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BACKGROUND: Conjugated pneumococcal vaccine is recommended for kidney transplant recipients, however, their immunogenicity and potential to trigger allograft rejection though generation of de novo anti-human leukocyte antigen antibodies has not been well studied. METHODS: Clinically stable kidney transplant recipients participated in a prospective cohort study and received a single dose of 13-valent conjugate pneumococcal vaccine. Anti-pneumococcal IgG was measured for the 13 vaccine serotypes pre and post vaccination and functional anti-pneumococcal IgG for 4 serotypes post vaccination. Anti-human leukocyte antigen antibodies antibodies were measured before and after vaccination. Kidney transplant recipients were followed clinically for 12 months for episodes of allograft rejection or invasive pneumococcal disease. RESULTS: Forty-five kidney transplant recipients participated. Median days between pre and post vaccination serology was 27 (range 21-59). Post vaccination, there was a median 1.1 to 1.7-fold increase in anti-pneumococcal IgG antibody concentrations for all 13 serotypes. Kidney transplant recipients displayed a functional antibody titer ≥1:8 for a median of 3 of the 4 serotypes. Post vaccination, there were no de novo anti-human leukocyte antigen antibodies, no episodes of biopsy proven rejection or invasive pneumococcal disease. CONCLUSION: A single dose of 13-valent conjugate pneumococcal vaccine elicits increased titers and breadth of functional anti-pneumococcal antibodies in kidney transplant recipients without stimulating rejection or donor-specific antibodies.
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Transplante de Rim , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/farmacologia , Anticorpos Antibacterianos/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , VacinaçãoRESUMO
The human immune system is a tightly regulated network that protects the host from disease. An important aspect of this is the balance between pro-inflammatory Th17 cells and anti-inflammatory T regulatory (Treg) cells in maintaining immune homeostasis. Foxp3+ Treg are critical for sustaining immune tolerance through IL-10 and transforming growth factor-ß while related orphan receptor-γt+ Th17 cells promote immunopathology and auto-inflammatory diseases through the actions of IL-17A, IL-21 and IL-22. Therefore, imbalance between Treg and Th17 cells can result in serious pathology in many organs and tissues. Recently, certain IL-17-producing cells have been found to be protective against infectious disease, particularly in relation to extracellular bacteria such Streptococcus pneumoniae; a number of other novel IL-17-secreting cell populations have also been reported to protect against a variety of other pathogens. In this mini-review, the dual roles of Treg and Th17 cells are discussed in the context of autoimmunity and infections, highlighting recent advances in the field. Development of novel strategies specifically designed to target these critical immune response pathways will become increasingly important in maintenance of human health.
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Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Doenças Autoimunes/patologia , Doenças Transmissíveis/imunologia , Humanos , Interleucinas/imunologiaRESUMO
BACKGROUND: A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. OBJECTIVE: This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. METHODS: Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. RESULTS: Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. CONCLUSION: Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.
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Imunidade , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Vacinas Conjugadas/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Criança , Pré-Escolar , Feminino , Fiji , Seguimentos , Vacina Pneumocócica Conjugada Heptavalente/administração & dosagem , Vacina Pneumocócica Conjugada Heptavalente/imunologia , Hospitalização , Humanos , Esquemas de Imunização , Imunização Secundária , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Masculino , Vacinas Pneumocócicas/administração & dosagem , VacinaçãoRESUMO
BACKGROUND: The Gambia was the first country in Africa to introduce conjugate Haemophilus influenzae type b (Hib) vaccine, which, as in other developing countries but unlike industrialized countries, is delivered as a 3-dose primary series with no booster. This study assessed its effectiveness 14 years after introduction. METHODS: Using methods standardized during >20 years in the study site, clinical and microbiological surveillance for invasive Hib disease (primarily meningitis) in the Western Region of The Gambia from 2007 to 2010 was complemented with studies of Hib carriage in children aged 1 to <2 years, Hib antibody levels in children aged <5 years, and Hib vaccine coverage and timing in children aged 1 to <2 years. RESULTS: The incidence of Hib meningitis remained low (averaging 1.3 per 100 000 children aged <5 years annually), as did the Hib oropharyngeal carriage rate (0.9%). Hib antibody levels were protective in >99% of those surveyed, albeit with lower titers in older children; and coverage of conjugate Hib vaccination was high (91% having 3 doses at 1-2 years of age) using a schedule that was delivered at median ages of 2.6 months, 4.3 months, and 6 months for the first, second, and third doses, respectively. CONCLUSIONS: Conjugate Hib vaccine was delivered on time in a 3-dose primary series without booster to a high proportion of eligible children and this was associated with effective disease control up to 14 years after introduction. It is important that surveillance continues in this first African country to introduce the vaccine to determine if effective control persists or if a booster dose becomes necessary as has been the case in industrialized countries.
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Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/administração & dosagem , Haemophilus influenzae tipo b/imunologia , Vacinas Conjugadas/imunologia , Portador Sadio/epidemiologia , Pré-Escolar , Estudos Transversais , Gâmbia/epidemiologia , Infecções por Haemophilus/epidemiologia , Infecções por Haemophilus/imunologia , Vacinas Anti-Haemophilus/imunologia , Humanos , Lactente , Vacinação em Massa , Vigilância em Saúde Pública , Vacinas Conjugadas/administração & dosagemRESUMO
BACKGROUND: Serotype-specific antibody responses to pneumococcal polysaccharide are important in evaluating humoral immune function. Multiplex technologies allow simultaneous quantitation of multiple serotype-specific antibodies however there has been limited validation against the gold-standard ELISA and assay performance in the clinical setting has not been examined. METHODS AND MATERIALS: Pre- and post-immunization samples were analysed by both methods. The ability to correctly identify an adequate response to polysaccharide vaccine (as defined by current AAAAI guidelines) was determined. RESULTS: The xMAP Pneumo 14 multiplex assay correlated poorly with the ELISA, particularly for pre-immunization and infant samples. An adequate response to pneumococcal immunization was 'correctly' predicted by xMAP Pneumo for 21 of 26 (81 %) adult pairs and 18 of 25 (72 %) infant pairs. Seven of 25 infants and 4 of 26 adults were identified as having an inadequate response by ELISA and an adequate response by xMAP. CONCLUSION: When applying current AAAAI guidelines, the xMAP Pneumo 14 assay does not allow reliable evaluation of antibody responses to polysaccharide antigens for the assessment of humoral immune competence. New guidelines for an adequate response should be established for new technologies when evaluating responses to polysaccharide vaccine in the clinical setting.
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Anticorpos Antibacterianos/imunologia , Imunidade Humoral , Imunoglobulina G/imunologia , Polissacarídeos Bacterianos/imunologia , Streptococcus pneumoniae/imunologia , Anticorpos Antibacterianos/sangue , Especificidade de Anticorpos , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Imunoglobulina G/sangue , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , VacinaçãoRESUMO
BACKGROUND: Infections with Streptococcus pneumoniae (pneumococcus) are a cause of significant child mortality. Pneumococcal glycoconjugate vaccines are expensive and provide limited serotype coverage. The 23-valent pneumococcal polysaccharide vaccine (Pneumovax) might provide wider serotype coverage but is reported to be weakly immunogenic in children less than 2 years of age. We have previously reported that Pneumovax administered to healthy 12-month-old Fijian infants elicits significant serotype-specific IgG responses. However, the functional capacity of these responses in 12-month-old infants is not known. OBJECTIVE: We sought to assess the functional, serotype-specific immune response of 12-month-old infants after immunization with Pneumovax. METHODS: Functional responses of 12-month-old infants were assessed by using the opsonophagocytic and antibody avidity assay against 8 serotypes and 23 serotypes, respectively. RESULTS: Seventy-one percent of infants produced strong opsonophagocytic activity against 4 of 8 serotypes, and 30% produced high-avidity serotype-specific IgG antibodies to 10 of 23 serotypes at 2 weeks after Pneumovax. Responses were protective for most serotypes that cause disease in Western countries, whereas responses to most of the epidemiologically relevant serotypes for developing countries were low. CONCLUSION: This is the first comprehensive study evaluating the functional antibody response to Pneumovax in 12-month-old infants. Pneumovax induced functional antibody responses to several serotypes causing disease in Western countries but induced poorer responses to serotypes that are responsible for the majority of disease in developing countries. Pneumovax might be of benefit in some populations, but further studies are required before this can be recommended in developing countries.
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Países em Desenvolvimento , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Estreptocócicas/administração & dosagem , Streptococcus pneumoniae/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Epitopos , Feminino , Fiji , Seguimentos , Humanos , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Masculino , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controleRESUMO
INTRODUCTION: Vaccination has dramatically reduced invasive Haemophilus influenzae type b (Hib) disease worldwide. Hib vaccination was introduced in the Lao PDR in 2009, as part of the pentavalent vaccine. To contribute to the understanding of the epidemiology of Hib in Lao PDR and the protection levels before and after the introduction of the vaccination, we tested serum samples from existing cohorts of vaccine age-eligible children and unvaccinated adolescents for antibodies against Hib. METHODS: Serum samples from 296 adolescents born before vaccine introduction and from 1017 children under 5 years (vaccinated and unvaccinated) were tested for anti-Hib antibodies by ELISA. Bivariate analyses were performed to investigate factors associated with long-term protection. RESULTS: The vast majority of all participants showed evidence of short- (42.7%) or long-term (56.1%) protection against Hib. Almost all of the unvaccinated adolescents had antibody titers indicating short-term protection and almost half (45.6%) were long-term protected. Nearly all children (>99.0%) were at least short-term protected, even those that were unvaccinated or whose vaccination status was unknown. Among vaccinated children, participants vaccinated more than 1 or 2 years ago and with a mid-upper arm circumference z-score < -2 were less likely to be long-term protected. DISCUSSION: Nearly all adolescents born before the introduction of Hib vaccination in the Lao PDR had antibody titers corresponding to at least short-term protection, indicating a high burden of Hib disease at that time. After vaccine introduction, all but four children (>99%) showed at least short-term protection. Possible explanations for the proportion of protected, yet apparently unvaccinated children, may be past infections, cross-reacting antibodies or faulty vaccination documentation. Our results highlight the need for robust surveillance and reporting of invasive Hib disease to determine the burden of disease despite vaccination.
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Infecções por Haemophilus , Vacinas Anti-Haemophilus , Haemophilus influenzae tipo b , Adolescente , Anticorpos Antibacterianos , Antígenos de Bactérias , Antígenos Virais , Criança , Pré-Escolar , Infecções por Haemophilus/epidemiologia , Infecções por Haemophilus/prevenção & controle , Humanos , Laos/epidemiologia , Estudos Soroepidemiológicos , Sorogrupo , Vacinas CombinadasRESUMO
Encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis cause significant morbidity and mortality in young children despite the availability of vaccines. Highly specific antibodies are the primary mechanism of protection against invasive disease. Robust and standardised assays that measure functional antibodies are also necessary for vaccine evaluation and allow for the accurate comparison of data between clinical studies. This mini review describes the current state of functional antibody assays and their importance in measuring protective immunity.
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INTRODUCTION: Reduced-dose schedules offer a more efficient and affordable way to use pneumococcal conjugate vaccines (PCVs). Such schedules rely primarily on the maintenance of herd protection. The Vietnam Pneumococcal Trial II (VPT-II) will evaluate reduced-dose schedules of PCV10 and PCV13 utilising an unvaccinated control group. Schedules will be compared in relation to their effect on nasopharyngeal carriage and immunogenicity. METHODS AND ANALYSIS: VPT-II is a single-blind open-label randomised controlled trial of 2500 infants in three districts of Ho Chi Minh City, Vietnam. Eligible infants have no clinically significant maternal or perinatal history and are born at or after 36 weeks' gestation. Participants are recruited at 2 months of age and randomly assigned (4:4:4:4:9) using block randomisation, stratified by district, to one of five groups: four intervention groups that receive PCV10 in a 0+1 (at 12 months) or 1+1 (at 2 and 12 months) schedule or PCV13 in the same 0+1 or 1+1 schedule; and a control group (that receives a single dose of PCV10 at 24 months). Participants are followed up to 24 months of age. The primary outcome is vaccine-type pneumococcal carriage at 24 months of age. Secondary outcomes are carriage at 6, 12 and 18 months of age and the comparative immunogenicity of the different schedules in terms of antibody responses, functional antibody responses and memory B cell responses. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee of the Royal Children's Hospital Melbourne and the Vietnam Ministry of Health Ethics Committee. The results, interpretation and conclusions will be presented to parents and guardians, at national and international conferences and published in peer-reviewed open access journals. TRIAL REGISTRATION NUMBER: NCT03098628.
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Células B de Memória , Infecções Pneumocócicas , Anticorpos Antibacterianos , Humanos , Esquemas de Imunização , Imunoglobulina G , Lactente , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Vacinas Conjugadas , VietnãRESUMO
BACKGROUND: Data are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam. METHODS: In this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9·5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3-18 months depending on group allocation, within 27-43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0·35 µg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual. FINDINGS: Between Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A-D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84·6% [95% CI 79·9-88·6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76·8% [70·9-82·0] of infants after two doses [group C]; risk difference 7·8% [90% CI 2·1-13·6]) and 23F (90·6% [95% CI 86·6-93·7] vs 77·6% [71·8-82·2]; 12·9% [90% CI 7·7-18·3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F. INTERPRETATION: A two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life. FUNDING: Australian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.
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Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Anticorpos Antibacterianos/sangue , Feminino , Humanos , Esquemas de Imunização , Lactente , Masculino , Infecções Pneumocócicas/sangue , Infecções Pneumocócicas/microbiologia , Método Simples-Cego , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/imunologia , VietnãRESUMO
BACKGROUND: This study investigated the immunogenicity and impact on nasopharyngeal carriage of a single dose of PCV10 given to 18-month-old Vietnamese children. This information is important for countries considering catch-up vaccination during PCV introduction and in the context of vaccination during humanitarian crises. METHODS: Two groups of PCV-naïve children within the Vietnam Pneumococcal Project received PCV10 (n=197) or no PCV (unvaccinated; n=199) at 18 months of age. Blood samples were collected at 18, 19, and 24 months of age, and nasopharyngeal swabs at 18 and 24 months of age. Immunogenicity was assessed by measuring serotype-specific IgG, opsonophagocytosis (OPA) and memory B cells (Bmem). Pneumococci were detected and quantified using real-time PCR and serotyped by microarray. FINDINGS: At 19 months of age, IgG and OPA responses were higher in the PCV10 group compared with the unvaccinated group for all PCV10 serotypes and cross-reactive serotypes 6A and 19A. This was sustained out to 24 months of age, at which point PCV10-type carriage was 60% lower in the PCV10 group than the unvaccinated group. Bmem levels increased between 18 and 24 months of age in the vaccinated group. INTERPRETATION: We demonstrate strong protective immune responses in vaccinees following a single dose of PCV10 at 18 months of age, and a potential impact on herd protection through a substantial reduction in vaccine-type carriage. A single dose of PCV10 in the second year of life could be considered as part of catch-up campaigns or in humanitarian crises to protect children at high-risk of pneumococcal disease.
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INTRODUCTION: Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to Haemophilus influenzae protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A. METHODS AND ANALYSES: Our randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported. ETHICS AND DISSEMINATION: Ethics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT01735084.
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Serviços de Saúde do Indígena , Otite Média , Infecções Pneumocócicas , Austrália , Criança , Pré-Escolar , Haemophilus influenzae/imunologia , Humanos , Lactente , Havaiano Nativo ou Outro Ilhéu do Pacífico , Otite Média/prevenção & controle , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Ensaios Clínicos Controlados Aleatórios como Assunto , Vacinas ConjugadasRESUMO
BACKGROUND: Few data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13. METHODS: In this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3â+â1 (group A), 3â+â0 (group B), 2â+â1 (group C), or two-dose schedule (group D); PCV13 in a 2â+â1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 µg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510. FINDINGS: Of 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 µg/mL did not differ between groups at the 10% level for any serotype (PCV10-PCV13 risk difference -2·1% [95% CI -4·8 to -0·1] for serotype 1; -1·3% [-3·7 to 0·6] for serotype 4; -3·4% [-6·8 to -0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; -1·3% [-3·7 to 0·6] for serotype 7F; -1·6% [-5·1 to 1·7] for serotype 9V; 0·0% [-2·7 to 2·9] for serotype 14; -2·1% [-5·3 to 0·9] for serotype 18C; 0·0% [-2·2 to 2·3] for serotype 19F; and -11·6% [-18·2 to -4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups. INTERPRETATION: PCV10 and PCV13 are similarly highly immunogenic when used in 2â+â1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings. FUNDING: National Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.
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Fatores Imunológicos/imunologia , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Anticorpos Antibacterianos/sangue , Feminino , Humanos , Imunoglobulina G/sangue , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Lactente , Masculino , Infecções Pneumocócicas/sangue , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Sorogrupo , Vacinação/métodos , Vacinas Conjugadas , Vietnã/epidemiologiaRESUMO
Pneumococcal conjugate vaccines (PCVs) have been very effective in reducing the disease burden caused by Streptococcus pneumoniae serotypes covered by the current vaccine formulations. However, the incidence of disease caused by serotypes not covered by the vaccine is increasing. Consequently, there are active efforts to develop new PCVs with additional serotypes in order to provide protection against the emergent serotypes. Due to costs and ethical issues associated with performing true vaccine efficacy studies, new PCVs are being licensed based on their immunogenicity, which may be assessed with 2 in vitro assays: enzyme-linked immunosorbent assay (ELISA) for quantitating antibody level and opsonophagocytic assay (OPA) for assessing protective function. While a standardized ELISA has been developed, OPA results from different laboratories can be quite disparate, even among laboratories utilizing the same platform. In order to harmonize OPA data, a recent international collaboration assigned opsonic indices to the US Food and Drug Administration (US FDA) reference serum, 007sp, as well as a panel of US FDA calibration sera. However, due to a low number of aliquots, the availability of these calibration sera is extremely limited. Because calibration sera are critical to establish the performance characteristics of an OPA, a second calibration serum panel was created, comprised of 20 sera collected from adults immunized with the 23-valent polysaccharide vaccine, with 150 to 500 aliquots prepared for each serum. In order to establish consensus OPA values of the 20 sera for the 13 serotypes in 13-valent PCV, the sera were tested by 4 laboratories in an international collaborative OPA study. The 007sp results of 1 laboratory deviated significantly from those obtained by the other laboratories, as well as from previously assigned values. Due to these discrepancies, the consensus values for the calibration sera were determined based on the data from the remaining laboratories. Thus, we were able to create a panel of sera with consensus opsonic values that could be used by outside laboratories to calibrate pneumococcal OPAs. Our results also confirmed findings of a previous study that normalization of OPA results significantly reduces interlaboratory variation, with normalization based on 007sp reducing variation by 43% to 74%, depending on serotype.
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Anticorpos Antibacterianos/sangue , Ensaio de Imunoadsorção Enzimática/normas , Proteínas Opsonizantes/sangue , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Calibragem , Consenso , Humanos , Cooperação Internacional , Padrões de Referência , Sorogrupo , Vacinas Conjugadas/imunologiaRESUMO
INTRODUCTION: WHO recommends the use of pneumococcal conjugate vaccine (PCV) as a priority. However, there are many countries yet to introduce PCV, especially in Asia. This trial aims to evaluate different PCV schedules and to provide a head-to-head comparison of PCV10 and PCV13 in order to generate evidence to assist with decisions regarding PCV introduction. Schedules will be compared in relation to their immunogenicity and impact on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae. METHODS AND ANALYSIS: This randomised, single-blind controlled trial involves 1200 infants recruited at 2 months of age to one of six infant PCV schedules: PCV10 in a 3+1, 3+0, 2+1 or two-dose schedule; PCV13 in a 2+1 schedule; and controls that receive two doses of PCV10 and 18 and 24 months. An additional control group of 200 children is recruited at 18 months that receive one dose of PCV10 at 24 months. All participants are followed up until 24 months of age. The primary outcome is the post-primary series immunogenicity, expressed as the proportions of participants with serotype-specific antibody levels ≥0.35 µg/mL for each serotype in PCV10. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (EC00153) and the Vietnam Ministry of Health Ethics Committee. The results, interpretation and conclusions will be presented to parents and guardians, at national and international conferences, and published in peer-reviewed open access journals. TRIAL REGISTRATION NUMBER: NCT01953510; Pre-results.
Assuntos
Anticorpos Antibacterianos/sangue , Esquemas de Imunização , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Resultado do Tratamento , Vacinação , VietnãRESUMO
BACKGROUND: Indigenous children in Australia's Northern Territory are densely colonised with the pneumococcus within weeks of birth antecedent to a high prevalence of acute lower respiratory infection (ALRI). We assessed the impact of the 23-valent pneumococcal polysaccharide vaccine (23vPPV) in pregnancy against infant ALRI in this setting. METHODS: In an open label, allocation concealed, outcome-assessor blinded, randomised controlled trial conducted in the Northern Territory of Australia, healthy Indigenous women aged 17-39 years were randomised to receive the 23vPPV during pregnancy (n = 75; 30-36 weeks gestation), at birth (n = 75), or at 7 months post-partum (n = 77). Randomisation was stratified by community of residence. In a secondary analysis, we compared the incidence of ALRI hospitalisations and ALRI clinic presentations (ascertained from electronic medical records) among infants of pregnancy vaccinees versus infants of mothers not vaccinated in pregnancy (controls) in the first year of life. RESULTS: ALRI hospitalisation incidence was 12.3 per 100 child-years among infants of pregnancy vaccinees compared with 15.8 per 100 child-years among controls (hazard ratio (HR) 0.77, 95%CI 0.29-2.03). ALRI hospitalisations were more common among remote compared to urban infants (27.7 versus 8.6 per 100 child-years). Stratification by dwelling highlighted a differential antenatal vaccine effect against ALRI hospitalisations (urban HR 2.45, 95%CI 0.60-9.99; remote HR 0.21, 95%CI 0.04-1.08). ALRI clinic presentation incidence was similar among infants of pregnancy vaccinees and controls. CONCLUSIONS: In this small study, antenatal 23vPPV vaccination was not associated with a reduced incidence of infant ALRI hospitalisations or ALRI clinic presentations during the first year of life. A potential differential effect between urban and remote settings warrants further investigation. TRIAL REGISTRATION: PneuMum; ClinicalTrials.gov NCT00714064.
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Indigenous Australians experience one of the highest rates of pneumococcal disease globally. In the Northern Territory of Australia, a unique government-funded vaccination schedule for Indigenous Australian adults comprising multiple lifetime doses of the pneumococcal polysaccharide vaccine is currently implemented. Despite this programme, rates of pneumococcal disease do not appear to be declining, with concerns raised over the potential for immune hyporesponse associated with the use of this vaccine. We undertook a study to examine the immunogenicity and immune function of a single and repeat pneumococcal polysaccharide vaccination among Indigenous adults compared to non-Indigenous adults. Our results found that immune function, as measured by opsonophagocytic and memory B-cell responses, were similar between the Indigenous groups but lower for some serotypes in comparison with the non-Indigenous group. This is the first study to document the immunogenicity following repeat 23-valent pneumococcal polysaccharide vaccine administration among Indigenous Australian adults, and reinforces the continued need for optimal pneumococcal vaccination programmes among high-risk populations.
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BACKGROUND: Indigenous adults residing in the Northern Territory of Australia experience elevated rates of invasive pneumococcal disease despite the routine use of 23-valent pneumococcal polysaccharide vaccine (23vPPV). We hypothesised that the limited protection from 23vPPV may be due to hyporesponsiveness as a result of vaccine failure from repeated vaccination. To explore this possibility, we evaluated the immune response to a first and second dose of 23vPPV in Indigenous adults and a first dose of 23vPPV in non-Indigenous adults. METHODS: Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline and at one month post-vaccination. Individuals were considered to have an adequate immune response if paired sera demonstrated either: a four-fold rise in antibody concentration; a two-fold rise if the post vaccination antibody was >1.3µg/ml but <4.0µg/ml; or a post-vaccination antibody concentration >4.0µg/ml for at least half of the serotypes tested (12/23). Our per-protocol analysis included the comparison of outcomes for three groups: Indigenous adults receiving a second 23vPPV dose (N=20) and Indigenous (N=60) and non-Indigenous adults (N=25) receiving their first 23vPPV dose. RESULTS: All non-Indigenous adults receiving a first dose of 23vPPV mounted an adequate immune response (25/25). There was no significant difference in the proportion of individuals with an adequate response using our definition (primary endpoint), with 88% of Indigenous adults mounted an adequate response following first dose 23vPPV (53/60) compared to 70% having an adequate response following a second dose of 23vPPV (14/20; p=0.05). The risk difference between Indigenous participants receiving first dose compared to non-Indigenous participants receiving first dose was significant when comparing a response threshold of at least 70% (-27%, 95% CI: -43% to -11%; p=0.01) and 90% (-38%, 95% CI: -60% to -16%; p=0.006) of serotypes with a positive response. CONCLUSION: Indigenous participants demonstrated a poorer response to a first dose 23vPPV compared to their non-Indigenous counterparts, with lower IgG following a second 23vPPV dose. These findings highlight the critical need to evaluate the efficacy of future pneumococcal vaccine programs in the Australian Indigenous populations that recommend repeated doses of 23vPPV.
Assuntos
Imunidade Humoral , Imunogenicidade da Vacina , Havaiano Nativo ou Outro Ilhéu do Pacífico , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Northern Territory/epidemiologia , Infecções Pneumocócicas/etnologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Sorotipagem , Vacinação , Potência de Vacina , Adulto JovemAssuntos
Anticorpos Antibacterianos/imunologia , Especificidade de Anticorpos/imunologia , Imunoglobulina G/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Anticorpos Antibacterianos/sangue , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Masculino , Infecções Pneumocócicas/sangue , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controleRESUMO
Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)2D3, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)2D3 significantly reduced pro-inflammatory cytokines TNF-α, IFN-γ, and IL-1ß as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL-10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-γ were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (<50 nmol/L) compared to sufficient adults (>50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)2D3 may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context.