Lecture of Professor Esposito at the course "The Paradigm of Immunostimulants", Mexico City, September 2014

1. OM ‐85: are the clinical trial results applicable
in routine clinical practice?
Prof Susanna Esposito
Pediatric Highly Intensive Care Unit
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Milan, Italy

2. DEFINITION OF RECCURENT RESPIRATORY TRACT
INFECTIONS (RTIs)
Absence of any pathological underlying condition that may
justify that may justify the recurrence of infections1
«THE FIRST CAUSE OF RECURRENT INFECTIONS IN CHILDREN
IS...CHILDHOOD ITSELF»2
1. Gruppo di studio di immunologia della società Italiana di pediatria. Le infezioni ricorrenti nel bambino: definizione ed approccio
diagnostico. Riv Immunol Allergol Pediatrica 1988; 2: 127–34. 2. J. Gary Wheeler Evaluating the child with recurrent infections - includes
patient information sheet. Nov 15, 1996.

3. Savitha MR, Nandeeshwara SB, Pradeep Kumar MJ, ul-Haque F, Raju CK. Modifiable risk factors for acute lower respiratory tract
infections. Indian J Pediatr. 2007 May;74(5):477-82.

4. EPIDEMIOLOGY AND ETIOLOGY OF RRTIs
• RRTIs affect up to 25% of children aged <1 year
and 18% of children aged 1-4 years in developed
countries1
• Bacteria such as Streptococcus pneumoniae,
Mycoplasma pneumoniae, Haemophilus
influenzae and Streptococcus pyogenes may play
a role3
• Viruses (mainly respiratory syncytial virus,
rhinovirus and influenza viruses) are the main
etiological agents of RRTIs2
1. Bellanti et al. Drugs 1997 2. Esposito et al. Eur J Clin Microbiol Infect Dis 2012 3. Purushothama V. Et al. Chapter 93.
Infections of the Respiratory System. Medical Microbiology. 4th edition. Baron S, editor. Galveston (TX): University of Texas
Medical Branch at Galveston; 1996.

5. VIRUSES ARE THE MAIN CAUSES OF RTIS
• ≥80% of RTIs are caused by viruses1
• Viruses that commonly cause RTIs include2:
• Secondary bacterial infection (bacterial superinfection)
is common following viral RTIs3
1. Esposito et al. Eur J Clin Microbiol Infect Dis 2012; 2. Heikkinen T, Järvinen A. The common cold. Lancet. 2003 Jan
4;361(9351):51-9. 3. Hament et al. FEMS Immunol Med Microbiol 1999

6. RECURRENT RTIs IN EARLY CHILDHOOD
ARE ASSOCIATED WITH SUBSEQUENT
ASTHMA
• Virus-induced wheezing episodes during the first 3 years of life are
significant predictors of the development of asthma by 6 years of age1
• These observations are consistent with findings of other prospective
studies reporting associations between RTIs and subsequent asthma2,3
1. Jackson et al. Am J Respir Crit Care Med 2008; 2. Kusel et al. Eur Respir J 2012; 3. von Mutius et al. Eur Respir J 1999

7. What can be done?
• Treatment
 controversial role of antibiotics
 role of symptomatic measures
• PREVENTION
 Firstly, based on risk factors
 Secondly, based on past history

8. PREVENTIVE Measures
• PARENT EDUCATION
• ACTIVE IMMUNIZATION
• Non specific IMMUNOSTIMULATION

9. RRTIs

10. I M M U N I Z A T I O N
• ACTIVE efective IMMUNIZATION
 ultimate objective
• Viral vaccines: Influenza, measles
(RSV, rhinovirus)
• Bacterial vaccines: Pneumococcus (PCV),
Haemophilus influenzae type b, Bordetella
pertussis (Staph. aureus)

11. Non specific IMMUNOSTIMULATION
• Stimulation – Modulation – Improvement
of the immune system
• Bacterial IMMUNOSTIMULATION, for example
OM - 85 BV (Broncho-Vaxom), a bacterial lysate
extract of 8 respiratory bacteria
• Fundaments: correlation between the RTIs and
immaturity / defects in the immune system

12. Alterations in immune system observed in
children with RRTI
JESENAK M et al. Chapter 8 – Infectious Diseases open access
DOI: 10.5772/19422

13. MoA
Increase the ability of APC to stimulate T cells specific for Ag in order to induce the maturation of B cells to plasma cells
To activate T cells and NK cells as well as stimulation of phagocytosis by macrophages and neutrophils against pathogens with IgG
Tratto da Rossi GA. Opinioni a confronto 2012

14. OM‐85
Overview of the clinical data in children

15. Concept of the "ideal" time window with the largest
absolute efficacy of OM‐85 in the Pediatric RTIs
Partial
IImmmmuunnoollooggiiccaall
immaturity
iimmmmaattuurriittyy
"Refractory"
Period
Day Care
Centers, etc.
N RTIs
Age
Placebo
BronchoVaxom
SSCCHHOOOOLL--
AAGGEE

16. Epidemiology of Viral Infections and Evaluation of the Potential
Benefit of OM‐85 BV on the Virologic Status of Children
Attending Day‐Care Centers
• Statistically significant differences in the
prevalence of Virus carriers in favor of
children treated with OM-85 BV.
• VSR: 10 placebo vs 5 BV (p < 0.05)
• Influenza A: 4 placebo vs 1 BV (p < 0.05)
• These results corroborate the clinical
findings.
M. Aymarda et al., Respiration 1994;6 l(suppl 1):24‐3 I
Laboratoire de Virologie, Centre Hospitalo‐Universitaire de Lyon,

17. Broncho-Vaxom® (OM-85 BV)

18. OM-85 en las IRTR en los niños
Visión General Clínica
Schaad et al. – Chest 2002
Objective:
Investigate further the therapeutic
benefit of OM-85 in children with
recurrent URTIs

19. OM-85 - URTIs in children
Schaad et al. Chest 2002 – Study design
•Double blind, randomized, controlled trial with placebo
•220 patients (ITT) aged between 36 and 96 months with URTIs (3 + / 12
months)
•OM‐85 or placebo 1 capsule/day

20. OM-85 : URTIs in children
OM-85 significantly reduces the rate of URTIs in children
In children 3-8 years of age, with upper respiratory tract infections
‐16%
• The average cumulative rate
reduction from 2.5 to 2.1 = ‐ 0.4
URTIs / 6 months
• Less Risk to develop infecctions
with Broncho‐Vaxom vs placebo:
at 4 months 15% vs 36%,
at 6 months 26% vs 40%
• Good safety and tolerability
comparable to placebo

21. Pediatric studies of BV double blind
and placebo controlled
L.P. Nicod. Eur Respir Rev 2005; 14: 95, 43–44

22. OM- 85 ARTIs in children (Mexico)
Gutiérrez-Tarango y Berber, Chest 2001
Objective
Assess the safety and efficacy
of OM-85 in the prevention of
the ARTIs in children (Mexico)

23. OM-85 . ARTIs in children (Mexico)
Gutiérrez-Tarango y Berber, Chest 2001 – Study design
• Double blind, randomized, controlled trial with placebo
• 54 patients aged 1 to 12 years old with acute recurrent ARTIs during the past 12
months: average of 12 ARTIs in both groups OM‐85 or placebo 1 caps /day : two
courses of 3 months in 12 months

24. OM-85 - ARTIs in children
OM-85 reduces the burden of ARTIs in children
OM-85
Placebo
Percentage of patients with less than six ARTIs over 12 consecutive months
Gutiérrez‐Tarango et al. Chest 2011;119:1742‐1748

25. ARTIs in children (Mexico)
OM-85 reduce the burden of ARTIs in children
• reduces the number of ARTIs
(up to 5/12 months 8/ 12 months
≤ 37%)
• reduces the duration of disease
• reduce the use of antibiotics and
absenteeism
Gutiérrez‐Tarango et al. Chest 2011;119:1742‐1748

26. BV–OM85 decreases antibiotic
treatments with in 1 year
Gutiérrez‐Tarango et al. Chest 2011;119:1742‐1748

27. OM85- Prevention of Wheezing attacks
Razi et al. 2010 – J Allergy Clin Immunol
Study Objectives:
Investigate the effect of OM-85 BV in the total number of wheezing
attacks induced by the ITRA for the period of 12 months.
Secondary objectives: the duration of episodes of wheezing, the use of
beta2‐agonists and steroids, the rate of hospitalization and the
number/type of RTIs for the period of 12 months.

28. OM-85 Prevention of Wheezing attacks
Razi et al. 2010 – Study Design
• A randomized, double blind, controlled study with placebo
was performed between August 2007 and September 2008.
• The study included 75 children with recurrent wheezing that
had between 1 and 6 years of age: > 6 episodes per 12
months, half in both groups = 8 for 12 months.
• OM‐85 (35) or placebo (40) (1 capsule per day for 10 days
each month for 3 consecutive months). It followed
participants for 12 months.

29. OM-85 Prevention of Wheezing attacks
Razi et al. 2010 – OM-85 reduced wheezing attacks in children
Cumulative number of wheezing attacks
per patient
-37.9%
p<0.001
-36%
p=0.001
-34.3%
p=0.003
-30.4%
p=0.013
The difference in the attacks of wheezing between 2 groups was - 2.18
attacks of wheezing per patient in 12 months (5.2 to 3); There was a
reduction of - 37.9% in the group receiving OM-85 compared to the
group receiving placebo.

30. Razi CH et al. J Allergy Clin Immunol 2010 – Significant reduction in
total RTIs observed with Broncho-Vaxom® vs placebo

31. Razi CH et al. J Allergy Clin Immunol 2010 – Significant reduction in
number of cases of nasopharyngitis observed with Broncho-Vaxom® vs
placebo

32. OM-85 PROTECTS CHILDREN FROM
RECURRENT VIRUS-INDUCED WHEEZING
ATTACKS
Razi CH et al. J Allergy Clin Immunol 2010 – Conclusions
• Cumulative number and duration of virus-induced wheezing attacks over
12 months significantly (p<0.001) reduced with OM-85 vs placebo
• Incidence of nasopharyngitis over 12 months significantly (p<0.001)
reduced with OM-85 vs placebo
• Reduction in number and duration of hospitalisations with OM-85 vs
placebo was not statistically significant
• Adverse events in 3 OM-85 and 2 placebo patients considered potentially
treatment related; all were minor and transient

33. SELECTIVE ACTIVATION OF HUMAN DENDRITIC
CELLS BY OM-85 THROUGH NF-KB AND MAPK
DEPENDANT PATHWAY
Parola C. et al. PloS One 2013
• Aim of the study
• to investigate the activation properties of Broncho-Vaxom®
(OM-85 BV) on human DC subsets.

34. SELECTIVE ACTIVATION OF HUMAN DENDRITIC
CELLS BY OM-85 THROUGH NF-KB AND MAPK
DEPENDANT PATHWAY
Parola C. et al. PloS One 2013 – Significant increase in the level of
IFNα with Broncho-Vaxom® vs placebo

35. OM-85 COULD PROTECT AGAINST VIRUS-INDUCED
RTIS
• Razi CH et al. J Allergy Clin Immunol 2010
Observation:
Reduction in ARTI-induced wheezing attacks was paralleled by a
reduction in acute nasopharyngitis (mainly caused by rhinoviruses).
Hypothesis:
Increase in IFN-γ production after OM-85 administration
could mediate this benefit (reduction in virus-induced
nasopharyngitis).
• Parola C et al. PloS One 2013
Observation:
OM-85 induced PDC to release low concentrations of IFNα, which
represents the most important cytokine for the defense against viral
infections.
Hypothesis:
OM-85 may help to set up a basal antiviral state.

36. OM-85 RTIs in children
Schaad 2010 – OM-85 in children, a meta-analysis
Objective
The main objective of this meta-analysis
was to provide a more accurate
estimate of the overall effects of
treatment of OM-85 from a clinical point
of view. 8 randomized, placebo-controlled
trials were included.

37. OM-85 - RTIs in Children
OM-85 in the children meta-analysis– Schaad, 2010
The population treated with OM‐85 had significantly and steadily fewer cases of
recurrent RTIs : ‐26% ( 3 or +/6 months )
Average reduction for 6 months from 2.9 to 1.8 = ‐1.1 RTIs ( ‐35% )
The data suggest that the effect is greater in patients who are at increased risk of
recurrent RTIs

38. OM-85 acute tonsilitis
Bitar and Saade 2013 - Int J Pediatr Otorhinolaryngol
Objective
Evaluate the efficacy of OM-85
in children with recurrent acute
tonsillitis.
Bitar et al. Int J Pediatr Otorhinolaryngol 2013;77(5):670‐3.

39. OM-85 acute tonsilitis
Bitar and Saade 2013 – Study design
• Retrospective cohort studies of 177 children with the
diagnosis of recurrent acute tonsillitis: ≥3 episodes in 12
months
• Average age 4.5 years (range from 1 to 15 years of age)
• OM‐85 was administered 1 capsule per day for 10 days
each month for 3 consecutive months 131 children of
cohort
• The response was defined as a decrease in the frequency of episodes of acute
tonsillitis after 3 months of therapy to 6 month :
– Total: >50%
– Parcial: ≤50%
Bitar et al. Int J Pediatr Otorhinolaryngol 2013;77(5):670‐3.

40. BV‐OM85 reduces episodes of
recurrent acute tonsillitis
A considerable proportion (75.6%) of children treated with OM-85 (Broncho-
Vaxom) for recurrent acute tonsillitis experienced a decrease in the
frequency of the episodes in the short term (6 months)
Bitar et al. Int J Pediatr Otorhinolaryngol 2013;77(5):670‐3.

41. OM 85 - acute tonsilitis
Bitar et al. 2013 – OM-85 reduced acute tonsillitis in children
100%
n=99
67.67%
n=67
Without
tonsillectomy in
this group
32.32%
n=32
0 10 20 30 40 50 60 70 80 90 100
Total response
Partial response
Type of response to OM‐85 among responders
(%)
Very few finally needed tonsillectomy in the long-term follow-up
(11 of 32 patients showing partial response at 6 months).
Bitar et al. Int J Pediatr Otorhinolaryngol 2013;77(5):670‐3.

42. IMPACT OF A MIXED BACTERIAL LYSATE (OM-85 BV) ON THE
IMMUNOGENICITY, SAFETY AND TOLERABILITY OF INACTIVATED
INFLUENZA VACCINE IN CHILDREN WITH RECURRENT
RESPIRATORY TRACT INFECTION
• Aim of the study
• To investigate the possible impact of Broncho-Vaxom® on
inactivated influenza vaccine (IIV) immunogenicity by comparing
humoral and cell responses to IIV in children receiving Broncho-
Vaxom® or not, as well as the safety and tolerability of the vaccine
itself.

43. IMPACT OF A MIXED BACTERIAL LYSATE (OM-85 BV) ON THE
IMMUNOGENICITY, SAFETY AND TOLERABILITY OF INACTIVATED
INFLUENZA VACCINE IN CHILDREN WITH RECURRENT
RESPIRATORY TRACT INFECTION
Esposito S et al. Vaccine. 2014 May 7;32(22):2546-52.

44. IMPACT OF A MIXED BACTERIAL LYSATE (OM-85 BV) ON THE
IMMUNOGENICITY, SAFETY AND TOLERABILITY OF INACTIVATED
INFLUENZA VACCINE IN CHILDREN WITH RECURRENT
RESPIRATORY TRACT INFECTION
Esposito S et al. Vaccine. 2014 May 7;32(22):2546-52.

45. IMPACT OF A MIXED BACTERIAL LYSATE (OM-85 BV) ON THE
IMMUNOGENICITY, SAFETY AND TOLERABILITY OF INACTIVATED
INFLUENZA VACCINE IN CHILDREN WITH RECURRENT
RESPIRATORY TRACT INFECTION
Esposito S et al. Vaccine. 2014 May 7;32(22):2546-52.
The administration
of both Broncho-
Vaxom® and IVV
in a short periodo f
time appeared to
be safe and well
tolerated

46. OM-85 Pharmaco-economy
Zaniolo et al 2005 – Pharmaco-economy OM-85 Pediatric RTIs
Farmeconomia e Percorsi Terapeutici 2005;6(3):181-194 (Italia)
– model decision‐making according to the clinical progress of an are included four trials double
blind, randomised, placebo‐controlled
– RTIs in children
– direct and indirect costs : medications, visits, consultations, x‐rays, hospitalization... absenteeism...
– For ‐1.65 episodes de ITRS evitado /niño/6 meses
–The savings for 6 monthsfueron
– Family 107 Euros (‐ 41%)
– Health system 48 Euros (‐ 48%)
– Society 231 Euros (‐ 45%)
OM‐85 It is profitable since the rate of prevention of 7% of the children are
(Suitzerland ‐16% / México ‐37% / Metaanálisis ‐35%)

47. In press
2013

48. Safety OM‐85

49. OM-85 Safety profile
DATA FROM THE POST-MARKETING SAFETY AND PEDIATRIC
TRIALS
 A long (30 years) post‐marketing experience, many
pediatric trials
 3.6 million patients treated per year worldwide (adults
and children)
 Very low incidence of adverse events
identified/observed in post‐marketing experience:
approximately 3 cases per 100'000 patients treated
 Good tolerance
 AEs mainly non serious (gastrointestinal, skin)
 Fuente: datos en archivo OM

50. CONCLUSIONS / 1
• First and always: the prevention and education of
parents, active immunization, non specific
interventions
 The effectiveness of OM-85 BV in the
recurring RTIs:
 OM-85 BV is particularly effective in
susceptible or overexposed children
 Number/severity/duration of the RTIs 
 Consumption of antibiotics (other drugs)
 Absenteism 

51. CONCLUSIONS / 2
• The effectiveness of OM-85 BV in the attacks of
wheezing (rate, duration) and recurrent tonsillitis (rate,
need for tonsillectomy)
 SAFETY of OM-85 BV
 Excellent tolerance and compliance
 Good safety - comparable to placebo profile
OM-85 / Broncho-Vaxom is
effective in children