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Advances in neglected tropical disease vaccines: Developing relative potency and functional assays for the Na-GST-1/Alhydrogel hookworm vaccine.

ABSTRACT: A new generation of vaccines for the neglected tropical diseases (NTDs) have now advanced into clinical development, with the Na-GST-1/Alhydrogel Hookworm Vaccine already being tested in Phase 1 studies in healthy adults. The current manuscript focuses on the often overlooked critical aspects of NTD vaccine product development, more specifically, vaccine stability testing programs. A key measure of vaccine stability testing is "relative potency" or the immunogenicity of the vaccine during storage. As with most NTD vaccines, the Na-GST-1/Alhydrogel Hookworm Vaccine was not developed by attenuation or inactivation of the pathogen (Necator americanus), so conventional methods for measuring relative potency are not relevant for this investigational product. Herein, we describe a novel relative potency testing program and report for the first time on the clinical lot of this NTD vaccine during its first 60 months of storage at 2-8°C. We also describe the development of a complementary functional assay that measures the ability of IgG from animals or humans immunized with Na-GST-1/Alhydrogel to neutralize this important hookworm enzyme. While 90% inhibition of the catalytic activity of Na-GST-1 was achieved in animals immunized with Na-GST-1/Alhydrogel, lower levels of inhibition were observed in immunized humans. Moreover, anti-Na-GST-1 antibodies from volunteers in non-hookworm endemic areas were better able to inhibit catalytic activity than anti-Na-GST-1 antibodies from volunteers resident in hookworm endemic areas. The results described herein provide the critical tools for the product development of NTD vaccines.

SUBMITTER: Brelsford JB

PROVIDER: S-EPMC5325600 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Advances in neglected tropical disease vaccines: Developing relative potency and functional assays for the Na-GST-1/Alhydrogel hookworm vaccine.

Brelsford Jill B JB Plieskatt Jordan L JL Yakovleva Anna A Jariwala Amar A Keegan Brian P BP Peng Jin J Xia Pengjun P Li Guangzhao G Campbell Doreen D Periago Maria Victoria MV Correa-Oliveira Rodrigo R Bottazzi Maria Elena ME Hotez Peter J PJ Diemert David D Bethony Jeffrey M JM

PLoS neglected tropical diseases 20170213 2

A new generation of vaccines for the neglected tropical diseases (NTDs) have now advanced into clinical development, with the Na-GST-1/Alhydrogel Hookworm Vaccine already being tested in Phase 1 studies in healthy adults. The current manuscript focuses on the often overlooked critical aspects of NTD vaccine product development, more specifically, vaccine stability testing programs. A key measure of vaccine stability testing is "relative potency" or the immunogenicity of the vaccine during storag ...[more]

PMID: 28192438

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Project description:Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 μg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies.Trial registrationClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial).

Project description:BackgroundSubcutaneous (deep) mycoses are a chronic infectious disease of the skin and underlying structures endemic in tropical countries. The disease has serious medical and socioeconomic consequences for patients, communities and health services in endemic areas. The inclusion of mycetoma and other subcutaneous mycoses in the list of Neglected Tropical Diseases by WHO highlights the need to assess the burden of these diseases and establish control programs where necessary. In Ethiopia no strategies can be devised because of a lack of epidemiologic information. To address this evidence gap, we performed a national rapid assessment of the geographic distribution of subcutaneous mycoses.MethodologyWe conducted a rapid retrospective assessment using hospital records to identify all suspected and confirmed cases of subcutaneous mycoses in 13 referral hospitals across the country between 2015 and 2022. In each hospital the logbooks were reviewed for diagnoses of subcutaneous mycosess, as diagnosed per routine practice. Descriptive analysis was done.ResultFrom 13 hospitals we extracted 143 cases of subcutaneous mycoses, registered from July 2018 to September 2022. 118 (82.5%) patients were diagnosed as mycetoma, 21 (14.7%) as chromoblastomycosis and the remaining 4 (2.8%) as sporotrichosis. The mean age of patients was 35.8 years (SD = 14.5). 101 (70.6%) patients were male and 96 (67.1%) patients were farmers. 64 (44.8%) cases were from the Tigray regional state. 56 (65.9%) patients had information on diagnostic microscopic evaluation: for mycetoma histopathologic evaluation and fine needle aspiration cytology had a higher positivity rate while for chromoblastomycosis potassium hydroxide (KOH) staining had a better yield. The main clinical presentations were nodules, sinuses and infiltrative plaques on the skin. Radiologic findings of bone involvement was present in some.ConclusionsMycetoma and other subcutaneous mycoses are endemic in Ethiopia, with cases reported from almost all regions with the highest cases numbers reported from the northern part of the country. A routine program and systems should be developed to identify and document the burden of subcutaneous fungal infections in the country. Diagnosis and treatment guidelines should be developed.

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Advances in neglected tropical disease vaccines: Developing relative potency and functional assays for the Na-GST-1/Alhydrogel hookworm vaccine.

Publications

Advances in neglected tropical disease vaccines: Developing relative potency and functional assays for the Na-GST-1/Alhydrogel hookworm vaccine.

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