Safety, Reactogenicity, Immunogenicity, and Dose Selection of 10-Valent Extraintestinal Pathogenic Escherichia coli Bioconjugate Vaccine (VAC52416) in Adults Aged 60-85 Years in a Randomized, Multicenter, Interventional, First-in-Human, Phase 1/2a Study

Abstract

Background: ExPEC10V is a bioconjugate vaccine containing O-antigen polysaccharides of 10 extraintestinal pathogenic Escherichia coli (ExPEC) serotypes. This phase 1/2a study (NCT03819049) assessed the safety, reactogenicity, and immunogenicity of ExPEC10V (VAC52416) to prevent invasive E coli disease in elderly adults.

Methods: The observer-blind, active-controlled design included a 28-day screening, vaccination, 181-day follow-up, and 1-year follow-up. Participants (60-85 years of age) were randomized to ExPEC10V low dose (antigen dose range, 4-8 µg), ExPEC10V medium dose (4-16 µg), or ExPEC10V high dose (8-16 µg); 4-valent ExPEC vaccine (ExPEC4V); or 13-valent pneumococcal conjugate vaccine (PCV13). The incidence of adverse events (AEs; solicited, day 15; unsolicited, day 30; serious AEs, day 181) and immunogenicity (electrochemiluminescent-based assay [ECL] and multiplex opsonophagocytic assay [MOPA]) were assessed. Optimal ExPEC10V dose was determined from safety data through day 30 and an immunogenicity dose selection algorithm based on day 15 ECL and MOPA results.

Results: A total of 416 participants were included (median age, 64.0 years; 54.8% female). The incidences of solicited local and systemic AEs were, respectively, 44.2% and 39.4% for low-dose, 52.9% and 46.1% for medium-dose, 57.7% and 45.2% for high-dose ExPEC10V, and 74.1% and 48.1% for PCV13. Five serious AEs, not vaccine related, were reported. The ECL revealed a robust antibody response to ExPEC10V through year 1. Opsonophagocytic killing activity was detected against all but serotype O8; this lack of response against serotype O8 was linked to low assay sensitivity. Based on the totality of data, high-dose ExPEC10V was considered optimal.

Conclusions: ExPEC10V was well tolerated and immunogenic in elderly adults against all but serotype O8.

Keywords: E coli; bacteremia; extraintestinal pathogenic E coli; invasive E coli disease; vaccine.

Figure 1.

Study disposition. ^aOne participant of the 13-valent pneumococcal conjugate vaccine group did not attend the day 30 visit but did complete the day 181 visit. ^bAmong the 10 participants, 8 withdrew because they did not provide consent to participate in long-term follow-up. ^cThe 2 participants who were reported to have discontinued due to other reasons did not consent to participate in long-term follow-up. ^dOne participant did not attend the day 181 visit, but the participant replied to a certified mail on day 218. ^eTwo participants of the high-dose ExPEC10V (10-valent extraintestinal pathogenic Escherichia coli vaccine) group withdrew after completing the year 1 visit; 75 participants in the high-dose ExPEC10V group continued after year 1. Abbreviations: ExPEC4V, 4-valent extraintestinal pathogenic Escherichia coli vaccine; ExPEC10V, 10-valent extraintestinal pathogenic Escherichia coli vaccine; PCV13, 13-valent pneumococcal conjugate vaccine.

Figure 2.

Solicited local (A) and systemic (B) adverse events (AEs) by worst severity grade. Data presented are percentage of participants with local and systemic solicited AEs from day 1 to day 15 in the full analysis set. Abbreviations: ExPEC4V, 4-valent extraintestinal pathogenic Escherichia coli vaccine; ExPEC10V, 10-valent extraintestinal pathogenic Escherichia coli vaccine; PCV13, 13-valent pneumococcal conjugate vaccine.

Figure 3.

Multiplex electrochemiluminescent-based assay–determined immunoassay immunoglobulin G geometric mean titers. Data presented are from the per-protocol immunogenicity analysis set. Abbreviations: ECL, electrochemiluminescent-based assay; EPA, genetically detoxified form of exotoxin A derived from Pseudomonas aeruginosa; ExPEC4V, 4-valent extraintestinal pathogenic Escherichia coli vaccine; ExPEC10V, 10-valent extraintestinal pathogenic Escherichia coli vaccine; PCV13, 13-valent pneumococcal conjugate vaccine.

Figure 4.

Multiplex opsonophagocytic assay (MOPA)–determined functional antibody geometric mean titers. Data presented are from the per-protocol immunogenicity analysis set. Clinical serum samples collected on days 1 and 15 were analyzed with a qualified MOPA, and those from day 30, day 181, and year 1 were analyzed with a validated assay; these data are not directly comparable. Abbreviations: ExPEC4V, 4-valent extraintestinal pathogenic Escherichia coli vaccine; ExPEC10V, 10-valent extraintestinal pathogenic Escherichia coli vaccine; MOPA, multiplex opsonophagocytic assay; PCV13, 13-valent pneumococcal conjugate vaccine.