Children's Hospital Oakland Research Institute

About: Children's Hospital Oakland Research Institute is a based out in . It is known for research contribution in the topics: Population & Human leukocyte antigen. The organization has 1568 authors who have published 2480 publications receiving 203418 citations.

Protective antibody responses elicited by a meningococcal outer membrane vesicle vaccine with overexpressed genome-derived neisserial antigen 1870.

Abstract: Outer membrane vesicle (OMV) vaccines elicit protective immunity against Neisseria meningitidis group B disease (reviewed in [1]). Recently, an OMV vaccine received a provisional license in New Zealand and was introduced for widespread immunization in response to a group B epidemic that has been ongoing there for more than a decade [2–4]. One important limitation of OMV vaccines is that they elicit bactericidal antibody responses that are largely directed against surface-exposed loops of PorA [5], a major porin protein, and there is considerable PorA antigenic diversity in strains causing endemic meningococcal disease [6]. Thus, OMV vaccines are of greatest use for prevention of epidemic disease caused by a predominant (clonal) meningococcal strain, such as in New Zealand [4]. Recent efforts to develop group B meningococcal vaccines have focused on antigenically conserved antigens, such as neisserial surface protein A (NspA) [7, 8], or a number of other novel proteins (referred to as “genome-derived neisserial antigens” [GNA]) discovered during the N. meningitidis MC58 genome sequencing project [9]. Among the latter is GNA1870, a lipoprotein of unknown function that is presently being evaluated for use in a recombinant protein vaccine [10, 11]. GNA1870 can be subdivided into 3 variant groups on the basis of amino-acid variability and antigenic cross-reactivity. Strains expressing GNA1870 in the variant 1 (v.1) group account for ~60% of the disease-producing group B isolates [11]. In a previous study, mice immunized with a recombinant GNA1870 (rGNA1870) v.1 protein vaccine developed serum bactericidal antibody responses against most, but not all, strains expressing subvariants of the GNA1870 v.1 protein [10]. Thus, GNA1870 is a promising antigen for inclusion in a protective meningococcal vaccine, but it would be desirable to improve the breadth of the protective antibody responses elicited by the recombinant protein. In the present study, we investigated serum antibody responses elicited in mice after immunization with an OMV vaccine prepared from a N. meningitidis strain genetically engineered to overexpress GNA1870 v.1 protein. Our hypothesis was that the functional activity of antibodies elicited by the overexpressed native GNA1870 v.1 protein anchored in the OMV might be greater than that elicited by a rGNA1870 protein vaccine or by a conventional OMV vaccine.

Sequential Immunization with Vesicles Prepared from Heterologous Neisseria meningitidis Strains Elicits Broadly Protective Serum Antibodies to Group B Strains

Abstract: The capsular polysaccharide of Neisseria meningitidis group B is an autoantigen, whereas noncapsular antigens are highly variable. These factors present formidable challenges for development of a broadly protective and safe group B vaccine. Mice and guinea pigs were sequentially immunized with three doses of micovesicles or outer membrane vesicles prepared from three meningococcal strains that were each antigenically heterologous with respect to the two major porin proteins, PorA and PorB, and the group capsular polysaccharide. The resulting antisera conferred passive protection against meningococcal group B bacteremia in infant rats and elicited complement-mediated bactericidal activity against genetically diverse group B strains that were either homologous or heterologous with respect to PorA of the strains used to prepare the vaccine. By using knockout strains, a portion of the bactericidal antibody was directed against the highly conserved protein, neisserial surface protein A (NspA). Further, an anti-NspA monoclonal antibody elicited by the sequential immunization was highly bactericidal against strains that were previously shown to be resistant to bacteriolysis by anti-NspA antibodies produced by immunization with recombinant NspA. Sequential immunization with heterologous vesicle preparations offers a novel approach to eliciting broadly protective immunity against N. meningitidis strains. An NspA-based vaccine prepared from protein expressed by Neisseria also may be more effective than the corresponding recombinant protein made in Escherichia coli.

Meningococcal factor H-binding protein variants expressed by epidemic capsular group A, W-135, and X strains from Africa.

Abstract: For more than 100 years, devastating epidemics of meningococcal disease have resulted in enormous suffering in sub-Saharan Africa (reviewed in [1]). From 1988 to 1997, >700,000 cases were reported, with >100,000 associated deaths [2]. The public health responses were expensive, only partially effective [3], and deflected scarce resources from efforts to control other diseases. Control of epidemic meningococcal disease in Africa therefore remains an important health priority. Most meningococcal disease in industrialized countries is caused by strains in capsular groups B, C, or Y, whereas most disease in sub-Saharan Africa is caused by group A strains. A promising group A polysaccharide-protein conjugate vaccine for sub-Saharan Africa is under development by the Meningitis Vaccine Project [4, 5]. However, because strains from other capsular groups, including groups W-135 [6] and X [7, 8], also can cause epidemics in this region, additional vaccine approaches may be needed. Genome mining [9, 10] and proteomics [11] have identified a large number of novel vaccine targets for the prevention of group B meningococcal disease. One of these targets is factor H–binding protein (fHbp), a surface-exposed lipoprotein that binds human complement factor H [12]. The binding of factor H to the surface of Neisseria meningitidis down-regulated complement activation and enhanced resistance of the organism to bactericidal activity [12–14]. This antigen is part of 2 promising recombinant protein vaccines being developed for the prevention of group B disease [15, 16]. However, it is inaccurate to describe fHbp or other protein antigens, such as NadA [17, 18] or genome-derived neisserial antigen (GNA) 2132 [10, 19], as group B–specific antigens, because they elicit antibodies independent of the capsular polysaccharide group. Therefore, these antigens potentially can protect against disease caused by strains from other capsular groups. Meningococcal fHbp can be subclassified into different antigenic variant groups on the basis of sequence similarity and antigenic cross-reactivity among fHbp groups [16, 20]. In general, antibodies prepared against fHbp in the variant 1 (v.1) group (also referred to as “subfamily B” [16]) were bactericidal against strains expressing fHbp from the homologous variant or subfamily group, but not against strains expressing fHbp in the variant 2 (v.2) or 3 (v.3) groups (also referred to as “subfamily A” [16]), and vice versa [18, 20]. The purpose of the present study was to investigate antigenic variants of fHbp expressed by epidemic group A, W-135, and X strains from Africa. As proof of concept for the use of an outer membrane vesicle (OMV) vaccine in Africa, we also measured the susceptibility of representative African strains to the bactericidal activity of serum samples obtained from mice vaccinated with prototype native (i.e., non–detergent-treated) OMV vaccines prepared from mutants engineered to express fHbp from different antigenic variant groups [21, 22].

High Rates of O ’ Nyong Nyong and Chikungunya Virus Transmission in Coastal Kenya

Abstract: Background Chikungunya virus (CHIKV) and o’nyong nyong virus (ONNV) are mosquito-borne alphaviruses endemic in East Africa that cause acute febrile illness and arthritis. The objectives of this study were to measure the seroprevalence of CHIKV and ONNV in coastal Kenya and link it to demographics and other risk factors. Methodology Demographic and exposure questionnaires were administered to 1,848 participants recruited from two village clusters (Milalani-Nganja and Vuga) in 2009. Sera were tested for alphavirus exposure using standardized CHIKV IgG ELISA protocols and confirmed with plaque reduction neutralization tests (PRNT). Logistic regression models were used to determine the variables associated with seropositivity. Weighted K test for global clustering of houses with alphavirus positive participants was performed for distance ranges of 50–1,000 meters, and G* statistic and kernel density mapping were used to identify locations of higher seroprevalence. Principal Findings 486 (26%) participants were seropositive by IgG ELISA. Of 443 PRNT confirmed positives, 25 samples (6%) were CHIKV+, 250 samples (56%) were ONNV+, and 168 samples (38%) had high titers for both. Age was significantly associated with seropositivity (OR 1.01 per year, 95% C.I. 1.00–1.01); however, younger adults were more likely to be seropositive than older adults. Males were less likely to be seropositive (p<0.05; OR 0.79, 95% C.I. 0.64–0.97). Adults who owned a bicycle (p<0.05; OR 1.37, 95% C.I. 1.00–1.85) or motor vehicle (p<0.05; OR 4.64, 95% C.I. 1.19–18.05) were more likely to be seropositive. Spatial analysis demonstrated hotspots of transmission within each village and clustering among local households in Milalani-Nganja, peaking at the 200–500m range. Conclusions/Significance Alphavirus exposure, particularly ONNV exposure, is common in coastal Kenya with ongoing interepidemic transmission of both ONNV and CHIKV. Women and adults were more likely to be seropositive. Household location may be a defining factor for the ecology of alphaviral transmission in this region.