Antibodies Elicited by the Shigella sonnei GMMA Vaccine in Adults Trigger Complement-Mediated Serum Bactericidal Activity: Results From a Phase 1 Dose Escalation Trial Followed by a Booster Extension.

Autor:	Micoli F; GSK Vaccines Institute for Global Health, Siena, Italy., Rossi O; GSK Vaccines Institute for Global Health, Siena, Italy., Conti V; GSK Vaccines Institute for Global Health, Siena, Italy., Launay O; Faculté de Médecine Paris Descartes, Université de Paris, Paris, France.; Inserm CIC 1417, F-CRIN I-REIVAC, Paris, France., Sciré AS; GSK Vaccines Institute for Global Health, Siena, Italy., Aruta MG; GSK Vaccines Institute for Global Health, Siena, Italy., Nakakana UN; GSK Vaccines Institute for Global Health, Siena, Italy., Marchetti E; GSK Vaccines Institute for Global Health, Siena, Italy., Rappuoli R; GSK Vaccines Institute for Global Health, Siena, Italy., Saul A; GSK Vaccines Institute for Global Health, Siena, Italy., Martin LB; GSK Vaccines Institute for Global Health, Siena, Italy., Necchi F; GSK Vaccines Institute for Global Health, Siena, Italy., Podda A; GSK Vaccines Institute for Global Health, Siena, Italy.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 May 04; Vol. 12, pp. 671325. Date of Electronic Publication: 2021 May 04 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.671325
Abstrakt:	Shigella is the second most deadly diarrheal disease among children under five years of age, after rotavirus, with high morbidity and mortality in developing countries. Currently, no vaccine is widely available, and the increasing levels of multidrug resistance make Shigella a high priority for vaccine development. The single-component candidate vaccine against Shigella sonnei (1790GAHB), developed using the GMMA technology, contains the O antigen (OAg) portion of lipopolysaccharide (LPS) as active moiety. The vaccine was well tolerated and immunogenic in early-phase clinical trials. In a phase 1 placebo-controlled dose escalation trial in France (NCT02017899), three doses of five different vaccine formulations (0.06/1, 0.3/5, 1.5/25, 3/50, 6/100 µg of OAg/protein) were administered to healthy adults. In the phase 1 extension trial (NCT03089879), conducted 2-3 years following the parent study, primed individuals who had undetectable antibody levels before the primary series received a 1790GAHB booster dose (1.5/25 µg OAg/protein). Controls were unprimed participants immunized with one 1790GAHB dose. The current analysis assessed the functionality of sera collected from both studies using a high-throughput luminescence-based serum bactericidal activity (SBA) assay optimized for testing human sera. Antibodies with complement-mediated bactericidal activity were detected in vaccinees but not in placebo recipients. SBA titers increased with OAg dose, with a persistent response up to six months after the primary vaccination with at least 1.5/25 µg of OAg/protein. The booster dose induced a strong increase of SBA titers in most primed participants. Correlation between SBA titers and anti- S. sonnei LPS serum immunoglobulin G levels was observed. Results suggest that GMMA is a promising OAg delivery system for the generation of functional antibody responses and persistent immunological memory. Competing Interests: FM, OR, VC, ASS, MA, UN, EM, RR, LM, FN, and AP are employees of the GSK group of companies and RR, LM, and AP hold shares in the GSK group of companies. AS was an employee of the GSK group of companies at the time of the study and holds shares in the GSK group of companies. FM and AS report grant from the Bill and Melinda Gates Foundation during the conduct of the study. LM reports grant from EU FP7 STOPENTERICS during the conduct of the study and from the Bill and Melinda Gates Foundation and Wellcome Trust outside the submitted work. LM and AS are inventors of patents owned by the GSK group of companies and relevant to Shigella vaccine. OL’s institution received grant from the GSK group of companies for conducting the study. All authors have no non-financial relationships and activities. (Copyright © 2021 Micoli, Rossi, Conti, Launay, Sciré, Aruta, Nakakana, Marchetti, Rappuoli, Saul, Martin, Necchi and Podda.)
Databáze:	MEDLINE
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