A vaccine to prevent extra-intestinal E. coli infection?
The four-valent ExPEC4V vaccine which contains O-antigens from the Escherichia coli (E. coli) serotypes O1A, O2, O6A, and O25B was well tolerated and immunogenic against extra-intestinal pathogenic E. coli (ExPEC) infections, according to the phase II US-based ESTELLA trial.
“All doses of ExPEC4V elicited robust increases in IgG and functional antibodies across all four serotypes,” said the authors led by Dr Robert Frenck Jr from the Cincinnati Children’s Hospital Medical Center, in Cincinnati, Ohio, US.
A total of 848 healthy adults (median age 55 years, 51 percent female, 77 percent Caucasian) were randomized to receive a single intramuscular dose (one of five different dosages) of the ExPEC4V vaccine (n=757) or placebo (n=86). The vaccine dosages – based on antigen content ratio – were as follows: O1A:O2:O6A:O25B; 4:4:4:4 μg (group 1), 4:4:4:8 μg (group 2), 8:8:8:8 μg (group 3), 8:8:8:16 μg (group 4), and 16:16:16:16 μg (group 5).
All participants were followed up for 180 days after vaccination to assess safety outcomes, with group 2 and 4 participants and placebo recipients followed up for 4 years. IgG antibodies were measured on days 1 (pre-vaccination) and days 15 and 30, as well as on days 180 and 360 for group 2 and 4 participants and placebo recipients. [Lancet Infect Dis 2019;19:631-640]
Solicited local adverse event (AE) incidence was higher in vaccine than placebo recipients (29 percent vs 13 percent), with pain or tenderness the most common solicited local AE among vaccine recipients (27.1 percent [vs 12 percent in the placebo group]). Solicited systemic AEs occurred in 43 and 35 percent of vaccine and placebo recipients, respectively, with fatigue, headache, and myalgia the most common solicited systemic AEs among vaccine recipients (28, 24, and 20 percent, respectively [vs 15, 19, and 12 percent, respectively, in the placebo group]).
Solicited local and systemic AEs occurred most frequently in group 5 participants (38 and 51 percent, respectively). Most solicited AEs were grade 1–2 in severity, with two percent of the study population experiencing grade 3 solicited AEs.
At day 15, ≥80 percent of participants in all groups achieved a ≥2-fold increase from baseline in all serotype-specific IgG antibodies except for the O25B serotype at the lowest dose (group 1; 72 percent of 144 participants). Geometric mean titres at day 15 for the O1A, O2, and O6A serotypes were highest in group 5 participants, and in groups 2 and 4 for the O25B serotype.
Among group 2 and 4 participants, ≥65 and ≥71 percent, respectively, maintained the ≥2-fold increase in serotype-specific IgG antibodies at 360 days.
Based on opsonophagocytic killing (OPK) assays, functional antibodies for each serotype were increased in all ExPEC4V vaccine doses, with ≥70 percent of vaccine recipients having titres of ≥100 for each serotype at day 15, and ≥55 participants from group 2 and 4 maintaining these titres at day 360.
“The threshold antibody response needed for protection against extraintestinal pathogenic E. coli bacteraemia is not known,” said the researchers. Nonetheless, despite declining in the 1 year following vaccination, the antibody titres and functional responses remained above pre-vaccination levels.
“The increasing global incidence and infectious disease burden associated with ExPEC, coupled with multidrug resistance, makes the need for an effective vaccine against ExPEC infections urgent,” said Frenck and co-authors, acknowledging that in clinical practice, a vaccine comprising more serotypes would likely provide better coverage.
“The results described in this study seem to be promising and it is a further proof of concept that a vaccine in humans might be effective against E. coli infections,” commented Professor Florian Wagenlehner from Justus Liebig University Giessen, Giessen, and Associate Professor Kurt Naber from the Technical University of Munich, Munich, Germany. They called for studies to assess the efficacy of the vaccine in different clinical scenarios, particular different types of urinary tract infections. [Lancet Infect Dis 2019;19:565-567]