Published online August 31 2004 Bacterial polysaccharide protein conjugate vaccines Adam Finn Institute of Child Health Department of Clinical Sciences South Bristol University of Bristol Bristol UK Following demonstration that chemical conjugation of polysaccharide antigens to proteins could enhance their immunogenicity in the 1920s interest in this approach to primary prevention of bacterial infections waned with the development and widespread use of antibiotics Emergence of resistant bacteria rekindled interest in the late 20th century which saw extremely rapid development and implementation of several vaccines which are already rapidly changing the epidemiology of childhood infections with Haemophilus influenzae type b Streptococcus pneumoniae and Neisseria meningitidis Others such as Group B streptococcus and Salmonella typhi infections may soon follow However several important questions about the immunology of these antigens remain unanswered and the long term implications of reducing or eliminating the circulation of organisms which are more commonly nasopharyngeal commensals than pathogenic invaders are uncertain Introduction Correspondence to Adam Finn Professor of Paediatrics Institute of Child Health Level 6 UBHT Education Centre Upper Maudlin Street Bristol BS2 8AE UK E mail adam finn bristol ac uk Young children are prone to infections There are now abundant data that this reflects not only their immunological na vety but also a degree of immunoincompetence relative to older children and adults No doubt to some extent structural immaturity such as fragility of integument and mucosae also contributes There is a large published literature comparing in infants and older individuals the size or function of almost every element of immunity cellular and humoral innate and adaptive studies which often demonstrate the former to be the weaker1 It is hard to know what to make of much of this observational information but in some instances the implications are clear Adaptive cell mediated immune responses to a wide variety of foreign microbial antigens in newborns are both weaker and slower than in older children Since all the necessary components for functional responses appear to be in place well before term2 perhaps this British Medical Bulletin 2004 70 1 14 DOI 10 1093 bmb ldh021 British Medical Bulletin Vol 70 The British Council 2004 all rights reserved Adam Finn incapacity reflects a post natal lag period in immunological regulation still set to tolerate foreign maternal antigens while living in the normally sterile environment of the uterus If this supposition is true it remains puzzling that a more rapid post natal immunological reboot has not evolved as this relative refractoriness often appears to persist for months at least for some aspects of specific antimicrobial immunity Interference by transplacentally acquired IgG a vital element of immune protection against infection during early life which disappears with a half life of approximately 28 days after delivery can to some extent account for the persistent suppression of antibody responses particularly to protein antigens but does not cause the down regulation of T cell function3 Nor does maternal antibody explain the profound and long lasting failure of infants to make antibodies to the polysaccharide PS capsular antigens which decorate many bacterial pathogens4 a failure which is presumably at least partly responsible for the high incidence of invasive infections due to these organisms in this age group Antibody responses to PS antigens are the subject of considerable modern myth Since they are not peptides PSs should not by definition be processed and presented by MHC class II antigens so that the recruitment of T cell help by this route for B cell function is not expected Nevertheless isotype switching does occur not only IgM but also abundant IgG and particularly IgA responses to these antigens are seen5 6 It appears that a distinct signalling pathway may regulate this important antibody response pathway7 whose size and character vary not only between individuals8 and with age but also with previous exposure9 and between antigens Complete and permanent tolerance to some bacterial capsular PS antigens is the rule For example Lancefield Group A streptococci Streptococcus pyogenes colonizing the nasopharynx an important cause of both mucosal and invasive disease in children are consistently encapsulated although to a variable extent However the PS in question is hyaluronic acid an antigen against which antibody responses would be unwanted as it is a major component of human connective tissues10 The capsule of Neisseria meningitidis group B is likewise poorly immunogenic as a vaccine11 an observation which may be explained at least in part by the structural similarity of the capsular PS with polysialic acid moieties which decorate components of mammalian tissues including the central nervous system12 Nevertheless the PS capsular antigens of many other pathogenic bacteria do induce substantial protective serum antibody responses when used as vaccines However for most of these antigens this is not true in young children Although the age of 2 years is often cited as that at which such responses start to be seen in fact the doses of these antigens needed to 2 British Medical Bulletin 2004 70 Conjugate vaccines elicit protective responses and the average age at which such responses become active vary quite substantially and predictably between antigens For example pneumococcus type 3 capsular PS is relatively immunogenic in infants whereas types 6A and 6B are extremely poor immunogens with other types ranging in between13 One is left wondering exactly why this is so Presumably it is no accident This implies some relative survival advantage of this temporary anergy perhaps less marked than for the fully invisible antigens described above but operative nonetheless On the other hand it is also possible that the encapsulated bacteria that infect human children today may not have been around long enough in evolutionary time for the survival advantage of vigorous early immune responses to their capsules yet to have taken effect In any case faced with the real problem of the serious morbidity of these infections in young children and evidence that serum antibodies to capsular antigens protect such theoretical considerations have taken second place to efforts to render these antigens immunogenic in this high risk group The