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European Biopharmaceutical Review
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Bacterial lysates, used as oral vaccines, were introduced in the 1970s
as immunostimulants, but they have recently gained renewed attention
and their use is steadily growing in medical practice.
In recent years, clinical trials have accumulated that show their
potential in a large array of clinical indications, in particular in
the prevention of infections of the upper and lower respiratory tract,
which represent a major public health concern around the world.
Moreover, scientific evidence of the immunomodulating power of this
particular class of active ingredients has grown and we are now
starting to gain a better understanding of their modes of action.
Bacterial Lysates: What are They?
Bacterial lysates are mixtures of antigens derived from different
inactivated pathogenic bacteria.The principle of these lysates is to
trigger immune surveillance and to up-regulate immune defences to
prevent and help fight infections. Bacterial lysates are sometimes
referred to as ‘oral vaccines’.
Polyvalent bacterial lysates are prepared from different species of
bacteria – typically the most commonly occurring pathogens of the upper
and lower respiratory tract. Each bacterial strain is grown
independently, harvested, inactivated and lysed using either mechanical
or chemical lysis in order to obtain the antigens. Based on the method
used for cellular lysis, two distinct types of bacterial lysates are
defined: polyvalent chemical bacterial lysates (PCBL) and polyvalent
mechanical bacterial lysates (PMBL). Table 1 shows the main
characteristics of both types.
While PCBL are obtained by the action of chemical alkaline substances
that may denature proteins, PMBL are obtained by increased pressure
which preserves the particulate antigens. After lyophilisation, the
different lysates are mixed in fixed proportions and formulated into
finished products (for example tablets, capsules or sachets).
The originality of PMBL also resides in their mode of administration.
PMBL are formulated in sublingual tablets. Indeed, the sublingual route
of administration allows direct contact of the antigens with the
mucosal immunocytes of the mouth and the pharynx, inducing a
locoregional activation of the immune system. The sublingual route also
offers better immune surveillance along the mucosal barrier, since
circulating memory cells preferentially return to the area of first
encounter with the antigen.
Applications of PMBL
In the past 20 years,
more and more randomised clinical trials have been conducted to
evaluate the efficacy of bacterial lysates as immunostimulants. A
recent review of literature was published in the World Allergy
Organisation Journal about such randomised trials (1). The authors found
positive trends in terms of overall reduction of infection rates and
duration, a beneficial effect on symptoms, reduction of antibiotic use
and a possibility to improve the patient’s quality of life.
The primary area of applications for bacterial lysates is the
prevention of bacterial or viral infections of the upper and lower
respiratory tract, both acute (including rhinosinusitis, common cold,
influenza, anginas, pharyngitis, laryngitis, bronchitis and otitis);
and chronic. According to a recent report by the World Lung Foundation,
acute respiratory infections (such as pneumonia, influenza and
respiratory syncytial virus), described as a forgotten pandemic, are
responsible for over four million deaths each year.They represent the
third largest cause of mortality in the world and the leading cause of
illness and death in children (2).
In an Italian study, sublingual PMBL treatment and oral PCBL were
tested in parallel in patients with recurrent upper respiratory tract
infections (URTI) for three months (both treatments were administered
for 10 consecutive days at the beginning of each month) (3). It
appeared that the number of URTIs per patient was significantly lower
in the PMBL group as compared to the PCBL and control groups, both
during the three months treatment and the follow up period. Furthermore,
the duration of the infectious episodes and the number of working days
lost were significantly lower in the PMBL group during both the
treatment and the follow-up period. The need for concomitant antibiotic
treatment was also reduced with PMBL: no patient needed antibiotic in
the PMBL group (n equals 38), while nine out of 38 patients in the CLBL
group received such treatment (P is less than 0.05). This study showed
the prophylactic efficacy of both treatments against URTI, however best
results were achieved with the use of PMBL in comparison with PCBL.
Similar results were obtained in children – an important target
population for preventive measures against respiratory infections. It
is admitted that immune defences in children are still immature and the
immunostimulant approach has shown promising results and is endorsed by
many clinicians. A comparative study was conducted in 120 children
(aged four to nine), which were prone to earnose- throat infections,
during the winter period. Sublingual administration of PMBL was
compared to orally administered PCBL (three months, treatment
administered for 10 consecutive days per month); a third control group
received no treatment. The prophylactic efficacy of the two treatments
was evaluated by looking at
the proportion of children who did not develop any infectious episodes
during the treatment and follow-up period. It was concluded that PMBL
were more effective than PCBL (P is less than 0.016) in preventing
infection occurrence in children, both during the vaccination period
and the five months follow-up phase. PMBL also reduced the duration of
infectious episodes and number of school days lost due to infections as
compared to the two other groups. PMBL also enabled the reduction of
the use of complementary treatments (such as antibiotics, antipyretics
and antiphlogistics) as compared to PCBL and control (4).
PMBL prophylactic efficacy was also shown in a randomised placebo
controlled study in 180 children (aged five to 10) with a history of
recurrent respiratory infections (otitis, laryngitis, sinusitis and
pharyngotonsillitis) (5). This study showed a significant reduction of
the average number of respiratory infections per patient with PMBL
treatment by 54 per cent as compared to placebo, and a significant
reduction of school absenteeism by 49.7 per cent. Consequently, the
need for antibiotherapy was also reduced (48 per cent reduction of the
number of days of antibiotic use).
In another randomised double-blind placebo controlled study, it was
shown that the immune status of the patients was significantly improved
with PMBL: serum immunoglobulins and salivary IgA were significantly
higher as compared to placebo (6).This was also correlated with a
reduction of the number of infections and duration.
Another important area of clinical investigation for bacterial lysates
are chronic pulmonary diseases such as chronic obstructive pulmonary
disease (COPD). COPD represents a major public health concern:
according to the latest World Health Organization (WHO) estimates, 210
million people suffer from COPD in the world, and three million people
died of COPD in 2005.WHO predicts that COPD will become the third
leading cause of mortality worldwide by 2030.The most recent trials
with PMBL show their efficacy in the prevention of acute exacerbations
in COPD (7,8). For example, in the most recent trial, the value of
adding PMBL to regular COPD therapy (salmeterol/fluticasone) in
patients was evaluated.This study was conducted over a nine-month
period on 63 patients in total and confirmed that PMBL administered in
addition to regular treatment reduced the rate of exacerbations per
patient per year by 20 per cent (0.54 versus 0.67 in control group).The
immunostimulant also reduced the number of exacerbations that needed
treatment with oral corticosteroids, as well as the total number of
hospitalisations and the need for antibiotics.The authors concluded
that since the mechanism of action of PMBL is distinctly different from
that of the inhaled standard treatments for COPD, its protective effect
may be additive to the other treatments (anti-inflammatory and/or
bronchodilator regimen) and could be combined for better protection
against COPD exacerbation.
Immunostimulating Effects
PMBL modes of action have been investigated by both in vivo and in
vitro studies, in order to help explain their efficacy shown in the
clinic: it appears that this particular type of bacterial lysates have
the ability to effectively stimulate both the specific and non-specific
immune response.
The role of the immune system is, first of all, to prevent pathogens
invasion (immune surveillance), and then, if this is unsuccessful, to
respond to invaders. Two types of immune response can be distinguished:
a systemic, circulating immune protection, and a local, mucosal
protection, concentrated along the body’s entry routes.This involves a
specific sub-type of immunoglobulins, the secretory IgA (SIgA) secreted
at mucosal surfaces (respiratory as well as gastrointestinal,
urogenital tracts), which represent the first mechanical barriers
against pathogens (9,10). As seen earlier, bacterial lysates aim at
reinforcing immune surveillance. While traditional vaccines do not seem
to elicit mucosal protection, local immunisation such as oral,
intranasal or sublingual, can stimulate an antigen-specific
immunoglobulin secretion at the application site, resulting in local
immune protection.
First of all, it has been shown that PMBL are able to induce dendritic
cells maturation and increase membrane expression of co-stimulating
molecules: CD83, CD80 and CD86 (11).Dendritic cells (DC) play an
important role as antigen presenting cells, and represent a link
between non-specific and specific immune response. DC capture bacterial
agents, transport them to loco-regional lymph nodes and present
specific antigens to promote the activation of both lymphocytes and
phagocytes.
PMBL have also shown the ability to induce antigen-specific antibodies
production by triggering B lymphocytes differentiation. A clinical
study has demonstrated that the administration of PMBL to 40 patients
induced the production of mucosal antigen-specific IgA at the
application site and in the secretions, resulting in a local protection
against bacterial infections (12). IgA allow pathogen opsonisation, a
process that will trigger its phagocytosis and killing by other immune
competent cells. Another study demonstrated that PMBL was able to
activate IL-2 receptor on different lymphocyte subsets (B, CD4+ and
CD8+ T cells), involved in both humoral and cellular immune response.
These results show the potential of PMBL to elicit both innate and
specific immune responses (13).These immunostimulating effects were
further demonstrated in patients with a medical history of recurrent
infections of the upper respiratory tract (14).
Conclusion
Bacterial lysates have shown potential benefits in preventing upper and
lower respiratory tract infections. Among them, the original PMBL,
thanks to their innovative production process (mechanical lysis) and
mode of administration (sublingual route), offers a higher immunogenic
profile demonstrated in several in vitro and in vivo studies and
corroborated by many clinical studies.
References
- Villa E, Garelli V, Braido F, Melioli G and Canonica GW, May we
strengthen the human natural defenses with bacterial lysates? World
Allergy Organization Journal 3(8): ppS17-S23, 2010
- World Lung Foundation report, www.worldlungfoundation.org, November 2010
- Macchi A and Vecchia LD, Open comparative, randomized controlled
clinical study of a new immunostimulating bacterial lysate in the
prophylaxis of upper respiratory tract infections,Arzneimittelforschung 55: pp276-281, 2005
- La Mantia I, Nicolosi F, Maiolino L and Serra A,
Immunoprophylaxis of recurring bacterial infections of respiratory
tracts in pediatric age: clinical experience through a new
immunestimulating vaccine (It), GIMMOC, Quaderni di Microbiologia e
Clinica XI: pp1-8, 2007
- Aksic OT, Cattaneo L and Rosaschino F, Evaluation of the
clinical efficacy of a new polyvalent bacterial lysate obtained by
mechanical lysis (PMBL) in a population of 180 school-aged children
with recurrent respiratory infections, European Journal of Aerobiology
Environmental Medicine and Air-borne Infections 1: p1, 2005
- Tricarico D, Varricchio A, D’Ambrosio S, Ascione E and Motta G,
Prevention of recurrent upper respiratory tract infections in a
community of cloistered nuns using a new immunostimulating bacterial
lysate: a randomized, double-blind clinical trial,Arzneimittelforschung 54: pp57-63, 2004
- Cazzola M, A new bacterial lysate protects by reducing
infectious exacerbations in moderate to very severe COPD: a
double-blind, randomized, placebo controlled trial, Trends in Med 6:
pp191-199, 2006
- Cazzola M, Noschese P and Di Perna F, Value of adding a
polyvalent mechanical bacterial lysate to therapy of COPD patients
under regular treatment with salmeterol/fluticasone, Therapeutics
Advances in Respiratory Diseases 3(2): pp59-63, 2009
- Singh K, Amdekar S, Singh DD, Tripathi P, Sharma GL and Yadav H,
Innate and specific gut-associated immunity and microbial interference,FEMS Immunol Med Microbiol 55: pp6-12, 2009
- Brandtzaeg P, Mucosal immunity: induction, dissemination, and effector functions, Scand J Immunol 70: pp505- 515, 2009
- Fuggetta MP and Lanzilli G, Attivazione delle risposte
immunitarie mediante vaccini batterici, Eur Respir News 15: pp69-77,
2007
- Braido F, Villa E, Schenone G, Canonica GW and Melioli G, A good
clinical outcome therapy with a polyvalent mechanical bacterial lysate
(PMBL) correlates with the capacity of inducing a specific locoregional
immunoresponse in patients with recurrent upper respiratory tract
infection, XXVII Congress of the European Academy of Allergology and
Clinical Immunology, 2008
- Lanzilli G, Falchetti R, Tricarico M, Ungheri D and Fuggetta MP,
In vitro effects of an immunostimulating bacterial lysate on human
lymphocyte function, Int J Immunopathol Pharmacol 18: pp245-254, 2005
- Lanzilli G, Falchetti R, Cottarelli A, Macchi A, Ungheri D and
Fuggetta MP, In vivo effect of an immunostimulating bacterial lysate on
human B lymphocytes, Int J Immunopathol Pharmacol 19: pp551-559, 2006
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Frédéric Durmont has been CEO of Lallemand Pharma, Switzerland, since 2007. In addition to his responsibilities with the company, Frédéric is in charge of Institut Rosell-Lallemand R&D, specialising in the clinical development of probiotic formulations. Prior to joining the Lallemand Group in 2005, he was Head of the Department of Internal Medicine ‘Polyclinic Champeau’ in Beziers, France, for nearly 20 years. Combining a solid clinical experience to market expertise, he is a dedicated spokesperson for PMBL around the world. Email: fdurmont@lallemand.com
Maxence de Villemeur is Marketing and Product Manager for Lallemand Pharma since October 2010, in charge of global business and marketing development of polyvalent mechanical bacterial lysates (PMBL). Prior to this, she was in charge of market intelligence (OTC sector) for Institut Rosell-Lallemand. Maxence de Villemeur has over 10 years of marketing and business experience in international healthcare and pharmaceutical markets. She holds a Master’s in International Management and graduated in Product Development engineering from Cergy-Pontoise Industrial Biology Engineering School, France. Email: mdevillemeur@lallemand.com
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