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European Biopharmaceutical Review

Implementing Immunostimulants

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
  1. 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
  2. World Lung Foundation report, www.worldlungfoundation.org, November 2010
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. Brandtzaeg P, Mucosal immunity: induction, dissemination, and effector functions, Scand J Immunol 70: pp505- 515, 2009
  11. Fuggetta MP and Lanzilli G, Attivazione delle risposte immunitarie mediante vaccini batterici, Eur Respir News 15: pp69-77, 2007
  12. 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
  13. 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
  14. 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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Maxence de Villemeur
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