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

Jakobsen, Håvard; Bjarnarson, Stefania P.; Giudice, Giuseppe Del; Moreau, Monique; Siegrist, Claire‐Anne; Jónsdóttir, Ingileif

doi:10.1128/iai.70.3.1443-1452.2002

Cited by 79 publications

(98 citation statements)

References 67 publications

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“…This impaired IgG2a response in neonatal mice was also shown by significantly higher IgG1/IgG2a ratio compared to adult mice (10.4 vs. 2.2; p = 0.014). In agreement with our previous results [34], the reduced protective efficacy of the Pnc1-TT vaccine in neonates was related to the impaired early life IgG response to its PS moiety and lack of IgG2a response.…”

Section: Resultssupporting

confidence: 93%

“…Our previous studies have shown that immunization of mice with conjugate vaccines can induce PS Abs and protective immunity in early infancy, but both immunogenicity and protective efficacy is significantly lower than in adults [34,42]. This murine infant immunization model against S. pneumoniae clearly reproduces the main features of human infant immune responses to native capsular PPS and pneumococcal conjugate vaccines, as shown for serotypes 1, 6B and 19F, as well as the relative protective efficacy of such vaccines.…”

Section: Discussionsupporting

confidence: 57%

“…Antibody responses to native PS are delayed during ontogeny and immunization with PS in the neonatal period fails to induce PS specific Ab responses [34,39]. However, a marked improvement in the immunogenicity of PS has been achieved by conjugation to various immunogenic proteins.…”

Section: Discussionmentioning

confidence: 99%

“…pneumococcal infection model. However, early life responses to conjugate vaccines were limited in an agedependent manner [34], and although this is without clinical relevance for Haemophilus influenzae type B (Hib) conjugate vaccines, given their strong immunogenicity and the low levels of Ab needed to protect against invasive Hib disease, it poses a challenge to induce early protection against less immunogenic pneumococcal serotypes, particularly against pneumonia for which high levels of Ab are needed. Agedependent limiting factors for Ab responses to conjugate vaccines have not yet been identified.…”

Section: Introductionmentioning

confidence: 99%

“…Such limitations could involve sub-optimal APC, T cell and/or B cell functions. To identify such age-related limitations, we used a neonatal and infant murine immunization and challenge model, recently shown to reproduce features of early life responses to pneumococcal conjugate vaccines [34]. The carrier-specific T cell responses to a TT-pneumococcal conjugate vaccine (Pnc1-TT) were investigated in mice in relation to PPS-specific Ab induced.…”

Section: Introductionmentioning

confidence: 99%

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Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

et al. 2006

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Immunization with a tetanus-protein (TT) pneumococcal polysaccharide (PPS) conjugate vaccine (Pnc1-TT) induces protective immunity against lethal pneumococcal infections in neonatal and infant mice, but anti-PPS IgG response and protective efficacy is lower than in adult mice. Here, we show that reduced antibody (Ab) response and protection against infections is directly related to impaired T cell response to the carrier. Whereas spleen cells from adult mice immunized with Pnc1-TT responded with proliferation and IFN-gamma secretion to in vitro stimulation with TT, spleen cells from neonatal and infant mice did not. However, significant, but age dependent, Th2-cytokine responses were observed in mice immunized with Pnc1-TT. Impaired IFN-gamma production upon TT-stimulation in vitro was also reflected in reduced IFN-gamma/IL-5 ratio. The IL--5 response correlated with IgG anti-PPS titers, and the lack of PPS Ab in the majority of neonatal mice was clearly associated with absence of carrier-specific IL-5 production. These results show that immunization with Pnc1-TT induces carrier-specific T cell responses that increase with age and determine the levels of PPS-specific Ab elicited. Whereas a weak and Th2-biased response was observed in neonatal mice, infant mice showed a mixed Th1-Th2 response as observed in adults

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

et al. 2006

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Adjuvants and Subunit Vaccines

Giudice¹,

Rappuoli²

2010

Topley &Amp; Wilson's Microbiology and Microbial Infections

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The advantage of mucosal immunization for polysaccharide‐specific memory responses in early life

et al. 2005

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The aim of vaccination is to rapidly elicit protective immunity and generate memory for sustained protection. We studied the induction and persistence of polysaccharide (PS)-specific memory in neonatal and infant mice primed with pneumococcal conjugate (Pnc1-TT) by assessing the response to native pneumococcal PS (PPS-1), the kinetics of the PPS-1-specific IgG response to a second Pnc1-TT dose and affinity maturation. A subcutaneous (s.c.) Pnc1-TT booster induced a rapid increase in PPS-1-specific IgG, indicating efficient priming for memory by a single dose of Pnc1-TT already at 1 week of age. High levels were maintained for >12 weeks. However, a PPS-1 booster induced no response in neonatal or infant mice. The adjuvant LT-K63 significantly enhanced the IgG response and affinity to Pnc1-TT by both the s.c. and the intranasal (i.n.) route in all age groups. In neonatal and infant mice, PPS-1 and LT-K63 induced a booster response only when given i.n. following either s.c. or i.n. priming with Pnc1-TT and LT-K63. In contrast, PPS-1 with or without LT-K63 administered s.c. compromised the ongoing PPS-1-specific response elicited in neonatal mice by either s.c. or i.n. priming with Pnc1-TT and LT-K63. These results demonstrate the advantage of the mucosal route for elicitation of PS-specific memory responses in early life.

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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

Abstract: Immunization with pneumococcal polysaccharides (PPS) conjugated to tetanus toxoid (TT)(

Cited by 79 publications

References 67 publications

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

Adjuvants and Subunit Vaccines

The advantage of mucosal immunization for polysaccharide‐specific memory responses in early life

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