Association of Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sectional study

Background Rift Valley fever virus is an emerging mosquito-borne virus that causes infections in animals and human beings in Africa and the Arabian Peninsula. Outbreaks of Rift Valley fever lead to mass abortions in livestock, but such abortions have not been identifi ed in human beings. Our aim was to investigate the cause of miscarriages in febrile pregnant women in an area endemic for Rift Valley fever. Methods Pregnant women with fever of unknown origin who attended the governmental hospital of Port Sudan, Sudan, between June 30, 2011, and Nov 17, 2012, were sampled at admission and included in this cross-sectional study. Medical records were retrieved and haematological tests were done on patient samples. Presence of viral RNA as well as antibodies against a variety of viruses were analysed. Any association of viral infections, symptoms, and laboratory parameters to pregnancy outcome was investigated using Pearson’s χ² test. Findings Of 130 pregnant women with febrile disease, 28 were infected with Rift Valley fever virus and 31 with chikungunya virus, with typical clinical and laboratory fi ndings for the infection in question. 15 (54%) of 28 women with an acute Rift Valley fever virus infection had miscarriages compared with 12 (12%) of 102 women negative for Rift Valley fever virus (p<0·0001). In a multiple logistic regression analysis, adjusting for age, haemorrhagic disease, and chikungunya virus infection, an acute Rift Valley fever virus infection was an independent predictor of having a miscarriage (odds ratio 7·4, 95% CI 2·7–20·1; p<0·0001). Interpretation This study is the fi rst to show an association between infection with Rift Valley fever virus and miscarriage in pregnant women. Further studies are warranted to investigate the possible mechanisms. Our fi ndings have implications for implementation of preventive measures, and evidence-based information to the public in endemic countries should be strongly recommended during Rift Valley fever outbreaks

Dissecting a Role for Polyamines in Rift Valley Fever Virus Infection

Bunyaviruses are emerging viral pathogens that cause encephalitis, hemorrhagic fevers, and meningitis. Rift Valley fever virus is a particularly devastating bunyavirus, infecting both humans and livestock with significant morbidity and mortality. By coordinating several host and viral processes Rift Valley fever virus is able to produce infectious virions. Polyamines are small, positively-charged host-derived molecules that play diverse roles in human cells and in infection. We previously demonstrated that polyamines are crucial for RNA viruses; however, the mechanisms by which polyamines function remain unknown. Here, we investigated polyamines\u27 role in the replication of the Rift Valley fever virus (vaccine strain MP-12). We found that polyamine depletion did not impact viral RNA or protein accumulation. Viral particles demonstrated no change in morphology, size, or density, however, targeting polyamines significantly reduced viral titers. In sum, polyamine depletion results in the accumulation of noninfectious particles which has important implications for targeting polyamines therapeutically, as well as enhancing vaccine strategies

Towards a better understanding of Rift Valley fever epidemiology in the south-west of the Indian Ocean.

International audience: Rift Valley fever virus (Phlebovirus, Bunyaviridae) is an arbovirus causing intermittent epizootics and sporadic epidemics primarily in East Africa. Infection causes severe and often fatal illness in young sheep, goats and cattle. Domestic animals and humans can be contaminated by close contact with infectious tissues or through mosquito infectious bites. Rift Valley fever virus was historically restricted to sub-Saharan countries. The probability of Rift Valley fever emerging in virgin areas is likely to be increasing. Its geographical range has extended over the past years. As a recent example, autochthonous cases of Rift Valley fever were recorded in 2007--2008 in Mayotte in the Indian Ocean. It has been proposed that a single infected animal that enters a naive country is sufficient to initiate a major outbreak before Rift Valley fever virus would ever be detected. Unless vaccines are available and widely used to limit its expansion, Rift Valley fever will continue to be a critical issue for human and animal health in the region of the Indian Ocean

Rift Valley fever virus vaccine strategies

Rift Valley fever virus circulates throughout Africa and the Arabian Peninsula and is of great concern for animal and public health. Infections in humans are often manifested as mild self‐limiting illness, although in some cases there are more severe symptoms such as neurological complications and hemorrhagic fever. Spontaneous abortions among livestock are a hallmark for Rift Valley fever virus outbreaks and disease in small ruminants often has a deadly outcome. At present, there is no vaccine available for use in humans and the ones used in livestock are either poorly immunogenic or cause severe adverse effects. The economic impact of this pathogen in the form of livestock losses and restrictions on the trade of animals and animal products as well as its significance in relation to public health underscores the importance of developing safe and effective vaccines. The main focus of this thesis was to evaluate existing vaccines and novel vaccine candidates, with special emphasis on vaccine platforms practical in resource‐poor areas. It is difficult to maintain a cold‐chain during transit in Mozambique and the inactivated Rift Valley fever virus vaccine is transported more than 2000 km within the country before it is administered to livestock in Zambezia Province. For that reason, the vaccine was evaluated for its ability to induce antibodies in cattle after storage at ambient temperatures. Importantly, the storage and transport conditions used in Mozambique did not have an adverse effect on the antibody responses induced by the vaccine. When performing the aforementioned study, we found evidence of previous Rift Valley fever virus infections in livestock in Maputo Province, a region where there had been no recorded evidence of the virus since 1969. A cross‐sectional seroprevalence study was undertaken to examine the need to implement a vaccination program in this particular province. Unexpectedly, seroconversion was observed in 37% of the investigated cattle, suggesting that this pathogen is widely distributed throughout Maputo Province. Rift Valley fever virus is highly pathogenic and to circumvent the handling of replicating virus during the vaccine manufacturing process would be advantageous. Other highly desirable vaccine‐characteristics are low production costs, high immunogenicity to reduce the number of doses, and a non‐invasive delivery route to avoid the challenge of maintaining sterility of hypodermic equipment. To fulfill some of those requirements we developed and evaluated three different vaccine strategies i) DNA vaccines, ii) vaccine based on virus‐like particles, and iii) plant‐derived protein subunit vaccines. All candidates induced vaccine‐specific antibody responses in mice and the DNA‐ and virus‐like particle‐based vaccines conferred protection against Rift Valley fever disease. Here, we raise the question of extending the vaccination program in Mozambique to include Maputo Province. We show that the inactivated virus vaccine is well‐suited for that purpose until more effective alternatives are available. In the search for such an alternative, we evaluated three vaccine candidates. One of those candidates, vaccine based on virus‐like particles, was found to have good prospects as a future Rift Valley fever virus vaccine

A Protective Monoclonal Antibody Targets a Site of Vulnerability on the Surface of Rift Valley Fever Virus

Summary: The Gn subcomponent of the Gn-Gc assembly that envelopes the human and animal pathogen, Rift Valley fever virus (RVFV), is a primary target of the neutralizing antibody response. To better understand the molecular basis for immune recognition, we raised a class of neutralizing monoclonal antibodies (nAbs) against RVFV Gn, which exhibited protective efficacy in a mouse infection model. Structural characterization revealed that these nAbs were directed to the membrane-distal domain of RVFV Gn and likely prevented virus entry into a host cell by blocking fusogenic rearrangements of the Gn-Gc lattice. Genome sequence analysis confirmed that this region of the RVFV Gn-Gc assembly was under selective pressure and constituted a site of vulnerability on the virion surface. These data provide a blueprint for the rational design of immunotherapeutics and vaccines capable of preventing RVFV infection and a model for understanding Ab-mediated neutralization of bunyaviruses more generally. : Allen et al. reveal a molecular basis of antibody-mediated neutralization of Rift Valley fever virus, an important human and animal pathogen. They isolate and demonstrate the protective efficacy of a monoclonal antibody in a murine model of virus infection, providing a blueprint for rational therapeutic and vaccine design. Keywords: phlebovirus, Rift Valley fever virus, antibody, structure, bunyavirus, virus-host interactions, immune response, vaccine, antiviral, neutralizatio

Vector competence of Aedes vexans (Meigen), Culex poicilipes (Theobald) and Cx. quinquefasciatus Say from Senegal for West and East African lineages of Rift Valley fever virus

Background Rift Valley fever virus (RVFV; Phlebovirus, Bunyaviridae) is a mosquito–borne, zoonotic pathogen. In Senegal, RVFV was first isolated in 1974 from Aedes dalzieli (Theobald) and thereafter from Ae. fowleri (de Charmoy), Ae. ochraceus Theobald, Ae. vexans (Meigen), Culex poicilipes (Theobald), Mansonia africana (Theobald) and Ma. uniformis (Theobald). However, the vector competence of these local species has never been demonstrated making hypothetical the transmission cycle proposed for West Africa based on serological data and mosquito isolates. Methods Aedes vexans and Cx. poicilipes, two common mosquito species most frequently associated with RVFV in Senegal, and Cx. quinquefasciatus, the most common domestic species, were assessed after oral feeding with three RVFV strains of the West and East/central African lineages. Fully engorged mosquitoes (420 Ae. vexans, 563 Cx. quinquefasciatus and 380 Cx. poicilipes) were maintained at 27 ± 1 °C and 70–80 % relative humidity. The saliva, legs/wings and bodies were tested individually for the RVFV genome using real-time RT-PCR at 5, 10, 15 and 20 days post exposure (dpe) to estimate the infection, dissemination, and transmission rates. Genotypic characterisation of the 3 strains used were performed to identify factors underlying the different patterns of transmission. Results The infection rates varied between 30.0–85.0 % for Ae. vexans, 3.3–27 % for Cx. quinquefasciatus and 8.3–46.7 % for Cx. poicilipes, and the dissemination rates varied between 10.5–37 % for Ae. vexans, 9.5–28.6 % for Cx. quinquefasciatus and 3.0–40.9 % for Cx. poicilipes. However only the East African lineage was transmitted, with transmission rates varying between 13.3–33.3 % in Ae. vexans, 50 % in Cx. quinquefasciatus and 11.1 % in Cx. poicilipes. Culex mosquitoes were less susceptible to infection than Ae. vexans. Compared to other strains, amino acid variation in the NSs M segment proteins of the East African RVFV lineage human-derived strain SH172805, might explain the differences in transmission potential. Conclusion Our findings revealed that all the species tested were competent for RVFV with a significant more important role of Ae. vexans compared to Culex species and a highest potential of the East African lineage to be transmitted

Emerging phleboviruses

The &lt;i&gt;Bunyavidae&lt;/i&gt; family is the largest grouping of RNA viruses and arguably the most diverse. Bunyaviruses have a truly global distribution and can infect vertebrates, invertebrates and plants. The majority of bunyaviruses are vectored by arthropods and thus have the remarkable capability to replicate in hosts of disparate phylogeny. The family has provided many examples of emerging viruses including Sin Nombre and related viruses responsible for hantavirus cardiopulmonary syndrome in the Americas, first identified in 1993, and Schmallenberg virus which emerged in Europe in 2011, causing foetal malformations in ruminants. In addition, some well-known bunyaviruses like Rift Valley fever and Crimean-Congo haemorrhagic fever viruses continue to emerge in new geographical locations. In this short review we focus on newly identified viruses associated with severe haemorrhagic disease in humans in China and the US

Non-structural proteins of arthropod-borne bunyaviruses: roles and functions

Viruses within the Bunyaviridae family are tri-segmented, negative-stranded RNA viruses. The family includes several emerging and re-emerging viruses of humans, animals and plants, such as Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, La Crosse virus, Schmallenberg virus and tomato spotted wilt virus. Many bunyaviruses are arthropod-borne, so-called arboviruses. Depending on the genus, bunyaviruses encode, in addition to the RNA-dependent RNA polymerase and the different structural proteins, one or several non-structural proteins. These non-structural proteins are not always essential for virus growth and replication but can play an important role in viral pathogenesis through their interaction with the host innate immune system. In this review, we will summarize current knowledge and understanding of insect-borne bunyavirus non-structural protein function(s) in vertebrate, plant and arthropod

Inter-Epidemic Transmission of Rift Valley Fever in\ud Livestock in the Kilombero River Valley, Tanzania:\ud A Cross-Sectional Survey

In recent years, evidence of Rift Valley fever (RVF) transmission during inter-epidemic periods in parts of Africa has increasingly been reported. The inter-epidemic transmissions generally pass undetected where there is no surveillance in the livestock or human populations. We studied the presence of and the determinants for inter-epidemic RVF transmission in an area experiencing annual flooding in southern Tanzania. A cross-sectional sero-survey was conducted in randomly selected cattle, sheep and goats in the Kilombero river valley from May to August 2011, approximately four years after the 2006/07 RVF outbreak in Tanzania. The exposure status to RVF virus (RVFV) was determined using two commercial ELISA kits, detecting IgM and IgG antibodies in serum. Information about determinants was obtained through structured interviews with herd owners. An overall seroprevalence of 11.3% (n = 1680) was recorded; 5.5% in animals born after the 2006/07 RVF outbreak and 22.7% in animals present during the outbreak. There was a linear increase in prevalence in the post-epidemic annual cohorts. Nine inhibition-ELISA positive samples were also positive for RVFV IgM antibodies indicating a recent infection. The spatial distribution of seroprevalence exhibited a few hotspots. The sex difference in seroprevalence in animals born after the previous epidemic was not significant (6.1% vs. 4.6% for females and males respectively, p = 0.158) whereas it was significant in animals present during the outbreak (26.0% vs. 7.8% for females and males respectively, p,0.001). Animals living .15 km from the flood plain were more likely to have antibodies than those living ,5 km (OR 1.92; 95% CI 1.04–3.56). Species, breed, herd composition, grazing practices and altitude were not associated with seropositivity. These findings indicate post-epidemic transmission of RVFV in the study area. The linear increase in seroprevalence in the post-epidemic annual cohorts implies a constant exposure and presence of active foci transmission preceding the survey