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Infection and Immunity, March 2002, p. 1443-1452, Vol. 70, No. 3
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.3.1443-1452.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Intranasal Immunization with Pneumococcal Conjugate Vaccines with LT-K63, a Nontoxic Mutant of Heat-Labile Enterotoxin, as Adjuvant Rapidly Induces Protective Immunity against Lethal Pneumococcal Infections in Neonatal Mice

Håvard Jakobsen,1 Stefania Bjarnarson,1 Giuseppe Del Giudice,2 Monique Moreau,3 Claire-Anne Siegrist,4 and Ingileif Jonsdottir1*

Department of Immunology, Landspitali-University Hospital, Reykjavik, Iceland,1 IRIS, Chiron SpA, Siena, Italy,2 Aventis Pasteur, Marcy l'Etoile, France,3 World Health Organization Collaborating Centre for Neonatal Vaccinology and Immunology, University of Geneva, Geneva, Switzerland4

Received 21 September 2001/ Returned for modification 26 November 2001/ Accepted 21 December 2001

Immunization with pneumococcal polysaccharides (PPS) conjugated to tetanus toxoid (TT) (Pnc-TT) elicits protective immunity in an adult murine pneumococcal infection model. To assess immunogenicity and protective immunity in early life, neonatal (1 week old) and infant (3 weeks old) mice were immunized intranasally (i.n.) or subcutaneously (s.c.) with Pnc-TT of serotype 1 (Pnc1-TT). Anti-PPS-1 and anti-TT immunoglobulin G (IgG) and IgM antibodies were measured in serum and saliva, and vaccine-induced protection was evaluated by i.n. challenge with serotype 1 pneumococci. Pnc1-TT was immunogenic in neonatal and infant mice when administered s.c. without adjuvant: a majority of the young mice were protected from bacteremia and a reduction of pneumococcal density in the lungs was observed, although antibody responses and protective efficacy remained lower than in adults. The addition of LT-K63, a nontoxic mutant of heat-labile enterotoxin, as adjuvant significantly enhanced PPS-1-specific IgG responses and protective efficacy following either s.c. or i.n. Pnc1-TT immunization. Mucosal immunization was particularly efficient in neonates, as a single i.n. dose of Pnc1-TT and LT-K63 induced significantly higher PPS-1-specific IgG responses than s.c. immunization and was sufficient to protect neonatal mice against pneumococcal infections, whereas two s.c. doses were required to induce complete protection. In addition, i.n. immunization with Pnc1-TT and LT-K63 induced a vigorous salivary IgA response. This suggests that mucosal immunization with pneumococcal conjugate vaccines and LT-K63 may be able to circumvent some of the limitations of neonatal antibody responses, which are required for protective immunity in early life.

* Corresponding author. Mailing address: Department of Immunology, Landspitali-University Hospital, 101 Reykjavik, Iceland. Phone: (354) 5601962. Fax: (354) 5601943. E-mail: ingileif{at}landspitali.is.

Infection and Immunity, March 2002, p. 1443-1452, Vol. 70, No. 3
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.3.1443-1452.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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