Immunomodulators can improve the immune response in some cases, but can also decrease it in other cases.
For years, immunologists have tried to devise immunomodulators that could be useful for the treatment of diseases in which there are defects in immunity, such as chronic and recurrent infections, cancer, or autoimmune diseases.
The term immunostimulant (IS) refers to a compound that produces a state of non-specific immunity that contributes to increased resistance to infection or malignancy.
On the other hand, immunosuppressants non-specifically interfere with the immune response, which in some cases can increase susceptibility to infections and cancer.
However, as Bomford (1989) and Hadden (1993) point out, it is often difficult to draw a clear line between immunomodulators and immunosuppressants.
Ribovac is an immunostimulant . Immunostimulants, also known as immunostimulators, are substances (drugs and nutrients) that stimulate the immune system by inducing the activation or increasing the activity of any of its components.
A notable example is granulocyte macrophage colony stimulating factor.
Ribovac is indicated for the prevention of bacterial affections of the respiratory system and pulmonary ENT sphere in children and adults: tonsillitis , pharyngitis , laryngitis, sinusitis, otitis, tracheitis, bronchitis and recurrent respiratory superinfections.
Immunomodulation promises to be an effective prophylactic and therapeutic modality for chronic and recurrent respiratory infections. Unlike vaccines, the term “immunostimulant” refers to a compound that produces a state of non-specific immunity.
Most immunostimulants are oral formulations of bacterial lysates that have been used in clinical practice for decades. One of the main obstacles in the development of immunostimulants is the poor understanding of the mechanism of action.
Except for some compounds, the mechanism of action of bacterial products is not well understood. Some appear to act through the activation of monocytic cells and macrophages and the increase in polyclonal proliferation of B cells.
In general, the use of immunostimulants produces beneficial clinical results, but the quality of some clinical trials for the prevention of acute respiratory tract infections (STIs) needs to be improved.
In the pediatric population, the use of immunostimulants for the prevention of acute respiratory tract infections should be limited to children with high susceptibility to acute respiratory tract infections or overexposed children.
While in adults it should be indicated for patients with chronic obstructive pulmonary diseases (COPD) at high risk of exacerbation.
Differences between a vaccine and an immunostimulant like Ribovac
The main difference between an immunostimulant and a vaccine is that the latter is supposed to produce a protective immune response against a specific microorganism, which is included in the formulation as a whole organism or a subunit thereof.
Many immunostimulants were developed in the pre-antibiotic era as an option to treat and prevent infectious diseases.
During the first part of the 20th century, the development of immunostimulants has developed in parallel with that of vaccines, that is, their empirical use preceded the understanding of the mechanism of action.
Most of the registered immunostimulants used today for the prevention of acute respiratory tract infections (ARTIs) are products derived from bacteria.
History of immunostimulants
Although upper and lower respiratory tract infections are usually mild and self-limited, they can sometimes be complicated by sinusitis, otitis media, and bronchopulmonary (PA) infections.
In addition, these infections can be recurrent or chronic and can trigger therapeutic difficulties.
Due to their frequency, recurrent upper and lower respiratory tract infections in children and adults constitute a major global health problem.
In developed countries, for example, up to 25% of children under 1 year of age, and of children 1 to 4 years of age, are subject to these recurrent infections.
In adults, exacerbations of chronic obstructive pulmonary disease caused by a respiratory infection are also very common.
Furthermore, these recurrent infections are not only responsible for significant morbidity and mortality, but are also frequent causes of school or work absenteeism, as well as important contributors to the socioeconomic burden of the disease.
Although the etiological agents responsible for these infections are not always easily identifiable, bacterial agents and, more frequently, viruses are the most frequent causes.
The bacteria most frequently involved in these infections are Streptococcus pneumoniae, Haemophilus infiuenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Streptococcus pyogenes group A.
The most common viral etiologic agents include respiratory syncytia virus, adenovirus and parainfluenza, and influenza virus.
Although most infectious episodes are managed with repeated courses of antibacterials, their use is not effective with viral infections.
Even in the case of bacterial infections, its short-term efficacy is not curative, does not prevent recurrences, and often leads to the development of antibacterial-resistant strains of bacteria.
Therefore, the high prevalence of these diseases, their ever-increasing socioeconomic burden, and the emerging global problem of antibacterial resistance warrant a preventive approach.
Although immunostimulating drugs have been used in the prevention of respiratory tract infections in the past, the results of recent clinical trials have been extremely encouraging.
For the prevention of exacerbations of chronic obstructive pulmonary disease and recurrent ear-nose-throat infections in adults, as well as recurrent upper respiratory tract infections in children in day care centers.
Together, these studies have provided renewed interest in the clinical use of these agents. While they do not eliminate acute infections, they provide immunoprotection, reducing the frequency and severity of such infections.
Ribovac is a drug (immunostimulant) with activities in both the innate and acquired immune systems.
It is approved in 60 countries (including several European countries) for the prevention of recurrent ear-nose-throat and bronchial infections in children and adults.
The product is composed of ribosomal fractions of K. pneumoniae, S. pneumoniae, S. pio-genes group A, H. infiuenzae and a membrane fraction of X. pneumoniae.
The immunogenic properties of ribosomes were first described for M and cobacteriff on tuberculosis ribosomes and subsequently confirmed.
The immunostimulant Ribovac has been shown to induce the production of specific humoral and secretory antibodies in humans against the four bacterial strains included in the compound.
Oral administration of Ribovac has been shown to stimulate the mucosal immune system.
In addition, non-specific immunostimulatory properties of the K. pneumoniae membrane fraction have been demonstrated in accordance with the following immune responses:
Polyclonal stimulation of B lymphocytes and T lymphocytes, activation of polymorphonuclear cells and macrophages through phagocytosis, cytokine production and natural killer cell stimulation.
Therefore, as a result of this original composition, Ribovac has a dual mechanism of action that allows a preventive efficacy against viral and bacterial infections.
Taken together, these immunological findings provide additional support for the immunostimulatory basis of the drug’s action and are consistent with its efficacy in preventing recurrence of infections or superinfections of the respiratory tract, demonstrated in clinical trials.
How Immunostimulants Work
Many immunostimulants activate innate immunity and promote the release of endogenous immune mediators (eg, cytokines) to aid in the treatment of immunodeficiency diseases, chronic infections, or cancer.
In the 1890s, New York Memorial Hospital surgeon Dr. William Coley used Streptococcus pyogenes and Serratia marcescens (Coley’s vaccine) to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas in his patients.
This treatment originated from the observation that tumors regressed when spontaneous acute infections occurred, especially with high fever.
Coley and others initially used live bacteria to induce infection and fever; however, fatal infections eventually led to the use of an inactivated organism.
Immunostimulants induce nonspecific activation of the immune system, unless associated with antigens.
As for example, adjuvants in vaccines, and can amplify different effectors of the immune response, including phagocytosis and intracellular destruction of organisms, antigen presentation, cytotoxic and antiviral activity.
Cytokine release, and antibody production.
Immunomodulators predominantly activate macrophages and dendritic cells in the liver, spleen, skin, and lungs. The route of administration is designed to bring the drug into contact with antigen presenting cells (APC).
In the horse, pulmonary intravascular macrophages are probably important for the recognition of circulating foreign antigens.
These large, mature and permanent resident macrophages of the pulmonary capillary lumen phagocytosis particulate matter in the circulation, including bacteria, endotoxins, fibrin, and leukocytes.
These cells probably secrete inflammatory mediators that produce alterations in systemic vascular resistance and permeability, are chemoattractants for the marginalization of neutrophils in the pulmonary vascular system, and produce additional pro-inflammatory mediators.
The innate immune response is a nonspecific recognition of a subsequent response to pathogens. Signal transduction pathways activate oxidative burst activity and the production of cytokines and chemokines.
These responses initiate microbial defenses and inflammation.
Toll-like receptors (TLRs) are type I transmembrane proteins expressed in cells responsible for this first encounter with a pathogen and the presentation of the processed peptide to lymphocytes:
- Macrophages, dendritic cells and, in some species, mucous epithelial cells and dermal epithelial cells.
In addition, certain types of Toll-like receptors are present in the cytosol for recognition of processed viral or bacterial components (eg, ribonucleic acid [RNA], deoxyribonucleic acid [DNA]).
Thus, activation of Toll-like receptors can be induced under conditions where an immune response is desired (eg, vaccination).
Blocking Toll-like receptor pathways may be beneficial in preventing life-threatening inflammation (eg, sepsis ).
In addition to Toll-like receptors, other important innate receptors, including:
- Protein containing nucleotide-binding oligomerization domain (NOD), retinoic acid-inducible RIG-like receptors (RLRs), mannose, and complement receptors are expressed on the cytosol or surface of antigen-presenting cells.
The contribution of Toll-like receptors to the immune response was first observed with Drosophila Aspergillus fumigatus infection. Since then, up to 13 Toll-like receptors have been identified, but their expression varies between species.
Each Toll-like receptor recognizes a molecular pattern associated with a different pathogen (PAMP); therefore, together they can mediate the response to a wide range of organisms. Furthermore, Toll-like receptors can recognize low molecular weight synthetic molecules.
After antigenic processing of an immunostimulant, the intracellular signaling pathways for the expression of pro-inflammatory genes and endogenous cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor alpha [TNF-α] and interferon alpha [ IFN-α]) are activated.
These mediators, while promoting desirable immune responses, exert adverse systemic effects, such as transient fever, lethargy, and decreased appetite.
The toxic effects of these raw or live bacterial products include increased vascular permeability, hypotension, pulmonary edema, diarrhea, hypersensitivity reactions with infiltrative / granulomatous cell reaction, autoantibody production, and collapse.
The use of immunostimulants in equine medicine is promoted for preventive or complementary therapy of respiratory diseases and other infectious diseases:
- Acquired immunosuppression secondary to stress (transport, training, weaning), immunosuppressive treatment, infiltrative diseases, metabolic or endocrine diseases, malnutrition or any condition that has reduced the ability of the immune system to fight opportunistic organisms and pathogens.
Immunostimulants are also recommended for antitumor treatment (eg sarcoids) in the horse.
Studies with the Ribovac
Nineteen randomized, double-blind, placebo-controlled clinical trials were conducted between 1983 and 1994 in Europe.
In children with ear-nose-throat (ENT) infections, immunostimulatory treatment with Ribovac for 3 months significantly reduced the mean number of relapses and reduced the duration of infection and the antibacterial requirement.
Immunostimulation with Ribovac was equally effective in children with ear-nose-throat and bronchopulmonary infections, reducing the mean number of relapses by 32 to 61% compared to placebo.
In children with otitis media, the immunostimulant Ribovac reduced recurrences by 10–53% and also reduced the duration of infection, the use of antibacterials, and the requirement for local surgery.
Results from 6-month studies confirmed or expanded on these results.
In adult patients with mixed ear-nose-throat or respiratory infections, the immunostimulant Ribovac produced reductions similar to those seen in children for recurrent infections, duration of infection, and antibacterial use.
Ribovac Mechanism of Action
The immune system is an intricate network of cells and a wide variety of signaling molecules. Regulation of the immune system depends on the points of interaction between cells and soluble substances that define the immune response.
One of the main obstacles in the development of immunostimulants is the poor understanding of the mechanism of action. It has been particularly difficult to identify a receptor or molecular target that would be associated with the prevention of acute respiratory tract infections.
Therefore, despite intensive research on the immune function of the immunostimulant, we still do not know what the definitive mechanism of action is for either the bacterial immunostimulant or the synthetic immunostimulant.
Pharmaceutical form and formulation
Each vial with lyophilisate contains Ribovac fractions of:
- Klebsiella pneumoniae en 0.0049 mg. Streptococcus pneumoniae en 0.0042 mg. Streptococcus pyogenes grupo A en 0,0042 mg. Haemophilus influenzae en 0.0007 mg. Klebsiella pneumoniae proteoglycans en 0.0250 mg.
Each vial with diluent contains:
- Injectable sodium chloride solution in 0.500 ml.
Dosage and route of administration
One dose deep subcutaneously. Minimum interval between 2 injections: 1 week. A treatment comprises at least 4 injections. No cases of overdose have been reported. Store at room temperature no more than 21ºC. If you need more information, ask the medical management.
The Ribovac in granulated sachets should be diluted the content of one sachet in half a glass with water, juice or milk; take in the morning for 8 continuous days.
Side and adverse reactions
For the assessment of undesirable effects, the following post-marketing experience data was issued. Frequencies are not known (cannot be estimated from the available data).
Respiratory, thoracic and mediastinal disorders: isolated cough and asthma attack. Skin and connective tissue disorders: erythema, eczema, vascular purpura and erythema nodosum.
General disorders: high fever (39 ° C) isolated, unexplained and sudden presentation.
Ribovac has no effects on carcinogenesis, mutagenesis, teratogenesis, or fertility. In the rare case of fever of unknown origin (39 ° C) that develops immediately after starting treatment, the drug should be discontinued.
In case of hypersensitivity reactions, treatment should be stopped immediately. In case of acute intestinal infections, Ribovac should not be administered. If an asthma attack occurs, stop the treatment and do not repeat it.
The safety of the Ribovac
The Cochrane Review on the use of Ribovac for the prevention of acute respiratory tract infections in children provides data on adverse events revealed during clinical trials.
Most of the trials reported a low incidence of adverse events or no adverse events at all.
The most frequent adverse events were found to be gastrointestinal complaints such as nausea, vomiting, malaise, and diarrhea, and skin disorders such as rash, urticaria, and pruritus.
According to an expert consensus, the incidence of adverse events in OM-85 BV clinical trials is 3% to 4% of treated children.
The most frequent adverse events were gastrointestinal complaints (gastric discomfort, abdominal pain, diarrhea, nausea, vomiting, and loss of appetite) and skin changes (rash, erythema, pruritus).
In the OM-85 BV pharmacovigilance survey, the most frequent complaints were fever, diarrhea, rash, urticaria, abdominal pain, asthma, pruritus, and rhinitis. The risk of an autoimmune disease was minimally pronounced.
In adult patients with chronic obstructive lung diseases, the bacteria-derived immunostimulant can cause an adverse reaction in 3.3% of the treated population, including itching and rashes. 8% of the patients presented low urinary symptoms.
The incidence of other complaints was not statistically different from the placebo group. The systematic review of OM-85 BV revealed that adverse events were mild and similar in frequency to the control population).
The most common adverse events reported were headache and gastrointestinal symptoms.
The search in the medical literature identified only two cases of serious adverse events associated with immunostimulants; a case of bullous pemphigoid, an autoimmune disease associated with autoantibodies directed against the hemidesmosomal antigens BP230 and B180.
Associated with RU41740, and a case of another rare autoimmune disorder, tubulointerstitial nephritis, associated with D53.
The use of immunostimulants such as Ribovac is not uncommon in some European and American countries as a means of reducing the incidence of acute respiratory infections in children and the number and severity of chronic obstructive pulmonary disease in adult patients.
However, as the mechanisms of action are not fully understood and the clinical evidence is not well established, their usefulness remains controversial.
The lack of enthusiasm, particularly among physicians educated in Anglo-Saxon countries, in embracing this type of medication may have been attributed, at least in part, to deficiencies in knowledge of the mechanism of immunostimulants.
The quality of clinical trials is generally poor, although some of the trials conducted recently have improved.
The most common problems in children and adults are the lack of selection of precise end points; lack of adequate control; poor selection criteria; poorly defined definitions and operating procedures; small sample size; and inept explanations for dropouts and adverse events.
All of these shortcomings in the clinical protocol resulted in a low power of data to reveal differences between the medication and placebo groups.
Trials in children have shown that the efficacy of immunostimulants such as Ribovac in preventing ≥ 1 incidents is not reliable, but improves with ≥ 2 and ≥ 3 incidents.
Failure to show significance in chronic obstructive pulmonary disease is believed to be due to confidence in the measurement of ≥ 1 incident as dichotomous outcome data.
The number of exacerbations (mean and standard deviation) is believed to be a better measure (scaled data).
It would be desirable to explore the relative risk of ≥2, ≥3 exacerbations in chronic obstructive pulmonary disease trials.
Results from clinical trials have shown that reducing the incidence of acute respiratory infections in children and reducing exacerbations in patients with chronic obstructive pulmonary disease are real possibilities.
However, the protective effect of Ribovac would be remarkable in patients who experience a large number of acute respiratory infections compared to their normal companions.
Therefore, in the pediatric population, the use of Ribovac for the prevention of acute respiratory tract infections should be limited to children with proven high susceptibility to acute respiratory tract infections or overexposed children.
While in adults it should be limited to patients at high risk of exacerbation of chronic obstructive pulmonary disease.
The quality of trials with immunostimulants for the prevention of acute respiratory infections needs to be improved, as well as the reporting of results and adverse events.
As a matter of public interest, larger clinical trials sponsored by health authorities are desirable to establish the true effect of each immunostimulant in addition to Ribovac.
Other indications to be explored in adults and children are the prevention of acute viral infections of the respiratory tract (including patients with asthma) and the prevention of recurrent otitis.
The mechanism of action of Ribovac must be clarified, particularly the site of action or the receptor involved, in order to create specific agonists and antagonists for clinical application.
For example, we need to identify the active ingredients in bacterial extracts and their affinity receptors to create new synthetic entities.
Exploring other possible paths is to search for different Toll Like Receptor agonists and antagonists or to create new series of molecules capable of forming Schiff bases on the surface of immune cells as suggested by Rhodes (2002).
Some years ago Hadden (1993) stated that the use of immunostimulants such as Ribovac was something like ‘trying to beat a television set’.
We now know that this distinctive ‘bump’ can fix the TV and we’re about to open it up with the right tools to find out what exactly happened.