Lactococcus lactis-based vaccines from laboratory bench to human use: an overview.

Developing effective vaccines is an important weapon in the battle against potential pathogens and their evolving antibiotic resistance trends. Several vaccine delivery vectors have been investigated among which the generally regarded as safe (GRAS) Lactococcus lactis has a distinguished position. In this review, different factors affecting the efficacy of L. lactis-based vaccines are discussed. In addition, the issues of biological containment and pharmaceutical quality assurance of L. lactis vaccines are highlighted. These issues are critical for the success of medical translation of L. lactis-based vaccines from research laboratories to clinical use by ensuring consistent manufacturing of safe and efficacious vaccines.

[1]  A. Eisenstark,et al.  Thymine metabolism and thymineless death in prokaryotes and eukaryotes. , 1998, Annual review of microbiology.

[2]  T. Klaenhammer,et al.  Development of an Expression Strategy Using a Lytic Phage to Trigger Explosive Plasmid Amplification and Gene Expression† , 1996, Bio/Technology.

[3]  S. Knudsen,et al.  Development and testing of improved suicide functions for biological containment of bacteria , 1995, Applied and environmental microbiology.

[4]  J. Villena,et al.  Administration of a probiotic associated with nasal vaccination with inactivated Lactococcus lactis‐PppA induces effective protection against pneumoccocal infection in young mice , 2010, Clinical and experimental immunology.

[5]  Plasmids of lactococci - genetic accessories or genetic necessities? , 2006, FEMS microbiology reviews.

[6]  Erik Remaut,et al.  A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[7]  G. Corthier,et al.  Bovine Rotavirus Nonstructural Protein 4 Produced by Lactococcus lactis Is Antigenic and Immunogenic , 2001, Applied and Environmental Microbiology.

[8]  G. Robillard,et al.  Mucosal vaccine delivery of antigens tightly bound to an adjuvant particle made from food-grade bacteria. , 2006, Methods.

[9]  J. Wells,et al.  Oral vaccination of mice against tetanus with recombinant Lactococcus lactis , 1997, Nature Biotechnology.

[10]  Michiel Kleerebezem,et al.  10 years of the nisin-controlled gene expression system (NICE) in Lactococcus lactis , 2005, Applied Microbiology and Biotechnology.

[11]  J. Wells,et al.  Mucosal and Cellular Immune Responses Elicited by Recombinant Lactococcus lactis Strains Expressing Tetanus Toxin Fragment C , 2004, Infection and Immunity.

[12]  C. Daniel,et al.  Protection against Yersinia pseudotuberculosis infection conferred by a Lactococcus lactis mucosal delivery vector secreting LcrV. , 2009, Vaccine.

[13]  R. Raya,et al.  Oral immunization with recombinant Lactococcus lactis confers protection against respiratory pneumococcal infection. , 2008, Canadian Journal of Microbiology (print).

[14]  C. Guzmán,et al.  Use of live bacterial vaccine vectors for antigen delivery: potential and limitations. , 2001, Vaccine.

[15]  C. Cantor,et al.  Streptavidin-based containment systems for genetically engineered microorganisms. , 1999, Biomolecular engineering.

[16]  Y. Le Loir,et al.  Intranasal Immunization with Recombinant Lactococcus lactis Secreting Murine Interleukin-12 Enhances Antigen-Specific Th1 Cytokine Production , 2003, Infection and Immunity.

[17]  T. Okamoto,et al.  Survival of lactococci during passage through mouse digestive tract. , 2003, Canadian journal of microbiology.

[18]  P. Langella,et al.  Nasal administration of Lactococcus lactis improves local and systemic immune responses against Streptococcus pneumoniae , 2008, Microbiology and immunology.

[19]  S. Winter,et al.  Pre-existing anti-Salmonella vector immunity prevents the development of protective antigen-specific CD8 T-cell frequencies against murine listeriosis. , 2007, Microbes and infection.

[20]  Barry C Buckland,et al.  The process development challenge for a new vaccine , 2005, Nature Medicine.

[21]  P. Renault,et al.  Survival, Physiology, and Lysis ofLactococcus lactis in the Digestive Tract , 1999, Applied and Environmental Microbiology.

[22]  G. Geginat,et al.  Protection Against Murine Listeriosis by Oral Vaccination with Recombinant Salmonella Expressing Hybrid Yersinia Type III Proteins1 , 2001, The Journal of Immunology.

[23]  C. Eichwald,et al.  Rotavirus vp7 antigen produced by Lactococcus lactis induces neutralizing antibodies in mice , 2005, Journal of applied microbiology.

[24]  J. Lieberman,et al.  Live attenuated Listeria monocytogenes expressing HIV Gag: immunogenicity in rhesus monkeys. , 2007, Vaccine.

[25]  E. Remaut,et al.  Intracellular Accumulation of Trehalose Protects Lactococcus lactis from Freeze-Drying Damage and Bile Toxicity and Increases Gastric Acid Resistance , 2006, Applied and Environmental Microbiology.

[26]  K. Hamajima,et al.  Immunogenicity and protective efficacy of orally administered recombinant Lactococcus lactis expressing surface-bound HIV Env. , 2003, Blood.

[27]  J. Wells,et al.  Mucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteria , 2008, Nature Reviews Microbiology.

[28]  B. Coulie,et al.  Actobiotics™ as a Novel Method for Cytokine Delivery , 2009, Annals of the New York Academy of Sciences.

[29]  A. T. Carter,et al.  Mucosal delivery of a pneumococcal vaccine using Lactococcus lactis affords protection against respiratory infection. , 2007, The Journal of infectious diseases.

[30]  Jean Paul Remon,et al.  Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10 , 2003, Nature Biotechnology.

[31]  W. Hinrichs,et al.  Intranasal Delivery of Influenza Subunit Vaccine Formulated with GEM Particles as an Adjuvant , 2010, The AAPS Journal.

[32]  J. Wells,et al.  Mucosal Immunization with Recombinant Lactococcus lactis , 1997 .

[33]  G. Moorthy,et al.  Mucosal immunisation of mice with malaria protein on lactic acid bacterial cell walls. , 2007, Vaccine.

[34]  W. Hinrichs,et al.  Influenza antigen-sparing by immune stimulation with Gram-positive enhancer matrix (GEM) particles. , 2010, Vaccine.

[35]  B. Griffin,et al.  Efficacy of a Lactococcus lactis ΔpyrG vaccine delivery platform expressing chromosomally integrated hly from Listeria monocytogenes , 2010, Bioengineered bugs.

[36]  W. Goebel,et al.  Listeria Pathogenesis and Molecular Virulence Determinants , 2001, Clinical Microbiology Reviews.

[37]  J. Remon,et al.  Development of an enteric-coated formulation containing freeze-dried, viable recombinant Lactococcus lactis for the ileal mucosal delivery of human interleukin-10. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[38]  W. D. de Vos,et al.  Characterization of the Lactococcus lactis lactose operon promoter: contribution of flanking sequences and LacR repressor to promoter activity , 1992, Journal of bacteriology.

[39]  B. Griffin,et al.  Lactococcus lactis as a cell factory for delivery of therapeutic proteins. , 2010, Current gene therapy.

[40]  Y. Le Loir,et al.  Heterologous protein production and delivery systems for Lactococcus lactis. , 2003, Genetics and molecular research : GMR.

[41]  K. Kim,et al.  A food-grade expression/secretion vector for Lactococcus lactis that uses an alpha-galactosidase gene as a selection marker. , 2006, Food microbiology.

[42]  M. Mock,et al.  Intracytoplasmic delivery of listeriolysin O by a vaccinal strain of Bacillus anthracis induces CD8-mediated protection against Listeria monocytogenes. , 1997, Journal of immunology.

[43]  Willem M. de Vos,et al.  Genetics of lactose utilization in lactic acid bacteria , 1994 .

[44]  Y. Le Loir,et al.  Protein secretion in Lactococcus lactis : an efficient way to increase the overall heterologous protein production , 2005, Microbial cell factories.

[45]  R. Raya,et al.  Nasal Immunization with Lactococcus lactis Expressing the Pneumococcal Protective Protein A Induces Protective Immunity in Mice , 2008, Infection and Immunity.

[46]  C. Hill,et al.  A Food-Grade Approach for Functional Analysis and Modification of Native Plasmids in Lactococcus lactis , 2003, Applied and Environmental Microbiology.

[47]  E. Pamer.  Immune responses to Listeria monocytogenes , 2004, Nature Reviews Immunology.

[48]  B. Griffin,et al.  Expression of two Listeria monocytogenes antigens (P60 and LLO) in Lactococcus lactis and examination for use as live vaccine vectors. , 2010, Journal of medical microbiology.

[49]  G. Venemâ,et al.  Isolation and characterization of Streptococcus cremoris Wg2-specific promoters , 1987, Applied and environmental microbiology.

[50]  M. Gasson,et al.  Lactococcus lactis: high‐level expression of tetanus toxin fragment C and protection against lethal challenge , 1993, Molecular microbiology.

[51]  G. Robillard,et al.  Lactococcus lactis GEM particles displaying pneumococcal antigens induce local and systemic immune responses following intranasal immunization. , 2006, Vaccine.

[52]  B. Griffin,et al.  Lactococcus lactis-expressing listeriolysin O (LLO) provides protection and specific CD8+ T cells against Listeria monocytogenes in the murine infection model , 2008, Vaccine.

[53]  Ramasamy,et al.  Immunogenicity of a malaria parasite antigen displayed by Lactococcus lactis in oral , 2006 .

[54]  H. Xiang,et al.  Expression of SARS-coronavirus nucleocapsid protein in Escherichia coli and Lactococcus lactis for serodiagnosis and mucosal vaccination , 2005, Applied Microbiology and Biotechnology.

[55]  Y. Le Loir,et al.  An inducible surface presentation system improves cellular immunity against human papillomavirus type 16 E7 antigen in mice after nasal administration with recombinant lactococci. , 2004, Journal of medical microbiology.

[56]  W. Picking,et al.  Neonatal mucosal immunization with a non-living, non-genetically modified Lactococcus lactis vaccine carrier induces systemic and local Th1-type immunity and protects against lethal bacterial infection , 2009, Mucosal Immunology.

[57]  V. Chow,et al.  Induction of neutralizing antibodies against dengue virus type 2 upon mucosal administration of a recombinant Lactococcus lactis strain expressing envelope domain III antigen. , 2008, Vaccine.

[58]  S. Rabot,et al.  A Novel Mucosal Vaccine Based on Live Lactococci Expressing E7 Antigen and IL-12 Induces Systemic and Mucosal Immune Responses and Protects Mice against Human Papillomavirus Type 16-Induced Tumors , 2005, The Journal of Immunology.

[59]  M. Wilks,et al.  Expression of Helicobacter pylori urease subunit B gene in Lactococcus lactis MG1363 and its use as a vaccine delivery system against H. pylori infection in mice. , 2001, Vaccine.

[60]  I. Margarit,et al.  Use of Lactococcus lactis expressing pili from group B Streptococcus as a broad-coverage vaccine against streptococcal disease. , 2006, The Journal of infectious diseases.

[61]  K. I. Sørensen,et al.  A Food-Grade Cloning System for Industrial Strains of Lactococcus lactis , 2000, Applied and Environmental Microbiology.

[62]  J. Remon,et al.  Evaluation of extrusion/spheronisation, layering and compaction for the preparation of an oral, multi-particulate formulation of viable, hIL-10 producing Lactococcus lactis. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[63]  G. Robillard,et al.  Novel Surface Display System for Proteins on Non-Genetically Modified Gram-Positive Bacteria , 2006, Applied and Environmental Microbiology.

[64]  K. Leenhouts,et al.  Development of lactococcal GEM-based pneumococcal vaccines. , 2007, Vaccine.

[65]  Y. Le Loir,et al.  Heterologous expression of Brucella abortus GroEL heat-shock protein in Lactococcus lactis , 2006, Microbial cell factories.

[66]  E. Remaut,et al.  Mucosal Delivery of Murine Interleukin-2 (IL-2) and IL-6 by Recombinant Strains of Lactococcus lactis Coexpressing Antigen and Cytokine , 1998, Infection and Immunity.

[67]  J. Villena,et al.  Stimulation of respiratory immunity by oral administration of Lactococcus lactis. , 2008, Canadian journal of microbiology.

[68]  J. García,et al.  A gene containment strategy based on a restriction-modification system. , 2000, Environmental microbiology.

[69]  G. Venema,et al.  A system to generate chromosomal mutations in Lactococcus lactis which allows fast analysis of targeted genes , 1995, Journal of bacteriology.