A Study to Test if the Vaccine is Working Well in Chronic Obstructive Pulmonary Disease (COPD) Patients Aged 40 to 80 Years Old to Reduce Episodes of Worsening Symptoms and to Gather Further Information on Safety and Immune Response.

The purpose of this Phase IIB proof-of-concept (POC) study in moderate to very severe COPD
patients (i.e. GOLD grade 2, 3 and 4) aged 40 to 80 years with a history of moderate or
severe acute exacerbations of COPD (AECOPD) in the previous 12 months is to evaluate whether
the NTHi-Mcat vaccine can reduce the frequency of AECOPD in this population and to assess the
vaccine's safety, reactogenicity and immunogenicity.

Several formulations of a vaccine containing the NTHi antigens (low or high formulation)
either non-adjuvanted or combined with different adjuvants (aluminium [Al], adjuvant system)
were already evaluated in two previous Phase I clinical trials (NTHI-002 in healthy adults
aged 18 - 40 years and NTHI-003 in current and former healthy smokers of 50-70 years old).
The investigational vaccines were well-tolerated, with an acceptable safety and
reactogenicity profile. These studies allowed the dose selection of the NTHi antigens (low
formulation) and the adjuvant system currently evaluated for the first time in moderate and
severe COPD patients aged 45 - 81 years in the Phase II study NTHI-004.

The safety, reactogenicity and immunogenicity of different formulations of the NTHi-Mcat
investigational vaccine have been evaluated in the Phase I study in healthy adults aged 19 -
40 years and in current and former smokers aged 50 - 70 years (study NTHI MCAT-001). Based on
results obtained up to 30 days post-Dose 2 from this study, the adjuvanted formulation
containing NTHi proteins PD and PE-PilA and of UspA2 has been selected for evaluation in the
current NTHI MCAT-002 study. Placebo will be used as a control. The NTHi-Mcat investigational
vaccine and placebo will be given on top of standard of care to subjects in the respective
study groups.

In the current study, moderate, severe and very severe COPD patients (i.e. GOLD grade 2, 3
and 4) with a history of AECOPD will receive 2 doses of the NTHi-Mcat investigational vaccine
or placebo intramuscularly (IM) according to a 0, 2 month vaccination schedule, in addition
to standard care.

Scheduled study visits, during which the effect of immunisation against NTHi and Mcat will be
evaluated, will take place at pre-defined timepoints.

In addition to the scheduled study visits, ad hoc AECOPD-driven study visit(s) and/ or phone
contact(s) will take place for each AECOPD occurring from first vaccination up to study
conclusion:

- An AECOPD visit will be scheduled as soon as possible after the onset of the AECOPD
symptoms (maximum 96 hours after the onset of the symptoms).

- Follow-up visit(s) and/or phone call(s) will take place to determine the end of the
AECOPD.

Rationale for the protocol amendment:

- CD8+ T cell component was removed from the secondary endpoint, but kept in the
exploratory/tertiary endpoint. Previous clinical studies have shown that the
investigational NTHi and NTHi-Mcat vaccines do not induce CD8+ T cell responses. This
was observed in all studies performed with the NTHi vaccine and seen in the interim
analysis of NTHi Mcat-001 study.

- An exclusion criterion was updated to clarify that only subjects with clinically
significant respiratory diseases other than COPD (e.g. clinically significant lung
fibrosis, clinically significant pulmonary embolism) need to be excluded from study
participation.

- The polymerase chain reaction (PCR) assay for sputum samples was not designed to
discriminate amongst Haemophilus influenzae (Hi) serotypes. Results from AERIS
epidemiological study [Wilkinson, 2017] showed that more than 99% of these bacteria
would be Non-Typeable Haemophilus influenzae (NTHi). Therefore, the protocol was updated
to clarify that the presence of Hi bacteria in sputum during exacerbation will be used
to determine AECOPD associated to NTHi.

- The list of potential immune mediated diseases was updated (effective June 30th 2017).

- The 87% confidence interval (CI) was removed from all secondary analyses. This
confidence interval will only be maintained for the primary analysis because the 95% CIs
are underpowered for this study. All other sensitivity analyses on different cohorts
will be described using 95% CIs. As the primary objective will have both 87% and 95%,
the sensitivity analyses can be interpreted with 95% CIs.

- A Full-Analysis Set (FAS) that corresponds to an intent-to-treat analysis was added. The
FAS will include all randomized subjects who will receive at least 1 vaccine
administration and, as per intention-to-treat principle, a subject in the FAS will be
analysed "as randomized" (i.e. according to the vaccine a subject was planned to receive
irrespectively of his/her real exposure).

- Cut-off values for anti-PE, anti-PilA and anti-UspA2 antibody ELISAs were updated
following the re-set up of the assays.

- Additional minor updates were based on the scientific and operational experience gained
from current COPD studies.

Inclusion Criteria:

- Subjects who, in the opinion of the investigator, can and will comply with the
requirements of the protocol.

- Written informed consent obtained from the subject prior to performing any study
specific procedure.

- A male or female between, and including, 40 and 80 years of age at the time of the
first vaccination.

- Confirmed diagnosis of COPD with forced expiratory volume in 1 second (FEV1) over
forced vital capacity (FVC) ratio (FEV1/FVC) < 0.7, AND FEV1 < 80% predicted (GOLD 2,
3 and 4).

- Current or former smoker with a cigarette smoking history of ≥ 10 pack-years.

- Stable COPD patient* with documented history** of at least 1 moderate or severe AECOPD
within the 12 months before Screening.

- Patient for whom the last episode of AECOPD is resolved for at least 30 days at
the time of first vaccination.

- A documented history of a COPD exacerbation is a medical record of worsening
COPD symptoms that required systemic/oral corticosteroids and/or antibiotics
(for a moderate exacerbation) or hospitalization (for a severe
exacerbation). Prior use of antibiotics alone does not qualify as an
exacerbation history unless the use was associated with treatment of
worsening symptoms of COPD, such as increased dyspnea, sputum volume, or
sputum purulence. Subject verbal reports are not acceptable.

- Capable of complying with the daily electronic Diary Card completion throughout the
study period, according to investigator's judgement at Visit 1.

- Female subjects of non-childbearing potential may be enrolled in the study.
Non-childbearing potential is defined as pre-menarche, current bilateral tubal
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.

- Female subjects of childbearing potential may be enrolled in the study, if the
subject:

has practiced adequate contraception for 30 days prior to vaccination, and has a negative
pregnancy test on the day of vaccination, and has agreed to continue adequate contraception
during the entire treatment period and for 2 months after completion of the vaccination
series.

Exclusion Criteria:

- Use of any investigational or non-registered product other than the study vaccine
during the period starting 30 days before the first dose of study vaccine (Day -29 to
Day 1), or planned use during the study period.

- Any medical condition that in the judgment of the investigator would make
intramuscular injection unsafe.

- Administration of immunoglobulins or any blood products within the 3 months preceding
the first dose of study vaccine or planned administration during the study period.

- Any confirmed or suspected immunosuppressive or immunodeficient condition, based on
medical history and physical examination.

- Planned administration/ administration of a vaccine not foreseen by the study protocol
in the period starting 30 days before the first dose and ending 30 days after the last
dose of vaccine, with the exception of any influenza or pneumococcal vaccine which may
be administered ≥15 days preceding or following any study vaccine dose.

- Concurrently participating in another clinical study, at any time during the study
period, in which the subject has been or will be exposed to an investigational or a
non-investigational vaccine/product.

- Chronic administration of immunosuppressants or other immune-modifying drugs during
the period starting six months prior to the first vaccine dose (e.g. methotrexate).

- Administration of systemic corticosteroids within the 30 days before first
vaccination.

Subjects who received systemic corticosteroids within this period may be enrolled at a
later date if enrolment is still open.

Inhaled and topical steroids are allowed.

• Administration of systemic antibiotics within the 30 days before first vaccination.

Subjects who received systemic antibiotics within this period may be enrolled at a later
date if enrolment is still open.

- Chronic use of antibiotics for prevention of AECOPD (e.g. azithromycin).

- Acute disease and/or fever at the time of first vaccination. Fever is defined as
temperature ≥37.5°C. The preferred location for measuring temperature in this study
will be the oral cavity or the axilla.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection)
without fever may be enrolled at the discretion of the investigator.

- Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen
therapy >3L/min (Oxygen use ≤3L/min flow is not exclusionary).

- Planned lung transplantation.

- Lung resection: Subjects with planned lung volume reduction surgery during the study
or within the 12 months prior to first vaccination.

- Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD.

- Diagnosed with a respiratory disorder other than COPD at time of enrolment (such as
sarcoidosis, active tuberculosis, clinically significant bronchiectasis, clinically
significant lung fibrosis, clinically significant pulmonary embolism, clinically
significant pneumothorax, current diagnosis of asthma in the opinion of the
investigator), or chest X-ray/ CT scan revealing evidence of clinically significant
abnormalities not believed to be due to the presence of COPD. Subjects with allergic
rhinitis do not need to be excluded and may be enrolled at the discretion of the
investigator.

- History of immune-mediated disease other than COPD. If the subject has any condition
on the non-exhaustive list of potential immune-mediated diseases defined in the
protocol, they must be excluded unless the aetiology is clearly documented to be
non-immune mediated.

- Previous vaccination with any vaccine containing NTHi and/ or Mcat antigens.

- History of any reaction or hypersensitivity likely to be exacerbated by any component
of the vaccines and/ or the bronchodilator used for spirometry assessment during the
study.

- Contraindication for spirometry testing.

- Unstable or life threatening cardiac disease: subjects with any of the following at
Screening (Visit 1) would be excluded:

Myocardial infarction or unstable angina in the last 6 months. Unstable or life threatening
cardiac arrhythmia requiring intervention in the last 3 months NYHA Class IV Heart failure

- Malignancies within the previous 5 years or lymphoproliferative disorder.

- Any known disease or condition likely to cause death during the study period.

- Pregnant or lactating female.

- Current alcoholism and/or drug abuse.

- Other condition which the investigator judges may put the safety of the subject at
risk through study participation or which may interfere with the study findings.

- Planned move to a location that will complicate participation in the trial through
study end.