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Prevention is better than cure... a saying that goes in many situations, and finds all its prime sense when it comes to infectious diseases! In particular, we will focus here on extremely common and easily transmittable infections: air-borne respiratory infections. From influenza flu to common cold or bronchitis, respiratory tract infections (RTIs) affect millions worldwide. In September 2013, the European Respiratory Society (ERS) announced that lung conditions altogether were responsible for one in ten of all deaths in Europe and cost European countries at least 380 billion EUR per year (1). The report linked the burden of lung diseases to two major factors: smoking and respiratory infections; both potentially preventable, thus placing prevention of respiratory infections as a key objective in the fight against lung diseases. After a brief overview of infections preventive methods, this paper focuses on immuni-sation. We will describe in particular the modes action and specificities of PMBL™ and injectable vaccines and their efficacy in RTI prevention. As we will see in these pages, both injectable vaccines and sub-lingual PMBL™ shouldn’t exclude each other, as their divergent yet complementary mechanisms of actions indicate that they could work in synergy. Finally, immunology expert Professor Melioli, will provide his expert’s view on the combined usage of both approaches, based on newest clinical results.

Prevention is better than cureBoth at an individual level and on a public health point of view, there are several major reasons to promote prevention of respiratory infections:

> First of all, the burden of respiratory infec-tions is very high, both in terms of mortality and morbidity. Both these parameters are taken into account in the loss of the disability-adjusted life-years (DALYs) calculation (DALY= ‘Years of Life Lost’ due to early death + ‘Years Lived with Disability’). According to the World Health Organization (WHO), lower respiratory infections alone were the first cause of DALYs lost worldwide in 2008, accounting for 79 million of DALYs lost, to which we can add 33 million DALYs due to COPD (1).

> On an economic point of view, significant treatment and hospitalisation costs are attri-butable to respiratory infections. ERS esti-mated that in Europe, about 7% of all hospital admissions are due to lung diseases, among which half are attributable to acute infections (including pneumonia) (Figure 1). Moreover,

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F r o m v a c c i n e s t o s u b - l i n g u a l i m m u n o s t i m u l a n t s , R T I

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No data

< 600

600–899

900–1199

Age-standardised rate per 100,000

> 1200

Figure 1: Age-standardised hospital admission rates for all respiratory conditions (asthma, COPD, bronchiectasis,

acute lower respiratory infections, pneumonia, lung cancer, tuberculosis and pulmonary vascular disease. Taken from

ERS Lung white book 2013.

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episodes of infection are also often a cause of exacerbations of asthma and COPD, which account for 249 000 and 1.1 million hospital admissions per year, respectively (1).

> Respiratory infections also represent significant socio-economic burden and indirect costs such as the loss of working days or school absenteeism for children for example. Patients’ quality of life is affected, with direct impact on their family and social life.

> Last but not least, RTIs are the main cause of antibiotic prescriptions: the emergence of antibiotic resistant strains (Fig 2-3) raises concern among health professionals, and more and more public institutions try to raise awareness for a reduction of antibiotic usage. During the last PMBL™ symposium in Toulouse in June 2012, Professor Clive Page, Director of the Sackler Institute of Pulmonary Pharmacology in London, warns us that, “with the emergence and spread of antibioresistance, worldwide healthcare is facing a major crisis”. According to him,” antibiotic are not used properly and it is about time to rethink the management of infectious diseases and reduce the use of antibiotics.“

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No data reported or less than 10 isolatesNot included

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Figure 2: Percentage of invasive Streptococcus pneumoniae isolates resistant to penicillins and macrolides, by country. Source : ECDC, 2012 (2)

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No data reported or less than 10 isolatesNot included

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Figure 3: Percentage of invasive Klebsiella pneumoniae isolates with multi drug resistance (resistance to third generation cephalosporins, fluoroquinolones and aminoglycosides), by

country. Source : ECDC, 2012 (2).

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How to prevent RTI?First of all, basic health and hygiene rules are the first step in RTI prevention, especially at times of increased epide-mic risks, to avoid spreading the germs. Table 1 shows the major risk factors for RTI: if we cannot do anything about our age or genetics, the external risk factors can be acted upon. A healthy lifestyle based on regular exercise, balance diet, avoiding polluted environments, tobacco smoke, drugs and alcohol consumption etc. is recommended to maintain a good level of natural defences and remain healthy. In particular, nutrition is seen by many experts as a key element to reinforce natural defences. The following guidelines are drawn from recommendations by WHO, the European Food Safety Authority (EFSA), ERS, the American Thoracic Society (ATS) and the Société de Pneumologie de Langue Française (SPLF) :

> Consuming foods rich in antioxidants can counter the damage done to the body by oxida-tive stress, by scavenging or inhibiting free radicals. These include food rich in Vitamin C, vitamin E, lycopene, selenium….

> Food rich in magnesium is important: this mineral is essential for good health, and may also help the airway smooth muscle to relax and help control the body’s response to infection.

> A balanced diet with a high intake of fruits, vegetables and fish reduces the risk of deve-loping lung diseases, especially asthma and COPD.

If these methods can be sufficient for most adults with no particular susceptibility to respi-ratory diseases, it can be insufficient for various at-risk populations: healthy subjects prone to recurrent infections, seniors, children in a community environment (school, nursery), subjects working in high risk environment (care taker, health professionals, teachers, com-munity workers...), people with chronic conditions such as COPD or asthma etc.For most of these patient groups, immunisation is recommended as a safe and effective preventive method. The ERS reckons that «population protection by vaccination against infections has been one of the major achievements of public health and is of considerable importance in controlling respiratory diseases.»

How to get immunised?Since Pasteur and his first anti-rabies vaccine, vaccination has come a long way! Today, various types of injectable vaccines are available against some of the most severe respiratory pathogens (see boxed text page 6). To put it simply, immunisation principle is to “educate” the specific arm of the immune response to react against a target antigen, in order to help the body defends itself when the antigen is encountered later on. Today, based on the immunisation approach, the development of PMBL™* sublingual tablets, an original polyvalent bacterial lysate, offers a complemen-tary prophylactic method for the prevention of RTI. Table 2 summarises the main differentiating characteristics of traditional injectable vaccines and these sublingual immunostimulants. The aim of this compilation is not to rate the two approaches, but to show their differences and hence their potential synergy or complementarities.

External Internal

Tobacco smoking Age: Children and elderly

Alcoholism Immunosuppression

Indoor and outdoor air pollution Genetic

Malnutrition Comorbidities

Table 1: Risk factors of respiratory infections(Adapted from ariatlas.org and F.Braido et al., Int J COPD, 2007)

« Population protection by vaccination against

infections has been one of the major achievements of public health and is of considerable importance in controlling respiratory

diseases. »ERS lung white book, 2013

*Ismigen, Immubron, Respibron, Provax, PIR-05

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Because both approaches have different administration routes and involve different modes of action, they have potential complementary activities:

Specific/ non specific immunityMonovalent or polyvalent injectable vaccines stimulate the specific (memory) immune response: their potential efficacy is limited to the target pathogen(s). Several studies have shown that polyvalent bacterial lysates such as PMBL™ tablets, which contain the antigens of a broad range of the most common respiratory pathogens (13 strains; see boxed text, page 6), is able to induce both a specific polyclonal and innate immune response in patients, protecting them against a wide range of pathogens, even viruses or bacteria not comprised in the formula. Studies have shown that PMBL™ have a dual action on both the innate (thanks to stimulation and maturation of dendritic cells, Natural Killer cells and Granulocytes…) and adaptive immunity (thanks to specific stimulation of T and B lymphocytes and secretion of targeted antibodies) (3,4,5,6). In particular, dendritic cells play a central role as an interface between innate and specific immunity (Figure 4). These specialized antigen-presenting cells have the ability to migrate to secondary lymphoid organs and present the antigens to T lymphocytes, activating Natural Killers. According to Professor Cazzola, “the main objective of an effective prophylactic vac-cination strategy aims to potentiate the function of dendritic cells”. A recent study has shown that dendritic cells maturation is stimulated by PMBL™, in a dose-dependent manner. The same study has shown that this maturation is better induced by polyvalent lysates than by single strain bacteria lysates. PMBL™ is also able to increase the number of Plasmacytoid dendritic cells, the type of dendritic cell able to recognize and target intracellular viruses (7).

Traditional injectable Sublingual PMBL™ tablets

Injection Needle free- less invasive

Highly specific target Broad target (13 strains, 8 species)

Stimulates specific (antibody mediated) immune response

Stimulates non specific and specific immune response, in particular thanks to the central role of dendritic cells

Long-lasting Repeated administration (yearly) necessary

Essentially systemic immunity. Systemic + mucosal immunity (production of secretory antibodies sIgA)

Table 2: Major characteristics of two preventive approaches: injectable vaccines and sub-lin-gual PMBL™ tablets.

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DC PRECURSORS

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T

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B

Figure 4: Role of dendritic cells in the cross-talk between innate and adaptive immunity.Ab: antibodies DC: Dendritic cells MF: MacrophagesNK: Natural Killer cells CTL: Cytotoxic T lympocytes

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Systemic/mucosal immunityIn respiratory infections, the oral, nasal and lung mucosa represent the pathogens entry route and mucosal immunosurveillance is an important first line of defence. This is the role of the mucosa-associated lymphoid tissue (MALT), which is essentially independent from the systemic immune system (8). Injectable vaccines exert a specific systemic immunisation, but fail to interact with the MALT. Only glycoconjugate vaccines elicit sufficient mucosal protec-tion, mainly through the translocation to the mucosal surface of vaccine-induced serum IgG. Foxwell et al. argue that the development of non-injectable vaccines that are able to induce appropriate mucosal immunisation is today necessary (9). Thanks to its administration route (sub-lingual), PMBL™ tablets favour the contact of the antigens with the oral mucosa (part of respiratory mucosa), and allows an effective sampling of these antigens by the dendritic cells which are numerous in this area, allowing an effective mucosal immune response. It has been shown that PMBL™ is able to stimulate mucosal defences (10) and increase specific salivary IgAs (2). In parallel, PMBL™ is also able to stimu-late the systemic immune response, increasing the levels of immune-competent cells and immunoglobulins (IgA, IgG, IgM) circulating in the blood. This systemic action also allows to relay action all along the mucosa of the upper and lower respiratory tract (11).Figure 5 gives a schematic overview of PMBL™ interactions with the immune system.All these contribute to show that both approaches are different but complementary and seve-ral practitioners even advocate the usage of both for a synergistic effect (see expert view p. 9).

Figure 5: Summarized mode of action of PMBLTM tablets.

T

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1. Sampling of antigens contained in PMBLTM tablets at the level of oral mucosa by dendritic cells.2. Maturation, activation and migration of the dendritic cells to the cervical lymph node and secondary lymphoid organs.3. Presentation of the antigens by the dendritic cells to the T lymphocytes, and secretion of pro-inflammatory cytokines by dendritic cells. Activated dendritic cells allow proliferation of polyclonal NK cells.4. Differentiation and increase of T helper cells allowing switch of B lymphocytes to plasma cells.5. Increase of early Memory B cells.6. Production of specific polyclonal immunoglobulins (IgA, IgG and IgM) by plasma cells.7. Circulation into the blood of the immune-competent cells (T helper, plasma cells, NK cells) and immunoglobulins.8. Secretion of polyclonal secretory IgA at the level of upper and lower respiratory mucosa.9. Phagocytosis of bacteria by granulocytes thanks to opsonizing immunoglobulins and destruction of viral infected cells by NK cells.

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To know more about RTI immunisationPneumococcal vaccinesDespite good access to antibiotics, Streptococcus pneumoniae is still a significant cause of illness and death worldwide. S. pneumoniae causes several acute, invasive and non-invasive clinical infections. It is one of the leading causative agents in COPD exacerbations, and the most frequently detected pathogen responsible for community- acquired pneumonia. There are two types of Pneumococcal vaccines: polysaccharide and conjugate vaccines.S. pneumoniae is an encapsulated bacteria, and its external capsular polysaccharides are its primary factor of virulence. Strain serotyping is based on the nature of these polysaccharides: 91 serotypes have been defined, 23 of which represent the most frequent pathogens. The purified polysac-charides from these serotypes have been included in the 23-valent Pneumococcal polysaccharide vaccine, which is today the most commonly used of this category. This vaccine is recommended for older children and adults. It is estimated to protect against 85% to 90% of the serotypes that cause invasive infections in these age groups.The conjugate vaccine (7 or-13 valents) consists of capsular polysaccharides covalently bound to the diphtheria toxoid CRM197, which is highly immunogenic but non-toxic (i). This combination leads to a significantly more robust immune response resulting in mucosal immunity and eventual establishment of lifelong immunity after several exposures, contrarily to polysaccharides vaccines. Conjugate vaccines efficacy to protect infants against invasive pneumococcal disease is above 90%. However, their efficacy against respiratory pneumonia is lower and varies according to the severity of the disease.

Haemophilus influenzae type b (Hib) vaccinesBefore the introduction of vaccines, nearly all Hib infections occurred among children younger than 5 years of age; Hib is very uncommon in adults. In addition to pneumonia, Hib causes epiglottitis, and, above all, meningitis.Several conjugated vaccines are available for infants, using different carrier proteins. These vaccines are highly immunogenic in infants: over 95% of infants will develop protective antibody levels after a primary series of two or three doses. Clinical efficacy has been estimated at 95% to 100% (ii).

BCG (Bacille Calmette Guérin)The only marketed vaccine directed against TB, BCG, is a live vaccine, using an attenuated form of the pathogen.BCG has been used for over 80 years and it has certainly been given to more people than any other vaccine worldwide. It is effective to prevent miliary and meningeal TB in young children to an appreciable degree. However, BCG fails to protect effectively against pulmonary TB in adults. Although a meta-analysis of all vaccination data available has yielded a theoretical efficacy rate of 50%, it has been estimated that only 5% of all vaccine-preventable deaths caused by TB could have been prevented by BCG. Thus, BCG is not a satisfactory vaccine to protect adults from pulmonary TB and many countries have started to put it on the non-compulsory list (iii, iv).

Seasonal Influenza A vaccineAfter the Second World War, vaccination became the main strategy for preventing and controlling seasonal and pandemic influenza worldwide. Type A virus causes the most severe disease and is associated with epidemics and pandemics. Spontaneous mutations in the viral surface proteins are responsible for so-called ‘antigenic drift’. If these mutations results in changes in the viral amino acid structure, pre-existing antibodies might be unable to bind to viral particles to a sufficient extent to prevent disease: every year a new seasonal influenza vaccine has to be developed to target the new form of the virus.Seasonal influenza vaccine has proved effective in preventing laboratory-confirmed influenza among healthy adults (16–65 years of age) and child-ren (6 years of age or older). But the evidence of vaccine effectiveness is much more limited in the prevention of complications such as pneumonia, hospitalisation and influenza-specific and overall mortality. The ERS/ESCMID guidelines recommend that influenza vaccine should be given yearly to immunocompetent people at increased risk of complications: over 65 years of age; resident in an institution (such as a nursing home); chronic cardiac disease; chronic lung disease; diabetes mellitus; chronic renal disease; haemoglobinopathies; and women who will be in the second or third trimester of pregnancy during the influenza season. In addition, healthcare personnel, especially in settings where elderly people or other high-risk groups are treated should also be vaccinated (1).

Pertussis vaccineBordetella pertussis infection (whooping cough), is one of the leading causes of vaccine- preventable deaths. Worldwide, an estimated 50 million cases of pertussis and 300 000 deaths occur every year, mainly in unvaccinated children younger than 12 months of age. Inactivated pertussis vaccines are increasingly replaced by acellular vaccines, comprising inactivated purified B. pertussis antigens, with less local reactions. Acellular pertussis vaccine efficacy to prevent typical whooping cough is estimated around 85%. Despite widespread vaccination, pertus-sis has persisted among vaccinated populations. The recent resurgence in pertussis infections is attributed to a combination of waning immunity and mutations in the pathogen that existing vaccines are unable to effectively control (v).

PMBL™ tabletsPMBL™* is a bacterial lysates obtained mechanically that contains a blend of the most common pathogens involved in infections of the upper and lower respiratory tract: Staphylococcus aureus, Streptococcus pyogenes, Streprococcus oralis (viridans), Streprococcus pneumoniae (6 different strains), Klebsiella pneumoniae, Klebsiella ozaenae, Haemophilus influenzae serotype B, Neisseria (Moraxella) catharralis.Bacterial lysates such as PMBL™ tablets, also refered to as oral vaccines, represent an interesting prophylactic strategy against bacterial and/or viral infections (ie, cold and influenza), acute and chronic bronchitis, anginas, pharyngitis, tonsillitis, laryngitis, rhinitis, sinusitis, and otitis. They have also demonstrated some benefits in preventing acute exacerbations in COPD patients

Antigen Children Adolescents Adults

BCG 1 dose (Recommended for children living in countries with a high-disease burden and high-risk children)

Pertussis (DTP= diphteria, tetanus, pertussis)

3 doses Booster 1-6 years of age Booster (Td) Booster (Td) in early adulthood or pregnancy

Haemophilus influenza type B 3 doses with DTP

Pneumococcal (Conjugate) Option 1 3 doses with DTP

Option 2 2 doses before months of age + booster dose at 9-15 months of age

Seasonal influenza (inactivated) First vaccine use: 2 doses Revaccinate annually: 1 dose only

1 dose from 9 yrs of age. Revaccinate annually

Table 3: WHO routine immunisation recommendations concerning respiratory diseases as of August 2013 (source : WHO recommendations for routine immunisation, 2013

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PMBL™ efficacy in RTI preventionThe sublingual immunostimulant PMBL™ has been launched on the market about 15 years ago: since then numerous clinical studies and post-market data have been analysed, evalua-ting its efficacy in the prophylaxis of lower and upper respiratory tract diseases. In summary, PMBL™ demonstrated some clinical benefits to:

> Prevent upper respiratory tract infections (otitis, rhino-sinusitis, laryngitis, tonsillitis, epiglotitis…)

> Prevent lower respiratory tract infections (bronchitis) > Have an interest in tuberculosis patients > Prevent the exacerbations in COPD patients > Prevent recurrent respiratory tract infections in children

Most of these clinical studies were recently compiled in a meta-analysis (12). The meta-analysis included 15 randomized double-blind control studies from 2557 patients, concerning both children and adult populations (Figure 6). The results of the meta-analysis have shown that, in adult or children populations, PMBL™ tablets were able to decrease the number of respiratory infections as compared to placebo. In conclusion the authors have suggested that PMBL™ tablets are “effective in both children and adults in preventing respiratory tract infections.”

Most importantly, in several studies, the use of antibiotics was significantly reduced thanks to the use of PMBL™, which, according to Prof. Page who participated in the meta-analysis, constitutes a very significant outcome in the fight against the spread of antiobioresistance.In addition, a marketing pharmacoeconomics study was recently compiled with PMBL™ (13), indicating its cost-effectiveness in the prevention of lower and upper RTI when taking into account both direct and some indirect (but largely underestimated) costs related to RTI for several population groups:

Figure 6: Results of meta-analysis comparing PMBL™ to placebo in both adult and paediatric populations.

Study Sample size

Di�erence in means and 95% CITreated Placebo Di�erence in means

Rossi, 2004 23 23 -0.200

Tricarico, 2004 24 23 -0.627

Macchi, 2005 38 38 -2.560

Vecchio 39 20 -0.170

Macchi 23 23 -1.410

Palmieri, 1987 30 30 -2.940

Boris, 2004 298 300 -1.130

La Mantia, 2007 40 40 -2.400

Rosaschino, 2004 62 23 -2.000

Aksic, 2005 90 90 -2.200

Boris 180 180 -0.420

Cogo, 2003 57 57 -0.900

Boris, 2003 150 150 -0.980

Cazzola, 2009 33 30 -0.130

Cazzola, 2006 215 248 -0.600

-0.513

-2.75 -1.38 0.00 1.38 2.75

Heterogeneity: Q-value:42.133; df=14(P=0.000); I square=67%; Tau2 = 0.060; Test of overall e�ect: Z=-4.797(P=0.000) (from-.722 to -.303)

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> Adults who are at risk of developing URTI (cost saving between 50-500 €/treated patient/year, depending on the country), due to a combination of lower treatments and consulta-tions costs, and reduced loss of working days.

> Children with recurrent URTI: lower need for antibiotics and school absenteeism. > Patients at risk of acute LRTI: reduction of both the frequency and severity of infectious

episodes, leading to reduced associated treatment costs and antibiotic usage and poten-tially indirect costs such as work absenteeism (not calculated).

> COPD patients: reduction of acute exacerbation episodes, hence of hospitalisation and treatment costs as well as indirect cost (work absenteeism). Based on COPD prevalence from the BOLD study (14), and country demographics, we extrapolated the potential total direct cost savings with PMBL™ for COPD patients to several billion in each of the country considered (Table 4)!

conclusion: a possible synergy?Prevention of RTI represents a key public and private heath objective. No one doubts that development of immunisation campaigns has allowed to save the life of millions and helped eradicate some very serious threatening diseases, such as whooping cough. However, the limitations of traditional vaccination approach (weak stimulation of mucosal immunity, spe-cific immunity only...), combined to the high mutation rates of certain viruses or bacteria (e.g. influenza viruses), has created the need for alternative immunisation approaches such as oral immunostimulant based on polyvalent bacterial lysates. Because they have a broad spec-trum of action and a dual effect on systemic and mucosal immunity, but also on specific and non specific immunity, PMBL™ sublingual tablets represent an interesting complementary approach to traditional vaccination. Because both approaches have a distinct mode of action, many practitioners even advocate the use of PMBL™ as an adjuvant to injectable vaccines (see interview). Moreover, none of the post-marketing studies conducted has shown any counter indication to the concomitant use of both strategies. A recently published ancillary study of a larger on-going clinical study conducted in elderly patients with COPD illustrated the vaccine boosting effect of PMBL™ tablets, even in elderly patients. In these patients, PMBL™ showed a stimulating effect against vaccinal antigens, thus indicating a possible synergy (2).

ITALY POLAND UKRAINE MEXICO

Total population (2012) 61261254 38415284 44854065 114975406

COPD median prevalence (BOLD study) 10,10% 10,10% 10,10% 10,10%

Cost saving/patient ($) 896,4 511,6 290,4 367,2

Estimated cost saving for the total population $ 5.5 bn $ 1.2 bn $ 1.3 bn $ 4. 3 bn

Table 4: Potential yearly direct cost-savings if all COPD patients were given PMBL prophylactic treatment in Italy, Poland, Ukraine and Mexico.

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The expert’s opinionQuestions to Pr. Giovanni Melioli, Director of the Department of Experimental and Laboratory Medicine at the Institute Giannina Gaslini in Genoa in Italy. He is also Professor of Biotech Application in Diagnosis, Clinical Pathology (School of Pediatrics) and Laboratory Management (School of Clinical Pathology) at the University of Genoa.

1 When do you think is the best moment to start immunisation with PMBL™ for RTI prevention?PMBL™ is a drug distributed worldwide and the different climates could suggest different strategies of administration. Under our temperate climates (Northern hemisphere), the highest frequency of RTI is in winter. For this reason, a treatment starting in fall seems to be the most efficient approach. A second cycle, starting from January, and covering the end of winter and beginning of spring, is also a good startegy. Patients from other countries, with different climates, could benefit from adapted treatment schedules. Indeed, the aim of PMBL™ administration is to improve immune defences before the beginning of the “at risk” period which is not always winter.

2 In case of severe infections (mononucleosis, measles, chicken pox...), when do you think is the best time to start an immunisation program, either with vaccines or PMBL™? (Concomitantly to the infection, right after the infection, or few weeks after?)An immunisation program aims at potentiating the immune system-mediated response. For this reason, it should be administered in a period of wellness for the patient. For example, some viral infections are correlated with a period of weakness of the immune system. For example, Herpesviridae (such as VZV, HSV EBV and CMV) infections are generally controlled by the immune system but may cause a disease when immune-surveillance is low.In my opinion (but we have no clinical controlled trials to support this), in similar cases, PMBL™ (as well as other vaccines) should be administered few weeks after the end of the acute phase of an infection.

3 You are involved in the AIACE clinical study**: a recently published ancillary study (2) shows that for these elderly patients PMBL™ also had for effect to increase immunisation against vaccine antigens, how can you explain this?This was one of the most important results obtained in our research. We already observed and published that PMBL™ has the capacity to trigger the maturation of human dendritic cells (DC). Following activation, DC not only are able to induce an efficient immune response against PMBL™ antigens (as demonstrated by the presence of IgA directed toward these microbes), but also toward any other antigen presented to the immune competent cells during the same period. For this reason, we observed that a specific immune response was raised also against other pathogens, circulating within the patients’ population, in the months of the AIACE ancillary study. Even more interesting, the recruitment of very early B cells, described in another publication, and observed only in the population of PMBL treated patients, was also interpreted as a functional polyclonal activation of B cells, increasing the specific mechanisms of defence against infectious diseases.

** Advanced Immunological Approach Against COPD Exacerbations, a Phase IV clinical trial in COPD patients.

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4 In your opinion, is there a counter-indication to use PMBL™ and traditional vaccination together?I do not see any kind of reasonable counter-indication. For example, if flu vaccine is considered within “traditional vaccinations”, it is a common notion that a significant fraction of “vaccinated” patients are unable to respond or, at least, the immunological response raised cannot be easily detected using standard sero-virology techniques. Any potentiation of maturation of dendritic cells, as observed with PMBL™, could then be extremely useful to enlarge the group of “responder” patients.

5 Do you think it is beneficial to use both vaccine and PMBL™? As stated before, I think that this should be a winning strategy

6 If you think there is a synergy, how do you recommend associating both approaches in practice? (concomitant administration or not...)I do not think that a concomitant administration of PMBL™ and flu vaccine is the best strategy. I would rather administer a cycle of PMBL™ and the flu vaccine in the middle of this cycle. Influenza antigens could be better engulfed, processed and presented by activated dendritic cells. However, it is important to remember that these opinions are based on other experiences, in the absence of controlled clinical trials using PMBL™ and flu vaccination.

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References1- ERS, The European Lung White Book 2013. http://www.erswhitebook.org

2- ECDC. Antimicrobial resistance surveillance in Europe 2012

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