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Human onchocerciasis – commonly known as river blindness – is one of the most devastating yet neglected tropical diseases, leaving many millions in sub-Saharan Africa blind and/or with chronic disabilities. Attempts to eliminate onchocerciasis, primarily through the mass drug administration of ivermectin, remains challenging and has been heightened by the recent news that drug-resistant parasites are developing in some populations after years of drug treatment. Needed, and needed now, in the fight to eliminate onchocerciasis are new tools, such as preventive and therapeutic vaccines. This review summarizes the progress made to advance the onchocerciasis vaccine from the research laboratory into the clinic. [ABSTRACT FROM AUTHOR]

The global efforts for onchocerciasis elimination may require additional tools (safe micro and macrofilaricidal drugs, vaccines and biomarkers) as elimination efforts move toward the “end game”. Efforts toward the identification of suitable biomarkers have focused on specific protein(s) and/or nucleic acids, but metabolites present an alternative option as they have limited half-lives and are the result of combinatorial effects. In comparison to previously used methodology of LC–MS for metabolomic approaches, we used a non-targeted capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) to analyze the serum metabolic profiles of Ov -infected and −uninfected individuals (n = 20). We identified 286 known metabolites (167 in the cation mode and 119 in the anion mode). In addition, putative metabolites were identified based on KEGG (51), HMDB (37) and HMT (6) databases. One hundred ten of these putative metabolites were quantified based on peak areas of internal standards and their ability to be mapped to known pathways (primary-, carbon-, lipid-, amino acid-, nucleotide and coenzyme-metabolism). Multivariate analysis demonstrated clustering and segregation of some of these metabolites to either the infected or control groups. The levels of serotonin, hypoxanthine, pipecolic acid and inosine were significantly elevated in those with onchocerciasis, whereas the levels of glycerophosphocholine, choline and adenine were significantly lower. This non-targeted metabolomic approach provides a global view of the metabolic variations that occur during Ov infection and thus allow the discovery of key metabolites (and associated pathways) that may serve as useful biomarkers in human onchocerciasis. [ABSTRACT FROM AUTHOR]

Human filarial infections are a leading cause of morbidity in the developing world. While a small arsenal of drugs exists to treat these infections, there remains a tremendous need for the development of additional interventions. Recent genome sequences and transcriptome analyses of filarial nematodes have provided novel biological insight and allowed for the prediction of novel drug targets as well as potential vaccine candidates. In this review, we discuss the currently available data, insights gained into the metabolism of these organisms, and how the filaria field can move forward by leveraging these data. [ABSTRACT FROM AUTHOR]

Brugia malayi , a parasitic nematode that causes lymphatic filariasis, harbors endosymbiotic intracellular bacteria, Wolbachia , that are required for the development and reproduction of the worm. The essential nature of this endosymbiosis led to the development of anti- Wolbachia chemotherapeutic approaches for the treatment of human filarial infections. Our study is aimed at identifying specific proteins that play a critical role in this endosymbiotic relationship leading to the identification of potential targets in the adult worms. Filarial cysteine proteases are known to be involved in molting and embryogenesis, processes shown to also be Wolbachia dependent. Based on the observation that cysteine protease transcripts are differentially regulated in response to tetracycline treatment, we focused on defining their role in symbiosis. We observe a bimodal regulation pattern of transcripts encoding cysteine proteases when in vitro tetracycline treated worms were examined. Using tetracycline-treated infertile female worms and purified embryos we established that the first peak of the bimodal pattern corresponds to embryonic transcripts while the second takes place within the hypodermis of the adult worms. Localization studies of the native proteins corresponding to Bm-cpl-3 and Bm-cpl-6 indicate that they are present in the area surrounding Wolbachia , and, in some cases, the proteins appear localized within the bacteria. Both proteins were also found in the inner bodies of microfilariae. The possible role of these cysteine proteases during development and endosymbiosis was further characterized using RNAi. Reduction in Bm-cpl-3 and Bm-cpl-6 transcript levels was accompanied by hindered microfilarial development and release, and reduced Wolbachia DNA levels, making these enzymes strong drug target candidates. [ABSTRACT FROM AUTHOR]

Helminth infections are the most common afflictions of humankind, affecting almost every single person living in profound poverty. Through mass drug administration (MDA) we have seen sharp declines in the global prevalence of some helminth infections, including lymphatic filariasis, onchocerciasis, and ascariasis. However, since 1990, there has been no appreciable decrease in the global prevalence of hookworm infection, schistosomiasis, or food-borne trematodiases. Through the activities of a non-profit product development partnerships and two research institutes, a total of five human anthelmintic vaccines for hookworm infection (two) and schistosomiasis (three) have advanced from discovery through manufacture and are now in Phase 1 clinical testing. At least three additional antigens, including two for onchocerciasis and one for schistosomiasis, are also advancing through preclinical development with the intention of moving into the clinic soon. These preventive human anthelmintic vaccines could be used as stand-alone technologies administered to infants as part of the Expanded Program on Immunization (EPI), or together with anthelmintic drugs in programs linked to MDA. Significant hurdles though could hinder the advancement of these vaccines into later-stage clinical and product development and licensure. They include the absence of a major pharma partner (and the resultant access to adjuvants and industrial scale manufacturing expertise), an uncharted roadmap for how to introduce anthelmintic vaccines into appropriate health systems, uncertain global access and regulatory strategies that might need to rely on developing country vaccine manufacturers and national regulatory authorities, and the lack of innovative financing schemes. However, the public health and economic benefits of introducing these vaccines could be massive and therefore deserve international attention and support. [ABSTRACT FROM AUTHOR]

• A SARS-CoV RBD vaccine on alum provides high neutralizing titers and 100% survival. • A SARS-CoV RBD vaccine on alum prevents pulmonary cellular infiltrates upon virus challenge. • A SARS-CoV RBD vaccine on alum greatly reduces lung eosinophils compared to a vaccine comprised of the SARS-CoV S protein. • The SARS-CoV RBD vaccine on alum is being developed as a human vaccine. We developed a severe acute respiratory syndrome (SARS) subunit recombinant protein vaccine candidate based on a high-yielding, yeast-engineered, receptor-binding domain (RBD219-N1) of the SARS beta-coronavirus (SARS-CoV) spike (S) protein. When formulated with Alhydrogel®, RBD219-N1 induced high levels of neutralizing antibodies against both pseudotyped virus and a clinical (mouse-adapted) isolate of SARS-CoV. Here, we report that mice immunized with RBD219-N1/Alhydrogel® were fully protected from lethal SARS-CoV challenge (0% mortality), compared to ~30% mortality in mice immunized with the SARS S protein formulated with Alhydrogel®, and 100% mortality in negative controls. An RBD219-N1 formulation with Alhydrogel® was also superior to the S protein, unadjuvanted RBD, and AddaVax (MF59-like adjuvant)-formulated RBD in inducing specific antibodies and preventing cellular infiltrates in the lungs upon SARS-CoV challenge. Specifically, a formulation with a 1:25 ratio of RBD219-N1 to Alhydrogel® provided high neutralizing antibody titers, 100% protection with non-detectable viral loads with minimal or no eosinophilic pulmonary infiltrates. As a result, this vaccine formulation is under consideration for further development against SARS-CoV and potentially other emerging and re-emerging beta-CoVs such as SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Immunization is the best way to prevent seasonal epidemics and pandemics of influenza. There are two kinds of influenza vaccines available in the United States: an inactivated vaccine (TIV) and an attenuated vaccine; however, only TIV is approved for immunization of the elderly population. While the aged population has the highest rate of influenza vaccination, the protective efficacy is low as evidenced by elderly individuals having the highest mortality associated with influenza. Recently, we reported that an adjuvant derived from the helminth parasite Onchocerca volvulus , named O. volvulus activation-associated secreted protein-1 ( Ov -ASP-1), can significantly enhance the protective efficacy of an inactivated vaccine (TIV) in young adult mice. In the current study, we examined whether this recombinant Ov -ASP-1 (r Ov -ASP-1) can enhance the efficacy of TIV in aged mice as well. While primary immunization with TIV alone produced only a low level of influenza-specific antibodies (total IgG, IgG1, and IgG2c) in aged mice, the antibody levels were significantly increased after immunization with TIV + r Ov -ASP-1. More importantly, the level of the total IgG in aged mice administered TIV + r Ov -ASP-1 was comparable to that of young adult mice immunized with TIV alone. Co-administration of r Ov -ASP-1 induced a low level of cross-reactive antibody and enhanced the protective efficacy of TIV in aged mice, reflected by significantly increased survival after challenge with a heterologous influenza virus. r Ov -ASP-1 was also superior to the conventional adjuvant alum in inducing specific IgG after TIV immunization in aged mice, and in conferring protection after challenge. These results demonstrate that r Ov -ASP-1 may serve as a potential adjuvant for influenza vaccine to improve the efficacy of protection in the elderly. [ABSTRACT FROM AUTHOR]

The complement of the Brugia malayi microRNA-71 was inserted into the 3′ untranslated region of a reporter plasmid, resulting in a decrease in reporter activity. Mutation of the seed sequence restored activity. Insertion of the 3′ untranslated regions from two algorithm-predicted putative target genes into the reporter resulted in a similar decrease in activity; mutation of the predicted target sequences restored activity. These experiments demonstrate that B. malayi microRNA targets may be predicted using current algorithms and describe a functional assay to confirm predicted targets. [ABSTRACT FROM AUTHOR]

The Onchocerca volvulus activation-associated secreted protein-1 ( Ov -ASP-1) has good adjuvanticity for a variety of antigens and vaccines, probably due to its ability activate antigen-processing cells (APCs). However, the functional domain of Ov -ASP-1 as an adjuvant is not clearly defined. Based on the structural prediction of this protein family, we constructed a 16-kDa recombinant protein of Ov -ASP-1 that contains only the core pathogenesis-related-1 (PR-1) domain (residues 10–153), designated ASPPR. We found that ASPPR exhibits adjuvanticity similar to that of the full-length Ov -ASP-1 (residues 10–220) for various antigens, including ovalbumin (OVA), HBsAg protein antigen, and the HIV peptide 5 (Pep5) antigen, but it is more suitable for vaccine design in ASPPR-antigen fusion proteins, and more stable in PBS than Ov -ASP-1 stored at −70 °C. These results suggest that ASPPR might be the functional region of Ov -ASP-1 as an adjuvant, and therefore could be developed as an adjuvant for human use. [ABSTRACT FROM AUTHOR]

Vaccination of Mongolian gerbils with Brugia malayi cysteine protease inhibitor-2 in which the amino acid Asn66 was mutated to Lys66 ( Bm -CPI-2M) resulted in reduced parasite numbers of 48.6% and 48.0% at 42 and 90 days p.i. with B. malayi L3s. Fertility of female worms was also affected at 90 days p.i. In vitro killing of L3s observed in the presence of gerbil peritoneal exudate cells and anti- Bm -CPI-2M sera suggests antibody-dependent cell-mediated cytotoxicity as a putative protective mechanism. These observations suggest that Bm -CPI-2M is a promising prophylactic and anti-fecundity vaccine candidate. [ABSTRACT FROM AUTHOR]

Human onchocerciasis is a neglected tropical disease caused by Onchocerca volvulus and an important cause of blindness and chronic disability in the developing world. Although mass drug administration of ivermectin has had a profound effect on control of the disease, additional tools are critically needed including the need for a vaccine against onchocerciasis. The objectives of the present study were to: (i) select antigens with known vaccine pedigrees as components of a vaccine; (ii) produce the selected vaccine antigens under controlled conditions, using two expression systems and in one laboratory and (iii) evaluate their vaccine efficacy using a single immunisation protocol in mice. In addition, we tested the hypothesis that joining protective antigens as a fusion protein or in combination, into a multivalent vaccine, would improve the ability of the vaccine to induce protective immunity. Out of eight vaccine candidates tested in this study, Ov-103, Ov-RAL-2 and Ov-CPI-2M were shown to reproducibly induce protective immunity when administered individually, as fusion proteins or in combination. Although there was no increase in the level of protective immunity induced by combining the antigens into one vaccine, these antigens remain strong candidates for inclusion in a vaccine to control onchocerciasis in humans. [ABSTRACT FROM AUTHOR]

The geographic spread and rapid increase in the cases of Middle East respiratory syndrome (MERS) caused by a novel coronavirus (MERS-CoV) during the past two months have raised concern about its pandemic potential. Here we call for the rapid development of an effective and safe MERS vaccine to control the spread of MERS-CoV. [ABSTRACT FROM AUTHOR]