Randomized, observer-blind, controlled Phase 1 study of the safety and immunogenicity of the Na-GST-1/Alhydrogel hookworm vaccine with or without a CpG ODN adjuvant in hookworm-naïve adults.

Autor: Diemert, David J., Zumer, Maria, Bova, Mark, Gibbs-Tewary, Christina, Malkin, Elissa M., Campbell, Doreen, Hoeweler, Lara, Li, Guangzhao, Bottazzi, Maria Elena, Hotez, Peter J., Bethony, Jeffrey M.
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Zdroj: PLoS Neglected Tropical Diseases; 12/30/2024, Vol. 18 Issue 12, p1-17, 17p
Abstrakt: Background: Recombinant Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) formulated on Alhydrogel (Na-GST-1/Alhydrogel) is being developed to prevent anemia and other complications of N. americanus infection. Antibodies induced by vaccination with recombinant Na-GST-1 are hypothesized to interfere with the blood digestion pathway of adult hookworms in the host. Phase 1 trials have demonstrated the safety of Na-GST-1 formulated on Alhydrogel, but further optimization of the vaccine adjuvant formulation may improve humoral immune responses, thereby increasing the likelihood of vaccine efficacy. Methods: A randomized, observer-blind, dose escalation Phase 1 trial was conducted in 24 healthy, hookworm-naïve adults. In each cohort of 12 participants, 4 were randomized to receive 100 µg of Na-GST-1/Alhydrogel and 8 to receive 30 µg or 100 µg of Na-GST-1/Alhydrogel plus the Cytosine-phospho-Guanine (CpG) oligodeoxynucleotide Toll-like receptor-9 agonist, CpG 10104, in the first and second cohorts, respectively. Progression to the second cohort was dependent upon evaluation of 7-day safety data after all participants in the first cohort had received the first dose of vaccine. Three intramuscular injections of study product were administered on days 0, 56, and 112, after which participants were followed for 6 months. IgG and IgG subclass antibody responses to Na-GST-1were measured by qualified indirect ELISAs at pre- and post-vaccination time points. Results: Na-GST-1/Alhydrogel administered with or without CpG 10104 was well-tolerated. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. There were no vaccine-related serious adverse events or adverse events of special interest. Both dose concentrations of Na-GST-1/Alhydrogel plus CpG 10104 had significantly higher post-vaccination levels of antigen-specific IgG antibody compared to Na-GST-1/Alhydrogel without CpG, starting after the second injection. Peak anti-Na-GST-1 IgG levels were observed between 2 and 4 weeks following the third dose, regardless of Na-GST-1 formulation. IgG levels decreased but remained significantly above baseline in all groups by day 290, at which point all participants (20 of 20 evaluable participants) still had detectable IgG. Longitudinal antigen-specific IgG1 and IgG3 subclass responses mirrored those of total IgG, whereas IgG4 responses were lower in the groups that received the vaccine with the CpG adjuvant compared to the non-CpG group. Conclusions: Vaccination of hookworm-naïve adults with Na-GST-1/Alhydrogel plus CpG 10104 was safe and minimally reactogenic. Addition of CpG 10104 to Na-GST-1/Alhydrogel resulted in significant improvement in IgG responses against the vaccine antigen. These promising results have led to inclusion of the CpG 10104 formulation of Na-GST-1/Alhydrogel in a Phase 2 proof-of-concept controlled human infection trial. Author summary: Infection caused by Necator americanus is a major neglected tropical disease with significant associated morbidity. New tools, including vaccines, are needed due to the inadequacy of current control strategies. N. americanus Glutathione-S-Transferase-1 (Na-GST-1) is a leading hookworm vaccine candidate. Antibodies induced by this vaccine are postulated to interfere with the host blood digestion pathway of adult N. americanus worms, thereby impairing their development and survival. We conducted a Phase 1 trial of recombinant Na-GST-1 adjuvanted with Alhydrogel in 24 healthy, hookworm-naïve adults living in the metropolitan Washington DC region. Each participant received three intramuscular injection every 2 months of the vaccine administered with or without a Cytosine-phospho-Guanine (CpG) oligodeoxynucleotide (ODN) Toll-like receptor-9 agonist, CpG 10104. Na-GST-1/Alhydrogel was well tolerated in this study, and no vaccine-related severe or serious adverse events were observed. Significant levels of antigen-specific IgG antibodies were induced with the highest responses seen 2 to 4 weeks after the third vaccination. The addition of CpG 10104 to the vaccine resulted in significant improvement in the antigen-specific IgG responses. Based on these results, the vaccine has been advanced into a Phase 1 clinical trial in a hookworm-endemic region of Africa as well as a Phase 2 controlled human infection study to test proof of efficacy. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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