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ThesisUniversity of Iceland>Heilbrigðisvísindasvið>Doktorsritgerðir>

Please use this identifier to cite or link to this item: http://hdl.handle.net/1946/2451

Title
is

Pneumococcal conjugate vaccines in Icelandic infants: Safety, immunogenicity and protective capacities

Abstract
is

Streptococcus pneumoniae (pneumococcus) is a major pathogen causing infection and death among infants and young children. Pneumococcal capsular polysaccharides (PPS) are T-cell independent antigens, unable to induce isotype switching and immunological memory in infants whereas PPS conjugated to proteins are T-cell dependent antigens, immunogenic at an early age.
The aim of the studies behind this PhD thesis was to investigate in Icelandic infants new pneumococcal conjugate vaccines (PCVs) asking the following questions: Are PCVs safe in infants? Do PCVs induce functional antibodies in infants? Can antibody responses to PCV be influenced by different protein carriers? Can immunogenicity of PCV be enhanced by mixing two conjugates of the same PPS with two different protein carriers? Can infants be successfully vaccinated with two primary PCV doses compared to three? Does PCV induce short-term and long-term immunological memory and does a booster with a 23-valent pneumococcal polysaccharide vaccine (PPV23) compromise the long term immunological memory? Does the PCV vaccination affect the nasopharyngeal carriage of pneumococci or influence the rate of otitis media and use of antibiotics?
Methods: Healthy infants were vaccinated with PCV administered concomitantly with regular infant vaccines. Serotype 6B-tetanus toxoid conjugate (6B-TT) was given to two infant age groups of different ages and compared to adults. Two protein carriers were compared by randomizing 8-valent diphtheria toxoid (PCV8-DT) or tetanus toxoid (PCV8-TT) PCVs and a booster with the same PCV or a full dose PPV23. An 11-valent DT and/or TT PCV (F3bis; two carriers for 6B, 9V, 18C and 23F) was first investigated in toddlers and then compared in infants with an 11-valent F3 single DT/TT carrier PCV. Two vs. three infant PCV doses were compared in a study on a 9-valent pneumococcal/meningococcal C saccharides conjugated with the cross reacting material 197 (CRM197) (9vPnCCMnCC) and a booster with PCV or PPV23. The comparison between vaccine formulations was done in a randomized design. The side-effects were recorded. Antibodies were measured by ELISA before and after primary and booster vaccinations and protective capacities evaluated in-vitro by opsonophagocytosis and in vivo in a mouse model of pneumococcal infection. Long-term memory to PCV-TT and the effect of full dose PPV23 booster at 13 months on immunological memory was investigated at 7 years of age. Nasopharyngeal cultures were obtained between 4 – 30 months of age. History of acute otitis media (AOM) and antibiotic treatments were compared with unvaccinated controls at 2 years of age.
Results: All the vaccines were safe. Immunogenicity of 6B-TT was demonstrated by antibody production and memory type of response in infants starting from 3 or 7 months of age. Antibody responses were dominated by IgG1 in infancy, and after booster at 18 months of age, the infants had adult levels of IgG1 and IgG2 started to appear. The antibodies were functional in vitro as shown by opsonophagocytosis. The 8-valent PCV-DT and PCV-TT induced serotype specific IgG that were functional in vitro and protective against serotype 6B bacteremia and lung infection in vivo in the mouse model. The 11-valent F3 and F3bis formulations induced significant functional IgG antibodies. No benefit was observed from mixed double carrier formulation for the poorly immunogenic serotypes.
Both two and three primary PCV doses induced significant IgG to all pneumococcal serotypes in the 9vPnCMnCC. Three doses induced higher primary IgG to seven out of nine serotypes but memory responses at 12 months were similar.
Immunological memory was demonstrated to PCV8-DT and PCV8-TT by significant IgG responses four weeks after a PPV23 booster at 13 months and to 9vPncCMnCC with a brisk IgG response as soon as one week after the PPV23 booster at 12 months. Long-term memory was demonstrated in 7-year-old children primed with PCV8-TT in infancy who responded to a 1/10 PPV23 dose with a significant rise in IgG in one week. A persistent memory was demonstrated, whether they had received PCV8-TT or PPV23 booster at 13 months of age, which was not observed in PCV naïve children. The PPV23 booster at 13 months did not significantly compromise the memory response at 7 years of age but a lower IgG1/IgG2 was observed.
An initial decrease in nasopharyngeal colonization with vaccine serotypes was observed but that effect waned by the age of 2 years when carriage was comparable between PCV vaccinated children and unvaccinated controls. Medical history at 2 years showed fewer AOM and antibiotic treatments between 18 and 24 months compared to controls. Children, repeatedly colonized after vaccination had significantly lower IgG antibodies to the colonizing serotype compared to children never colonized with same serotype.
Conclusion. The six pneumococcal conjugate vaccines tested were shown to be safe when used in Icelandic children. They induced functional antibody responses when administered concomitantly with regular infant vaccinations. Although primary vaccinations with two doses resulted in lower antibody levels than three doses, it induced significant antibody responses and immunological memory. Booster vaccinations during second year of life and six years later demonstrated sustained immunological memory that was not exhausted by a full dose of PPV23 during the second year of life. The results support the protective potential of these vaccines against invasive pneumococcal diseases in the young. With general usage of protein conjugated pneumococcal vaccines in infants, these vaccines can prevent numerous deaths and other serious consequences from pneumococcal infections.

Issued Date
05/05/2009


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