Intranasal Immunization with Pneumococcal Polysaccharide Conjugate Vaccines with Nontoxic Mutants of Escherichia coli Heat-Labile Enterotoxins as Adjuvants Protects Mice against Invasive Pneumococcal Infections

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Infection and Immunity, November 1999, p. 5892-5897, Vol. 67, No. 11
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Intranasal Immunization with Pneumococcal Polysaccharide Conjugate Vaccines with Nontoxic Mutants of Escherichia coli Heat-Labile Enterotoxins as Adjuvants Protects Mice against Invasive Pneumococcal Infections

Håvard Jakobsen,¹ Dominique Schulz,² Mariagrazia Pizza,³ Rino Rappuoli,³ and Ingileif Jónsdóttir¹^,^*

National University Hospital, Department of Immunology, 101 Reykjavík, Iceland¹; Pasteur Mérieux Connaught, Marcy l'Etoile, France²; and Immunobiology Research Institute Siena, 53100 Siena, Italy³

Received 6 May 1999/Returned for modification 16 July 1999/Accepted 27 August 1999

Host defenses against Streptococcus pneumoniae depend largely on phagocytosis following opsonization by polysaccharide-specificimmunoglobulin G (IgG) antibodies and complement. Since colonizationof the respiratory mucosa is the first step in pneumococcal pathogenesis,mucosal immune responses may play a significant role. In additionto inducing systemic immune responses, mucosal vaccination withan effective adjuvant has the advantage of inducing mucosal IgAantibodies. The heat-labile enterotoxin (LT) of Escherichia coliis a well-studied mucosal adjuvant, and adjuvant activity of nontoxicLT mutants has been demonstrated for several protein antigens.We investigated the immunogenicity of pneumococcal polysaccharideconjugate vaccines (PNC) of serotypes 1 and 3 in mice after intranasal(i.n.) immunization by using as an adjuvant the nontoxic LT mutantLT-K63 or LT-R72, which has minimal residual toxicity. Pneumococcalserotype-specific antibodies were measured in serum (IgM, IgG,and IgA) and saliva (IgA), and vaccine-induced protection wasevaluated by i.n. challenge with virulent pneumococci of the homologousserotype. When administered with LT mutants, i.n. immunizationwith both conjugates induced systemic and mucosal immune responses,and serum IgG antibody levels were significantly higher than aftersubcutaneous immunization. All mice immunized i.n. with PNC-1and LT mutants were protected against bacteremia and cleared thepneumococci from the lung 24 h after i.n. challenge; pneumococcaldensity correlated significantly with serum IgG antibody levels.Similarly, the survival of mice immunized i.n. with PNC-3 andLT mutants was significantly prolonged. These results demonstratethat i.n. vaccination with PNC and potent adjuvants can protectmice against invasive and lethal pneumococcal infections, indicatingthat mucosal vaccination with PNC may be an alternative vaccinationstrategy forhumans.

^* Corresponding author. Mailing address: Department of Immunology, National University Hospital, 101 Reykjavík, Iceland. Phone:354-5601962. Fax: 354-5601943. E-mail: ingileif{at}rsp.is.

Infection and Immunity, November 1999, p. 5892-5897, Vol. 67, No. 11
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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