Immunogenicity of Haemophilus influenzae Type b Conjugate Vaccines in Korean Infants: A Meta-analysis

A meta-analysis was performed on the immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines after 2 (2 and 4 months) and 3 doses (2, 4, and 6 months) in Korean infants. A database search of MEDLINE, KoreaMed, and Korean Medical Database was done. The primary outcome measure was the proportion of infants with anti-polyribosylribitol phosphate (PRP) concentrations ≥1.0 µg/mL. Eight studies including eleven trials were retrieved. One trial reported on the diphtheria toxoid conjugate vaccine (PRP-D) and 2 trials each on the mutant diphtheria toxin (PRP-CRM) and Neisseria meningitidis outer-membrane protein (PRP-OMP) conjugate vaccine. Heterogeneity in study designs between trials on PRP-CRM was noted and one trial reported on a monovalent and another on a combination PRP-OMP vaccine. Thus, a meta-analysis was conducted only on the tetanus toxoid conjugate vaccine (PRP-T). After a primary series of 2 doses and 3 doses, 80.6% (95% confidence interval [CI]; 76.0-85.1%) and 95.7% (95% CI; 94.0-98.0%) of infants achieved an antibody level ≥1.0 µg/mL, respectively. The immunogenic response to the PRP-T vaccine was acceptable after a primary series of 3 doses and also 2 doses. A reduced number of doses as a primary series could be carefully considered in Korean infants.     

Use of vaccine in the era of antimicrobial resistance: need of effective pneumococcal vaccines

Streptococcus pneumoniae is an important pathogen causing invasive infections particularly in children. Penicillin-nonsusceptible pneumococci are very prevalent in Korea and a difficult problem in antimicrobial treatment. Immunization with effective vaccines including viral and bacterial vaccines has proven to be the most effective and reliable method to prevent the target disease. Universal immunization to infants with Haemophilus influenzae type b conjugate vaccine has dramatically proven to be very effective in reducing invasive Hib diseases and also the carriage rate. The 23-valent pneumococcal polysaccharide vaccine is effective in preventing invasive diseases in young adults and covers most of the penicillin-nonsusceptible types. It has not proven very effective in the prevention of otitis media, and is unable to elicit adequate antibody response in children younger than 2 years of age. Recently a new polysaccharide-protein conjugate vaccine was developed which can elicit antibody response in children younger than 2 years of age. However, the vaccine is only 8-valent at the moment. Studies are required to determine the possible idiotypic modulation and nonproductive immune response when polysaccharide vaccine is administered to infants. Part of the problem of antimicrobial-resistant pneumococcal infection may be solved in the future with the use of improved vaccine. Preventing pneumococcal infections with safe and effective vaccines will not only reduce the development of antibiotic resistance, but could also be the most cost-effective method to control pneumococcal disease.     

The V-region repertoire of Haemophilus influenzae type b polysaccharide antibodies induced by immunization of infants.

Haemophilus influenzae type b (Hib) is a significant pathogen for young children, and three Hib vaccines (named PRP-OMPC, HbOC, and PRP-T) are currently available for young children. Extensive studies of anti-Hib polysaccharide (PS) antibodies (Abs) have shown that the V regions of Abs against the Hib PS comprise a VH gene in the VH3 gene family and a VL gene from various K kappa and V lambda subgroups. To study immunogenic properties of the three vaccines in young children, we determined the VL subgroups and avidities of anti-Hib-PS Abs induced by the three clinically available conjugate vaccines. Ab avidity was measured by determining the concentration of a Hib-PS oligomer that abrogates half of the binding of immunoglobulin G anti-Hib-PS Abs to microwells. The PRP-OMPC vaccine induced lower-avidity Abs than the prelicensure HbOC vaccine (P = 0.05). When we compared anti-Hib-PS Abs expressing V kappa Ia, V kappa II, and V lambda subgroups, a greater Ab response was induced by the prelicensure HbOC vaccine than other vaccines (P < 0.05). When anti-Hib-PS Abs with the V kappa III subgroup were compared, however, both PRP-T and prelicensure HbOC vaccines induced a comparable response, which in turn was greater than those induced by the PRP-OMPC or the postlicensure HbOC vaccine (P < 0.001). The VL repertoire of Abs induced with the prelicensure HbOC or PRP-T vaccine in young children is dominated (about 80%) by anti-Hib-PS Abs using subgroup V kappa II. However, anti-Hib-PS using V kappa II VL accounts for only about 40% of the total anti-Hib-PS Abs induced with the PRP-OMPC vaccine or the postlicensure HbOC. Our data suggest that immunogenic properties of Hib vaccines in young children vary depending on the vaccine preparations as well as the vaccine types.     

Hypothesis: conjugate vaccines may predispose children to autism spectrum disorders

The first conjugate vaccine was approved for use in the US in 1988 to protect infants and young children against the capsular bacteria Haemophilus influenzae type b (Hib). Since its introduction in the US, this vaccine has been approved in most developed countries, including Denmark and Israel where the vaccine was added to their national vaccine programs in 1993 and 1994, respectively.There have been marked increases in the reported prevalence of autism spectrum disorders (ASDs) among children in the US beginning with birth cohorts in the late 1980s and in Denmark and Israel starting approximately 4-5 years later. Although these increases may partly reflect ascertainment biases, an exogenous trigger could explain a significant portion of the reported increases in ASDs. It is hypothesized here that the introduction of the Hib conjugate vaccine in the US in 1988 and its subsequent introduction in Denmark and Israel could explain a substantial portion of the initial increases in ASDs in those countries. The continuation of the trend toward increased rates of ASDs could be further explained by increased usage of the vaccine, a change in 1990 in the recommended age of vaccination in the US from 15 to 2 months, increased immunogenicity of the vaccine through changes in its carrier protein, and the subsequent introduction of the conjugate vaccine for Streptococcus pneumoniae.Although conjugate vaccines have been highly effective in protecting infants and young children from the significant morbidity and mortality caused by Hib and S. pneumoniae, the potential effects of conjugate vaccines on neural development merit close examination. Conjugate vaccines fundamentally change the manner in which the immune systems of infants and young children function by deviating their immune responses to the targeted carbohydrate antigens from a state of hypo-responsiveness to a robust B2 B cell mediated response. This period of hypo-responsiveness to carbohydrate antigens coincides with the intense myelination process in infants and young children, and conjugate vaccines may have disrupted evolutionary forces that favored early brain development over the need to protect infants and young children from capsular bacteria.     

Reduced Response to Multiple Vaccines Sharing Common Protein Epitopes That Are Administered Simultaneously to Infants

The plethora of newly discovered vaccines implies that, in the future, many vaccines will have to be administered simultaneously to infants. We examined the potential interference with the immune response of several coadministered vaccines containing the same protein component, namely, tetanus toxoid (TT). Infants simultaneously receiving a tetravalent pneumococcal vaccine conjugated to TT (PncT) and a diphtheria-tetanus-pertussis–poliovirus–Haemophilus influenzae type b-tetanus conjugate vaccine showed significantly lower anti-H. influenzae type b polysaccharide (polyribosylribitol phosphate [PRP]) antibody concentrations than those receiving either a tetravalent pneumococcal vaccine conjugated to diphtheria toxoid or placebo. A dose range study showed that anti-PRP antibody concentrations were inversely related to the TT content of the PncT vaccines administered in infancy. Postimmunization antitetanus antibody concentrations were also affected adversely as the TT content of the coadministered vaccines was increased. This phenomenon, which we believe derives from interference by a common protein carrier, should be taken into account when the introduction of an immunization program including multiple conjugate vaccines is considered.     

MenACWY-TT vaccine for active immunization against invasive meningococcal disease

Meningococcal disease remains a significant global cause of morbidity and mortality despite the availability of polysaccharide and conjugate vaccines. The implementation of monovalent meningococcal serogroup C vaccine in developed countries has significantly decreased the incidence of meningococcal disease, while the recent introduction of monovalent serogroup A conjugate vaccine in the African meningitis belt aims to reduce the incidence of high endemic disease in this area. Three quadrivalent meningococcal vaccines have already been licensed; a polysaccharide (MenACWY-PS) and two conjugated (MenACWY-DT and MenACWY-CRM) vaccines. An investigational MenACWY-TT vaccine is described in this article. Clinical trials in infants older than 9 months of age, toddlers, children, adolescents and adults have indicated that this vaccine is well tolerated and immunogenic. The inclusion of a spacer molecule coupled with the polysaccharide (for serogroups A and C) and tetanus toxoid as the carrier protein aims to elicit robust immune responses. The tolerability of this vaccine is comparable to that of polysaccharide quadrivalent vaccines and monovalent meningococcal serogroup C vaccines. More importantly, the immunogenicity, antibody persistence and induction of immune memory aim to provide protection to a wide range of susceptible subjects.     

Immunogenicity of a Heptavalent Conjugate Pneumococcal Vaccine Administered Concurrently with a Combination Diphtheria,Tetanus, Five-Component Acellular Pertussis,Inactivated Polio,and Haemophilus influenzae Type b Vaccine and a Meningococcal Group C Conjugate Vaccine at 2, 3, and 4 Months of Age

The immunogenicities of conjugate pneumococcal vaccines have been demonstrated when they are administered at 2, 3, and 4 months of age. There is a paucity of data on the immunogenicity of this vaccine when it is administered concurrently with other vaccines in the primary immunization schedule of the United Kingdom. We immunized 55 term infants at 2, 3, and 4 months of age with the seven-valent pneumococcal conjugate vaccine (PCV7), the meningococcal group C conjugate (MCC) vaccine, and the diphtheria, tetanus, five-component acellular pertussis, inactivated polio, and Haemophilus influenzae type b (DTaP₅/IPV/Hib-TT) vaccine. The immune responses to the H. influenzae type b (Hib), MCC, and tetanus vaccines were measured at 2, 5, and 12 months of age; and the immune responses to PCV7 were measured at 2 and 5 months and then either at 12 months or following a 4th dose of PCV7. There were increases in the geometric mean concentrations (GMCs) of all antigens postimmunization. Greater than or equal to 90% of the infants achieved putatively protective levels postimmunization for all vaccine antigens except pneumococcal serotype 6B and Hib. The GMCs of the PCV7 serotypes increased following a 4th dose, although one infant had not reached putative levels of protection against serotype 6B. In conclusion, when infants were vaccinated according to the schedule described above, they had lower postprimary immunization responses to Hib, meningococcus group C capsular polysaccharide, and pneumococcal serotype 6B than the responses demonstrated by use of the other schedules. Despite this finding, there was a good response following a 4th dose of PCV7.The primary immunization schedule of the United Kingdom is continually evolving. While a vaccine may have been demonstrated to be immunogenic when it was administered according to one schedule, minor changes to that schedule can have an adverse impact on the response to the vaccine (2). In 2002, the chief medical officer of the United Kingdom recommended that infants considered to be at increased risk of invasive pneumococcal disease receive the seven-valent pneumococcal conjugate vaccine (PCV7) at 2, 3, and 4 months of age with their primary immunizations as well as a booster dose in the second year of life (8). In September 2004, the combined diphtheria, tetanus, five-component acellular pertussis, inactivated polio, and Haemophilus influenzae type b conjugate (DTaP₅/IPV/Hib-TT) vaccine was introduced into the United Kingdom primary immunization schedule.PCV7 has previously been demonstrated to have good immunogenicity when it is administered at 2, 4, and 6 months of age (3) and at 2, 3, and 4 months of age (7). There is a paucity of data examining the immunogenicity of PCV7 when it is administered concurrently with the DTaP₅/IPV/Hib-TT vaccine and a meningococcal group C conjugate (MCC) vaccine. Additionally, at the time of this study, no other immunizations were boosted during the second year of life, and a questionnaire survey of neonatal units suggested that many at-risk infants were not receiving the recommended booster dose (14).We therefore recruited healthy term infants to determine the immunogenicity of PCV7 when it was administered at 2, 3, and 4 months of age with the other vaccines in the primary immunization schedule of the United Kingdom in effect at that time. Additionally, we examined the effect of a booster dose in infants who responded poorly to the primary schedule and examined the antibody response at 12 months of age in infants who had had a good response to the primary immunization schedule.     

The new pneumococcal vaccine

Pneumococcal disease is now the leading cause of vaccine-preventable bacterial disease in children worldwide. Although a pneumococcal polysaccharide vaccine has been available for over three decades, its use has been limited due to poor immunogenicity in the most vulnerable children, aged less than 2 years. The prevalence of pneumococcal disease worldwide and the alarming global escalation of multiresistant strains of Streptococcus pneumoniae (pneumococcus) during the past decade have provided the impetus for the development and application of a new pneumococcal vaccine. The outstanding success of Haemophilus influenzae type b (Hib) conjugate vaccine in the control of invasive Hib disease is a reason to be optimistic that the pneumococcal conjugate vaccines will achieve similar results for the control of invasive pneumococcal disease. Remarkable efficacy against invasive pneumococcal disease with a seven-valent pneumococcal conjugate vaccine was demonstrated in infants and toddlers in the USA, and in February 2000 the first pneumococcal conjugate vaccine was licensed. Licensure and widespread use is likely to follow in other countries in which there is a need and the means to afford this live-saving vaccine. Active disease surveillance must be sustained globally, while active research, development of other multivalent conjugate formulations and the search for new candidate protein-based vaccines are in progress.     

Avidity of specific IgG antibodies elicited by immunisation against Haemophilus influenzae type b.

AIM--To investigate the avidity of specific IgG polyribosyl ribitol phosphate (PRP) antibodies induced by three Haemophilus influenzae type b (Hib) conjugate vaccines: PRP-meningococcal outer membrane protein complex (PRP-OMP), PRP-non-toxic mutant diphtheria toxin, CRM197 (HbOC) and PRP-tetanus toxoid (PRP-T). METHODS--One hundred and ten infants were immunised with one of the vaccines at two, three and four months of age. Blood samples were taken after each vaccination and serum stored at -20 degrees C. Serum samples collected after the third course (that is, at five months of age) were submitted to antibody avidity assessment, using a urea enzyme linked immunosorbent assay (ELISA). RESULTS--All three conjugate vaccines elicited IgG PRP antibodies of high median avidity. The resultant antibody populations were heterogeneous with regard to avidity, which in turn was independent of PRP antibody concentration. CONCLUSIONS--With the recent findings of a correlation between bactericidal killing and affinity, our data highlight the need for a protective level to be expressed qualitatively as well as quantitatively.     

Experience with pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) in children and adults

Streptococcus pneumoniae-related infections are a major cause of morbidity and mortality in people of all ages worldwide. Pneumococcal vaccine development started in 1911 with a whole cell vaccine and more recently multivalent plain polysaccharide and polysaccharide conjugate vaccines have been developed. The recent vaccines rely on capsular polysaccharide antigens to induce serotype-specific immune responses. We summarize here the presentations on pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) given during the integrated symposium organized and funded by Pfizer International Operations during the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 31 March to 3 April 2012, London, UK. A dramatic reduction in the incidence of invasive pneumococcal diseases (IPD) due to vaccine serotypes (VST-IPD) has been reported since the introduction of a hepta-valent pneumococcal conjugate vaccine (PCV7). An indirect (herd) effect has been demonstrated to be associated with PCV7 infant vaccination programmes, with many studies reporting reductions in VST-IPD in populations that are not eligible for PCV7 vaccination. Since 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) has been introduced into national immunization programmes and results from early surveillance suggest that this vaccine also has an impact on the serotypes unique to PCV13, as well as continuing to protect against the PCV7 serotypes. Data from a passive surveillance system in Europe in 2009, for instance, showed that the highest incidence of IPD remains in those aged >65 years and in children <5 years. PCV13 has now been licensed for vaccination of adults >50 years based on safety and immunogenicity data; an efficacy trial is being conducted. Regardless of previous pneumococcal vaccination status, if the use of 23-valent polysaccharide is considered appropriate, it is recommended to give PCV13 first. Novel immunization strategies remain the only practical means to reduce significantly the remaining global mortality and morbidity due to S. pneumoniae in adults.     

Antibodies to Haemophilus influenzae type b polysaccharide affect bacterial adherence and multiplication.

Since immunization of infants with conjugated Haemophilus influenzae type b (Hib) capsular polysaccharide (PS) vaccines results in a reduction of colonization, we determined the inhibitory effect of anti-Hib PS on two steps in the colonization, i.e., adherence of H. influenzae to nasopharyngeal epithelium and bacterial growth. Monoclonal antibody (MAb) E117-5 specific for Hib PS inhibited at a concentration of at least 80 microg/ml in vitro the adherence of Hib strain 770235f+b+ to oropharyngeal epithelial cells by 50% (P <, 0.02), but this MAb and sera from children immunized with Hib PS conjugate vaccine (n = 10) were not inhibitory in final dilutions containing up to 20 microg of anti-Hib PS per ml. The growth of Hib strain 770235f+b+ did completely stop in the presence of 5 microg of anti-Hib PS MAb E117-5 per ml and human sera with an anti-Hib PS concentration of 2 microg/ml or more, in contrast to the growth of the nonencapsular variant strain 770235f+b0.     

Safety and immunogenicity of coadministering a combined meningococcal serogroup C and Haemophilus influenzae type b conjugate vaccine with 7-valent pneumococcal conjugate vaccine and measles, mumps, and rubella vaccine at 12 months of age

The coadministration of the combined meningococcal serogroup C conjugate (MCC)/Haemophilus influenzae type b (Hib) vaccine with pneumococcal conjugate vaccine (PCV7) and measles, mumps, and rubella (MMR) vaccine at 12 months of age was investigated to assess the safety and immunogenicity of this regimen compared with separate administration of the conjugate vaccines. Children were randomized to receive MCC/Hib vaccine alone followed 1 month later by PCV7 with MMR vaccine or to receive all three vaccines concomitantly. Immunogenicity endpoints were MCC serum bactericidal antibody (SBA) titers of ≥8, Hib-polyribosylribitol phosphate (PRP) IgG antibody concentrations of ≥0.15 μg/ml, PCV serotype-specific IgG concentrations of ≥0.35 μg/ml, measles and mumps IgG concentrations of >120 arbitrary units (AU)/ml, and rubella IgG concentrations of ≥11 AU/ml. For safety assessment, the proportions of children with erythema, swelling, or tenderness at site of injection or fever or other systemic symptoms for 7 days after immunization were compared between regimens. No adverse consequences for either safety or immunogenicity were demonstrated when MCC/Hib vaccine was given concomitantly with PCV and MMR vaccine at 12 months of age or separately at 12 and 13 months of age. Any small differences in immunogenicity were largely in the direction of a higher response when all three vaccines were given concomitantly. For systemic symptoms, there was no evidence of an additive effect; rather, any differences between schedules showed benefit from the concomitant administration of all three vaccines, such as lower overall proportions with postvaccination fevers. The United Kingdom infant immunization schedule now recommends that these three vaccines may be offered at one visit at between 12 and 13 months of age.     

Cost-benefit analysis of haemophilus influenzae type B immunization in Korea

An economic evaluation of Haemophilus influenzae type b (Hib) immunization was conducted to examine whether Hib immunization should be included in Korea's national immunization program. The costs and benefits included direct and indirect values and an estimation of the economic efficiency. We determined that a universal Hib immunization program in Korea would prevent 17 deaths and 280 invasive Hib cases. When we assumed the one Hib immunization cost as 26,000 won, the national Hib immunization would cost 34.6 billion won. Costs for various Hib diseases were estimated at 26.8 billion won (11.8 billion won from direct costs and 14.9 billion won from indirect costs). A benefit-cost ratio of 0.77 showed that the economic efficiency of the integration of Hib immunization in Korea is low because of the low incidence rate of Hib disease and high price of vaccine. However, if the Hib immunization cost decrease to less than 20,000 won, a benefit-cost ratio increase to 1.0 and above, integrating Hib immunization into the national immunization program with economic efficiency can be considered.     

Kinetics of Antibody Persistence following Administration of a Combination Meningococcal Serogroup C and Haemophilus influenzae Type b Conjugate Vaccine in Healthy Infants in the United Kingdom Primed with a Monovalent Meningococcal Serogroup C Vaccine

The kinetics of antibody persistence following the administration of a combination meningococcal serogroup C and Haemophilus influenzae type b (Hib) conjugate vaccine (Menitorix) in the second year of life in children primed with two doses of one of three monovalent meningococcal serogroup C (MCC) vaccines was investigated. The study subjects were administered either Menitorix at 12 to 15 months of age, followed by the seven-valent pneumococcal conjugate vaccine (PCV7) and the measles, mumps, and rubella vaccine 4 to 6 weeks later, or all three vaccines concomitantly at 12 to 15 months of age. Blood samples were collected before and 1, 2, 12, and 24 months after the boosting. Sera were analyzed for meningococcal serogroup C serum bactericidal antibody (SBA) and IgG as well as Hib-polyribosylribitol phosphate (PRP)-specific IgG. The antibody persistence data from this study were compared to those of a prior study of Southern et al. (Clin. Vaccine Immunol. 14:1328-1333, 2007) in which children were given three primary doses of a vaccine containing both the MCC and the Hib vaccines but were boosted only with a Hib conjugate vaccine. The magnitude of the meningococcal SBA geometric mean titer was higher for those subjects primed with the MCC vaccine conjugated to tetanus toxoid (NeisVac-C) than for those primed with one of two MCC vaccines conjugated to CRM₁₉₇ (Menjugate or Meningitec) up to 1 year following boosting. Two years after boosting, the percentages of subjects with putatively protective SBA titers of ≥8 for children primed with NeisVac-C, Menjugate, and Meningitec were 43%, 22%, and 23%, respectively. Additional booster doses of the MCC vaccine may be required in the future to maintain good antibody levels; however, there is no immediate need for a booster during adolescence, as mathematical modeling has shown that persisting herd immunity is likely to control disease for a number of years.A booster dose of meningococcal serogroup C conjugate (MCC) and Haemophilus influenzae type b (Hib) conjugate vaccine was introduced in September 2006 in England and Wales for children in the second year of life in the form of a combined vaccine, Menitorix (GlaxoSmithKline [GSK]), which has tetanus toxoid (TT) as the carrier protein. In England and Wales, infants receive a combined diphtheria toxoid (D), TT, acellular pertussis (aP₅), inactivated poliovirus (IPV), and Hib-TT conjugate vaccine (DTaP₅/IPV/Hib-TT; Pediacel; Sanofi Pasteur) at 2, 3, and 4 months of age; MCC vaccination at 3 and either 4 or 5 months of age; and a seven-valent pneumococcal conjugate vaccine (PCV7; Prevenar; Wyeth Vaccines) at 2 and 4 months of age. Three different MCC vaccine manufacturers'' vaccines are available: two are conjugated to CRM₁₉₇, a nontoxigenic natural variant of diphtheria toxin (Meningitec [Wyeth Vaccines] and Menjugate [Novartis Vaccines]), and one is conjugated to TT (NeisVac-C; Baxter Bioscience). Although the data obtained following the administration of the current primary vaccine series in the United Kingdom have been reported (16), antibody persistence following boosting with Menitorix and priming with two doses of each of the licensed MCC vaccines has not been reported. This report details the immunogenicity data for those receiving the MCC and Hib vaccines, by primary MCC vaccine, for before and at 1, 2, 12, and 24 months after a booster dose of Menitorix administered at 12 to 15 months of age. The rates of antibody decline for those receiving the Hib and MCC vaccines are also compared.     

Reduction of antibody response to an 11-valent pneumococcal vaccine coadministered with a vaccine containing acellular pertussis components

In pneumococcal conjugate vaccines (PCVs), polysaccharide antigens are often conjugated to protein carriers related to other common vaccines. It is therefore important to test PCV interaction with other pediatric vaccines when administered simultaneously. We assessed the immune response to an 11-valent PCV conjugated to diphtheria and tetanus carriers (PncD/T11), administered concomitantly, but in separate sites, with a combined vaccine containing epitopes related antigenically to the carriers: polyribosylribitol phosphate-tetanus tox oid (PRP-T), diphtheria toxoid (DT), and tetanus toxoid (TT). In addition, these combinations contained inactivated poliovirus vaccine (IPV) and either whole-cell pertussis (wP) or acellular pertussis (aP) components. After coadministration of PncD/T11 with the combined vaccine containing wP (DTwP/IPV/PRP-T), the responses to all polysaccharides in the PncD/T11 were satisfactory. In contrast, when coadministered with an aP-containing combination (DTaP/IPV/PRP-T), the response to all seven pneumococcal conjugates to TT was significantly reduced after primary and booster immunization. The pneumococcal conjugates to DT were not significantly reduced after the primary series, but were somewhat reduced after booster. It is likely that some suppression of the tetanus-mediated response occurred even when the PncD/T11 was coadministered with wP, but this suppression was masked by the adjuvant effect of wP. By replacing wP with aP, this adjuvant effect was removed, unmasking the suppression of the tetanus-mediated response. With the increasing use of multiple aP-containing vaccines in infancy, novel approaches to adjuvants and carrier protein technology are likely to be required.     

The Immunogenicity and Safety of a Combined DTaP-IPV//Hib Vaccine Compared with Individual DTaP-IPV and Hib (PRP~T) Vaccines: a Randomized Clinical Trial in South Korean Infants

Recommended infant vaccination in Korea includes DTaP-IPV and Hib vaccines administered as separate injections. In this randomized, open, controlled study we assessed the non-inferiority of immunogenicity of DTaP-IPV//Hib pentavalent combination vaccine (Pentaxim™) compared with licensed DTaP-IPV and Hib (PRP~T) vaccines. We enrolled 418 healthy Korean infants to receive either separate DTaP-IPV and Hib vaccines (n = 206) or the pentavalent DTaP-IPV//Hib (n = 208) vaccine at 2, 4, 6 months of age. Antibodies to all components were measured before the first vaccination and one month after the third, and safety was assessed after each vaccination including recording of reactions by parents. We confirmed the non-inferiority of DTaP-IPV//Hib compared with DTaP-IPV and Hib vaccines; 100% of both groups achieved seroprotection against D, T, IPV and PRP~T, and 97.5%–99.0% demonstrated seroresponses to pertussis antigens. Antibody levels were similar in both groups, except for those to the Hib component, PRP~T. In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 µg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 µg/mL, indicative of long-term protection. All vaccines were well tolerated, with no vaccine-related serious adverse event. Both groups had similar safety profiles, but the combined vaccine group had fewer injection site reactions. The immunological non-inferiority and similar safety profile of DTaP-IPV//Hib vaccine to separate DTaP-IPV and Hib vaccines, with the advantage of fewer injections and injection site reactions, supports the licensure and incorporation of DTaP-IPV//Hib into the Korean national vaccination schedule (Clinical trial registry, {"type":"clinical-trial","attrs":{"text":"NCT01214889","term_id":"NCT01214889"}}NCT01214889).     

Response to a Haemophilus influenzae type b diphtheria CRM197 conjugate vaccine in children with a defect of antibody production to Haemophilus influenzae type b polysaccharide

A defect in antibody response to immunization with Haemophilus influenzae type b (Hib) capsular polysaccharide vaccine has been reported in children with recurrent infections and normal immunoglobin levels. We identified 15 children, aged 2 to 6 years, with this defect, and we evaluated their response to immunization with an Hib capsular oligosaccharide diphtheria CRM197 protein-conjugate vaccine (HbOC). The children received a series of three vaccines: HbOC at 0 and 8 weeks, and the Hib polysaccharide vaccine at 16 weeks. Levels of antibody to the Hib capsular polysaccharide (polyribosyl ribitol phosphate, PRP) and to diphtheria toxoid were obtained before and 4 weeks after each vaccination. The geometric mean serum anti-PRP concentration was 0.17 microgram/ml before immunization and 29.3 micrograms/ml after the second HbOC immunization (week 12). All 15 children had postvaccination anti-PRP antibody levels greater than 1.0 microgram/ml after receiving the second HbOC (week 12). In addition, booster responses were observed after the second Hib conjugate in 13 of the patients and after the Hib polysaccharide in four of the patients. All patients with low preimmunization diphtheria titers had a response to the diphtheria toxoid. These results suggest that conjugation of Hib polysaccharide with diphtheria CRM197 overcomes the defective antibody response to Hib oligosaccharide in children who are initially observed with recurrent infections and inability to respond to the Hib polysaccharide vaccine.     

Low Genetic Diversity of Haemophilus influenzae Type b Compared to Nonencapsulated H. influenzae in a Population in Which H. influenzae Is Highly Endemic

Immunization with Haemophilus influenzae type b (Hib) conjugate polysaccharide vaccines has dramatically reduced Hib disease worldwide. As in other populations, nasopharyngeal carriage of Hib declined markedly in Aboriginal infants following vaccination, although carriage has not been entirely eliminated. In this study, we describe the genetic characteristics and the carriage dynamics of longitudinal isolates of Hib, characterized by using several typing methods. In addition, carriage rates of nonencapsulated H. influenzae (NCHi) are high, and concurrent colonization with Hib and NCHi is common; we also observed NCHi isolates which were genetically similar to Hib. There is a continuing need to promote Hib immunization and monitor H. influenzae carriage in populations in which the organism is highly endemic, not least because of the possibility of genetic exchange between Hib and NCHi strains in such populations.     

Responses to a Conjugate Pneumococcal Vaccine in Preterm Infants Immunized at 2, 3, and 4 Months of Age

Preterm infants are at an increased risk of invasive pneumococcal disease infection and, additionally, have a diminished response to Haemophilus influenzae type b (Hib) conjugate vaccines. There are little data examining the response of preterm infants to a seven-valent pneumococcal conjugate vaccine (PCV7). We examined the responses of preterm infants immunized at 2, 3, and 4 months of age to PCV7. A total of 133 preterm and 54 term infants were immunized with PCV7 and the Neisseria meningitidis group C (MCC), diphtheria, tetanus, pertussis, polio, and Hib vaccines. Pneumococcal serotype-specific IgG was measured by enzyme-linked immunosorbent assay (ELISA) pre- and postimmunization and at 12 months or following a booster of PCV7. Term and preterm responses were compared using linear and logistic regression analyses. Term infants had higher preimmunization geometric mean concentrations (GMCs) for all serotypes. Preterm infants had lower postimmunization GMCs for serotype 23F. Gestational age affected postimmunization GMCs for serotypes 4, 6B, and 23F. Preterm infants were as likely to have levels of ≥0.35 μg/ml as term infants for all serotypes except 23F. The proportions of infants with titers of ≥0.35 μg/ml for all 7 serotypes were comparable between groups. A total of 28 of 29 term infants who received a booster had levels of ≥0.35 μg/ml for all serotypes. One infant had undetectable levels for serotype 6B. Of the 32 preterm infants boosted, 9 had levels of <0.35 μg/ml for 1 serotype, and 1 had levels of <0.35 μg/ml for 2 serotypes. In nonboosted infants, GMCs for all serotypes except 6B had fallen by 12 months of age. These results support the need for a booster dose in the second year of life.The primary immunization schedule of the United Kingdom (UK) is continually evolving. While a vaccine may be demonstrated to be immunogenic in one population when administered according to one schedule, apparently, minor changes to that schedule can have an adverse effect on vaccine response. Preterm infants are at an increased risk of many of the infections we immunize against, for example, pertussis (9). Almost half the children who develop pertussis are under 4 months of age (9). Preterm infants are currently recommended to be vaccinated at the same chronological age as term infants rather than at the same age postconception.The UK primary immunization schedule in place between September 2004 and September 2006 consisted of a combined vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (diphtheria-tetanus-acellular pertussis [DTaP]/inactivated polio vaccine [IPV]/Haemophilus influenzae type b [Hib]) (Pediacel; Aventis Pasteur MSD) and a conjugate vaccine against Neisseria meningitidis group C (MCC) given at 2, 3, and 4 months of age, with no booster in the second year of life (5). In 2002, the chief medical officer advised that children under 2 years of age at risk of invasive pneumococcal disease (IPD) should receive three doses of the seven-valent pneumococcal conjugate vaccine (PCV7; pneumococcal capsular polysaccharide conjugated to the carrier protein CRM₁₉₇), with their primary immunizations followed by a booster in the second year of life (4). Infants were considered to be at increased risk of IPD if they had a chronic respiratory, cardiac, renal, or liver disease or an immunodeficiency. Many preterm infants are included in these categories.A postal questionnaire survey of 73 UK neonatal intensive care units highlighted the fact that many preterm infants who are at an increased risk of IPD were not being adequately immunized because of the lack of evidence that these infants are protected by the conjugate pneumococcal vaccine (11). This survey indicated that many infants who were immunized were not receiving the recommended booster dose in the second year of life. In the UK immunization schedule at this time, none of the other vaccines in the primary schedule were boosted.The immunogenicity of PCV7 when administered to preterm infants according to the then-current UK immunization schedule was examined and compared to the response of a cohort of term infants that was previously described. As many preterm infants were not routinely receiving their 12 -month booster, we also measured antibody levels at 12 months of age.     

Spotlight on DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa™)†

Infanrix hexa?, administered intramuscularly, is a diphtheria, tetanus, acellular pertussis, hepatitis B (HBV), inactivated poliomyelitis and Haemophilus influenzae type b (Hib) conjugate vaccine, indicated for primary and booster vaccination of infants. Infanrix hexa? should be administered as a two- or three-dose primary vaccination course in infants aged ≤6 months, followed by booster vaccination between 11 and 18 months of age, with an interval of at least 6 months between the last dose of primary vaccination and the booster dose. This spotlight reviews the immunogenicity and protective effectiveness, as well as the reactogenicity and safety of Infanrix hexa?. Infanrix hexa? as primary and booster vaccination was safe and highly immunogenic for all its component toxoids/antigens in infants aged <2 years, regardless of vaccination schedules. Its immunogenicity and safety profiles were generally similar to those of currently available vaccines, the diphtheria, tetanus and acellular pertussis-based pentavalent vaccines plus monovalent HBV or Hib vaccines. In large clinical studies, Infanrix hexa? elicited a strong immune response against vaccine toxoids/antigens, as indicated by high seroprotection/seropositivity/vaccine response rates and geometric mean titers. Moreover, antibodies against vaccine toxoids/antigens persisted for up to a mean of ≈6 years after booster vaccination, and the vaccine induced long-term immune memory against hepatitis B surface antigen and Hib antigen. A strong immune response against Infanrix hexaTm toxoids/antigens after primary vaccination was also induced in infants who had received a dose of HBV vaccine at birth and in pre-term infants, although the response in the latter group was somewhat lower than that in full-term infants. In addition, when coadministered with other childhood vaccines, the immunogenicity of Infanrix hexa? or that of the concomitantly administered vaccine was generally not altered. Hexavalent vaccines, including Infanrix hexa?, were protective against invasive Hib disease; Infanrix hexa? is also expected to be protective against pertussis. Most solicited local and general symptoms with Infanrix hexa? were mild to moderate in intensity and the vaccine was associated with few unsolicited adverse events. Available clinical data from more than 10 years’ experience with the vaccine suggest that Infanrix hexa? as primary and booster vaccination is a safe and useful option for providing protection against the common childhood diseases of diphtheria, tetanus, poliomyelitis, pertussis, hepatitis B and invasive Hib disease. ? Adapted and reproduced from Drugs 2010; 70 (8): 1021–1058. The full text article^[1] was reviewed by: S.L. Block, Kentucky Pediatric Research, Bardstown, Kentucky, USA; G. Gabutti, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy; M.E. Pichichero, Rochester General Hospital, Research Institute, Center for Infectious Diseases and Immunology, Rochester, New York, USA; R. Prymula, Department of Epidemiology, University of Defence, Hradec Kralove, Czech Republic. The manufacturer of the agent under review was offered an opportunity to comment on the original article during the peer review process. Changes based on any comments received were made on the basis of scientific and editorial merit. The preparation of the original article and this spotlight was not supported by an external funding.