Metabolomics provides a powerful tool to study physiological changes in response to various perturbations such as vaccination. We explored whether metabolomic changes could be seen after vaccination ...in a phase I trial where Gabonese adults living either in rural or semi-urban areas received the subunit hookworm vaccine candidates (Na-GST-1 and Na-APR-1 (M74) adjuvanted with Alhydrogel plus GLA-AF (n = 24) or the hepatitis B vaccine (n = 8) as control. Urine samples were collected and assayed using targeted .sup.1 H NMR spectroscopy. At baseline, a set of metabolites significantly distinguished rural from semi-urban individuals. The pre- and post-vaccination comparisons indicated significant changes in few metabolites but only one day after the first vaccination. There was no relationship with immunogenicity. In conclusion, in a small phase 1 trial, urinary metabolomics could distinguish volunteers with different environmental exposures and reflected the safety of the vaccines but did not show a relationship to immunogenicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hookworm infection affects 430 million people worldwide, causing iron deficiency, impaired cognitive development, and stunting in children. Because of the environmental conditions needed for the ...hookworm life-cycle, this parasite is endemic to resource-limited countries.
was endemic in the southern United States before improvement of sewage disposal systems and eradication programs. With continued poverty, poor sanitation, and an environment suitable for the hookworm life-cycle in some regions of the southern United States, a current prevalence study using modern molecular diagnostics is warranted. Lowndes County, Alabama, was chosen as the study site given previous high hookworm burdens, degree of poverty, and use of open-sewage systems. Participants were interviewed, and stool, serum, and soil samples were tested for nine intestinal parasites using a multiparallel quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assays. We found that, among 24 households, 42.4% reported exposure to raw sewage within their home, and from 55 stool samples, 19 (34.5%) tested positive for
, four (7.3%) for
, and one (1.8%) for
. Stool tested positive for
contained low levels of parasite DNA (geometric mean 0.0302 fg/μL). Soil studies detected one (2.9%)
species, and
serology assay detected one (5.2%) positive in this population. Individuals living in this high-risk environment within the United States continue to have stool samples positive for
. Gastrointestinal parasites known to be endemic to developing countries are identifiable in American poverty regions, and areas with lower disease burden are more likely to be identified by using qPCR.
Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although ...vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.
Metabolomics provides a powerful tool to study physiological changes in response to various perturbations such as vaccination. We explored whether metabolomic changes could be seen after vaccination ...in a phase I trial where Gabonese adults living either in rural or semi-urban areas received the subunit hookworm vaccine candidates (Na-GST-1 and Na-APR-1 (M74) adjuvanted with Alhydrogel plus GLA-AF (n = 24) or the hepatitis B vaccine (n = 8) as control. Urine samples were collected and assayed using targeted 1H NMR spectroscopy. At baseline, a set of metabolites significantly distinguished rural from semi-urban individuals. The pre- and post-vaccination comparisons indicated significant changes in few metabolites but only one day after the first vaccination. There was no relationship with immunogenicity. In conclusion, in a small phase 1 trial, urinary metabolomics could distinguish volunteers with different environmental exposures and reflected the safety of the vaccines but did not show a relationship to immunogenicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An estimated 100 million people in the Latin American and Caribbean (LAC) region live on less than US$2 per day, while another 46 million people in the US live below that nation's poverty line. ...Almost all of the 'bottom 100 million' people suffer from at least one neglected tropical disease (NTD), including one-half of the poorest people in the region infected with hookworms, 10% with Chagas disease, and up to 1-2% with dengue, schistosomiasis, and/or leishmaniasis. In the US, NTDs such as Chagas disease, cysticercosis, toxocariasis, and trichomoniasis are also common among poor populations. These NTDs trap the poorest people in the region in poverty, because of their impact on maternal and child health, and occupational productivity. Through mass drug administration (MDA), several NTDs are on the verge of elimination in the Americas, including lymphatic filariasis, onchocerciasis, trachoma, and possibly leprosy. In addition, schistosomiasis may soon be eliminated in the Caribbean. However, for other NTDs including hookworm infection, Chagas disease, dengue, schistosomiasis, and leishmaniasis, a new generation of 'anti-poverty vaccines' will be required. Several vaccines for dengue are under development by multinational pharmaceutical companies, whereas others are being pursued through non-profit product development partnerships (PDPs), in collaboration with developing country manufacturers in Brazil and Mexico. The Sabin Vaccine Institute PDP is developing a primarily preventive bivalent recombinant human hookworm vaccine, which is about to enter phase 1 clinical testing in Brazil, as well as a new therapeutic Chagas disease vaccine in collaboration with several Mexican institutions. The Chagas disease vaccine would be administered to seropositive patients to delay or prevent the onset of Chagasic cardiomyopathy (secondary prevention). Together, MDA and the development of new anti-poverty vaccines afford an opportunity to implement effective control and elimination strategies for the major NTDs in the Americas.
Over the next decade, a new generation of vaccines will target the neglected tropical diseases (NTDs). The goal of most NTD vaccines will be to reduce the morbidity and decrease the chronic ...debilitating nature of these often-forgotten infections - outcomes that are hard to measure in the traditional potency testing paradigm. The absence of measurable correlates of protection, a lack of permissive animal models for lethal infection, and a lack of clinical indications that do not include the induction of sterilizing immunity required us to reconsider the traditional bioassay methods for determining vaccine potency. Owing to these limitations, potency assay design for NTD vaccines will increasingly rely on a paradigm where potency testing is one among many tools to ensure that a manufacturing process yields a product of consistent quality. Herein, we discuss the evolution of our thinking regarding the design of a potency assay along these newly defined lines and its application to the release of the experimental Necator americanus-glutathione-S- transferase-1 (Na-GST-1) vaccine to prevent human hookworm infection. We discuss the necessary steps to accomplish the design and implementation of such a new potency assay as a resource for the burgeoning NTD vaccine community. Our experience is that much of the existing information is proprietary and needs to be pulled together in a single source to aid in our overall understanding of potency testing.
Native Chlamydia trachomatis mouse pneumonitis major outer membrane protein (nMOMP) induces effective protection against genital infection in a mouse challenge model. The conformation of nMOMP is ...crucial to confer this protective immunity. To achieve a better understanding of the conformational behavior and stability of nMOMP, a number of spectroscopic techniques are employed to characterize the secondary structure (circular dichroism), tertiary structure (intrinsic fluorescence) and aggregation properties (static light scattering and optical density) as a function of pH (3−8) and temperature (10−87.5 °C). The data are summarized in an empirical phase diagram (EPD) which demonstrates that the thermal stability of nMOMP is strongly pH-dependent. Three distinctive regions are seen in the EPD. Below the major thermal transition regions, nMOMP remains in its native conformation over the pH range of 3−8. Above the thermal transitions, nMOMP appears in two different structurally altered states; one at pH 3−5 and the other at pH 6−8. The EPD shows that the highest thermal transition point (∼65 °C) of nMOMP is near pH 6. Several potential excipients such as arginine, sodium citrate, Brij 35, sucrose and guanidine are also selected to evaluate their effects on the stability of nMOMP. These particular compounds increase the aggregation onset temperature of nMOMP by more than 10οC, without affecting its secondary and tertiary structure. These results should help formulate a vaccine using a recombinant MOMP.
Several global efforts are underway to develop COVID-19 vaccines, and interim analyses from phase 3 clinical testing have been announced by nine organisations: Pfizer, the Gamaleya Research Institute ...of Epidemiology and Microbiology, Moderna, AstraZeneca, Sinopharm Group, Sinovac Biotech, Johnson & Johnson, Novavax, and CanSino Biologics. The US programme known as Operation Warp Speed provided US$18 billion in funding for development of vaccines that were intended for US populations. Depending on safety and efficacy, vaccines can become available through mechanisms for emergency use, expanded access with informed consent, or full licensure. An important question is: how will these Operation Warp Speed vaccines be used for COVID-19 prevention in global health settings? We address some key questions that arise in the transition from US to global vaccine prevention efforts and from ethical and logistical issues to those that are relevant to global vaccine security, justice, equity, and diplomacy.
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