferritin and haemoglobin, adjusting for age, sex and CRP levels. Results: In the meta analysis including all 4 African ancestry cohorts, we replicated previously reported associations with lowered haemoglobin concentrations for rs2413450 (β = -0.19, P = 0.02) and rs4820268 (β = -0.16, P = 0.04) in TMPRSS6. An association with increased ferritin concentrations was also confirmed for rs1867504 in TF (β = 1.04, P = <0.0001) in the meta analysis including the African cohorts only. Conclusions: In all meta analyses, we only replicated 4 of the 20 single nucleotide polymorphisms reported to be associated with iron status in large GWA studies of European ancestry individuals. While there is now evidence for the associations of a number of genetic variants with iron status in both European and African ancestry populations, the considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of iron status in ethnically diverse populations. [ABSTRACT FROM AUTHOR]

Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge. [ABSTRACT FROM AUTHOR]

Background: Malaria and HIV infections are both highly prevalent in sub-Saharan Africa, with HIV-infected patients being at higher risk of acquiring malaria. HIV-1 infection is known to impair the immune response and may increase the incidence of clinical malaria. However, a positive association between HIV-1 and malaria parasitaemia is still evolving. Equally, the effect of malaria on HIV-1 disease stage has not been well established, but when fever and parasitemia are high, malaria may be associated with transient increases in HIV-1 viral load, and progression of HIV-1 asymptomatic disease phase to AIDS. Objective: To determine the effects of HIV-1 infection on malaria parasitaemia among consented residents of Milo sub-location, Bungoma County in western Kenya. Study design: Census study evaluating malaria parasitaemia in asymptomatic individuals with unknown HIV-1 status. Methods: After ethical approvals from both Moi University and MTRH research ethics committees, data of 3,258 participants were retrieved from both Webuye health demographic surveillance system (WHDSS), and Academic Model Providing Access to Healthcare (AMPATH) in the year 2010. The current study was identifying only un-diagnosed HIV-1 individuals at the time the primary data was collected. The data was then analysed for significant statistical association for malaria parasitemia and HIV-1 infection, using SPSS version 19. Demographic characteristics such as age and sex were summarized as means and percentages, while relationship between malaria parasitaemia and HIV-1 (serostatus) was analyzed using Chi square. Results: Age distribution for the 3,258 individuals ranged between 2 and 94 years, with a mean age of 26 years old. Females constituted 54.3%, while males were 45.8%. In terms of age distribution, 2-4 years old formed 15.1% of the study population, 5-9 years old were 8.8%, 10-14 years old were 8.6% while 15 years old and above were 67.5%. Of the 3,258 individuals whose data was eligible for analysis, 1.4% was newly diagnosed HIV-1 positive. Our findings showed a higher prevalence of malaria in children aged 2-10 years (73.4%), against the one reported in children in lake Victoria endemic region by the Kenya malaria indicator survey in the year 2010 (38.1%). There was no significant associations between the prevalence of asymptomatic malaria and HIV-1 status (p = 0.327). However, HIV-1/malaria co-infected individuals showed elevated mean malaria parasite density, compared to HIV-1 negative individuals, p = 0.002. Conclusion: HIV-1 status was not found to have effect on malaria infection, but the mean malaria parsite density was significantly higher in HIV-1 positive than the HIV-1 negative population. [ABSTRACT FROM AUTHOR]

Background: Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood. Methodology/Principal Findings: To characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (ΔNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7–9 days post-infection. In contrast, inoculation of ΔNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response. Conclusions/Significance: Comparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) ΔNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options. Author Summary: Rift Valley fever virus (RVFV) is a mosquito-borne virus that causes severe disease in people and livestock throughout Africa and the Arabian Peninsula. Human disease is usually self-limiting, but a small proportion of individuals develop fatal encephalitis. The role of the host immune response in determining disease outcome is largely unknown. In order to compare the quality and character of immune responses in nonfatal and fatal cases, we used an attenuated RVFV to inoculate mice by two routes. Subcutaneous inoculation resulted in a subclinical systemic infection that was rapidly cleared due to a robust adaptive response. In contrast, intranasal inoculation stimulated weaker immune responses that failed to control virus replication and culminated in uniformly fatal encephalitis. With many encephalitic viruses, the onset of disease is mediated by changes in blood brain barrier permeability and often, subsequent injury to the CNS by an uncontrolled immune response. However, our results suggest that development of RVFV disease does not depend on either mechanism, but rather results from direct virus-mediated damage in the CNS. Future therapeutic drug design should take into account all possible routes of virus exposure as well as the role of therapies that boost the adaptive response to better combat disease. [ABSTRACT FROM AUTHOR]

Background: Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood. Methodology/Principal Findings: To characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (ΔNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7–9 days post-infection. In contrast, inoculation of ΔNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response. Conclusions/Significance: Comparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) ΔNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is common in developing countries, and it is often associated with parasitic infections. We investigated the relationship between exposure to parasitic infections, particularly multiple infections and active convulsive epilepsy (ACE), in five sites across sub-Saharan Africa. Methods and Findings: A case-control design that matched on age and location was used. Blood samples were collected from 986 prevalent cases and 1,313 age-matched community controls and tested for presence of antibodies to Onchocerca volvulus, Toxocara canis, Toxoplasma gondii, Plasmodium falciparum, Taenia solium and HIV. Exposure (seropositivity) to Onchocerca volvulus (OR = 1.98; 95%CI: 1.52–2.58, p<0.001), Toxocara canis (OR = 1.52; 95%CI: 1.23–1.87, p<0.001), Toxoplasma gondii (OR = 1.28; 95%CI: 1.04–1.56, p = 0.018) and higher antibody levels (top tertile) to Toxocara canis (OR = 1.70; 95%CI: 1.30–2.24, p<0.001) were associated with an increased prevalence of ACE. Exposure to multiple infections was common (73.8% of cases and 65.5% of controls had been exposed to two or more infections), and for T. gondii and O. volvulus co-infection, their combined effect on the prevalence of ACE, as determined by the relative excess risk due to interaction (RERI), was more than additive (T. gondii and O. volvulus, RERI = 1.19). The prevalence of T. solium antibodies was low (2.8% of cases and 2.2% of controls) and was not associated with ACE in the study areas. Conclusion: This study investigates how the degree of exposure to parasites and multiple parasitic infections are associated with ACE and may explain conflicting results obtained when only seropositivity is considered. The findings from this study should be further validated. [ABSTRACT FROM AUTHOR]

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 cellline 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-c 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. [ABSTRACT FROM AUTHOR]

Plasmodium vivax malaria is a neglected tropical disease, despite being more geographically widespread than any other form of malaria. The documentation of P. vivax infections in different parts of Africa where Duffy-negative individuals are predominant suggested that there are alternative pathways for P. vivax to invade human erythrocytes. Duffy-negative individuals may be just as fit as Duffy-positive individuals and are no longer resistant to P.vivax malaria. In this review, we describe the complexity of P. vivax malaria, characterize pathogenesis and candidate invasion genes of P. vivax, and host immune responses to P. vivax infections. We provide a comprehensive review on parasite ligands in several Plasmodium species that further justify candidate genes in P. vivax. We also summarize previous genomic and transcriptomic studies related to the identification of ligand and receptor proteins in P. vivax erythrocyte invasion. Finally, we identify topics that remain unclear and propose future studies that will greatly contribute to our knowledge of P. vivax. [ABSTRACT FROM AUTHOR]

Rift Valley fever virus (RVFV), which causes Rift Valley fever (RVF), is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. RVF is a World Health Organization (WHO) priority disease and, together with rabies, is a major health burden in Africa. Here, we present the development and characterization of an inactivated recombinant RVFV and rabies virus (RABV) vaccine candidate (rSRV9-eGn). Immunization with rSRV9-eGn stimulated the production of RVFV-specific IgG antibodies and induced humoral and cellular immunity in mice but did not induce the production of neutralizing antibodies. IgG1 and IgG2a were the main isotypes observed by IgG subtype detection, and IgG3 antibodies were not detected. The ratios of IgG1/IgG2a > 1 indicated a Type 2 humoral immune response. An effective vaccine is intended to establish a long-lived population of memory T cells, and mice generated memory cells among the proliferating T cell population after immunization with rSRV9-eGn, with effector memory T cells (TEM) as the major population. Due to the lack of prophylactic treatment experiments, it is impossible to predict whether this vaccine can protect animals from RVFV infection with only high titres of anti-RVFV IgG antibodies and no neutralizing antibodies induced, and thus, protection confirmation needs further verification. However, this RVFV vaccine designed with RABV as the vector provides ideas for the development of vaccines that prevent RVFV and RABV infections. [ABSTRACT FROM AUTHOR]