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Background: Naja annulifera is a medically important venomous snake occurring in some of the countries in Sub-Saharan Africa. Accidental bites result in severe coagulation disturbances, systemic inflammation and heart damage, as reported in dogs, and death, by respiratory arrest, in humans. Despite the medical importance of N. annulifera, little is known about its venom composition and the pathogenesis of envenomation. In this paper, the toxic, inflammatory and immunogenic properties of N. annulifera venom were analyzed. Methodology/Principal findings: Venom proteomic analysis identified 79 different proteins, including Three Finger Toxins, Cysteine Rich Secretory Proteins, Metalloproteinases, Phospholipases A2 (PLA2), Hyaluronidase, L-amino-acid oxidase, Cobra Venom Factor and Serine Proteinase. The presence of PLA2, hyaluronidase, fibrinogenolytic and anticoagulant activities was detected using functional assays. The venom was cytotoxic to human keratinocytes. In an experimental murine model of envenomation, it was found that the venom induced local changes, such as swelling, which was controlled by anti-inflammatory drugs. Moreover, the venom caused death, which was preceded by systemic inflammation and pulmonary hemorrhage. The venom was shown to be immunogenic, inducing a strong humoral immune response, with the production of antibodies able to recognize venom components with high molecular weight and to neutralize its lethal activity. Conclusions/Significance: The results obtained in this study demonstrate that N. annulifera venom contains toxins able to induce local and systemic inflammation, which can contribute to lung damage and death. Moreover, the venom is immunogenic, an important feature that must be considered during the production of a therapeutic anti-N. annulifera antivenom. [ABSTRACT FROM AUTHOR]

Extensive control efforts have significantly reduced malaria cases and deaths over the past two decades, but in recent years, coupled with the COVID-19 pandemic, success has stalled. The WHO has urged the implementation of a number of interventions, including vaccines. The modestly effective RTS,S/AS01 pre-erythrocytic vaccine has been recommended by the WHO for use in sub-Saharan Africa against Plasmodium falciparum in children residing in moderate to high malaria transmission regions. A second pre-erythrocytic vaccine, R21/Matrix-M, was also recommended by the WHO on 3 October 2023. However, the paucity and limitations of pre-erythrocytic vaccines highlight the need for asexual blood-stage malaria vaccines that prevent disease caused by blood-stage parasites. Few asexual blood-stage vaccine candidates have reached phase 2 clinical development, and the challenges in terms of their efficacy include antigen polymorphisms and low immunogenicity in humans. This review summarizes the history and progress of asexual blood-stage malaria vaccine development, highlighting the need for novel candidate vaccine antigens/molecules. [ABSTRACT FROM AUTHOR]

Helminth infections are among the neglected tropical diseases affecting billions of people globally, predominantly in developing countries. Helminths' effects are augmented by coincident tuberculosis disease, which infects a third of the world's population. The role of helminth infections on the pathogenesis and pathology of active tuberculosis (T.B.) remains controversial. Parasite-induced suppression of the efficacy of Bacille Calmette-Guerin (BCG) has been widely reported in helminth-endemic areas worldwide. T.B. immune response is predominantly proinflammatory T-helper type 1 (Th1)-dependent. On the other hand, helminth infections induce an opposing anti-inflammatory Th2 and Th3 immune-regulatory response. This review summarizes the literature focusing on host immune response profiles during single-helminth, T.B. and dual infections. It also aims to necessitate investigations into the complexity of immunity in helminth/T.B. coinfected patients since the research data are limited and contradictory. Helminths overlap geographically with T.B., particularly in Sub-Saharan Africa. Each disease elicits a response which may skew the immune responses. However, these effects are helminth species-dependent, where some parasites have no impact on the immune responses to concurrent T.B. The implications for the complex immunological interactions that occur during coinfection are highlighted to inform government treatment policies and encourage the development of high-efficacy T.B. vaccines in areas where helminths are prevalent. [ABSTRACT FROM AUTHOR]

Taenia solium cysticercosis and taeniasis (TSCT), caused by the tapeworm T. solium, is a foodborne and zoonotic disease classified since 2010 by WHO as a neglected tropical isease. It causes considerable impact on health and economy and is one of the leading causes of acquired epilepsy in most endemic countries of Latin America, Sub-Saharan Africa, and Asia. There is some evidence that the prevalence of TSCT in high-income countries has recently increased, mainly due to immigration from endemic areas. In regions endemic for TSCT, human cysticercosis can manifest clinically as neurocysticercosis (NCC), resulting in epileptic seizures and severe progressive headaches, amongst other neurological signs and/or symptoms. The development of these symptoms results from a complex interplay between anatomical cyst localization, environmental factors, parasite's infective potential, host genetics, and, especially, host immune responses. Treatment of individuals with active NCC (presence of viable cerebral cysts) with anthelmintic drugs together with steroids is usually effective and, in the majority, reduces the number and/or size of cerebral lesions as well as the neurological symptoms. However, in some cases, treatment may profoundly enhance anthelmintic inflammatory responses with ensuing symptoms, which, otherwise, would have remained silent as long as the cysts are viable. This intriguing silencing process is not yet fully understood but may involve active modulation of host responses by cyst-derived immunomodulatory components released directly into the surrounding brain tissue or by the induction of regulatory networks including regulatory T cells (Treg) or regulatory B cells (Breg). These processes might be disturbed once the cysts undergo treatment-induced apoptosis and necrosis or in a coinfection setting such as HIV. Herein, we review the current literature regarding the immunology and pathogenesis of NCC with a highlight on the mobilization of immune cells during human NCC and their interaction with viable and degenerating cysticerci. Moreover, the immunological parameters associated with NCC in people living with HIV/AIDS and treatments are discussed. Eventually, we propose open questions to understand the role of the immune system and its impact in this intriguing host–parasite crosstalk. [ABSTRACT FROM AUTHOR]

Salmonella serovar typhi still remains a serious problem in South Asia, South-East Asia, and sub-Saharan Africa. The emergence of multidrug resistance, lack of proper diagnosis and chronic typhoid carrier are the main causes of such a high level of morbidity and mortality. Presently, three vaccines have been licensed for typhoid infection but none of them is optimum for complete eradication for want of safety and long lasting immunity. Several subunit and attenuated candidate vaccines are under trial. Recently, in India Typbar TCV conjugate vaccine has been licensed. However, this vaccine being subunit may not induce appropriate immune response and also it cannot be given to infants. We need a multivalent attenuated vaccine which can induce both cellular as well as humoral immunity against different pathogenic serovar of Salmonella. Live attenuated vaccine could be an attractive choice taking care of all the above points. In this review, we focus on the pathogenesis of Salmonella serovar typhi, role of humoral as well as Cell-Mediated Immune (CMI) response, different licensed vaccines with their pros and cons, and also the targets which are already been put on clinical trials. We have discussed the attenuation of the candidates by modification of certain structural and functional genes especially looking for induction of CMI. [ABSTRACT FROM AUTHOR]

The genital tract of African women has been shown to differ from what is currently accepted as ‘normal’, defined by a pH≤4.5 and lactobacilli-dominated microbiota. Adolescent girls and young women (AGYW) from sub-Saharan Africa are at high risk for HIV, and we hypothesized that specific biological factors are likely to be influential. This study aimed to compare characteristics of vaginal health in HIV-negative AGYW (16-22-years-old), from two South African communities, to international norms. We measured plasma hormones, vaginal pH, presence of BV (Nugent scoring), sexually transmitted infections (multiplex PCR for Chlamydia trachomatis, Neisseria gonorrhoea, Trichomonas vaginalis, Mycoplasma genitalium) and candidiasis (Gram stain) in AGYW (n = 298) from Cape Town and Soweto. Cervicovaginal microbiota was determined by 16S pyrosequencing; 44 genital cytokines were measured by Luminex; and cervical T-cell activation/proliferation (CCR5, HLA-DR, CD38, Ki67) was measured by multiparametric flow cytometry. 90/298 (30.2%) AGYW were negative for BV, candidiasis and bacterial STIs. L. crispatus and L. iners were the dominant bacteria in cervicovaginal swabs, and the median vaginal pH was 4.7. AGYW with L. crispatus-dominant microbiota (42.4%) generally had the lowest cytokine concentrations compared to women with more diverse microbiota (34/44 significantly upregulated cytokines). Frequencies of CCR5+CD4+ T-cells co-expressing CD38 and HLA-DR correlated positively with interleukin (IL)-6, TNF-α, GRO-α, macrophage inflammatory protein (MIP)-1α, and IL-9. While endogenous oestrogen had an immune-dampening effect on IL-6, TNF-related apoptosis-inducing ligand (TRAIL) and IL-16, injectable hormone contraceptives (DMPA and Net-EN) were associated with significantly lower endogenous hormone concentrations (p<0.0001 for oestrogen and progesterone) and upregulation of 34/44 cytokines. Since genital inflammation and the presence of activated CD4+ T cells in the genital tract have been implicated in increased HIV risk in South African women, the observed high levels of genital cellular activation and cytokines from AGYW may point towards biological factors increasing HIV risk in this region. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to evaluate differences in immunovirological response to combination antiretroviral therapy ( cART) in migrant and native men and women within a European collaboration of HIV cohorts Collaboration of Observational HIV Epidemiological Research in Europ ( COHERE) in EuroCoord, 2004-2013. Methods Migrants were defined as those with geographical origin ( GO) different from the reporting country and were grouped as originating from Western Europe and Western Countries ( WEWC), Eastern Europe ( EE), North Africa and the Middle East ( NAME), sub-Saharan Africa ( SSA), Latin America ( LA), Caribbean ( CRB) and Asia/Oceania ( ASIA/ OCE). Native ( NAT) individuals were defined as those originating from the reporting country. CD4 cell counts were modelled using piecewise linear mixed-effects models with two slopes, whereas models to estimate subdistribution hazard ratios ( sHRs) were used for time to virological response ( VR) (i.e. time from cART initiation to the first of two successive HIV RNA measurements < 400 HIV-1 RNA copies/ ml). Results Of 32 817 individuals, 25 799 (78.6%) were men. The percentage of migrants was higher in women (48.9%) than in men (21.2%) and migrants from SSA accounted for the largest migrant group (29.9% in men and 63.3% in women). Migrant men and women from SSA started at lower CD4 cell counts than NAT individuals, which remained lower over time. VR was ≥ 85% at 12 months for all groups except CRB women (77.7%). Compared with NAT men and women, lower VR was experienced by NAME [ sHR 0.91; 95% confidence interval ( CI) 0.86-0.97] and SSA ( sHR 0.88; 95% CI 0.82-0.95) men and CRB ( sHR 0.77; 85% CI 0.67-0.89) women, respectively. Conclusions Immunovirological response to cART in Western Europe varies by GO and sex of patients. ART benefits are not equal for all, underlining the point that efforts need to prioritize those most in need. [ABSTRACT FROM AUTHOR]

Over 90% of HIV/AIDS positive individuals in sub-Saharan Africa are infected with highly heterogeneous HIV-1 subtype C (HIV-1C) viruses. One of the best ways to reduce the burden of this disease is the development of an affordable and effective prophylactic vaccine. Mosaic immunogens are computationally designed to overcome the hurdle of HIV diversity by maximizing the expression of potential T cell epitopes. Mycobacterium bovis BCG ΔpanCD auxotroph and modified vaccinia Ankara (MVA) vaccines expressing HIV-1C mosaic Gag (GagM) were tested in a prime-boost regimen to demonstrate immunogenicity in a mouse study. The BCG-GagM vaccine was stable and persisted 11.5 weeks post vaccination in BALB/c mice. Priming with BCG-GagM and boosting with MVA-GagM elicited higher Gag-specific IFN-γ ELISPOT responses than the BCG-GagM only and MVA-GagM only homologous vaccination regimens. The heterologous vaccination also generated a more balanced and persistent CD4+ and CD8+ T cell Gag-specific IFN-γ ELISPOT response with a predominant effector memory phenotype. A Th1 bias was induced by the vaccines as determined by the predominant secretion of IFN-γ, TNF-α, and IL-2. This study shows that a low dose of MVA (104 pfu) can effectively boost a BCG prime expressing the same mosaic immunogen, generating strong, cellular immune responses against Gag in mice. Our data warrants further evaluation in non-human primates. A low dose vaccine would be an advantage in the resource limited countries of sub-Saharan Africa and India (where the predominating virus is HIV-1 subtype C). [ABSTRACT FROM AUTHOR]

Human African trypanosomiasis due to Trypanosoma brucei rhodesiense is invariably fatal if untreated with up to 12.3 million people at a risk of developing the disease in Sub-Saharan Africa. The disease is characterized by a wide spectrum of clinical presentation coupled with differences in disease progression and severity. While the factors determining this varied response have not been clearly characterized, inflammatory cytokines have been partially implicated as key players. In this review, we consolidate available literature on the role of specific cytokines in the pathogenesis of T. b. rhodesiense sleeping sickness and further discuss their potential as stage biomarkers. Such information would guide upcoming research on the immunology of sleeping sickness and further assist in the selection and evaluation of cytokines as disease stage or diagnostic biomarkers [ABSTRACT FROM AUTHOR]

Background. A meningococcal group A conjugate vaccine, PsA-TT (MenAfriVac), developed through the Meningitis Vaccine Project and manufactured by the Serum Institute of India, Ltd, was tested in multiple clinical trials conducted mainly in Africa. The impact of age at which subjects were vaccinated on immune response and persistence postimmunization with PsA-TT was the main focus of the current analysis. Methods. Subjects who were vaccinated with a single dose of 10 μg of PsA-TT at 12–23 months or 22–33 months of age in study A conducted in Mali and The Gambia; at 2–10 years, 11–17 years, or 18–29 years of age in study B conducted in Mali, The Gambia, and Senegal; and at 14–18 weeks, 9–12 months, or 12–18 months of age in study C conducted in Ghana are included in the current analysis. Immunogenicity was measured by group A serum bactericidal antibody (SBA) titer with baby rabbit complement. Results. Significant differences in SBA titers were found among the age groups in studies B and C both 28 days and 1 year postimmunization. A significant difference in SBA titers between age groups 12–23 months and 22–33 months was only observed 1 year postimmunization in study A. Antibody titers remained at similar levels from 1 to 2 years postimmunization for subjects vaccinated at 12–23 months in study A and at 9–12 months or 12–18 months of age in study C. Conclusions. Subjects immunized at different ages had different postimmunization immune responses as measured by SBA titers. Toddlers tended to have higher immune responses than infants. This pattern persisted at least 1 year postimmunization. [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]

Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis. Author Summary: Onchocerciasis, also known as river blindness is a tropical disease causing health and socioeconomic problems in endemic communities especially sub-Saharan Africa. The disease is transmitted by a filarial nematode called Onchocerca volvulus, which is spread by the bite of infected Simulium black flies. Characteristic disease symptoms include dermatological disorders and eye lesions that can lead to blindness. Two polar forms of clinical manifestations can occur: generalized onchocerciasis (GEO) presenting mild skin disease or the hyperreactive form (HO) exhibiting severe skin disorders and inflammation. The immunological determinants behind such disease polarization are still not fully clarified. Here, we compared the immune profiles of individuals presenting these two polar forms with those of endemic normals (EN): individuals who have no clinical or parasitological evidence of infection despite ongoing exposure to the infectious agent. We could show that HO individuals, in contrast to GEO and EN, simultaneously presented elevated Th17 and Th2 profiles which were accompanied by reduced numbers of Foxp3+ regulatory T cells. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network associated with severe onchocerciasis. [ABSTRACT FROM AUTHOR]

The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies. [ABSTRACT FROM AUTHOR]

Background: In sub-Saharan Africa, men living with HIV often start ART at more advanced stages of disease and have higher early mortality than women. We investigated gender difference in long-term immune reconstitution. Methods/Principal Findings: Antiretroviral-naïve adults who received ART for at least 9 months in four HIV programs in sub- Saharan Africa were included. Multivariate mixed linear models were used to examine gender differences in immune reconstitution on first line ART. A total of 21,708 patients (68% women) contributed to 61,912 person-years of follow-up. At ART start,. Median CD4 at ART were 149 [IQR 85-206] for women and 125 cells/mL [IQR 63-187] for men. After the first year on ART, immune recovery was higher in women than in men, and gender-based differences increased by 20 CD4 cells/μL per year on average (95% CI 16-23; P<0.001). Up to 6 years after ART start, patients with low initial CD4 levels experienced similar gains compared to patients with high initial levels, including those with CD4>250cells/μL (difference between patients with <50 cells/μL and those with >250 was 284 cells/μL; 95% CI 272-296; LR test for interaction with time p = 0.63). Among patients with initial CD4 count of 150-200 cells/μL, women reached 500 CD4 cells after 2.4 years on ART (95% CI 2.4-2.5) and men after 4.5 years (95% CI 4.1-4.8) of ART use. Conclusion: Women achieved better long-term immune response to ART, reaching CD4 level associated with lower risks of AIDS related morbidity and mortality quicker than men. [ABSTRACT FROM AUTHOR]

Background: Malaria caused by Plasmodium falciparum remains a major cause of death in sub-Saharan Africa. Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly immunogenic or that the development of effective immune responses to malaria may be impaired. Methods: We carried out two age-stratified cross-sectional surveys of anti-malarial humoral immune responses in a Gambian village where P. falciparum malaria transmission is low and sporadic. Circulating antibodies and memory B cells (MBC) to four malarial antigens were measured using ELISA and cultured B cell ELISpot. Findings and Conclusions: The proportion of individuals with malaria-specific MBC and antibodies, and the average number of antigens recognised by each individual, increased with age but the magnitude of these responses did not. Malaria-specific antibody levels did not correlate with either the prevalence or median number of MBC, indicating that these two assays are measuring different aspects of the humoral immune response. Among those with immunological evidence of malaria exposure (defined as a positive response to at least one malarial antigen either by ELISA or ELISPOT), the median number of malaria-specific MBC was similar to median numbers of diphtheria-specific MBC, suggesting that the circulating memory cell pool for malaria antigens is of similar size to that for other antigens. [ABSTRACT FROM AUTHOR]

Background: Snakebite is a significant cause of death and disability in subsistent farming populations of sub-Saharan Africa. Antivenom is the most effective treatment of envenoming and is manufactured from IgG of venom-immunised horses/sheep but, because of complex fiscal reasons, there is a paucity of antivenom in sub-Saharan Africa. To address the plight of thousands of snakebite victims in savannah Nigeria, the EchiTAb Study Group organised the production, testing and delivery of antivenoms designed to treat envenoming by the most medically-important snakes in the region. The Echis sawscaled vipers have a wide African distribution and medical importance. In an effort to maximise the clinical utility of scarce antivenom resources in Africa, we aimed to ascertain, at the pre-clinical level, to what extent the E. ocellatus-specific EchiTAbG antivenom, which was designed specifically for Nigeria, neutralised the lethal activity of venom from two other African species, E. pyramidum leakeyi and E. coloratus. Methodology/Principal Findings: Despite apparently quite distinctive venom protein profiles, we observed extensive crossspecies similarity in the immuno-reactivity profiles of Echis species-specific antisera. Using WHO standard pre-clinical in vivo tests, we determined that the monospecific EchiTAbG antivenom was as effective at neutralising the venom-induced lethal effects of E. pyramidum leakeyi and E. coloratus as it was against E. ocellatus venom. Under the restricted conditions of this assay, the antivenom was ineffective against the lethal effects of venom from the non-African Echis species, E. carinatus sochureki. Conclusions/Significance: Using WHO-recommended pre-clinical tests we have demonstrated that the new anti-E. ocellatus monospecific antivenom EchiTAbG, developed in response to the considerable snakebite-induced mortality and morbidity in Nigeria, neutralised the lethal effects of venoms from Echis species representing each taxonomic group of this genus in Africa. This suggests that this monospecific antivenom has potential to treat envenoming by most, perhaps all, African Echis species. [ABSTRACT FROM AUTHOR]