Hib Antibody Concentrations Research Articles

The impact of administration of conjugate vaccines containing cross reacting material on Haemophilus influenzae type b antibody responses in infants: A systematic review and meta-analysis of randomised controlled trials

BackgroundProtein-polysaccharide conjugate vaccines such as Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal vaccine, induce immunological memory and longer lasting protection than plain polysaccharide vaccines. The most common proteins used as carriers are tetanus toxoid (TT) and cross reacting material-197 (CRM), a mutant form of diphtheria toxoid. CRM conjugate vaccines have been reported to suppress antibody responses to co-administered Hib-TT vaccine. MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials in which infants were randomised to receive meningococcal or pneumococcal conjugate vaccines along with Hib-TT. Trials of licensed vaccines with different carrier proteins were included for group C meningococcal (MenC), quadrivalent ACWY meningococcal (MenACWY), and pneumococcal vaccines. ResultsTwenty-three trials were included in the meta-analyses. Overall, administration of MenC-CRM in a 2 or 3 dose schedule resulted in a 45% reduction in Hib antibody concentrations (GMR 0.55, 95% CI 0.49–0.62). MenACWY-CRM boosted Hib antibody responses by 22% (GMR 1.22, 95% CI 1.06–1.41) whilst pneumococcal CRM conjugate vaccines had no impact on Hib antibody responses (GMR 0.91, 95% CI 0.68–1.22). ConclusionsThe effect of CRM protein-polysaccharide conjugate vaccines on Hib antibody responses varies greatly between vaccines. Co-administration of a CRM conjugate vaccine can produce either positive or negative effects on Hib antibody responses. These inconsistencies suggest that CRM itself may not be the main driver of variability in Hib responses, and challenge current perspectives on this issue.

Delayed BCG immunization does not alter antibody responses to EPI vaccines in HIV-exposed and -unexposed South African infants

BackgroundBacille Calmette-Guérin (BCG) is routinely given at birth in tuberculosis-endemic settings due to its protective effect against disseminated tuberculosis in infants. BCG is however contraindicated in HIV-infected infants. We investigated whether delaying BCG vaccination to 14 weeks of age affected vaccine-induced antibody responses to Haemophilus influenzae type b (Hib)-conjugate, pertussis, tetanus and Hepatitis B (HBV) vaccines, in HIV-exposed uninfected (HEU) and -unexposed uninfected (HUU) infants. MethodsInfants were randomized to receive BCG at birth or at 14 weeks of age. Blood was taken at 14, 24, and 52 weeks of age and analyzed for Hib, pertussis, tetanus and HBV specific antibodies. ResultsBCG was given either at birth (106 infants, 51 HEU) or at 14 weeks of age (74 infants, 50 HEU). The timing of BCG vaccination did not influence the antibody response to any antigen studied. However, in a non-randomized comparison, HEU infants had higher Hib antibody concentrations at weeks 14 and 24 (p=0.001 and <0.001, respectively) and pertussis at week 24 (p=0.003). Conversely, HEU infants had lower antibody concentrations to HBV at 14 and 52 weeks (p=0.032 and p=0.031) with no differences in tetanus titres. ConclusionsHIV exposure, but not the timing of BCG vaccination, was associated with antibody concentrations to Hib, pertussis, HBV and tetanus primary immunization.Clinical Trial Registration: DOH-27-1106-1520.

Effect of Haemophilus influenzae type b vaccination without a booster dose on invasive H influenzae type b disease, nasopharyngeal carriage, and population immunity in Kilifi, Kenya: a 15-year regional surveillance study.

SummaryBackgroundHaemophilus influenzae type b (Hib) conjugate vaccine, delivered as a three-dose series without a booster, was introduced into the childhood vaccination programme in Kenya in 2001. The duration of protection and need for a booster dose are unknown. We aimed to assess vaccine effectiveness, the impact of the vaccine on nasopharyngeal carriage, and population immunity after introduction of conjugate Hib vaccine in infancy without a booster dose in Kenya.MethodsThis study took place in the Kilifi Health and Demographic Surveillance System (KHDSS), an area of Kenya that has been monitored for vital events and migration every 4 months since 2000. We analysed sterile site cultures for H influenzae type b from children (aged ≤12 years) admitted to the Kilifi County Hospital (KCH) from Jan 1, 2000, through to Dec 31, 2014. We determined the prevalence of nasopharyngeal carriage by undertaking cross-sectional surveys in random samples of KHDSS residents (of all ages) once every year from 2009 to 2012, and measured Hib antibody concentrations in five cross-sectional samples of children (aged ≤12 years) within the KHDSS (in 1998, 2000, 2004–05, 2007, and 2009). We calculated incidence rate ratios between the prevaccine era (2000–01) and the routine-use era (2004–14) and defined vaccine effectiveness as 1 minus the incidence rate ratio, expressed as a percentage.Findings40 482 children younger than 13 years resident in KHDSS were admitted to KCH between 2000 and 2014, 38 206 (94%) of whom had their blood cultured. The incidence of invasive H influenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0–83·3) per 100 000 in 2000–01 to 4·5 (2·5–7·5) per 100 000 in 2004–14, giving a vaccine effectiveness of 93% (95% CI 87–96). In the final 5 years of observation (2010–14), only one case of invasive H influenzae type b disease was detected in a child younger than 5 years. Nasopharyngeal H influenzae type b carriage was detected in one (0·2%) of 623 children younger than 5 years between 2009 and 2012. In the 2009 serosurvey, 92 (79%; 95% CI 70–86) of 117 children aged 4–35 months had long-term protective antibody concentrations.InterpretationIn this region of Kenya, use of a three-dose primary series of Hib vaccine without a booster dose has resulted in a significant and sustained reduction in invasive H influenzae type b disease. The prevalence of nasopharyngeal carriage is low and the profile of Hib antibodies suggests that protection wanes only after the age at greatest risk of disease. Although continued surveillance is important to determine whether effective control persists, these findings suggest that a booster dose is not currently required in Kenya.FundingGavi, the Vaccine Alliance, Wellcome Trust, European Society for Paediatric Infectious Diseases, and National Institute for Health Research.

Antibodies against Haemophilus influenzae type b in The Gambia: Investigating the extent of protection across age groups

Following a landmark clinical trial, the vaccine against Haemophilus influenzae type b (Hib) was introduced in The Gambia in 1997. Whilst the immunogenicity of this vaccine is well established subsequent to the doses administered under the EPI schedule, little data exists assessing longevity of protection, using serology. Such data are needed however to predict the susceptibility to Hib at the population level.To determine antibody persistence in 5–6 year old fully vaccinated Gambian children compared with older children, adolescents and young adults, 427 serum samples from healthy 5–37 year old participants were tested for Hib antibodies using VaccZyme Human Anti-Hib ELISA kits.86% of the children who had received 3 doses of Hib vaccine in infancy had Hib antibody concentrations ≥0.15mg/l at the age of 5–6 years. This proportion was 76% for adolescents who had also largely been vaccinated and 90% for adults who had never received Hib vaccine.Although most participants had anti-Hib antibody above concentrations putatively defined as protective, significantly fewer had concentrations thought to confer long-term protection. This suggests a population with insufficient or waning antibody that may be susceptible to breakthrough disease and transmission.

Haemophilus influenzae serotype B (Hib) seroprevalence in England and Wales in 2009

A national seroprevalence study was performed to determine the prevalence of Haemophilus influenzae type b (Hib) antibodies in England and Wales in 2009, when Hib disease incidence was the lowest ever recorded. A total of 2,693 anonymised residual sera from routine diagnostic testing submitted by participating National Health Service hospital laboratories were tested for Hib anti-polyribosyl-ribitol phosphate (PRP) IgG antibodies using a fluorescent bead assay. Median anti-PRP IgG concentrations were highest in toddlers aged 1–4 years (2.65 μg/ml), followed by children aged 5–9 years (1.95 μg/ml). Antibody concentrations were significantly lower after this age, but were still significantly higher among 10–19 year-olds (0.54 μg/ml) compared with adults aged >20 years (0.16 μg/ ml; p<0.0001). Half of the adults (51%) did not have Hib antibody concentrations ≥0.15 μg/ml, the level considered to confer short-term protection. Thus, the current excellent Hib control appears to be the result of high anti-PRP antibody concentrations in children aged up to 10 years, achieved through the various childhood vaccination campaigns offering booster immunisation. The lack of seroprotection in adults emphasises the importance of maintaining control of the disease and, most probably carriage, in children, therefore raising the question as to whether long-term routine boosting of either pre-school children or adolescents may be required.

Immune response to Haemophilus influenzae type b conjugate vaccine in preterm infants

Haemophilus influenzae type b (Hib) vaccine became available for use in Japan in December 2008. The aim of the present study was to evaluate the immunogenicity of Hib vaccine in Japanese preterm infants. Serum samples were obtained from 54 preterm infants before the first vaccination and 1 month after the third. Anti-polyribosylribitol phosphate (PRP) antibodies were measured using an enzyme-linked immunosorbent assay method. Antibody positivity was defined as levels >1 µg/mL. Of the 54 preterm infants, 46 (85.2%) achieved antibody levels >1 µg/mL. This compares with the 92.4% reported in full-term infants. The antibody seroconversion rate of infants starting vaccination at 2 months of age was close to being significantly lower than when vaccination was started at 3 months of age (P= 0.060). In addition, the percentage of infants achieving a positive response in the group with a history of antenatal steroid exposure was significantly higher than in those not exposed (P= 0.046). Thus, risk factors for lower Hib antibody concentrations after three doses of vaccine were age at first vaccination and lack of use of antenatal steroids. There is a possibility that perinatal factors and the environment unique to preterm infants are related to their lower antibody positivity rates compared to full-term infants. It may therefore be preferable to modify the proposed immunization schedule.

Haemophilus influenzae serotype b conjugate vaccine failure in twelve countries with established national childhood immunization programmes

The present study describes the clinical and immunological features of children with Hib vaccine failure, who were identified through national surveillance between 1996 and 2001 in Europe, Israel and Australia. True vaccine failure was defined as invasive Hib disease occurring ≥2 weeks after one dose, given after the first birthday, or ≥1 week after ≥2 doses, given at <1 year of age. Of the 423 cases (representing 0.2 cases per 100 000 child-years at risk) reported, 330 (78%) had received three doses in the first year of life and developed disease at a median age of 28 months. Of the remaining 93, 48 had received two doses in infancy, 34 had received four doses including a booster, and 11 had received a single dose after 12 months of age. These children developed disease at a median age of 12, 33 and 71 months, respectively. In total, 47 out of 258 children (18%) with available information had an underlying medical problem (including prematurity) and 53 out of 161 (33%) had immunoglobulin deficiency. Convalescent Hib antibody concentrations were above the putative protective concentration of 1.0 mg/L in 147/194 (76%) children; low concentrations were associated with both the presence of an underlying medical problem and young age at the time of Hib disease. Almost all children who received an additional vaccine dose developed antibodies at protective concentrations. Thus, Hib vaccine failure is rare, but can occur with any immunization schedule. Children with Hib vaccine failure should have immunoglobulin and convalescent Hib antibody concentrations measured after infection and receive additional vaccination, if required.

A Randomized, Multicenter, Open-Label Clinical Trial to Assess the Immunogenicity of a Meningococcal C Vaccine Booster Dose Administered to Children Aged 14 to 18 Months

A booster meningococcal C (MenC) vaccine dose is recommended after the first year of life. The objective of this study was to assess its immunogenicity and factors that modify the immunoresponse. An open label study in which 389 children 14 to 18 months of age, previously primed with 3 doses of a MenC vaccine conjugated with CRM197 (MenC-CRM) or with 2 doses of a MenC vaccine conjugated with tetanus toxoid (MenC-TT), were randomized to be boosted with either of these vaccines and a DTaP-IPV-Hib vaccine at the same time. Immunogenicity against MenC and Haemophilus influenzae type b was assessed before and 1 month after the booster dose. Before the second year booster, 44.9% of the studied children had MenC bactericidal (SBA) seroprotection rate of > or =1:8, with no differences related to the vaccine used for priming, whereas the anti Hib antibody concentration was higher in children primed with the MenC-TT (0.59; 95% CI: 0.49-0.71 vs. 0.39; 95% CI: 0.32-0.48).One month after the MenC vaccine booster 99.5% of the children had SBA > or =1:128. Children primed with MenC-TT reached higher SBA titers: 6520 (95% CI: 5359-7932) than those primed with MenC-CRM: 1903 (95% CI: 1600-2262). Children primed with MenC-CRM had SBA titers of 2061 (95% CI: 1599-2627) when boosted with MenC-TT and 1746 (95% CI: 1378-2213) when boosted with MenC-CRM. Children primed with MenC-TT had SBA titers of 6786 (95% CI: 5023-9167) and 6278 (95% CI: 4841-8144) when boosted with MenC-TT or MenC-CRM. There was no difference in the PRP antibody concentration after boosting. A booster MenC dose induces high SBA and anti Hib response with over 99% of children seroprotected. Children primed with a MenC-TT vaccine reached SBA titers 3.5 times higher no matter which vaccine was used for boosting.

Levels of Haemophilus influenzae type B (Hib) antibody in Turkey before routine immunization

The Haemophilus influenzae type b (Hib) vaccine was introduced into the routine immunization schedule in Turkey on January 1, 2007. This study investigates the immunity to Hib prior to the introduction of the vaccine. Materials and methods: Serum samples were collected from healthy volunteers between the ages of 6 months and 50 + years of age, living in the area of 26 health centers in the Samsun, Antalya, and Diyarbakir provinces during 2000-2001. In total, 1713 sera were selected for this study, and the younger age groups were given priority (range 0-82). A commercial ELISA test was used to measure anti-Hib IgG. Hib antibody concentrations of 0.15 to < 1.0, and >= 1.0 µg/mL were considered as non protective, short-term protection, and long term protection, respectively. The statistical analyses performed were the chi-square test and logistic regression. Results: The antibody levels considered non-protective were 58.0%, 35.3%, 28.1%, 19.8%, 18.4%, 15.3%, and 20.6% among < 5, 5-9, 10-19, 20-29, 30-39, 40-49, and 50 and over age groups, respectively. Protection against Hib infection increased by age in all 3 provinces. Conclusion: This study provides important baseline data on anti-Hib antibody levels in Turkey before routine immunization was introduced, and shows that there is a considerable percentage of subjects with non-protective antibody levels.

Long‐Term Immunological Follow‐Up of Children withHaemophilus influenzaeSerotype b Vaccine Failure in the United Kingdom

It is not known how long children with Haemophilus influenzae serotype b (Hib) vaccine failure retain protective Hib antibody concentrations after infection. The objective of this study was to determine Hib antibody concentrations in children several years after infection and to identify risk factors for low antibody concentrations. The families of children from the United Kingdom who developed invasive Hib disease after prior immunization with Hib conjugate vaccine (i.e., Hib vaccine failure) from October 1992 through December 2005 were asked to complete a questionnaire. A blood sample was also obtained from each child. Of 323 families approached, 260 (80.5%) returned a completed questionnaire, and 175 (54.2%) children provided a blood sample. The median age at follow-up was 8.4 years (interquartile range [IQR], 6.2-15.4 years), and the median duration of follow-up was 4.1 years (IQR, 3.5-9.7 years). Twenty-seven children (16.1%) had been born prematurely and/or had an underlying medical condition, and 18 (10.8%) had immunoglobulin deficiency. The median Hib antibody concentration was 0.70 microg/mL (IQR, 0.22-5.8 microg/mL). Overall, 95 children (56.9%) had antibody concentrations <1.0 microg/mL, and 27 (16.2%) had antibody concentrations <0.15 microg/mL. All 3 children with Down syndrome and 10 (42%) of 24 children aged <5 years at follow-up had Hib antibody concentrations <0.15 microg/mL. An antibody concentration <0.15 microg/mL was independently associated with underlying conditions, young age at onset of Hib disease, and shorter time from Hib disease to follow-up. More than one-half of the children with Hib vaccine failure had antibody concentrations below those considered to confer long-term protection, which suggests that these children might be at further risk of invasive Hib disease and would benefit from another dose of Hib vaccine.

School‐Aged Children: A Reservoir for Continued Circulation ofHaemophilus influenzaeType b in the United Kingdom

A resurgence of Haemophilus influenzae type b (Hib) disease occurred in the United Kingdom between 1999 and 2003 and was partially attributed to lower immunogenicity of combination vaccines. The reservoir for Hib that led to transmission in this period is unknown. We estimated the point prevalence of Hib carriage in school-aged children and adults, using oropharyngeal swabbing and selective media. We characterized the Hib isolates by multilocus sequence typing (MLST) and measured Hib antibody concentrations in adults by enzyme-linked immunosorbent assay. Point prevalence for Hib carriage in 855 children aged 6-16 years was 4.2% (95% confidence interval [CI], 2.5%-5.9%). Five clonal groups of Hib were identified by MLST, 86% from the lineage of sequence type 6. No Hib was isolated in 385 adults (upper limit of 95% CI, 0.95%). The geometric mean concentration of serum antibody to polyribosylribitol phosphate was 0.47 microg/mL (95% CI, 0.37-0.59 mirog/mL) in adults. Hib carriage is common in school-aged children, who are a significant reservoir for ongoing transmission of Hib to susceptible individuals in the United Kingdom. Surveillance of transmission and immunity across all ages of the population is essential to monitor the evolution of Hib epidemiology.

Immunogenicity of a Fourth Dose of Haemophilus influenzae Type b (Hib) Conjugate Vaccine and Antibody Persistence in Young Children from the United Kingdom Who Were Primed with Acellular or Whole-Cell Pertussis Component-Containing Hib Combinations in Infancy

In response to the rising incidence of Haemophilus influenzae type b (Hib) disease in the United Kingdom, a national campaign to give a booster dose of single-antigen Hib conjugate vaccine to children aged 6 months to 4 years was undertaken in 2003. Children (n = 386) eligible for Hib vaccine in the campaign were recruited. Hib antibody concentrations were measured before boost and at 1 month, 6 months, 1 year, and 2 years after boost and were analyzed according to children's ages at booster dose and whether a Hib combination vaccine containing acellular pertussis (aP) or whole-cell pertussis (wP) components was given in infancy. The geometric mean antibody concentrations (GMCs) before the booster declined as the time since primary immunization increased (P < 0.001), and GMCs were threefold higher in recipients of wP-Hib than aP-Hib combination vaccines (P < 0.001). GMCs 1 month after the booster increased with age (P < 0.001) as follows: 6 to 11 months; 30 microg/ml (95% confidence interval [CI], 22 to 40); 12 to 17 months, 68 microg/ml (95% CI, 38 to 124); and 2 to 4 years, 182 microg/ml (151 to 220), with no difference according to the type of priming vaccine received. Antibody levels declined after the booster, but 2 years later, GMCs were more than 1.0 microg/ml for all age groups. By extrapolating data for the decline in antibody levels, we found the GMCs 4 years after boosting were predicted to be 0.6, 1.4, and 2.6 microg/ml for those boosted at 6 to 11 months, 12 to 17 months, and 2 to 4 years, respectively, with levels of at least 0.15 microg/ml in about 90% of individuals. A booster dose of Hib vaccine given after the first year of life should provide long-lasting protection.

A randomized study on donor immunization with tetanus–diphtheria, Haemophilus influenzae type b and inactivated poliovirus vaccines to improve the recipient responses to the same vaccines after allogeneic bone marrow transplantation

The HLA-identical sibling donors of 111 bone marrow transplantation (BMT) recipients were randomised to receive or not to receive tetanus-diphtheria (T-d), Haemophilus influenzae type b (Hib), and inactivated poliovirus (IPV) vaccines 2-10 weeks before BM harvest. Fifty-three (DV+ group) recipients received the graft from a vaccinated donor and 58 (DV- group) from an unvaccinated donor. All recipients were vaccinated with the T-d, Hib and IPV vaccines at 3, 6 and 12 months after BMT. Diphtheria and Hib antibody concentrations were consistently higher in the DV+ than in the DV- group from 6 months post transplantation onwards. The differences were significant at 6 and 13 months for diphtheria and at 12 months for Hib antibody concentrations. Tetanus, PV1, PV2 and PV3 antibody levels were similar in both groups. Patients transplanted from donors with high tetanus, diphtheria and Hib antibody concentrations had higher respective antibody concentrations after BMT than those transplanted from donors with low antibody concentrations. Especially patients whose donors have low-specific antibody concentrations may benefit from donor vaccination with protein and conjugate vaccines.

Effect of probiotics on vaccine antibody responses in infancy – a randomized placebo‐controlled double‐blind trial

Probiotics are immunomodulatory and may thus affect vaccine antibody responses. With the accumulating evidence of their health-promoting effects, probiotics are increasingly administered in allergy-prone infants. Therefore, we studied the effect of probiotics on antibody responses to diphtheria, tetanus and Haemophilus influenzae type b (Hib) vaccines in 6-month-old infants participating in a randomized placebo-controlled double-blind allergy-prevention trial. Mothers of unborn children at increased risk for atopy used a combination of four probiotic strains, or a placebo, for 4 wk before delivery. During 6 months from birth, their infants received the same probiotics and galacto-oligosaccharides, or a placebo. The infants were immunized with a DTwP (diphtheria, tetanus and whole cell pertussis) at ages 3, 4, and 5 months, and with a Hib polysaccharide conjugate at 4 months. Serum diphtheria, tetanus, and Hib IgG antibodies were measured at 6 months. In the probiotic group, protective Hib antibody concentrations (>/=1 microg/ml) occurred more frequently, 16 of 32 (50%) vs. six of 29 (21%) (p = 0.020), and the geometric mean (inter-quartile range) Hib IgG concentration tended to be higher 0.75 (0.15-2.71) microg/ml than in the placebo group 0.40 (0.15-0.92) microg/ml (p = 0.064). In these respective groups, diphtheria, 0.38 (0.14-0.78) vs. 0.47 (0.19-1.40) IU/ml (p = 0.449), and tetanus, 1.01(0.47-1.49) vs. 0.81 (0.56-1.39) IU/ml (p = 0.310), IgG titers were comparable. In conclusion, in allergy-prone infants probiotics seem not to impair antibody responses to diphtheria, tetanus, or Hib, but may improve response to Hib immunization.

Trends in Haemophilus influenzae type b infections in adults in England and Wales: surveillance study

Objective To describe invasive Haemophilus influenzae type b (Hib) infections in individuals aged 15 years or older in England and Wales between 1991 and 2003.Design Prospective, laboratory based surveillance of...

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure

Aims: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic...

Long term enhancement of the IgG2 antibody response to Haemophilus influenzae type b by breast-feeding.

Sets of sera were obtained from 30 children <6 years of age with invasive type b (Hib) infection and their mothers. Duration and mode of breast-feeding were monitored. Titers of IgG1, IgG2, IgA and IgM antibodies against Hib capsular polysaccharide were determined in sera taken during the acute illness and during early and late convalescence. Children 18 months or older with longer durations of exclusive breast-feeding (13 weeks or more; mean, 19.3 weeks) had higher Hib antibody concentrations of the IgG1, IgG2, IgA and IgM isotypes than those with a shorter duration of exclusive breast-feeding (<13 weeks; mean, 5.4 weeks). The difference was greatest for the IgG2 isotype. In regression analyses the association between the duration of exclusive breast-feeding and the anti-Hib IgG2 concentration was significant when breast-feeding, type of Hib infection, maternal Hib antibody titer and age were used as explanatory factors. In the group of 14 children <18 months of age no significant differences were noted. This study indicates the presence of a long lasting enhancing effect of breast-feeding on the antibody response to Hib in children, in particular on IgG2 Hib antibody production. This may result from the content in the milk of IFN-gamma and IFN-gamma-producing cells and possibly other factors, which can support IgG2 antibody production.

Haemophilus Influenzae Type b (Hib) Antibody Concentrations and Vaccination Responses in Patients with Chronic Lymphocytic Leukaemia: Predicting Factors for Response

We have recently demonstrated a moderate vaccination response rate of 43% against Haemophilus influenzae type b (Hib) conjugate vaccine among adult and elderly patients with chronic lymphocytic leukaemia (CLL). We now investigated demographic and immunological factors predicting the favourable response and protective antibody concentrations for Hib conjugate vaccine in CLL. Lower age was associated with protective pre- and post-vaccination antibody concentrations. High IgG1 and IgA concentrations were also associated with the protective efficacy. High IgM, in turn, was the best predictor of a significant vaccination response. Again, lower age seemed to be involved in this outcome. Judging from these findings, it would seem beneficial to vaccinate all CLL patients with conjugate vaccines at the presentation of the disease. Investigations of a new pneumococcal conjugate vaccine in CLL are warranted.

Antibody concentration and clinical protection after Hib conjugate vaccination in the United Kingdom.

The schedule for Haemophilus influenzae type b (Hib) vaccination of infants in the United Kingdom consists of 3 doses given at 2, 3, and 4 months of age. Many countries include a fourth dose (booster) of Hib vaccine in the second year of life on the basis of declining Hib antibody concentrations after the primary series. Few data are available to show that this fourth dose is actually necessary. To evaluate long-term clinical protection against Hib disease and Hib antibody concentrations following primary Hib vaccination without a booster dose. Clinical protection study conducted between October 1992 and March 1999 in the United Kingdom, in which children developing invasive Hib disease despite vaccination in infancy with 3 doses of Hib conjugate vaccine were reported by pediatricians through an active, prospective, national survey. Separate antibody studies were conducted among 2 cohorts of children (n = 153 and n = 107) vaccinated at 2, 3, and 4 months of age with Hib conjugate vaccine and followed up to 43 and 72 months of age. Age-specific vaccine effectiveness, derived from the observed number of true vaccine failures after 3 Hib vaccine doses compared with the number of cases expected based on the age-specific rates of invasive Hib disease obtained prior to the introduction of Hib vaccines; and proportion of children in the 2 cohorts with Hib antibody concentrations of less than 0.15 and less than 1.0 microg/mL. Ninety-six true vaccine failures occurring after 3 vaccine doses were detected. During the study period, an estimated 4,368,200 infants in the United Kingdom received 3 doses of vaccine; therefore, the vaccine failure rate was 2.2 per 100,000 vaccinees (95% confidence interval, 1.8-2.7 per 100,000). Although vaccine effectiveness declined significantly after the first year of life (P<.001), it remained high until the sixth year of life (99.4% in children aged 5-11 months vs 97.3% in those aged 12-71 months). The proportion of cohorts 1 and 2 with anti-PRP antibody levels of less than 0.15 microg/mL increased between 12 and 72 months of age (6% at 12 months, 8% at 43 months, and 32% at 72 months; chi(2)(1) = 18.25; P<.001 for trend). Our results suggest that anti-PRP antibody levels and clinical protection against Hib disease wane over time after Hib vaccination at 2, 3, and 4 months of age without a booster dose at 2 years of age. The decline in clinical protection is minimal, however, suggesting that a booster dose of Hib vaccine following infant vaccination is not essential. JAMA. 2000;284:2334-2340.

Studies on a Hib-tetanus toxoid conjugate vaccine: effects of co-administered tetanus toxoid vaccine, of administration route and of combined administration with an inactivated polio vaccine

A freeze-dried tetanus toxoid (T) conjugated Haemophilus influenzae type b (Hib) vaccine, was reconstituted in either diphtheria toxoid (D), DT or a combined DT and inactivated polio vaccine (IPV), and administered in an open randomized trial either intramuscularly (i.m.) or subcutaneously (s.c.) to 287 Swedish infants at three, five and 12 months of age. When not included in the mixture, IPV was administered s.c. at a separate site. The geometric mean concentrations of Hib antibodies after primary and booster vaccinations were 1.0 and 11.6 μg/ml, respectively, with no differences related to co-administration of the carrier protein T. Antibodies against T were induced by the T conjugated Hib vaccine (Hib-T) alone in 69/95 infants aged six months, and in 87/93 children aged 13 months, although infants receiving both Hib-T and T had significantly higher concentrations. Antibody responses to Hib, D, T or polio were not negatively influenced by administration route or by mixing with IPV, except that the mixed vaccine DT-IPV induced lower anti-polio GM titers after primary vaccination than did separate IPV. More local reactions were induced by the s.c. than by the i.m. route ( P-values from 0.001 to 0.01). Slight increases in rates of local reactions and febrile events (≥38°C) occurred by order of dose. The low Hib antibody concentrations after the first two doses in this and other Swedish studies are unlikely to be of clinical relevance. The tetanus antibody response from T as a carrier protein alone was not sufficient for basic tetanus immunization, but should be considered in future use of additional T conjugated vaccines.