Endemic Areas Of West Africa Research Articles

Inactivated rabies-based Lassa fever virus vaccine candidate LASSARAB protects nonhuman primates from lethal disease

Lassa fever virus (LASV), a member of the Arenavirus family, is the etiological agent of Lassa fever, a severe hemorrhagic disease that causes considerable morbidity and mortality in the endemic areas of West Africa. LASV is a rodent-borne CDC Tier One biological threat agent and is on the World Health Organization’s (WHO) Priority Pathogen list. Currently, no FDA-licensed vaccines or specific therapeutics are available. Here, we describe the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of LASV (LASSARAB). Nonhuman primates (NHPs) were administered a two-dose regimen of LASSARAB or an irrelevant RABV-based vaccine to serve as a negative control. NHPs immunized with LASSARAB developed strong humoral responses to LASV-GPC. Upon challenge, NHPs vaccinated with LASSARAB survived to the study endpoint, whereas NHPs in the control group did not. This study demonstrates that LASSARAB is a worthy candidate for continued development.

A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge.

Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus.

Rodents as Natural Hosts of Zoonotic Schistosoma Species and Hybrids: An Epidemiological and Evolutionary Perspective From West Africa.

The complex multi-host disease dynamics of schistosomiasis and Schistosoma spp., including the emergence of zoonotic parasite hybrids, remain largely unexplored in West Africa. We elucidated the role of wild small mammals as reservoir for zoonotic Schistosoma species and hybrids in endemic areas of Senegal. We identified Schistosoma mansoni, Schistosoma bovis, and a Schistosoma haematobium/S. bovis hybrid, with local prevalence in wild rodents ranging from 1.9% to 28.6%. Our findings indicate that rodents may be an important local reservoir for zoonotic schistosomiasis in endemic areas of West Africa, amplifying transmission to humans and acting as natural definitive hosts of schistosome hybrids.

Current and Emerging Strategies for the Diagnosis, Prevention and Treatment of Lassa Fever

ABSTRACT Lassa fever (LF) is a potentially fatal disease that affects an estimated 300,000–500,000 people in endemic areas of west Africa each year. Though past studies have identified fatality rates of 5–20% in patients suspected to have contracted Lassa virus (LASV), new studies using more precise clinical diagnoses and modern diagnostic assays show fatalities rates above 60% in acutely ill patients from endemic regions. Currently, there are no approved vaccines or therapeutics, and only one Comformité Européenne (CE) marked rapid immunodiagnostic for acute LASV infection. Therefore, preventing LASV transmission is the primary goal in endemic regions. Development of rapid immunodiagnostics and research into the efficacy of current treatment options continues toward saving lives in west Africa as well as creating a line of defense against the nefarious use of LASV in bioterrorism settings.

English

Cholera epidemic is a recurrent disease in developing countries with poor environmental sanitation and inadequate supply of potable water. In endemic areas of West Africa, opinions and myths surrounding the real causes of cholera diseases have given rise to varying methods of control. This review gives an insight into these various opinions and myths. Some of these are that magico-religious factors, witchcraft, eating soil, god’s will and evil air in the community are responsible for cholera outbreaks. Wrong perception and myth of cholera hinders acceptance and accessibility to launch effective operational response to affected communities during an outbreak. This also lead to delay in providing intervention and treatment during an outbreak. Key words: Myths, aetiology, Vibrio cholerae, epidemic, perception

Patterns of malaria indices across three consecutive seasons in children in a highly endemic area of West Africa: a three times-repeated cross-sectional study.

ObjectivesTo study the manifestations of Plasmodium infection, and its relations with the malaria disease, especially when comparing dry and rainy seasons in a hyperendemic area of West Africa.MethodsThe study was carried out in an area where malaria transmission is high, showing important seasonal variations. One thousand children, representing the total child population (1–12 year old), were observed transversally at the end of three consecutive seasons (dry/rainy/dry). The usual indicators, such as parasite density, splenomegaly, anaemia, or febrile disease were recorded and analysed.ResultsThe prevalence of Plasmodium falciparum was high in all age groups and seasons, constantly around 60%. The high transmission season (rainy) showed higher rates of anaemia and spleen enlargement and, in the youngest children only, higher parasite densities. There were also differences between the two dry seasons: in the first one, there was a higher rate of fever than in the second one (p < 0.001). Low parasite density (<2,000 p/μl) was never associated with fever during any season, raising some concern with regard to the usefulness of parasite detection. The possible origins of fever are discussed, together with the potential usefulness of analyzing these indices on a population sample, at a time when fever incidence rises and malaria is one potential cause among others. The distinction to be made between the Plasmodium infection and the malaria disease is highlighted.ConclusionsThese data confirm previous hypotheses of a strong difference in malaria infection and disease between dry and rainy seasons. The most relevant seasonal indicator was not mainly parasite rate and density but anaemia, spleen enlargement, prevalence and possible origin of fever.RecommendationsIn any situation (i.e. fever or not) and especially during the dry season, one must consider that detection of parasites in the blood is only evidence of a Plasmodium infection and not necessarily of a malaria disease. In such a situation, it seems suitable to obtain, through national malaria teams, a well-defined situation of transmission and prevalence of Plasmodium infection following zones and seasons, in order to adapt control strategies. For researchers, a systematic management of data separately for dry and rainy season appears mandatory.

An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity

BackgroundLassa hemorrhagic fever (LHF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs pathognomonic for arenavirus disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge. However, since the LHF endemic area of West Africa also has high HIV seroprevalence, it is important to determine whether vaccination could be safe in the context of HIV infection.ResultsSIV-infected and uninfected rhesus macaques were vaccinated with the ML29 virus and monitored for specific humoral and cellular immune responses, as well as for classical and non-classical signs of arenavirus disease. Classical disease signs included viremia, rash, respiratory distress, malaise, high liver enzyme levels, and virus invasion of the central nervous system. Non-classical signs, derived from profiling the blood transcriptome of virulent and non-virulent arenavirus infections, included increased expression of interferon-stimulated genes (ISG) and decreased expression of COX2, IL-1β, coagulation intermediates and nuclear receptors needed for stress signaling. All vaccinated monkeys showed ML29-specific antibody responses and ML29-specific cell-mediated immunity.ConclusionSIV-infected and uninfected rhesus macaques responded similarly to ML29 vaccination, and none developed chronic arenavirus infection. Importantly, none of the macaques developed signs, classical or non-classical, of arenavirus disease.

Host Cell Factors as Antiviral Targets in Arenavirus Infection

Among the members of the Arenaviridae family, Lassa virus and Junin virus generate periodic annual outbreaks of severe human hemorrhagic fever (HF) in endemic areas of West Africa and Argentina, respectively. Given the human health threat that arenaviruses represent and the lack of a specific and safe chemotherapy, the search for effective antiviral compounds is a continuous demanding effort. Since diverse host cell pathways and enzymes are used by RNA viruses to fulfill their replicative cycle, the targeting of a host process has turned an attractive antiviral approach in the last years for many unrelated virus types. This strategy has the additional benefit to reduce the serious challenge for therapy of RNA viruses to escape from drug effects through selection of resistant variants triggered by their high mutation rate. This article focuses on novel strategies to identify inhibitors for arenavirus therapy, analyzing the potential for antiviral developments of diverse host factors essential for virus infection.

Vaccine Platforms to Control Arenaviral Hemorrhagic Fevers

Arenaviruses are rodent-borne emerging human pathogens. Diseases caused by these viruses, e.g., Lassa fever (LF) in West Africa and South American hemorrhagic fevers (HFs), are serious public health problems in endemic areas. We have employed replication-competent and replication-deficient strategies to design vaccine candidates potentially targeting different groups "at risk". Our leader LF vaccine candidate, the live reassortant vaccine ML29, is safe and efficacious in all tested animal models including non-human primates. In this study we showed that treatment of fatally infected animals with ML29 two days after Lassa virus (LASV) challenge protected 80% of the treated animals. In endemic areas, where most of the target population is poor and many live far from health care facilities, a single-dose vaccination with ML29 would be ideal solution. Once there is an outbreak, a fast-acting vaccine or post-exposure prophylaxis would be best. The 2(nd) vaccine technology is based on Yellow Fever (YF) 17D vaccine. We designed YF17D-based recombinant viruses expressing LASV glycoproteins (GP) and showed protective efficacy of these recombinants. In the current study we developed a novel technology to clone LASV nucleocapsid within YF17D C gene. Low immunogenicity and stability of foreign inserts must be addressed to design successful LASV/YFV bivalent vaccines to control LF and YF in overlapping endemic areas of West Africa. The 3(rd) platform is based on the new generation of alphavirus replicon virus-like-particle vectors (VLPV). Using this technology we designed VLPV expressing LASV GP with enhanced immunogenicity and bivalent VLPV expressing cross-reactive GP of Junin virus (JUNV) and Machupo virus (MACV), causative agents of Argentinian and Bolivian HF, respectively. A prime-boost regimen required for VLPV immunization might be practical for medical providers, military, lab personnel, and visitors in endemic areas.

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection.

BackgroundLassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF.ResultsAnalyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa.ConclusionOnly LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In addition to suggesting that the current diagnostic paradigm for acute LF should be reconsidered, these studies present new opportunities for therapeutic interventions based on potential prognostic markers in LF.

HIV-2 CRF01_AB: First Circulating Recombinant Form of HIV-2

Five HIV-2-seropositive cases were recently identified in Japan, outside the HIV-2 endemic area of West Africa. To clarify the molecular epidemiology of HIV-2 in Japan, we analyzed sequences of these cases in detail. HIV-2 genetic groups were determined by gag and env sequences. For suspected recombinant isolates, the genetic structure was determined by full-length genomic analyses. To understand the history and evolution of HIV-2 recombinant isolates, we estimated the time of most recent common ancestor by Bayesian Markov chain Monte Carlo method. Three isolates were determined as recombinants of groups A and B, and their mosaic genome structures were identical with that of 7312A, a recombinant isolate reported in 1990 from Côte d'Ivoire. Our 3 isolates and 7312A fulfilled the criteria for determining a circulating recombinant form (CRF). These isolates were verified by the Los Alamos HIV sequence database as the first CRF of HIV-2, HIV-2 CRF01_AB. The mean time of most recent common ancestor of CRF01_AB was estimated as between 1964 and 1973, several decades after the estimated emergence of HIV-2. We recently identified HIV-2 CRF01_AB cases in Japan. This ectopic observation of the virus outside its original endemic area suggests an ongoing global spread of HIV-2 CRF01_AB.

Lymphoproliferative responses to a merozoite surface antigen of Plasmodium falciparum: preliminary evidence for seasonal activation of CD8+/HLA-DQ-restricted suppressor cells.

We have investigated the phenotype of human lymphocytes responding to a defined Plasmodium falciparum malaria antigen in vitro. Cells were obtained from the peripheral blood of malaria-immune donors from an endemic area of West Africa and were tested for proliferation in response to cloned fragments of a merozoite surface protein (PfMSP1). Depletion and inhibition studies indicated that the majority of proliferating cells were CD4+ and restricted by HLA-DR or -DQ. A proportion of responding cells appeared to be CD8+, but their response was dependent on help from CD4+ cells. In two donors there was evidence that low responses could be enhanced by removal of CD8+ cells and/or blocking of antigen presentation by anti-HLA-DQ antibodies. This phenomenon was observed in cells collected during the wet (malaria transmission) season but not in cells collected from the same individual during the dry season.

MHC and malaria: the relationship between HLA class II alleles and immune responses to Plasmodium falciparum.

In mice, immune responses to subunits of defined malaria antigens are regulated by genes mapping within the MHC and it has been suggested that such genetic restriction will be a major obstacle in the development of a human malaria vaccine. The relationship between class II human leukocyte antigen (HLA) genes and immune recognition of three candidate antigens for a vaccine against Plasmodium falciparum malaria has been investigated in a human population living in a malaria endemic area of West Africa. The study population was shown to be extremely heterogeneous for HLA class II alleles and marked differences in allelic frequency were detected between members of different ethnic groups. One class II DQA-DQB combination (serological specificity DQw2) was particularly common among members of the Fula ethnic group. This haplotype was significantly associated with higher than average levels of antibody to a peptide epitope, (EENV)6, of the malaria antigen Pf155/RESA. There was little evidence of association between HLA class II genotype and cellular proliferative or interferon gamma responses to the antigens tested. Overall, the number of significant associations between immune responses and specific HLA class II haplotypes was greater than would be expected by chance but less than would be expected if class II-dependent genetic restriction were a major factor governing human immune responses to malaria antigens. Thus, although some qualitative variation in the immune response to vaccine antigens may occur in ethnically different target populations, widespread HLA-associated nonresponsiveness to a multivalent subunit malaria vaccine is unlikely.

Structural features of T-cell recognition: applications to vaccine design

T lymphocytes, in contrast to antibodies, appear to recognize primarily a limited number of antigenic sites on any given antigenic protein. We find that a single site can so dominate the T-cell repertoire that the presence or absence of a response to one immunodominant site can make the difference between a high responder and a low responder, even though low responders respond to other sites almost as well as high responders. Besides interaction with major histocompatibility complex (MHC) molecules, the mode by which the antigen is processed into fragments for T-cell recognition also determines which sites are seen. The products of natural processing of the protein appear to be larger than the synthetic peptides and contain structures which hinder binding to certain MHC molecules or to the T-cell receptor. A third factor in immunodominance is the intrinsic structure of the antigenic site. We have shown that amphipathic helices have a higher than random chance of being immunodominant, and have developed a computer program to locate such structures in protein amino acid sequences. We prospectively predicted sites in the malaria circumsporozoite protein and found that the four most widely recognized sites in an endemic area of West Africa were all predicted. Similarly, we identified two helper T-cell sites from the HIV (AIDS virus) envelope, and have now shown that immunization with these elicits enhanced antibody responses to the whole envelope when injected into monkeys. These sites are also recognized by human T cells from volunteers who had been immunized with a recombinant vaccinia virus expressing the HIV envelope. Also, because cytotoxic T lymphocytes (CTLS) may play a critical role in defence against AIDS, we have used a recombinant vaccinia virus and transfectants expressing the HIV envelope gene to induce specific CTLS against the HIV envelope. Using synthetic peptides, we were able to identify the first CTL recognition site in the AIDS virus. These results may contribute to the rational design of vaccines.

Human T cell recognition of polymorphic epitopes from malaria circumsporozoite protein.

Lymphocytes obtained from forty individuals living in a malaria endemic area of West Africa were tested for in vitro proliferative responses to peptides representing variant regions of the immunodominant T cell domain of the circumsporozoite protein (amino acids 326 to 345, referred to as Th2R, and 361 to 380, referred to as Th3R) from three distinct strains of Plasmodium falciparum. A total of 83% of the individuals responded to at least one of the six peptides tested, confirming that these epitopes are immunodominant. A much greater number of individuals than expected by chance (32% of the responders to Th2R and 27% of the responders to Th3R) reacted to all three of the variant peptides for that epitope, indicating interdependency of the T cell responses, suggestive of cross-reactivity. Nevertheless, some subjects' T cells were clearly able to distinguish each variant peptide from the others. Using EBV transformed B cells, lymphocytes from 10 of the individuals were HLA typed. In this small group, HLA DRw13 was associated with a positive response to any of the peptides, whereas there was a negative association between DQw3 and response to any of the peptides. These results, although limited by the small sample size, suggest that recognition of T epitopes may be Ir gene linked. Our findings suggest that it may be possible to broaden the immunogenicity of an anti-sporozoite malaria vaccine.