Bacterial Mucosal Immunotherapy with MV130 Prevents Recurrent Wheezing in Children: A Randomized, Double-Blind, Placebo-controlled Clinical Trial

Antonio Nieto, Angel Mazón, María Nieto, Rafael Calderón, Susana Calaforra, Blanca Selva, Sonia Uixera, Maria José Palao, Paola Brandi, Laura Conejero, Paula Saz-Leal, Cristina Fernández-Pérez, David Sancho, José Luis Subiza, Miguel Casanovas, Antonio Nieto, Angel Mazón, María Nieto, Rafael Calderón, Susana Calaforra, Blanca Selva, Sonia Uixera, Maria José Palao, Paola Brandi, Laura Conejero, Paula Saz-Leal, Cristina Fernández-Pérez, David Sancho, José Luis Subiza, Miguel Casanovas

Abstract

Rationale: Recurrent wheezing in children represents a severe public health concern. Wheezing attacks (WA), mainly associated with viral infections, lack effective preventive therapies. Objectives: To evaluate the efficacy and safety of mucosal sublingual immunotherapy based on whole inactivated bacteria (MV130) in preventing WA in children. Methods: A Phase 3 randomized, double-blind, placebo-controlled, parallel-group trial including a cohort of 120 children <3 years old with ⩾3 WA during the previous year was conducted. Children with a positive skin test to common aeroallergens in the area where the clinical trial was performed were excluded from the trial. Subjects received MV130 or placebo daily for 6 months. The primary endpoint was the number of WA within 1 year after the first dose comparing MV130 and placebo. Measurements and Main Results: There was a significant lower number of WA in MV130 versus the placebo group, 3.0 (interquartile range [IQR], 2.0-4.0) versus 5.0 (IQR, 3.0-7.0) (P < 0.001). As secondary outcomes, a decrease in the duration of WA and a reduction in symptoms and medication scores in the MV130 versus placebo group were found. No adverse events were reported related to the active treatment. Conclusions: Mucosal bacterial immunotherapy with MV130 shows safety and clinical efficacy against recurrent WA in children.Clinical trial registered with www.clinicaltrials.gov (NCT01734811).

Keywords: MV130; clinical trial; mucosal vaccination; wheezing attacks.

Figures

Figure 1.
Figure 1.
Trial profile.
Figure 2.
Figure 2.
MV130 reduces the number and duration of wheezing attacks (WA). (A–C) WA episodes during the whole study: (A) number of WA, (B) days with WA, and (C) duration of WA. The results in the scatter plots represent values from single patients; the horizontal lines indicate medians, and error bars show the interquartile range. The P values were calculated using a Mann-Whitney U test. (D and E) A survival analysis (Kaplan-Meier estimator) representing the number of days until the appearance of the first WA (D) during the whole study period (1 yr) and (E) during the posttreatment period of the study (6 mo). The P values were calculated using log-rank (Mantel-Cox) test. CI = confidence interval.
Figure 3.
Figure 3.
MV130 decreases symptom and medication scores (SMS). (A–C) The combination of SMS (A), overall symptom scores (B), and medication scores (C) during wheezing attacks. (D–F) The combination of SMS (D), overall symptom scores (E), and medication scores (F) throughout the study. Data are displayed in scatter dot plots in which values from single patients are represented. The line indicates the median, and error bars show the interquartile range. The P values were calculated using Mann-Whitney U test.

References

    1. Camargo CA, Jr, Rachelefsky G, Schatz M. Managing asthma exacerbations in the emergency department: summary of the National Asthma Education and Prevention Program Expert Panel Report 3 guidelines for the management of asthma exacerbations. J Emerg Med . 2009;37(Suppl):S6–S17.
    1. Meissner HC. Viral bronchiolitis in children. N Engl J Med . 2016;374:62–72.
    1. Alvarez-Alvarez I, Niu H, Guillen-Grima F, Aguinaga-Ontoso I. Meta-analysis of prevalence of wheezing and recurrent wheezing in infants. Allergol Immunopathol (Madr) . 2018;46:210–217.
    1. Jartti T, Smits HH, Bønnelykke K, Bircan O, Elenius V, Konradsen JR, et al. EAACI Task Force on Clinical Practice Recommendations on Preschool Wheeze. Bronchiolitis needs a revisit: distinguishing between virus entities and their treatments. Allergy . 2019;74:40–52.
    1. Garcia-Marcos L, Mallol J, Solé D, Brand PL. EISL Study Group. International study of wheezing in infants: risk factors in affluent and non-affluent countries during the first year of life. Pediatr Allergy Immunol . 2010;21:878–888.
    1. Jartti T, Gern JE. Role of viral infections in the development and exacerbation of asthma in children. J Allergy Clin Immunol . 2017;140:895–906.
    1. Ascough S, Vlachantoni I, Kalyan M, Haijema BJ, Wallin-Weber S, Dijkstra-Tiekstra M, et al. Local and systemic immunity against respiratory syncytial virus induced by a novel intranasal vaccine: a randomized, double-blind, placebo-controlled clinical trial. Am J Respir Crit Care Med . 2019;200:481–492.
    1. Beigelman A, Bacharier LB. Management of preschool children with recurrent wheezing: lessons from the NHLBI’s asthma research networks. J Allergy Clin Immunol Pract . 2016;4:1–8, quiz 9–10.
    1. Beigelman A, Bacharier LB. Management of preschool recurrent wheezing and asthma: a phenotype-based approach. Curr Opin Allergy Clin Immunol . 2017;17:131–138.
    1. Beigelman A, Bacharier LB, Baty J, Buller R, Mason S, Schechtman KB, et al. Does azithromycin modify viral load during severe respiratory syncytial virus bronchiolitis? J Allergy Clin Immunol . 2015;136:1129–1131.
    1. Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A, Malice MP, et al. Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. Am J Respir Crit Care Med . 2008;178:854–860.
    1. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med . 2005;171:315–322.
    1. Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe . 2011;9:355–361.
    1. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: a program of innate immune memory in health and disease. Science . 2016;352:aaf1098.
    1. Ciarlo E, Heinonen T, Théroude C, Asgari F, Le Roy D, Netea MG, et al. Trained immunity confers broad-spectrum protection against bacterial infections. J Infect Dis . 2020;222:1869–1881.
    1. Cirauqui C, Benito-Villalvilla C, Sánchez-Ramón S, Sirvent S, Diez-Rivero CM, Conejero L, et al. Human dendritic cells activated with MV130 induce Th1, Th17 and IL-10 responses via RIPK2 and MyD88 signalling pathways. Eur J Immunol . 2018;48:180–193.
    1. Alecsandru D, Valor L, Sánchez-Ramón S, Gil J, Carbone J, Navarro J, et al. Sublingual therapeutic immunization with a polyvalent bacterial preparation in patients with recurrent respiratory infections: immunomodulatory effect on antigen-specific memory CD4+ T cells and impact on clinical outcome. Clin Exp Immunol . 2011;164:100–107.
    1. García González LA, Arrutia Díez F. Mucosal bacterial immunotherapy with MV130 highly reduces the need of tonsillectomy in adults with recurrent tonsillitis. Hum Vaccin Immunother . 2019;15:2150–2153.
    1. Guevara-Hoyer K, Saz-Leal P, Diez-Rivero CM, Ochoa-Grullón J, Fernández-Arquero M, Pérez de Diego R, et al. Trained immunity based-vaccines as a prophylactic strategy in common variable immunodeficiency: a proof of concept study. Biomedicines . 2020;8:203.
    1. Selva B, Nieto M, Bartoll E, Mazon A, Calaforra S, Calderón R, et al. Sublingual therapeutic immunotherapy with a polyvalent bacterial preparation in preschool children with recurrent respiratory tract infections [abstract] Allergy . 2017;72:196.
    1. Hall LC, García AN, Brandi P, Cid MN, Mazón A, Cueto FJ, et al. Bacterial immunotherapy in children with wheezing attacks: clinical impact and mechanism of action. Eur Respir J . 2019;54:PA4998.
    1. Teo SM, Tang HHF, Mok D, Judd LM, Watts SC, Pham K, et al. Airway microbiota dynamics uncover a critical window for interplay of pathogenic bacteria and allergy in childhood respiratory disease. Cell Host Microbe . 2018;24:341–352, e5.
    1. Liu L, Pan Y, Zhu Y, Song Y, Su X, Yang L, et al. Association between rhinovirus wheezing illness and the development of childhood asthma: a meta-analysis. BMJ Open . 2017;7:e013034.
    1. Dreborg S, Agrell B, Foucard T, Kjellman NI, Koivikko A, Nilsson S. A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation: I. Clinical results. Allergy . 1986;41:131–140.
    1. Gutiérrez-Tarango MD, Berber A. Safety and efficacy of two courses of OM-85 BV in the prevention of respiratory tract infections in children during 12 months. Chest . 2001;119:1742–1748.
    1. Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JL. Cochrane Review: immunostimulants for preventing respiratory tract infection in children. Evid Based Child Health . 2012;7:629–717.
    1. Esposito S, Soto-Martinez ME, Feleszko W, Jones MH, Shen KL, Schaad UB. Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence. Curr Opin Allergy Clin Immunol . 2018;18:198–209.
    1. Sackett D, Richardson S, Rosenberg W, Haynes R. Evidence-based medicine: how to practice and teach EBM. London: Churchill Livingstone; 1997.
    1. Kraan H, Vrieling H, Czerkinsky C, Jiskoot W, Kersten G, Amorij JP. Buccal and sublingual vaccine delivery. J Control Release . 2014;190:580–592.
    1. Negri DR, Riccomi A, Pinto D, Vendetti S, Rossi A, Cicconi R, et al. Persistence of mucosal and systemic immune responses following sublingual immunization. Vaccine . 2010;28:4175–4180.
    1. Benito-Villalvilla C, Cirauqui C, Diez-Rivero CM, Casanovas M, Subiza JL, Palomares O. MV140, a sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human dendritic cells for generating Th1, Th17, and IL-10 responses via Syk and MyD88. Mucosal Immunol . 2017;10:924–935.
    1. Lorenzo-Gómez MF, Padilla-Fernández B, García-Cenador MB, Virseda-Rodríguez AJ, Martín-García I, Sánchez-Escudero A, et al. Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections. Front Cell Infect Microbiol . 2015;5:50.
    1. Yang B, Foley S. First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune. BJU Int . 2018;121:289–292.
    1. Subiza JL, El-Qutob D, Fernandez-Caldas E. New developments in oral vaccines and mucosal adjuvants. Recent Pat Inflamm Allergy Drug Discov . 2015;9:4–15.
    1. Tejera-Alhambra M, Palomares O, Pérez de Diego R, Díaz-Lezcano I, Sánchez-Ramón S. New biological insights in the immunomodulatory effects of mucosal polybacterial vaccines in clinical practice. Curr Pharm Des . 2016;22:6283–6293.
    1. Razi CH, Harmancı K, Abacı A, Özdemir O, Hızlı S, Renda R, et al. The immunostimulant OM-85 BV prevents wheezing attacks in preschool children. J Allergy Clin Immunol . 2010;126:763–769.
    1. Sly PD, Galbraith S, Islam Z, Holt B, Troy N, Holt PG. Primary prevention of severe lower respiratory illnesses in at-risk infants using the immunomodulator OM-85. J Allergy Clin Immunol . 2019;144:870–872, e11.
    1. Edwards MR, Strong K, Cameron A, Walton RP, Jackson DJ, Johnston SL. Viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness. J Allergy Clin Immunol . 2017;140:909–920.
    1. Turi KN, Shankar J, Anderson LJ, Rajan D, Gaston K, Gebretsadik T, et al. Infant viral respiratory infection nasal immune-response patterns and their association with subsequent childhood recurrent wheeze. Am J Respir Crit Care Med . 2018;198:1064–1073.
    1. Sánchez-Ramón S, Conejero L, Netea MG, Sancho D, Palomares Ó, Subiza JL. Trained immunity-based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations. Front Immunol . 2018;9:2936.
    1. Molero-Abraham M, Sanchez-Trincado JL, Gomez-Perosanz M, Torres-Gomez A, Subiza JL, Lafuente EM, et al. Human oral epithelial cells impair bacteria-mediated maturation of dendritic cells and render T cells unresponsive to stimulation. Front Immunol . 2019;10:1434.
    1. Altman MC, Beigelman A, Ciaccio C, Gern JE, Heymann PW, Jackson DJ, et al. Evolving concepts in how viruses impact asthma: a work group report of the microbes in allergy committee of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol . 2020;145:1332–1344.
    1. Pasquali C, Salami O, Taneja M, Gollwitzer ES, Trompette A, Pattaroni C, et al. Enhanced mucosal antibody production and protection against respiratory infections following an orally administered bacterial extract. Front Med (Lausanne) . 2014;1:41.
    1. Bessler WG, Vor dem Esche U, Masihi N. The bacterial extract OM-85 BV protects mice against influenza and Salmonella infection. Int Immunopharmacol . 2010;10:1086–1090.
    1. Soerens AG, Da Costa A, Lund JM. Regulatory T cells are essential to promote proper CD4 T-cell priming upon mucosal infection. Mucosal Immunol . 2016;9:1395–1406.
    1. Rossi GA, Pohunek P, Feleszko W, Ballarini S, Colin AA. Viral infections and wheezing-asthma inception in childhood: is there a role for immunomodulation by oral bacterial lysates? Clin Transl Allergy . 2020;10:17.
    1. Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe . 2012;12:223–232.
    1. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA . 2012;109:17537–17542.
    1. Aaby P, Kollmann TR, Benn CS. Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges. Nat Immunol . 2014;15:895–899.
    1. Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG, et al. Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol . 2016;16:392–400.
    1. Uthayakumar D, Paris S, Chapat L, Freyburger L, Poulet H, De Luca K. Non-specific effects of vaccines illustrated through the BCG example: from observations to demonstrations. Front Immunol . 2018;9:2869.
    1. Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol . 2013;34:431–439.
    1. de Bree LCJ, Koeken VACM, Joosten LAB, Aaby P, Benn CS, van Crevel R, et al. Non-specific effects of vaccines: current evidence and potential implications. Semin Immunol . 2018;39:35–43.
    1. Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol . 2015;98:347–356.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj