Protecting late-moderate preterm infants from respiratory tract infections and wheeze in their first yearsof life by using bacterial lysates.

Approximately 10% of all births occur prematurely; mostly between 30-36 weeks
of pregnancy (*moderate-late* prematurity). Respiratory tract infections (RTI)
and viral wheezing illnesses disproportionally affect preterms both early and
later in life. Underdeveloped lungs, an unfavorable microbiome and aberrant
immune maturation are considered causes of this increased RTI susceptibility in
preterms. Moreover, they experience viral infections earlier in their life
trajectory. Early- and severe RTI increase the likelihood of subsequent poor
respiratory health and antibiotic prescriptions; further deviating microbiota
development. There is a clear unmet clinical need for preventive therapies that
decrease the burden of RTI and wheezing illnesses in young children.
Early childhood immune priming via gut microbial exposure is beneficial for the
development of a healthy immune system. Oral bacterial lysates have shown
effectiveness and safety in the prevention of recurrent RTI in pre-school
children through Toll-like receptor engagement on epithelia and immune cells
within the gut and the activation of beneficial innate- and regulatory immune
responses. A recent trial showed that primary prevention and postponement of
lower RTI was achieved with bacterial lysate administration in 3-6 month-old
infants at risk for atopy. Studies using such bacterial lysates were
exclusively performed on term children, while studies on preterms, the group
with the highest respiratory disease burden, are lacking. In addition, the
intervention was started at a time the first RTI might already have occurred.
Therefore, we focus on moderate-late preterm infants and investigate whether we
can achieve a reduction in first-years-of-life respiratory illnesses by early
bacterial lysate administration, thereby probably optimizing chances for
life-long respiratory health.
We hypothesize that early education of the neonatal immune system by daily
stimulation with microbial elements leads to better protection against lower
RTI and subsequent wheezing episodes. It enhances self-initiated immunity
against pathogens by improved and accelerated immune maturation. This will lead
to a significant health gain in preterm-born infants with enhanced risk for
respiratory diseases.

This study has been transitioned to CTIS with ID 2024-518498-32-01 check the CTIS register for the current data.

The project*s overarching aim is to diminish respiratory disease burden in
moderate-late preterm born infants in their first year of life.

We have formulated the following specific aims:
1. Determine whether bacterial lysates reduce the number and/or severity of
lower RTI and wheezing episodes in the first year of life
2. To compare the efficacy of 1 versus 2-year bacterial lysate therapy for the
prevention of lower respiratory episodes in moderate-late preterm infants in
their first two years of life.
3. Analyze the impact of bacterial lysates on mucosal and systemic immune
maturation and microbiome diversity and maturation
4. Identify biomarkers predicting development of early respiratory episodes
(high risk group) and response to bacterial lysate administration in order to
facilitate personalized treatment
5.To calculate cost-effectiveness of all bacterial lysate treatment regimens.

This multi-center randomized controlled trial includes 500 preterm infants
(gestational age 30+0-35+6 weeks) without other significant morbidity. From age
6-8 weeks participants will receive blinded 3.5 mg OM-85 or placebo powder for
10 consecutive days per month till age 1 year, easily dissolved in breast- or
formula milk. Clinical data (eg. RTI, medication use, health care visits, lung
function) will be collected by e-Health and (live and digital) study visits. In
case of a lower respiratory episode, the patient is seen by the local doctor
and a nose swab will be taken by the parents or doctor. In a subset of patients
(optional, N=250), biological samples (nasal fluid, swab, blood) will be
collected at baseline, 6, and 12 months for immunological and microbiota
typing. The patients having received OM-85 in the first year of life will be
offered a follow-up study with new randomisation to OM-85 or placebo with
otherwise identical treatment regimen in the 2nd year of life (N=206 patients
needed). One optional study visit at 24 months for biosampling and/or lung
function.

OM-85 versus placebo

We expect a possible positive effect on respiratory health.
Safety is important in pediatric studies. Therefore, dosing and starting age
were carefully considered; literature review, collegial and pharmaceutical
consultation were performed. There are no known related safety issues when
orally administering lysates (OM-85 and other) at a pediatric age. Lysates
contain inactivated fragments of bacteria and cannot induce infections.
Moreover, the oral route of application is the natural route for microbial
exposure and the gut filled with live microorganisms is designed to cope with
these signals. In longer-term follow-up studies, the safety profile was good
(see introduction).

Bacterial lysates have been given to infants from 6-12 weeks onwards without
(short and longer term) side effects. The window of prevention might be small -
before the start of first RTI. Moreover, repeated exposure seems to be needed
to preserve the positive effect on RTI. Regular vaccinations are also
administered from 6 weeks onwards; live-attenuated BCG-vaccine (also conferring
aspecific immune protection) is even given immediately after birth. Therefore,
we have decided to start early after birth and continue treatment till age 1
year; and in a subgroup till age 2 years.

Summarized, no important safety issues are expected. Nevertheless, a DSMB and
individual physicians will regularly assess safety. Infants will be removed
from the protocol if needed for well-being.