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Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice.

ABSTRACT: Streptococcus pneumoniae is an important human pathogen causing both mucosal (otitis media and pneumonia) and systemic (sepsis and meningitis) diseases. Due to increasing rates of antibiotic resistance, there is an urgent need to improve prevention of pneumococcal disease. Two currently licensed vaccines have been successful in reducing pneumococcal disease, but there are limitations with their use and effectiveness. Another approach for prevention is the use of live attenuated vaccines. Here we investigate the safety and protection induced by live attenuated strains of S. pneumoniae containing combinations of deletions in genes encoding three of its major virulence determinants: capsular polysaccharide (cps), pneumolysin (ply), and pneumococcal surface protein A (pspA). Both the cps and ply/pspA mutants of a virulent type 6A isolate were significantly attenuated in a mouse model of sepsis. These attenuated strains retained the ability to colonize the upper respiratory tract. A single intranasal administration of live attenuated vaccine without adjuvant was sufficient to induce both systemic and mucosal protection from challenge with a high dose of the parent strain. Immunization with cps mutants demonstrated cross-protective immunity following challenge with a distantly related isolate. Serum and mucosal antibody titers were significantly increased in mice immunized with the vaccine strains, and this antibody is required for full protection, as microMT mice, which do not make functional, specific antibody, were not protected by immunization with vaccine strains. Thus, colonization by live attenuated S. pneumoniae is a potentially safe and less complex vaccine strategy that may offer broad protection.

SUBMITTER: Roche AM

PROVIDER: S-EPMC1865756 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice.

Roche Aoife M AM King Samantha J SJ Weiser Jeffrey N JN

Infection and immunity 20070305 5

Streptococcus pneumoniae is an important human pathogen causing both mucosal (otitis media and pneumonia) and systemic (sepsis and meningitis) diseases. Due to increasing rates of antibiotic resistance, there is an urgent need to improve prevention of pneumococcal disease. Two currently licensed vaccines have been successful in reducing pneumococcal disease, but there are limitations with their use and effectiveness. Another approach for prevention is the use of live attenuated vaccines. Here we ...[more]

PMID: 17339359

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Project description:Community interactions at mucosal surfaces between viruses, like influenza virus, and respiratory bacterial pathogens are important contributors toward pathogenesis of bacterial disease. What has not been considered is the natural extension of these interactions to live attenuated immunizations, and in particular, live attenuated influenza vaccines (LAIVs). Using a mouse-adapted LAIV against influenza A (H3N2) virus carrying the same mutations as the human FluMist vaccine, we find that LAIV vaccination reverses normal bacterial clearance from the nasopharynx and significantly increases bacterial carriage densities of the clinically important bacterial pathogens Streptococcus pneumoniae (serotypes 19F and 7F) and Staphylococcus aureus (strains Newman and Wright) within the upper respiratory tract of mice. Vaccination with LAIV also resulted in 2- to 5-fold increases in mean durations of bacterial carriage. Furthermore, we show that the increases in carriage density and duration were nearly identical in all aspects to changes in bacterial colonizing dynamics following infection with wild-type (WT) influenza virus. Importantly, LAIV, unlike WT influenza viruses, had no effect on severe bacterial disease or mortality within the lower respiratory tract. Our findings are, to the best of our knowledge, the first to demonstrate that vaccination with a live attenuated viral vaccine can directly modulate colonizing dynamics of important and unrelated human bacterial pathogens, and does so in a manner highly analogous to that seen following wild-type virus infection.Following infection with an influenza virus, infected or recently recovered individuals become transiently susceptible to excess bacterial infections, particularly Streptococcus pneumoniae and Staphylococcus aureus. Indeed, in the absence of preexisting comorbidities, bacterial infections are a leading cause of severe disease during influenza epidemics. While this synergy has been known and is well studied, what has not been explored is the natural extension of these interactions to live attenuated influenza vaccines (LAIVs). Here we show, in mice, that vaccination with LAIV primes the upper respiratory tract for increased bacterial growth and persistence of bacterial carriage, in a manner nearly identical to that seen following wild-type influenza virus infections. Importantly, LAIV, unlike wild-type virus, did not increase severe bacterial disease of the lower respiratory tract. These findings may have consequences for individual bacterial disease processes within the upper respiratory tract, as well as bacterial transmission dynamics within LAIV-vaccinated populations.

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Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice.

Publications

Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice.

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