Safety and immunogenicity of three doses of non-typeable Haemophilus influenzae-Moraxella catarrhalis (NTHi-Mcat) vaccine when administered according to two different schedules: a phase 2, randomised, observer-blind study

Abstract

Background: Non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) infections are frequently associated with exacerbations of chronic obstructive pulmonary disease (COPD). Results were reported with a two-dose (0-2 months) schedule of an investigational AS01E-adjuvanted NTHi-Mcat vaccine containing three surface proteins from NTHi and one from Mcat. We evaluated the safety and immunogenicity of three NTHi-Mcat vaccine doses administered in two different schedules to adults with a smoking history (≥ 10 pack-years), immunologically representing the COPD population.

Methods: In this 18-month, randomised (1:1), observer-blind study with 6-month open follow-up, 200 healthy adults aged 40-80 years received NTHi-Mcat vaccine at 0-2-6 months and placebo at 12 months (0-2-6 group), or vaccine at 0-2-12 months and placebo at 6 months (0-2-12 group). Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days, respectively, post-vaccination, and potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) throughout the study. Immune responses were assessed.

Results: No safety concerns were identified with the third vaccine dose or overall. Most solicited AEs were mild/moderate. Unsolicited AEs were reported in 16%, 16.1% and 14.4% of participants in the 0-2-6 group post-dose 1, 2 and 3, respectively, and 20%, 20.4% and 9.7%, respectively, in the 0-2-12 group. In 24 months, SAEs were reported in 12 participants in the 0-2-6 group and 9 in the 0-2-12 group (18 events in each group). There were three deaths (unknown cause, 0-2-6 group; myocardial infarction, lung cancer in 0-2-12 group). pIMDs were reported in three participants in the 0-2-6 group (non-serious inflammatory bowel disease, gout, psoriasis) and three in the 0-2-12 group (serious ulcerative colitis, two with non-serious gout). The SAEs, deaths and pIMDs were considered not causally related to vaccination. Antigen-specific antibody concentrations were higher at 12 months post-dose 1 with the 0-2-6 schedule than with the 0-2-12 schedule and at 12 months post-dose 3 were similar between schedules, remaining higher than baseline.

Conclusions: No safety concerns were identified when the investigational NTHi-Mcat vaccine was administered via a 0-2-6 months or 0-2-12 months schedule to older adults with a smoking history. Persistent immune responses were observed after the third vaccine dose. Trial registration https://ichgcp.net/clinical-trials-registry/NCT03443427" title="See in ClinicalTrials.gov">NCT03443427, registered February 23, 2018.

Keywords: COPD; Exacerbation; Immunogenicity; Moraxella catarrhalis; Non-typeable Haemophilus influenzae; Safety; Vaccination.

Conflict of interest statement

IG, MA, DC, GDM, MJ, AT, and AKA are employed by the GSK group of companies. IG holds shares in the GSK group of companies. DC declares two pending patents (unpublished) and AKA declares a published patent application ‘Methods of Boosting the Immune Response’. TS has received honoraria for lecturing from the GSK group of companies, Pfizer, Bavarian Nordic, Janssen-Cilag, AstraZeneca and Sanofi and personal fees during the conduct of this study from the GSK group of companies, Pfizer, Biogen, Merck Serono, Biotest, Sequirus, Bavarian Nordic, and Sanofi. MF is employed by the Colchester Research Group which received payment from the GSK group of companies for the conduct of this study. The wife of MF is the owner of the Colchester Research Group. IG, MA, DC, GDM, MJ, AT, AKA, TS and MF declare no other financial and non-financial relationships and activities.

© 2022. GlaxoSmithKline Biologicals S.A.

Figures

Fig. 1

Plain language summary

Fig. 2

Study design. CMI, cell-mediated immunity; D, study day; M, study month; N, number of participants; Mcat, Moraxella catarrhalis; NTHi, non-typeable Haemophilus influenzae

Fig. 3

Disposition of the study participants and reasons for withdrawal. N, number of participants; AE, adverse event; SAE, serious adverse event (considered not causally related to study vaccination). 0–2–6 group was given vaccine at 0–2–6 months and placebo at 12 months; 0–2–12 group was given vaccine at 0–2–12 months and placebo at 6 months

Fig. 4

Percentages of participants (with exact 95% confidence intervals) reporting solicited local (pain, redness and swelling) and general (fatigue, gastrointestinal symptoms, headache, myalgia, chills and fever) adverse events (any intensity and grade 3 intensity) during the 7-day period after each injection and overall per participant (total vaccinated cohort). Injections 1 and 2, vaccine doses in both groups; injection 3, vaccine dose in 0–2–6 group, placebo in 0–2–12 group; injection 4, placebo in 0–2–6 group, vaccine dose in 0–2–12 group. GI (gastrointestinal) symptoms defined as nausea, vomiting, diarrhoea and/or abdominal pain. Fever defined as temperature ≥ 37.5 °C. Grade 3 intensity defined as redness or swelling of diameter > 100 mm, temperature ≥ 39 °C and, for all other adverse events, prevention of normal activities. Number of participants: 100, 92, 89 and 84 post-injection 1, 2, 3 and 4, respectively, for 0–2–6 group; 100, 97, 97, 93, respectively, for 0–2–12 group

Fig. 5

Adjusted geometric mean concentrations (GMCs with 95% confidence intervals) of antibodies against non-typeable Haemophilus influenzae antigens (PD, PE, PilA) and Moraxella catarrhalis antigen (UspA2) (per-protocol immunogenicity cohort). EU, ELISA units; PD, protein D; PE, protein E; PilA, Pilin A; UspA2, ubiquitous surface protein A2. 0–2–6 group was given vaccine at 0–2–6 months and placebo at 12 months; 0–2–12 group was given vaccine at 0–2–12 months and placebo at 6 months. Number of participants with available results at each time point: between 77 and 82 in 0–2–6 group, between 79 and 87 in 0–2–12 group

Fig. 6

Geometric mean ratio (GMR) of log10 ratio of antibody concentrations at time points after the third vaccine dose versus baseline or immediately before the third dose was administered (pre-dose 3) (per-protocol immunogenicity cohort). 95% CI, 95% confidence interval; PD, protein D; PE, protein E; PilA, Pilin A; UspA2, ubiquitous surface protein A2. 0–2–6 group was given vaccine at 0–2–6 months and placebo at 12 months; 0–2–12 group was given vaccine at 0–2–12 months and placebo at 6 months. Number of participants with available results at each time point: between 77 and 82 in 0–2–6 group, between 79 and 87 in 0–2–12 group

Fig. 7

Frequency of non-typeable Haemophilus influenzae antigen (PD, PE, PilA) and Moraxella catarrhalis antigen (UspA2) specific CD4+ T cells expressing at least two markers among CD40 ligand (CD40L), interleukin (IL)-2, tumour necrosis factor (TNF)-α, interferon (IFN)-ɣ, IL-13 and IL-17 (cell-mediated immune response analysis subset). Median, first/third quartile (Q1/Q3) and maximum/minimum (Max/Min) percentages shown. PD, protein D; PE, protein E; PilA, Pilin A; UspA2, ubiquitous surface protein A2. 0–2–6 schedule, group given vaccine at 0–2–6 months and placebo at 12 months; 0–2–12 schedule, group given vaccine at 0–2–12 months and placebo at 6 months. Number of participants with available results at each time point: between 17 and 21 in 0–2–6 group, 17 or 19 in 0–2–12 group