Anti-glycan antibodies: roles in human disease.

Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.

Accuracy and quality of immunization data in Iran: findings from data quality self-assessment survey in 2017.

BACKGROUND: The aim of this study was to assess the accuracy and quality of immunization data on the pentavalent (diphtheria, pertussis, tetanus, hepatitis B and Haemophilus influenzae type B (Hib)) and MMR vaccines as the administrative data of the expanded program on immunization (EPI) in Iran. METHODS: We conducted a Data Quality Self-assessment (DQS) survey from October to December 2017. Standardized DQS tools were used to assess the accuracy of reported immunizations data and quality of the immunization monitoring system at the provincial level of the healthcare system including health houses, health posts, rural and urban health centers and district health centers. Multistage cluster random sampling with proportional to size (PPS) weights was used to select target provinces and related health units. Accuracy ratio, quality index (QI), completeness and relevant quality indices of first dose of MMR (MMR1) and third dose of pentavalent vaccines were reported. Corresponding period of the survey was limited to reported administrative immunization data during the first 6 months of 2016. RESULTS: In relation to accuracy ratio, there was some evidence of under reporting of pentavalent (3rd dose) and MMR1 vaccines in health house units which were 100.94 and 101.1%, respectively. Completeness of reporting for both vaccines at different provincial levels was near 100%. However, the corresponding value for pentavalent (3rd dose) and MMR1 vaccines at the level of urban health centers was 96.67 and 94.17% respectively. Among the five components of a monitoring system data usage and core output had the lowest QI scores in either rural or urban as well as district healthcare centers. CONCLUSIONS: Findings from our DQS survey reveals that administrative reporting of the immunization data was adequate at provincial and district levels of the healthcare centers. Although, addressing the existing concerns regarding timelines of the reporting by health authorities and staffs of EPI is warranted.

Current Epidemiology and Trends in Invasive Haemophilus influenzae Disease-United States, 2009-2015.

Background: Following Haemophilus influenzae serotype b (Hib) conjugate vaccine introduction in the 1980s, Hib disease in young children dramatically decreased, and epidemiology of invasive H. influenzae changed. Methods: Active surveillance for invasive H. influenzae disease was conducted through Active Bacterial Core surveillance sites. Incidence rates were directly standardized to the age and race distribution of the US population. Results: During 2009-2015, the estimated mean annual incidence of invasive H. influenzae disease was 1.70 cases per 100000 population. Incidence was highest among adults aged ≥65 years (6.30) and children aged <1 year (8.45); many cases in infants aged <1 year occurred during the first month of life in preterm or low-birth-weight infants. Among children aged <5 years (incidence: 2.84), incidence was substantially higher in American Indian and Alaska Natives AI/AN (15.19) than in all other races (2.62). Overall, 14.5% of cases were fatal; case fatality was highest among adults aged ≥65 years (20%). Nontypeable H. influenzae had the highest incidence (1.22) and case fatality (16%), as compared with Hib (0.03; 4%) and non-b encapsulated serotypes (0.45; 11%). Compared with 2002-2008, the estimated incidence of invasive H. influenzae disease increased by 16%, driven by increases in disease caused by serotype a and nontypeable strains. Conclusions: Invasive H. influenzae disease has increased, particularly due to nontypeable strains and serotype a. A considerable burden of invasive H. influenzae disease affects the oldest and youngest age groups, particularly AI/AN children. These data can inform prevention strategies, including vaccine development.

Expanded program of immunization in the Maghreb. Case study of Tunisia.Systematic review of the literature.

BACKGROUND: Vaccination is the most cost-effective intervention for primary prevention. The Maghreb countries had joined the The Expanded Programme on Immunization (EPI). Tunisia had also introduced the vaccine against hepatitis B and Haemophilus influenzae type B (Hib). OBJECTIVE: To describ, through a systematic review, the specific documentation on the EPI in Tunisia. METHOD: Target publications were collected using Medline database and Google Scholar from published articles from January 01 1998 to December 12 2017. The synthesis of the data was done according to four axes: "input", "process", "output" and "outcome". RESULTS: 17 articles were analyzed, with an average of 4 publications every 5 years. The author's specialty was community and preventive medicine in 56% of cases. Six articles focused on the "input" vaccination program, five related to the immunization process and the other five articles examined output and outcomes. CONCLUSION: Tunisian publications concerning vaccination were rare, their efficiency and impact on the change of national vaccination strategy was crucial. Research coordination between Maghreb countries is highly recommended to meet the growing information needs.

Vaccines to prevent pneumonia in children - a developing country perspective.

Pneumonia accounted for 15% of the 6.3 million deaths among children younger than five years in 2013, a total of approximately 935,000 deaths worldwide. Routine vaccination against common childhood illnesses has been identified as one of the most cost-effective strategies to prevent death from pneumonia. Vaccine-preventable or potentially preventable diseases commonly linked with respiratory tract infections include Streptococcus pneumoniae, Haemophilus influenza type-b (Hib), pertussis, influenza, measles, and tuberculosis. Although here have been great strides in the development and administration of effective vaccines, the countries that carry the largest disease burdens still struggle to vaccinate their children and newer conjugated vaccines remain out of reach for many. The Global Vaccine Action Plan (GVAP) has identified priority areas for innovation in research in all aspects of immunisation development and delivery to ensure equitable access to vaccines for all.

Child pneumonia - focus on the Western Pacific Region.

Worldwide, pneumonia is the leading cause of death in infants and young children (aged <5 years). We provide an overview of the global pneumonia disease burden, as well as the aetiology and management practices in different parts of the world, with a specific focus on the WHO Western Pacific Region. In 2011, the Western Pacific region had an estimated 0.11 pneumonia episodes per child-year with 61,900 pneumonia-related deaths in children less than 5 years of age. The majority (>75%) of pneumonia deaths occurred in six countries; Cambodia, China, Laos, Papua New Guinea, the Philippines and Viet Nam. Historically Streptococcus pneumoniae and Haemophilus influenzae were the commonest causes of severe pneumonia and pneumonia-related deaths in young children, but this is changing with the introduction of highly effective conjugate vaccines and socio-economic development. The relative contribution of viruses and atypical bacteria appear to be increasing and traditional case management approaches may require revision to accommodate increased uptake of conjugated vaccines in the Western Pacific region. Careful consideration should be given to risk reduction strategies, enhanced vaccination coverage, improved management of hypoxaemia and antibiotic stewardship.

Immunization Status of NICU Graduates at a Tertiary Care Children's Hospital.

BACKGROUND: Approximately 500,000 infants are born prematurely each year in the United States. Immunization of infants in a neonatal intensive care unit (NICU) set a precedence for future immunizations. PURPOSES: The objectives of this study were to determine the current rates of immunization and identify variables associated with immunizations of NICU graduates who were aged 60 days or older at time of discharge. METHODS: This descriptive pilot study utilized retrospective paper medical record review in one tertiary children's hospital. The relationships between immunization status and study variables were examined using t tests and logistic regression. RESULTS: Of 43 infants discharged at least 60 days of age or older from the NICU, 74.4% were fully immunized in accordance with American Academy of Pediatrics (AAP) recommendations. Significant predictors were age at discharge for immunization and steroid use for nonimmunization. IMPLICATIONS FOR PRACTICE: Immunization needs to be a priority in order to give NICU infants every advantage regarding their future health status. Nurses need to implement hospital policies ensuring immunizations of NICU graduates. IMPLICATIONS FOR RESEARCH: Future studies should focus on samples from diverse hospitals and levels of NICUs. Qualitative studies exploring and describing parent and provider knowledge of current AAP guidelines will strengthen our understanding of potential barriers to immunization.

A high throughput serum bactericidal assay for antibodies to Haemophilus influenzae type b.

BACKGROUND: The protective capacities of antibodies induced with Haemophilus influenzae type b (Hib) vaccines can be directly assessed in vitro with a Hib-specific serum bactericidal assay (SBA). However, the conventional SBA requires several tedious steps including manual counting of bacterial colonies, and therefore, it is seldom used. METHODS: To overcome these limitations, we have improved the conventional SBA by using frozen target bacteria and by developing an automated colony counting method based on agar plates with the chromogenic dye 2, 3, 5-triphenyl tetrazolium chloride (TTC). RESULTS: These changes enabled us to analyze about 100 serum samples per day per person by SBA. When the intra- and inter-assay precisions were studied, this assay showed a coefficient of variation (CV) ranging from 1 to 38 %. To monitor the long term assay stability for assays involving different bacteria lots, complement lots, and operators, we analyzed bactericidal indices of quality control samples obtained over a 6 year period and found the CV to be about 35-50 %. Lastly, our SBA results were compared with the ELISA results obtained using 90 serum samples from children. We showed that the bactericidal index correlated with IgG anti-Hib antibody levels (r = 0.84), with a bactericidal index of 10 corresponding approximately to 0.15 µg/mL IgG, the widely accepted protective level of antibody. CONCLUSION: We describe a simple high throughput SBA for anti-Hib antibodies that would be useful for evaluating various Hib vaccines. While additional work will be needed to standardize the assay, this SBA should greatly facilitate studies of Hib vaccines.

Public health impact of Infanrix hexa™ (DTPa-HBV-IPV/Hib) reimbursement: A study programme in France. Part 2: Evolution of the acceptability of infants' vaccination against hepatitis B in general and pediatric practices - the PRALINE study.

BACKGROUND: The reimbursement of the hexavalent vaccine (Infanrix hexa™), comprising the DTPa-IPV-Hib components and the hepatitis B recombinant in a single vaccine, was approved in France in March of 2008. The impact of its reimbursement on physicians' decisions to vaccinate infants against hepatitis B was assessed in a study conducted with general practitioners and pediatricians. METHODS: The PRALINE study (NCT01777074) was a national, cross-sectional, repeated study with two measurement periods (T1 and T2) that measured the changes in physicians' acceptance of hepatitis B vaccination of infants before and for the 3 years after the approval of the hexavalent vaccine reimbursement. Two patient registers were created for each measurement period to enroll the first 15 12- to 15-month-old infants and the first 15 24- to 27-month-old children seen by the practitioners. The proportion of eligible children receiving a hepatitis B vaccine for each physician's practice was calculated. Practitioners also answered a vaccination practice questionnaire via telephone interviews. RESULTS: Across the two study periods, 418 general practitioners and 463 pediatricians were recruited and responded to the telephone interview on their vaccination practices. The overall number of children included in the study in both study periods reached almost 20,000. In the general practitioners group, there was a significant increase in the proportion of physicians "practicing hepatitis B vaccination" (i.e., at least 50% of eligible children receiving the initial hepatitis B vaccination) in children 24-27 months old (79% T2 versus 47% T1, P-value [P]<0.001). Similarly, the proportion of pediatricians initiating hepatitis B vaccination increased from 51% (T1) to 94% (T2) (P<0.0001). General practitioners offered hepatitis B vaccination to infants more systematically in the second study period (87% T2 versus 73% T1, P<0.001) and also suggested the use of the hexavalent vaccine to more patients after reimbursement (92% T2 versus 78% T1, P<0.0001). The proportion of pediatricians offering vaccination to every infant was high at T1 (94%) and remained steady (97%) with a high use of the hexavalent vaccine (94% T1 and 96% T2). CONCLUSION: The PRALINE study shows a significant and immediate change in the hepatitis B vaccination practices of general practitioners and pediatricians following hexavalent vaccine reimbursement with a significant increase in hepatitis B vaccine coverage in infants.

Public health impact of Infanrix hexa (DTPa-HBV-IPV/Hib) reimbursement: A study programme in France. Part 1: Evolution of hepatitis B vaccine coverage rates in infants aged less than 27 months, in the general population - the PopCorn study.

BACKGROUND: Reimbursement of the hexavalent vaccine (Infanrix hexa) comprising the DTPa-IPV-Hib components and the hepatitis B valence in a single vaccine was decided in March 2008 in France. The impact of its reimbursement on the hepatitis B vaccine coverage rate was assessed in a study conducted in the general population prior to and after implementation of the reimbursement policy. METHODS: The PopCorn study (NCT01782794) was a national, cross-sectional and repeated study, with four assessment periods over 3 years, from 2009 to 2012, to assess the hepatitis B vaccine coverage in 12- to 15- and 24- to 27-month-old children, vaccinated between 2007 and 2011 and selected by the quota sampling method. Face-to-face interviews were conducted at their homes and vaccination status was collected using their child's health record. Parents were also interviewed on their perceptions and acceptance of hepatitis B vaccination. Three indicators were calculated to assess hepatitis B vaccination coverage: proportions of infants with at least one dose before 6 months of age, with at least two doses before 6 months of age and with a complete schedule at 24 months of age. RESULTS: A total of 4903 children were enrolled in the study. An overall significant increase (P-value [P<0.05]) of the three indicators of interest over the four periods of time was observed for both age groups. The proportion of children receiving hepatitis B vaccination before 6 months increased from 21% at baseline (before vaccine reimbursement) to almost 75% at the last assessment period in 2012. More than 60% of 24- to 27-month-old children received a complete schedule in 2012 compared to 33% at baseline. No significant increases in the proportions of parents "favourable" and "moderately in favour" of hepatitis B vaccination were observed across the four evaluation periods (respectively, 17-22% and 48-50%, P=0.09). CONCLUSION: The rapid increase of hepatitis B vaccination coverage suggests a significant change in hepatitis B vaccination practice related to the hexavalent vaccine's reimbursement. This change was observed in a context of stability regarding parents' perceptions and acceptance of hepatitis B vaccination and of coverage rates for other infant vaccinations.

Evaluation of introduction of the Haemophilus influenzae vaccine in Côte d'Ivoire / Évaluation de l'introduction du vaccin anti-haemophilus influenzae en Côte d'Ivoire.

Introduction: Côte d'Ivoire introduced the Haemophilus influenzae type b vaccine into the EPI in March 2009. Following this introduction, an evaluation was conducted in 2012 in order to evaluate the vaccine introduction process. Methods: Data collection methods consisted of document review, structured interviews and direct observation. This study collected information from six health region officials, 12 health districts and 36 healthcare institutions. Seventy-two mothers or child carers were also interviewed. Collected data were processed and analysed by Excel, Epi Info and SPSS. Results: A vaccine introduction plan was developed, but was not communicated at the operational level. The planned training for district health care providers was conducted eighteen months after introduction of the vaccine. None of the vaccinating centres had communication support about the new vaccine. Temperature recording was regularly performed in 92% of district deposits and 68% of vaccinating centres. Deteriorated vaccines were observed in 6% of vaccinating centres. Only 3.5% of parents had been informed about introduction of the vaccine. Increased immunization coverage for the third dose of pentavalent vaccine was observed in one half of health districts. Conclusion: Evaluation of the introduction of Haemophilus influenzae type b vaccine highlightsthe strengths and weaknesses of the health system and provides lessons for the introduction of other vaccines into the expanded programme on immunization.

The effect of rituximab on vaccine responses in patients with immune thrombocytopenia.

B-cell depletion may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). We investigated the effects of rituximab on antibody and cellular responses to Streptococcus pneumoniae polysaccharide and Haemophilus influenzae type b (Hib) vaccines in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n = 17) or placebo (n = 7). Among 20 evaluable patients, 3 of 14 (21%) in the rituximab group and 4 of 6 (67%) in the placebo group achieved a fourfold increase in anti-pneumococcal antibodies (P = .12). For anti-Hib antibodies, 4 of 14 (29%) and 5 of 6 (83%), respectively, achieved a fourfold increase (P < .05). Fewer patients in the rituximab group demonstrated Hib killing (2 of 14 [14%], 5 of 6 [83%], P < .05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, preplasma cell blasts and interferon-γ-secreting T cells were reduced in rituximab-treated patients. Antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with depleted B-cell pools. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in ITP patients.

Reduced middle ear infection with non-typeable Haemophilus influenzae, but not Streptococcus pneumoniae, after transition to 10-valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine.

BACKGROUND: In October 2009, 7-valent pneumococcal conjugate vaccine (PCV7: Prevenar(TM) Pfizer) was replaced in the Northern Territory childhood vaccination schedule by 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; Synflorix(™) GlaxoSmithKline Vaccines). This analysis aims to determine whether the reduced prevalence of suppurative otitis media measured in the PHiD-CV10 era was associated with changes in nasopharyngeal (NP) carriage and middle ear discharge (ED) microbiology in vaccinated Indigenous children. METHODS: Swabs of the NP and ED were collected in remote Indigenous communities between September 2008 and December 2012. Swabs were cultured using standardised methods for otitis media pathogens. Children less than 3 years of age and having received a primary course of 2 or more doses of one PCV formulation and not more than one dose of another PCV formulation were included in the primary analysis; children with non-mixed single formulation PCV schedules were also compared. RESULTS: NP swabs were obtained from 421 of 444 (95%) children in the PCV7 group and 443 of 451 (98%) children in the PHiD-CV10 group. Non-mixed PCV schedules were received by 333 (79%) and 315 (71%) children, respectively. Pneumococcal (Spn) NP carriage was 76% and 82%, and non-typeable Haemophilus influenzae (NTHi) carriage was 68% and 73%, respectively. ED was obtained from 60 children (85 perforations) in the PCV7 group and from 47 children (59 perforations) in the PHiD-CV10 group. Data from bilateral perforations were combined. Spn was cultured from 25% and 18%, respectively, and NTHi was cultured from 61% and 34% respectively (p = 0.008). CONCLUSIONS: The observed reduction in the prevalence of suppurative OM in this population was not associated with reduced NP carriage of OM pathogens. The prevalence of NTHi-infected ED was lower in PHiD-CV10 vaccinated children compared to PCV7 vaccinated children. Changes in clinical severity may be explained by the action of PHiD-CV10 on NTHi infection in the middle ear. Randomised controlled trials are needed to answer this question.

Evaluation of Haemophilus influenzae type b carrier status among children 10 years after the introduction of Hib vaccine in Brazil.

The aim of the present study was to assess the prevalence of Haemophilus influenzae type b (Hib) nasopharyngeal (NP) colonisation among healthy children where Hib vaccination using a 3p+0 dosing schedule has been routinely administered for 10 years with sustained coverage (> 90%). NP swabs were collected from 2,558 children who had received the Hib vaccine, of whom 1,379 were 12-< 24 months (m) old and 1,179 were 48-< 60 m old. Hi strains were identified by molecular methods. Hi carriage prevalence was 45.1% (1,153/2,558) and the prevalence in the 12-< 24 m and 48-< 60 m age groups were 37.5% (517/1,379) and 53.9% (636/1,179), respectively. Hib was identified in 0.6% (16/2,558) of all children in the study, being 0.8% (11/1,379) and 0.4% (5/1,179) among the 12-< 24 m and 48-< 60 m age groups, respectively. The nonencapsulate Hi colonisation was 43% (n = 1,099) and was significantly more frequent at 48-< 60 m of age (51.6%, n = 608) compared with that at 12-< 24 m of age (35.6%, n = 491). The overall resistance rates to ampicillin and chloramphenicol were 16.5% and 3.7%, respectively; the co-resistance was detected in 2.6%. Our findings showed that the Hib carrier rate in healthy children under five years was very low after 10 years of the introduction of the Hib vaccine.

Pneumonia Prevention during a Humanitarian Emergency: Cost-effectiveness of Haemophilus Influenzae Type B Conjugate Vaccine and Pneumococcal Conjugate Vaccine in Somalia.

BACKGROUND: Pneumonia is a leading cause of death among children less than five years old during humanitarian emergencies. Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae are the leading causes of bacterial pneumonia. Vaccines for both of these pathogens are available to prevent pneumonia. Problem This study describes an economic analysis from a publicly funded health care system perspective performed on a birth cohort in Somalia, a country that has experienced a protracted humanitarian emergency. METHODS: An impact and cost-effectiveness analysis was performed comparing: no vaccine, Hib vaccine only, pneumococcal conjugate vaccine 10 (PCV10) only, and both together administered through supplemental immunization activities (SIAs). The main summary measure was the incremental cost per disability-adjusted life-years (DALYs) averted. One-way sensitivity analysis was conducted for uncertainty in parameter values. RESULTS: Each SIA would avert a substantial number of cases and deaths. Compared with no vaccine, the DALYs averted by two SIAs for two doses of Hib vaccine was US $202.93 (lower and upper limits: $121.80-$623.52), two doses of PCV10 was US $161.51 ($107.24-$227.21), and two doses of both vaccines was US $152.42 ($101.20-$214.42). Variables that influenced the cost-effectiveness for each strategy most substantially were vaccine effectiveness, case fatality rates (CFRs), and disease burden. CONCLUSIONS: The World Health Organization (WHO) defines a cost-effective intervention as costing one to three times the per capita gross domestic product (GDP; in 2011, for Somalia=US $112). Based on the presented model, Hib vaccine alone, PCV10 alone, or Hib vaccine and PCV10 given together in SIAs are cost-effective interventions in Somalia. The WHO/Strategic Advisory Group of Experts decision-making factors for vaccine deployment appear to have all been met: the disease burden is large, the vaccine-related risk is low, prevention in this setting is more feasible than treatment, the vaccine duration probably is sufficient for the vulnerable period of the child's life, cost is reasonable, and herd immunity is possible.

Long-term persistence of immunity and B-cell memory following Haemophilus influenzae type B conjugate vaccination in early childhood and response to booster.

BACKGROUND: Protection against Haemophilus influenzae type b (Hib), a rapidly invading encapsulated bacteria, is dependent on maintenance of an adequate level of serum antibody through early childhood. In many countries, Hib vaccine booster doses have been implemented after infant immunization to sustain immunity. We investigated the long-term persistence of antibody and immunological memory in primary-school children following infant (with or without booster) Hib vaccination. METHODS: Anti-polyribosylribitol phosphate (PRP) immunoglobulin G (IgG) concentration and the frequency of circulating Hib-specific memory B cells were measured before a booster of a Hib-serogroup C meningococcal (MenC) conjugate vaccine and again 1 week, 1 month, and 1 year after the booster in 250 healthy children aged 6-12 years in an open-label phase 4 clinical study. RESULTS: Six to 12 years following infant priming with 3 doses of Hib conjugate vaccine, anti-PRP IgG geometric mean concentrations were 3.11 µg/mL and 0.71 µg/mL and proportions with anti-PRP IgG ≥1.0 µg/mL were 79% and 43% in children who had or had not, respectively, received a fourth Hib conjugate vaccine dose (mean age, 3.9 years). Higher baseline and post-Hib-MenC booster responses (anti-PRP IgG and memory B cells) were found in younger children and in those who had received a fourth Hib dose. CONCLUSIONS: Sustained Hib conjugate vaccine-induced immunity in children is dependent on time since infant priming and receipt of a booster. Understanding the relationship between humoral and cellular immunity following immunization with conjugate vaccines may direct vaccine design and boosting strategies to sustain individual and population immunity against encapsulated bacteria in early childhood. Clinical Trials Registration ISRCTN728588998.

The relationship between pediatric combination vaccines and market effects.

We explored market factors that affect pediatric combination vaccine uptake in the US public-sector pediatric vaccine market. We specifically examined how Pediarix and Pentacel earned a place in the 2009-2012 lowest overall cost formulary. Direct competition between Pediarix and Pentacel is driven by the indirect presence of the Merck Haemophilus influenzae type b vaccine and the Recommended Childhood Immunization Schedule requirement for a hepatitis B birth dose. The resulting analysis suggests that Pentacel would never have earned a place in the lowest overall cost formulary for 2009-2012 federal contract prices for any cost of an injection unless the Merck H influenzae type b advantage was ignored and the hepatitis B birth dose administration cost was recognized by health care providers in designing the lowest overall cost formularies.

A sham case-control study of effectiveness of DTP-Hib-hepatitis B vaccine against rotavirus acute gastroenteritis in Kenya.

BACKGROUND: In many GAVI-eligible countries, effectiveness of new vaccines will be evaluated by case-control methodology. To inform the design and assess selection bias of a future case-control study of rotavirus vaccine effectiveness (VE) in western Kenya, we performed a sham case-control study evaluating VE of pentavalent vaccine (DTP-Hib-HepB) against rotavirus acute gastroenteritis (AGE). METHODS: From ongoing rotavirus surveillance, we defined cases as children 12 weeks to 23 months old with EIA-confirmed rotavirus AGE. We enrolled one community-based and two hospital-based control groups. We collected vaccination status from cards at enrollment, or later in homes, and evaluated VE by logistic regression. RESULTS: We enrolled 91 cases (64 inpatient, 27 outpatient), 252 non-rotavirus AGE facility-based controls (unmatched), 203 non-AGE facility-based controls (age-matched) and 271 community controls (age-matched). Documented receipt of 3 pentavalent doses was 77% among cases and ranged from 81-86% among controls. One percent of cases and 0-2% of controls had no pentavalent doses. The adjusted odds ratio of three versus zero doses for being a case was 3.27 (95% CI 0.01-1010) for community controls and 0.69 (95% CI 0.06-7.75) for non-rotavirus hospital-based AGE controls, translating to VE of -227% and 31%, respectively, with wide confidence intervals. (No facility-based non-AGE controls were unvaccinated.) Similar results were found for ≥2 pentavalent doses and for severe rotavirus AGE. CONCLUSIONS: The study showed that it is feasible to carry out a real case control in the study area, but this needs to be done as soon as the vaccine is introduced to capture the real impact. Sham case-control or pilot studies before vaccine introduction can be useful in designing case-control VE studies.

Combined effects of antenatal receipt of influenza vaccine by mothers and pneumococcal conjugate vaccine receipt by infants: results from a randomized, blinded, controlled trial.

A 2 × 2 factorial trial was performed to determine the efficacy of antennal influenza vaccination of mothers plus pneumococcal conjugate vaccination of their infants against respiratory illness during early infancy. The efficacy of trivalent inactivated influenza vaccine (TIV; delivered to mothers) plus 7-valent pneumococcal vaccine (PCV7; delivered to infants) was higher than the efficacy of TIV alone or PCV7 alone. During the period of the study in which influenza was circulating, the efficacy of TIV plus PCV7 was 72.4% (95% confidence interval, 30.2%-89.1%) against febrile respiratory illness and 66.4% (95% CI, 14.3%-86.9%) against medically attended acute respiratory illness.

The effect of Haemophilus influenzae type B and pneumococcal conjugate vaccines on childhood meningitis mortality: a systematic review.

BACKGROUND: Two of the most prevalent causes of severe bacterial meningitis in children, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, are preventable by existing vaccines increasingly available in developing countries. Our objective was to estimate the dose-specific effect of Hib and pneumococcal conjugate vaccines (PCV) on childhood meningitis mortality in low-income countries for use in the Lives Saved Tool (LiST). METHODS: We systematically searched and reviewed published vaccine efficacy trials and observational studies reporting the effect of Hib or PCV vaccines on organism-specific meningitis, bacterial meningitis and all-cause meningitis incidence and mortality among children less than five years old in low- and middle-income countries. Data collection and quality assessments were performed using standardized guidelines. For outcomes available across multiple studies (≥ 2) and approximating meningitis mortality, we pooled estimates reporting dose-specific effects using random effects meta-analytic methods, then combined these with meningitis etiology data to determine the preventable fraction of childhood meningitis mortality for inclusion in LiST. RESULTS: We identified 18 studies of Hib conjugate vaccines reporting relevant meningitis morbidity and mortality outcomes (2 randomized controlled trials [RCTs], 16 observational studies) but few provided dose-specific effects. A meta-analysis of four case-control studies examined the dose-specific effect of Hib conjugate vaccines on Hib meningitis morbidity (1 dose: RR=0.64, 95% CI 0.38-1.06; 2 doses: RR=0.09, 95% CI 0.03-0.27; 3 doses: RR=0.06, 95% CI 0.02-0.22), consistent with results from single RCTs. Pooled estimates of two RCTs provided evidence for the effect of three doses of PCV on vaccine-serotype meningitis morbidity (RR=0.16, 95% CI 0.02-1.20). We considered these outcomes of severe disease as proxy estimates for meningitis mortality and combined the estimates of protective effects with meningitis etiology data to provide an estimate of the preventable fraction of childhood meningitis mortality with three doses of Hib (38-43%) and pneumococcal conjugate vaccines (28-35%) for use in LiST. CONCLUSIONS: Few RCTs or vaccine effectiveness studies evaluated the dose-specific impact of Hib and PCV vaccines on childhood meningitis mortality, necessitating use of proxy measures to estimate population impact in LiST. Our analysis indicates that approximately three-quarters of meningitis deaths are preventable with existing Hib and PCV vaccines.