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Background: In sub-Saharan Africa, systematic surveillance of young children with suspected invasive bacterial disease (e.g., septicemia, meningitis) has revealed non-typhoidal Salmonella (NTS) to be a major pathogen exhibiting high case fatality (~20%). Where infant vaccination against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae has been introduced to prevent invasive disease caused by these pathogens, as in Bamako, Mali, their burden has decreased markedly. In parallel, NTS has become the predominant invasive bacterial pathogen in children aged <5 years. While NTS is believed to be acquired orally via contaminated food/water, epidemiologic studies have failed to identify the reservoir of infection or vehicles of transmission. This has precluded targeting food chain interventions to diminish disease transmission but conversely has fostered the development of vaccines to prevent invasive NTS (iNTS) disease. We developed a mathematical model to estimate the potential impact of NTS vaccination programs in Bamako., Methodology/principal Findings: A Markov chain transmission model was developed utilizing age-specific Bamako demographic data and hospital surveillance data for iNTS disease in children aged <5 years and assuming vaccine coverage and efficacy similar to the existing, successfully implemented, Hib vaccine. Annual iNTS hospitalizations and deaths in children <5 years, with and without a Salmonella Enteritidis/Salmonella Typhimurium vaccine, were the model's outcomes of interest. Per the model, high coverage/high efficacy iNTS vaccination programs would drastically diminish iNTS disease except among infants age <8 weeks., Conclusions/significance: The public health impact of NTS vaccination shifts as disease burden, vaccine coverage, and serovar distribution vary. Our model shows that implementing an iNTS vaccine through an analogous strategy to the Hib vaccination program in Bamako would markedly reduce cases and deaths due to iNTS among the pediatric population. The model can be adjusted for use elsewhere in Africa where NTS epidemiologic patterns, serovar prevalence, and immunization schedules differ from Bamako., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SMT, RS and MML are inventors on US patents 9,050,283 and 9,011,871 which describe vaccines against non-typhoidal Salmonella.

Invasive infections associated with non-typhoidal Salmonella (NTS) serovars Enteritidis (SE), Typhimurium (STm) and monophasic variant 1,4,[5],12:i:- are a major health problem in infants and young children in sub-Saharan Africa, and currently, there are no approved human NTS vaccines. NTS O-polysaccharides and flagellin proteins are protective antigens in animal models of invasive NTS infection. Conjugates of SE core and O-polysaccharide (COPS) chemically linked to SE flagellin have enhanced the anti-COPS immune response and protected mice against fatal challenge with a Malian SE blood isolate. We report herein the development of a STm glycoconjugate vaccine comprised of STm COPS conjugated to the homologous serovar phase 1 flagellin protein (FliC) with assessment of the role of COPS O-acetyls for functional immunity. Sun-type COPS conjugates linked through the polysaccharide reducing end to FliC were more immunogenic and protective in mice challenged with a Malian STm blood isolate than multipoint lattice conjugates (>95% vaccine efficacy [VE] versus 30–43% VE). Immunization with de-O-acetylated STm-COPS conjugated to CRM197 provided significant but reduced protection against STm challenge compared to mice immunized with native STm-COPS:CRM197 (63–74% VE versus 100% VE). Although OPS O-acetyls were highly immunogenic, post-vaccination sera that contained various O-acetyl epitope-specific antibody profiles displayed similar in vitro bactericidal activity when equivalent titers of anti-COPS IgG were assayed. In-silico molecular modeling further indicated that STm OPS forms a single dominant conformation, irrespective of O-acetylation, in which O-acetyls extend outward and are highly solvent exposed. These preclinical results establish important quality attributes for an STm vaccine that could be co-formulated with an SE-COPS:FliC glycoconjugate as a bivalent NTS vaccine for use in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Among more than 2500 nontyphoidal Salmonella enterica (NTS) serovars, S. enterica serovar Typhimurium and S. enterica serovar Enteritidis account for approximately fifty percent of all human isolates of NTS reported globally. The global incidence of NTS gastroenteritis in 2010 was estimated to be 93 million cases, approximately 80 million of which were contracted via food-borne transmission. It is estimated that 155,000 deaths resulted from NTS in 2010. NTS also causes severe, extra-intestinal, invasive bacteremia, referred to as invasive nontyphoidal Salmonella (iNTS) disease. iNTS disease usually presents as a febrile illness, frequently without gastrointestinal symptoms, in both adults and children. Symptoms of iNTS are similar to malaria, often including fever (>90%) and splenomegaly (>40%). The underlying reasons for the high rates of iNTS disease in Africa are still being elucidated. Evidence from animal and human studies supports the feasibility of developing a safe and effective vaccine against iNTS. Both antibodies and complement can kill Salmonella species in vitro . Proof-of-principle studies in animal models have demonstrated efficacy for live attenuated and subunit vaccines that target the O-antigens, flagellin proteins, and other outer membrane proteins of serovars Typhimurium and Enteritidis. More recently, a novel delivery strategy for NTS vaccines has been developed: the Generalized Modules for Membrane Antigens (GMMA) technology which presents surface polysaccharides and outer membrane proteins in their native conformation. GMMA technology is self-adjuvanting, as it delivers multiple pathogen-associated molecular pattern molecules. GMMA may be particularly relevant for low- and middle-income countries as it has the potential for high immunologic potency at a low cost and involves a relatively simple production process without the need for complex conjugation. Several vaccines for the predominant NTS serovars Typhimurium and Enteritidis, are currently under development. [ABSTRACT FROM AUTHOR]

Human cryptosporidiosis, caused primarily by Cryptosporidium hominis and a subset of Cryptosporidium parvum, is a major cause of moderate-to-severe diarrhea in children under 5 years of age in developing countries and can lead to nutritional stunting and death. Cryptosporidiosis is particularly severe and potentially lethal in immunocompromised hosts. Biological and technical challenges have impeded traditional vaccinology approaches to identify novel targets for the development of vaccines against C. hominis, the predominant species associated with human disease. We deemed that the existence of genomic resources for multiple species in the genus, including a muchimproved genome assembly and annotation for C. hominis, makes a reverse vaccinology approach feasible. To this end, we sought to generate a searchable online resource, termed C. hominis gene catalog, which registers all C. hominis genes and their properties relevant for the identification and prioritization of candidate vaccine antigens, including physical attributes, properties related to antigenic potential and expression data. Using bioinformatic approaches, we identified ~400 C. hominis genes containing properties typical of surface-exposed antigens, such as predicted glycosylphosphatidylinositol (GPI)-anchor motifs, multiple transmembrane motifs and/or signal peptides targeting the encoded protein to the secretory pathway. This set can be narrowed further, e.g. by focusing on potential GPI-anchored proteins lacking homologs in the human genome, but with homologs in the other Cryptosporidium species for which genomic data are available, and with low amino acid polymorphism. Additional selection criteria related to recombinant expression and purification include minimizing predicted post-translation modifications and potential disulfide bonds. Forty proteins satisfying these criteria were selected from 3745 proteins in the updated C. hominis annotation. The immunogenic potential of a few of these is currently being tested. [ABSTRACT FROM AUTHOR]

Highlights: [ • ] An attenuated nontyphoidal Salmonella live oral vaccine is designed by deleting genes guaBA and clpP. [ • ] We test the safety of this vaccine in monkeys infected with simian immunodeficiency virus. [ • ] The vaccine was safe and well-tolerated, establishing basis for efficacy and protection studies. [Copyright &y& Elsevier]

Non-typhoidal Salmonella (NTS) serovars S. Enteritidis and S. Typhimurium are a major cause of invasive bacterial disease (e.g., bacteremia, meningitis) in infants and young children in sub-Saharan Africa and also occasionally cause invasive disease in highly susceptible hosts (young infants, the elderly, and immunocompromised subjects) in industrialized countries. No licensed vaccines exist against human NTS infections. NTS core and O polysaccharide (COPS) and FliC (Phase 1 flagellin subunits) each constitute protective antigens in murine models. S. Enteritidis COPS conjugated to FliC represents a promising vaccine approach that elicits binding and opsonophagocytic antibodies and protects mice against lethal challenge with virulent S. Enteritidis. We examined the protective efficacy of fractional dosages of S. Enteritidis COPS:FliC conjugate vaccines in mice, and also established that protection can be passively transferred to naïve mice by administering sera from mice immunized with conjugate. Mice were immunized with three doses of either 10 µg, 2.5 µg (full dose), 0.25 µg, or 0.025 µg S. Enteritidis COPS:FliC conjugate at 28 day intervals. Antibody titers to COPS and FliC measured by ELISA fell consonant with progressively smaller vaccine dosage levels; anti-FliC IgG responses remained robust at fractional dosages for which anti-COPS serum IgG titers were decreased. Nevertheless, >90% protection against intraperitoneal challenge was observed in mice immunized with fractional dosages of conjugate that elicited diminished titers to both FliC and COPS. Passive transfer of immune sera from mice immunized with the highest dose of COPS:FliC to naïve mice was also protective, demonstrating the role of antibodies in mediating protection. These results provide important insights regarding the potency of Salmonella glycoconjugate vaccines that use flagellin as a carrier protein. [ABSTRACT FROM AUTHOR]

Abstract: Non-typhoidal Salmonella enterica (NTS) serovars Typhimurium and Enteritidis are important causes of bacterial gastroenteritis in the USA and worldwide. In sub-Saharan Africa these two serovars are emerging as agents associated with lethal invasive disease (e.g., bacteremia, meningitis). The development of NTS vaccines, based on mucosally administered live attenuated strains and parenteral non-living antigens, could diminish the NTS disease burden globally. Mouse models of S. Typhimurium and S. Enteritidis invasive disease can accelerate the development of NTS vaccines. Live attenuated NTS vaccines elicit both cellular and humoral immunity in mice and their efficacy is well established. In contrast, non-living vaccines that primarily elicit humoral immunity have demonstrated variable efficacy. An analysis of the reported studies with non-living vaccines against S. Typhimurium and S. Enteritidis reveals that efficacy is influenced by two important independent variables: (1) the innate susceptibility to NTS infection that differs dramatically between commonly used mouse strains and (2) the virulence of the NTS strain used for challenge. Protection by non-living vaccines has generally been seen only in host–pathogen interactions where a sub-lethal infection results, such as challenging resistant mice with either highly virulent or weakly virulent strains or susceptible mice with weakly virulent strains. The immunologic basis of this discrepancy and the implications for human NTS vaccine development are reviewed herein. [Copyright &y& Elsevier]

Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed Salmonella Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon but may become dominant again), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella ). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines. [ABSTRACT FROM AUTHOR]

Older adults are more susceptible to viral and bacterial infection, and experience higher incidence and severity of infectious diseases. Although vaccination is the most logical solution in preventing infectious diseases, primary vaccine responses in individuals aged ≥65 years-old fail to generate complete protection. This is presumably attributed to immunosenescence, a term that describes functional differences associated with the immune system and natural age advancement. Both the innate and adaptive immune systems experience age-related impairments that contribute to insufficient protection following vaccination. This review addresses current knowledge of age-related changes that affect vaccine responsiveness; including the deficits in innate cell functions, dampened humoral and cell-mediated immune responses, current vaccination schedules for older adults, and concludes with potential strategies for improving vaccine efficacy specifically for this age group. Due to an age-related decline in immunity and poor vaccine responses, infectious diseases remain a burden among the aged population. [ABSTRACT FROM AUTHOR]