Vaccine using an inactivated strain of Lactobacillus
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Lactobacillus vaccines are used in the therapy and prophylaxis of non-specific bacterial vaginitis and trichomoniasis. The vaccines consist of specific inactivated strains of "Lactobacilli", called "aberrant" strains in the relevant literature dating from the 1980s. These strains were isolated from the vaginal secretions of patients with acute colpitis. The lactobacilli in question are polymorphic, often shortened or coccoid in shape and do not produce an acidic, anti-pathogenic vaginal environment. A colonization with aberrant lactobacilli has been associated with an increased susceptibility to vaginal infections and a high rate of relapse following antimicrobial treatment. Intramuscular administration of inactivated aberrant lactobacilli provokes a humoral immune response. The production of specific antibodies both in serum and in the vaginal secretion has been demonstrated. As a result of the immune stimulation, the abnormal lactobacilli are inhibited, the population of normal, rod-shaped lactobacilli can grow and exert its defense functions against pathogenic microorganisms.
Medical uses.
Lactobacillus vaccines are primarily used in the therapy and prophylaxis of dysbiotic conditions of the vaginal ecosystem (bacterial vaginitis, vaginal trichomoniasis, and to a lesser extent, vaginal candidiasis). Secondarily, they are used in the prophylaxis and complementary treatment of various urogenital diseases, if vaginal dysbiosis is suspected to be the root cause of the condition. These include (chronic) upper genital tract infections, urinary tract infections and cervical dysplasias. The prophylactic use in patients with a history of late miscarriage and preterm labor is practiced preferably before conception.
Effectiveness.
Bacterial vaginitis.
Rüttgers studied the benefit of vaccination with Gynatren in preventing bacterial vaginitis in a patient group with frequent vaginal infections. All of the 192 patients participating in the prospective, randomized, double-blind, placebo-controlled study received local treatment with a tetracycline-amphotericin B vaginal suppository. 95 patients additionally received vaccination with Gynatren, whereas 97 patients were treated with a placebo preparation of identical outward appearance. One month after the start of the treatment 85% of the patients in the active treatment group and 83% in the placebo group were cured (asymptomatic and free from pathogenic bacteria). After 3 months 78% of the verum group and 60% of the placebo group remained free from infection. After 6 months 76% and 40%, and after 12 months 75% and 37% of women in the respective groups were still free from infection.
Another study by Boos and Rüttgers investigated the therapeutic effect of SolcoTrichovac when used as a sole therapeutic agent. The 182 patients enrolled into the study showed symptoms of acute vaginitis, and most of them had been treated for months with topical or oral antibiotics or antimycotics without success. For the course of the study they were advised to refrain from using such preparations. Six months after the first injection 71% of the patients showed a normal vaginal flora according to the classification of Jirovec and Peter. Further studies on the therapeutic and preventive efficacy of lactobacillus vaccines alone or in combination to antimicrobial treatment in bacterial vaginitis have produced similar results.
Vaginal trichomoniasis.
Litschgi has investigated the use of SolcoTrichovac both as a therapeutic and as a recurrence prophylactic measure. On the latter subject he reported enrolling 114 women with trichomoniasis into a randomized, double-blind, placebo-controlled study, 66% of whom had case histories of recurrent vulvovaginitis. All patients as well as their sexual partners received systemic and/or local nitroimidazole treatment. 61 patients were additionally vaccinated with SolcoTrichovac, 53 patients with placebo. At the first follow-up check, 6 weeks after the first injection, 3 patients in each group still had motile trichomonads. Among the patients that were pronounced cured at this visit, a total of 15 reinfections (33.3%) were recorded in the placebo group during the follow-up period from month 4 to month 12 after the first injection, whilst in the verum group there were no new infections. Harris designed a similar randomized, double-blind, placebo-controlled study with 198 participants and reported a reinfection rate of 21.6% in the placebo group, in contrast to 3.1% in the SolcoTrichovac group 8 months after completing the course of three injections. Further studies have confirmed the efficacy of lactobacillus vaccines as a powerful complementary treatment and recurrence prophylactic measure in trichomoniasis.
Vaginal candidiasis.
Vaginal mycoses are considered a weak indicator that the lactobacillus flora is compromised, since "Candida albicans" and "Lactobacilli" can coexist symbiotically. Consequently, immunotherapeutic modulation of the lactobacillus flora has a lesser success rate in this condition than in bacterial and trichomonal vaginitis. Verling reported vaccinating 42 patients with candida-induced chronic colpo-vaginitis with SolcoTrichovac, who had shown resistance to usual fungicidal treatment such as topical amphotericin B, nystatin and povidone-iodine. Of these, 7 patients (17%) have healed and another 18 patients (43%) showed only mild symptoms one month after the third injection.
Urinary tract infections.
In many women prone to recurrent urinary tract infections, the mucosal surfaces of the vaginal introitus are colonized by "Escherichia coli" and "Enterococci", rather than "Lactobacilli". Reid and Burton have postulated that the vagina may act as a reservoir for uropathogens. In the proposed scenario, the dysbiotic vaginal environment is continually seeding the bladder with infectious microbes leading to a persistent or recurrent urinary tract infection. As they suggested, by recolonizing the vagina with lactobacilli and displacing the pathogens, the infection of the bladder may resolve. No studies have been conducted on the use of lactobacillus vaccines in recurrent urinary tract infections using modern formulations of the vaccine. The inventor of lactobacillus vaccines, Újhelyi reported initial success in preventing uropoietic infections in pregnant women under therapy with experimental single-strain vaccines.
Intrauterine infections during pregnancy.
The relationship between intrauterine infections and second-trimester pregnancy loss as well as early preterm delivery has been established. Most bacteria found in the uterus in association with preterm labor are of vaginal origin, with only a small minority originating from the abdominal cavity or from an inadvertent needle contamination at the time of amniocentesis. Pathogenic bacteria may ascend through the cervix and maintain a subacute infection of the upper genital tract and the fetal membranes for months before the infection is eventually detected. These infections tend to remain asymptomatic and are not associated with fever, a tender uterus, or peripheral-blood leukocytosis. Often the first symptoms are the rupture of membranes and preterm labor, at which point the conservation of pregnancy becomes difficult. Early treatment and prophylaxis of vaginal infections are crucially important especially in those patients, that have already experienced a second-trimester miscarriage, which is associated with 27% rate of recurrence (pregnancy loss between 14 and ;templatestyles src="Fraction/styles.css" / ;23+6⁄7 weeks of gestation), 10% rate of extremely preterm delivery (24 to ;templatestyles src="Fraction/styles.css" / ;27+6⁄7 weeks), and further 23% rate of very, moderate or late preterm delivery (28 to ;templatestyles src="Fraction/styles.css" / ;36+6⁄7 weeks) in the subsequent pregnancy.
A study performed by Lázár and her coworkers examined the incidence of low-birth-weight offspring among therapeutically and preventively vaccinated women. Out of 413 pregnant women presenting with acute urogenital infections, 209 were vaccinated with Gynevac additionally to conventional antimicrobial treatment, whereas 204 women only received antimicrobial therapy. A birth-weight below 2500 g was recorded in 10.4% of vaccinated patients compared to 24.1% among patients that had not received lactobacillus vaccination. The rate of perinatal mortality was 1.42% in the vaccinated group in contrast to 3.86% among non-vaccinated patients. On average the gestational period was longer in vaccinated patients, 81.3% of whom reached full term, in contrast to only 66.7% of the non-vaccinated patients. Preventive lactobacillus vaccination with Gynevac was performed on 1396 healthy women, partly before conception and partly during early pregnancy. The reported incidence of low birth weight was 7.9% among vaccinated women compared to 14.0% among healthy controls. In a subsequent prospective study with the participation of 1852 vaccinated pregnant women and 1418 controls, Lázár and coworkers reported a preterm birth rate of 7.1% among vaccinated women and 12.2% among those that declined lactobacillus vaccination.
Formulation.
Each ampoule of Gynatren contains at least inactivated microorganisms of eight "Lactobacillus" strains in approximately equal amounts ( microorganisms per strain). Three strains belong to the species "L. vaginalis", three strains to "L. rhamnosus", one strain to "L. fermentum" and one to "L. salivarius". The eight specific aberrant polymorphous "Lactobacillus" strains have been deposited at the Westerdijk Institute (Centraalbureau voor Schimmelcultures) in 1977 under the strain numbers CBS 465.77 to CBS 472.77. Inactivated material from the eight strains is mixed and diluted with physiological sodium chloride solution. Phenol is added as a preservative. The vaccine usually has a total nitrogen content of 3.68 mg in 100 ml solution (based on the dry material, using the Kjeldahl method). Using the conversion factor of 6.25 to convert nitrogen concentration to protein concentration, this means that there is on average 0.115 mg bacterial proteins in each ampoule of 0.5 ml.
Gynevac is composed of five specific aberrant polymorphous "Lactobacillus" strains, four belonging to the species "L. fermentum" and one to the species "L. reuteri". The further ingredients are formaldehyde and sodium ethylmercuric thiosalicylate (Thiomersal) as preservatives and sodium chloride solution as a diluent. Each ampoule of 1 ml contains between 0.08 mg and 0.32 mg bacterial proteins.
Schedule.
The usual vaccination schedule of Gynatren is 3 intramuscular injections of 0.5 ml vaccine at intervals of 2 weeks, followed by a booster dose of 0.5 ml 6–12 months after the first injection. The booster injection raises the serum antibody titres in most cases back to similar levels to those found shortly after primary vaccination and ensures renewed immune protection for about 2 further years. Grčić et al. recommends the periodic administration of booster doses every 2 years to maintain protective immunity for many years.
The schedule of Gynevac includes 5 intragluteal injections of 1 ml vaccine at intervals of 10 days. Protective immunity is conferred for about a year. The primary immunization program may be repeated, if reinfection or relapse occurs.
Side effects.
Common side effects include pain, redness and swelling or hardening of the tissues at the injection site. Systemic vaccination reactions commonly include fatigue, flu-like symptoms, a raised temperature between , shivering, headache, dizziness, nausea and a swelling of the inguinal lymph nodes. Symptoms usually subside within days after injection and are less pronounced or absent at subsequent injections.
Contraindications.
Gynatren is contraindicated in patients with a history of allergic reaction to the bacterial antigens or phenol contained in the vaccine. Further contraindications are acute fever, active tuberculosis, severe hematopoietic disorders, decompensated cardiac or renal insufficiency, autoimmune and immunoproliferative diseases. Gynevac is additionally contraindicated in arthritides affecting several joints, under immunosuppressive- or radiotherapy.
Pregnancy.
Lactobacillus vaccines are not contraindicated during pregnancy and breastfeeding. Both Gynatren and Gynevac may be prescribed during pregnancy upon careful individual consideration of the potential risks and benefits. Lázár reported vaccinating 3457 pregnant patients with Gynevac between 1976 and 1982, usually starting the vaccination schedule at the first prenatal care visit, and has not observed any impairment of pregnancy or teratogenic effect in association to the lactobacillus vaccine. Rüttgers made similar observations about Gynatren when administered in the second trimester.
Mechanism of action.
The mechanism of action of lactobacillus vaccines is far from being completely understood. At least three theories have been proposed. The most commonly accepted one, as formulated by Påhlson and Larsson, suggests that the vaccine breaks the immune tolerance of the host and makes it possible for the immune defense to attack aberrant, "ecologically wrong" lactobacilli and create an environment for beneficial strains to become dominant. Rüttgers on the other hand described SolcoTrichovac as an anti-adhesive vaccine, suggesting that the induced antibodies and perhaps other mechanisms inhibit the adhesion of microbes to epithelial cells in a largely nonspecific manner. A third hypothesis, advanced by Goisis among others, involves the possibility of an immunomodulation resulting in tolerance, rather than defense against the bacterial antigens used in the vaccine.
Multiple authors have proposed cellular immunological phenomena as the primary mediators of protective effect of lactobacillus vaccines. Studies into cellular immunity are technically challenging in humans owing to the difficulty of sampling lymphoid tissues as opposed to secretions, and none has been performed so far on lactobacillus vaccines. A number of studies have been published on the humoral responses to primary and booster immunization in serum and in the vaginal secretions. Rüttgers identified mucosal secretory IgA as a strong immune correlate of vaccine efficacy.
Humoral immune response.
Mucosal surfaces are a major portal of entry for pathogens into the body. Antibodies in mucosal secretions represent the first line of immune defense of the mucosae. They are capable to bind to specific