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Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial

Abstract

Background/Objectives:

Live-attenuated influenza vaccine (LAIV) protects against influenza by mucosal activation of the immune system. Studies in animals and adults have demonstrated that probiotics improve the immune response to mucosally delivered vaccines. We hypothesized that Lactobacillus GG (LGG) would function as an immune adjuvant to increase rates of seroconversion after LAIV administration.

Subjects/Methods:

We conducted a randomized double-blind placebo-controlled pilot study to determine whether LGG improved rates of seroconversion after administration of LAIV. We studied 42 healthy adults during the 2007–2008 influenza season. All subjects received LAIV and then were randomized to LGG or placebo, twice daily for 28 days. Hemagglutinin inhibition titers were assessed at baseline, at day 28 and at day 56 to determine the rates of seroconversion. Subjects were assessed for adverse events throughout the study period.

Results:

A total of 39 subjects completed the per-protocol analysis. Both LGG and LAIV were well tolerated. Protection rates against the vaccine H1N1 and B strains were suboptimal in subjects receiving LGG and placebo. For the H3N2 strain, 84% receiving LGG vs 55% receiving placebo had a protective titer 28 days after vaccination (odds of having a protective titer was 1.84 95% confidence interval 1.04–3.22, P=0.048).

Conclusion:

Lactobacillus GG is potential as an important adjuvant to improve influenza vaccine immunogenicity. Future studies of probiotics as immune adjuvants might need to specifically consider examining vaccine-naïve or sero-negative subjects, target mucosal immune responses or focus on groups known to have poor response to influenza vaccines.

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References

  • Alvarez MM, Lopez-Pacheco F, guilar-Yanez JM, Portillo-Lara R, Mendoza-Ochoa GI, Garcia-Echauri S et al. (2010). Specific recognition of influenza A/H1N1/2009 antibodies in human serum: a simple virus-free ELISA method. PLoS One 5, e10176.

    Article  PubMed  PubMed Central  Google Scholar 

  • Beyer WE, Palache AM, de Jong JC, Osterhaus AD (2002). Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis. Vaccine 20, 1340–1353.

    Article  CAS  PubMed  Google Scholar 

  • Boge T, Remigy M, Vaudaine S, Tanguy J, Bourdet-Sicard R, van der WS (2009). A probiotic fermented dairy drink improves antibody response to influenza vaccination in the elderly in two randomised controlled trials. Vaccine 27, 5677–5684.

    Article  CAS  PubMed  Google Scholar 

  • Bridges CB, Thompson WW, Meltzer MI, Reeve GR, Talamonti WJ, Cox NJ et al. (2000). Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA 284, 1655–1663.

    Article  CAS  PubMed  Google Scholar 

  • Bunout D, Barrera G, Hirsch S, Gattas V, de la Maza MP, Haschke F et al. (2004). Effects of a nutritional supplement on the immune response and cytokine production in free-living Chilean elderly. JPEN J Parenter Enteral Nutr 28, 348–354.

    Article  CAS  PubMed  Google Scholar 

  • Centers for Disease Control, Prevention (2010). Licensure of a high-dose inactivated influenza vaccine for persons aged ≥65 years (Fluzone High-Dose) and guidance for use—United States, 2010. MMWR Morb Mortal Wkly Rep 59, 485–486.

    Google Scholar 

  • Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N et al. (2009). Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med 361, 2424–2435.

    Article  CAS  PubMed  Google Scholar 

  • Cooper CL, Davis HL, Morris ML, Efler SM, Krieg AM, Li Y et al. (2004). Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine. Vaccine 22, 3136–3143.

    Article  CAS  PubMed  Google Scholar 

  • De Villiers PJ, Steele AD, Hiemstra LA, Rappaport R, Dunning AJ, Gruber WC et al. (2009). Efficacy and safety of a live attenuated influenza vaccine in adults 60 years of age and older 1. Vaccine 28, 228–234.

    Article  PubMed  Google Scholar 

  • De Vrese M, Rautenberg P, Laue C, Koopmans M, Herremans T, Schrezenmeir J (2005). Probiotic bacteria stimulate virus-specific neutralizing antibodies following a booster polio vaccination. Eur J Nutr 44, 406–413.

    Article  CAS  PubMed  Google Scholar 

  • Fang H, Elina T, Heikki A, Seppo S (2000). Modulation of humoral immune response through probiotic intake. FEMS Immunol Med Microbiol 29, 47–52.

    Article  CAS  PubMed  Google Scholar 

  • Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA et al. (2010). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep 59, 1–62.

    PubMed  Google Scholar 

  • Frey S, Poland G, Percell S, Podda A (2003). Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults. Vaccine 21, 4234–4237.

    Article  CAS  PubMed  Google Scholar 

  • Harata G, He F, Hiruta N, Kawase M, Kubota A, Hiramatsu M et al. (2010). Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses 2. Lett Appl Microbiol 50, 597–602.

    Article  CAS  PubMed  Google Scholar 

  • Hatakka K, Savilahti E, Ponka A, Meurman JH, Poussa T, Nase L et al. (2001). Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. BMJ 322, 1327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hojsak I, Abdovic S, Szajewska H, Milosevic M, Krznaric Z, Kolacek S (2010). Lactobacillus GG in the prevention of nosocomial gastrointestinal and respiratory tract infections. Pediatrics 125, e1171–e1177.

    Article  PubMed  Google Scholar 

  • Holland D, Booy R, De LF, Eizenberg P, McDonald J, Karrasch J et al. (2008). Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 198, 650–658.

    Article  PubMed  Google Scholar 

  • Isolauri E, Joensuu J, Suomalainen H, Luomala M, Vesikari T (1995). Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Vaccine 13, 310–312.

    Article  CAS  PubMed  Google Scholar 

  • Jefferson TO, Rivetti D, Di PC, Rivetti A, Demicheli V (2010). Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 1, CD001269.

    Google Scholar 

  • Kawase M, He F, Kubota A, Harata G, Hiramatsu M (2010). Oral administration of lactobacilli from human intestinal tract protects mice against influenza virus infection 3. Lett Appl Microbiol 51, 6–10.

    CAS  PubMed  Google Scholar 

  • Link-Amster H, Rochat F, Saudan KY, Mignot O, Aeschlimann JM (1994). Modulation of a specific humoral immune response and changes in intestinal flora mediated through fermented milk intake. FEMS Immunol Med Microbiol 10, 55–63.

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Jacobson DL, Ashworth LA, Grand RJ, Meyer AL, McNeal MM et al. (2009). Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol 104, 444–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacDonald TT, Bell I (2010). Probiotics and the immune response to vaccines. Proc Nutr Soc 69, 442–446.

    Article  CAS  PubMed  Google Scholar 

  • Monto AS, Ohmit SE, Petrie JG, Johnson E, Truscon R, Teich E et al. (2009). Comparative efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med 361, 1260–1267.

    Article  CAS  PubMed  Google Scholar 

  • Muszkat M, Greenbaum E, Ben Yehuda A, Oster M, Yeu′l E, Heimann S et al. (2003). Local and systemic immune response in nursing-home elderly following intranasal or intramuscular immunization with inactivated influenza vaccine. Vaccine 21, 1180–1186.

    Article  CAS  PubMed  Google Scholar 

  • Nichol KL, Mendelman PM, Mallon KP, Jackson LA, Gorse GJ, Belshe RB et al. (1999). Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA 282, 137–144.

    Article  CAS  PubMed  Google Scholar 

  • Nichol KL, Treanor JJ (2006). Vaccines for seasonal and pandemic influenza. J Infect Dis 194 (Suppl 2), S111–S118.

    Article  PubMed  Google Scholar 

  • Ohmit SE, Gross J, Victor JC, Monto AS (2009). Reduced reaction frequencies with repeated inactivated or live-attenuated influenza vaccination. Vaccine 27, 1050–1054.

    Article  PubMed  Google Scholar 

  • Ohmit SE, Victor JC, Rotthoff JR, Teich ER, Truscon RK, Baum LL et al. (2006). Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 355, 2513–2522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olivares M, az-Ropero MP, Sierra S, Lara-Villoslada F, Fonolla J, Navas M et al. (2007). Oral intake of Lactobacillus fermentum CECT5716 enhances the effects of influenza vaccination. Nutrition 23, 254–260.

    Article  CAS  PubMed  Google Scholar 

  • Sasaki S, He XS, Holmes TH, Dekker CL, Kemble GW, Arvin AM et al. (2008). Influence of prior influenza vaccination on antibody and B-cell responses. PLoS One 3, e2975.

    Article  PubMed  PubMed Central  Google Scholar 

  • Soh SE, Ong DQ, Gerez I, Zhang X, Chollate P, Shek LP et al. (2010). Effect of probiotic supplementation in the first 6 months of life on specific antibody responses to infant Hepatitis B vaccination. Vaccine 28, 2577–2579.

    Article  CAS  PubMed  Google Scholar 

  • Treanor J, Wright PF (2003). Immune correlates of protection against influenza in the human challenge model. Dev Biol (Basel) 115, 97–104.

    CAS  Google Scholar 

  • Wang Z, Tobler S, Roayaei J, Eick A (2009). Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel. JAMA 301, 945–953.

    Article  CAS  PubMed  Google Scholar 

  • Wilde JA, McMillan JA, Serwint J, Butta J, O′Riordan MA, Steinhoff MC (1999). Effectiveness of influenza vaccine in health care professionals: a randomized trial. JAMA 281, 908–913.

    Article  CAS  PubMed  Google Scholar 

  • Yasui H, Kiyoshima J, Hori T (2004). Reduction of influenza virus titer and protection against influenza virus infection in infant mice fed Lactobacillus Casei Shirota. Clin Diagn Lab Immunol 11, 675–679.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully acknowledge Irina Andreyeva, Leah Morey, Katie Jors and Dr Ambarish Athavale for their assistance in patient recruitment and study visits. This study was supported by NIH grant M01RR00054 and from Amerifit Brands, Cromwell, CT, USA. Please note that the Laboratory for Specialized Clinical Studies, located at the Cincinnati Children's Hospital Medical Center, was contracted to run the HAI assays on the sera. The lab was blinded to the treatment and vaccine given to study subjects. This lab does contract work with a number of sponsors, but has no conflict of interest and received no financial gain because of the results of this study.

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Correspondence to L E Davidson.

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Davidson, L., Fiorino, AM., Snydman, D. et al. Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial. Eur J Clin Nutr 65, 501–507 (2011). https://doi.org/10.1038/ejcn.2010.289

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