RESUMEN
BACKGROUND: Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. METHODS: We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). FINDINGS: 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0-66·9; p=0·0013) and 56·4% (36·6-70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37-97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1·5 in the vaccine group and 3·2 in the placebo group, with an incidence rate ratio of 0·46 (95% CI 0·33-0·65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. INTERPRETATION: Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. FUNDING: Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.
Asunto(s)
Gastroenteritis/prevención & control , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , Método Doble Ciego , Femenino , Humanos , India , Lactante , MasculinoRESUMEN
BACKGROUND: Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children. We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a randomized, double-blind study in Soweto, South Africa. METHODS: At 6, 10, and 14 weeks of age, 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197), and 19,914 received placebo. All children received Haemophilus influenzae type b conjugate vaccine. Efficacy and safety were analyzed according to the intention-to-treat principle. RESULTS: Among children without human immunodeficiency virus (HIV) infection, the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent (95 percent confidence interval, 39 to 97; 17 cases among controls and 3 among vaccine recipients). Among HIV-infected children, the efficacy was 65 percent (95 percent confidence interval, 24 to 86; 26 and 9 cases, respectively). Among children without HIV infection, the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent (95 percent confidence interval, 2 to 35; 212 cases in the control group and 169 in the vaccinated group) in the intention-to-treat analysis and by 25 percent (95 percent confidence interval, 4 to 41; 158 and 119 cases, respectively) in the per-protocol analysis (i.e., among fully vaccinated children). The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent (95 percent confidence interval, 19 to 88; 21 cases in the control group and 7 in the vaccinated group), and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent (95 percent confidence interval, 16 to 78; 32 and 14 cases, respectively). CONCLUSIONS: Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia. The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection.
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Infecciones por VIH/complicaciones , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas , Cápsulas Bacterianas , Método Doble Ciego , Farmacorresistencia Bacteriana , Femenino , Vacunas contra Haemophilus , Humanos , Incidencia , Lactante , Masculino , Infecciones Neumocócicas/mortalidad , Vacunas Neumococicas/efectos adversos , Neumonía Neumocócica/prevención & control , Polisacáridos Bacterianos , Serotipificación , Streptococcus pneumoniae/clasificación , Streptococcus pneumoniae/aislamiento & purificación , Vacunas Conjugadas/efectos adversosRESUMEN
BACKGROUND: Live oral rhesus-rhesus-human rotavirus reassortant tetravalent (RRV-TV) vaccine was efficacious against rotavirus gastroenteritis but was withdrawn because of a rare association with intussusception. A corresponding tetravalent (types G1, G2, G3, and G4) reassortant vaccine based on bovine-human (UK) rotavirus reassortant tetravalent (BRV-TV) vaccine was developed concurrently. METHODS: Before the withdrawal of RRV-TV vaccine, parallel placebo-controlled trials of BRV-TV vaccine (observer blinded) versus RRV-TV vaccine (double blinded) with a 2 : 1 ratio of vaccine : placebo were conducted in Finland in a total of 510 infants. Two doses of study vaccine or placebo were administered at ages 3 and 5 months. RESULTS: The first dose of RRV-TV vaccine was followed by a significant excess rate of febrile reactions (36%), whereas the rate of fever after the administration of BRV-TV vaccine did not differ significantly from that in the placebo group. Neither vaccine induced diarrhea. A seroresponse was detected in 97% of BRV-TV vaccine recipients and 94% of RRV-TV vaccine recipients. Both vaccines were equally effective, with 68%-69% efficacy against any and 88%-100% efficacy against severe rotavirus gastroenteritis during the first epidemic season. CONCLUSIONS: BRV-TV vaccine is a promising new candidate rotavirus vaccine, with low reactogenicity and high efficacy. Two doses of BRV-TV or RRV-TV vaccine are sufficient for the induction of protection against severe rotavirus disease.
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Gastroenteritis/prevención & control , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , Animales , Bovinos , Método Doble Ciego , Femenino , Finlandia , Gastroenteritis/inmunología , Gastroenteritis/virología , Humanos , Enfermedades del Íleon/etiología , Lactante , Recién Nacido , Intususcepción/etiología , Macaca mulatta , Masculino , Rotavirus/inmunología , Infecciones por Rotavirus/inmunología , Vacunas contra Rotavirus/efectos adversos , Vacunas contra Rotavirus/inmunologíaRESUMEN
BACKGROUND: Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years. Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world. We aimed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine (PnCRM7) against such disease. METHODS: In a group-randomised study, we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations; meningococcal type C conjugate vaccine (MnCC) served as the control vaccine. Vaccine schedules were determined by age at enrollment. We recorded episodes of invasive pneumococcal disease and serotyped isolates. Analyses were by intention to treat and per protocol. FINDINGS: 8292 children enrolled in the trial. In the per protocol analysis of the primary efficacy group (children enrolled by 7 months of age) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group. After group randomisation had been controlled for, the per protocol primary efficacy of PnCRM7 was 76.8% (95% CI -9.4% to 95.1%) and the intention-to-treat total primary efficacy was 82.6% (21.4% to 96.1%). INTERPRETATION: PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population. Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule.
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Indígenas Norteamericanos/estadística & datos numéricos , Vacunas Neumococicas/uso terapéutico , Neumonía Neumocócica/prevención & control , Arizona/epidemiología , Femenino , Vacuna Neumocócica Conjugada Heptavalente , Humanos , Esquemas de Inmunización , Lactante , Masculino , Vacunas Meningococicas/inmunología , Vacunas Neumococicas/inmunología , Neumonía Neumocócica/epidemiología , Neumonía Neumocócica/inmunología , Serotipificación , Streptococcus pneumoniae/inmunología , Vacunas Conjugadas/inmunología , Vacunas Conjugadas/uso terapéuticoRESUMEN
Chlamydia trachomatis is the causative agent of the most frequently reported bacterial sexually transmitted infection, the total burden of which is underestimated due to the asymptomatic nature of the infection. Untreated C. trachomatis infections can cause significant morbidities, including pelvic inflammatory disease and tubal factor infertility (TFI). The human immune response against C. trachomatis, an obligate intracellular bacterium, is poorly characterized but is thought to rely on cell-mediated immunity, with CD4(+) and CD8(+) T cells implicated in protection. In this report, we present immune profiling data of subjects enrolled in a multicenter study of C. trachomatis genital infection. CD4(+) and CD8(+) T cells from subjects grouped into disease-specific cohorts were screened using a C. trachomatis proteomic library to identify the antigen specificities of recall T cell responses after natural exposure by measuring interferon gamma (IFN-γ) levels. We identified specific T cell responses associated with the resolution of infection, including unique antigens identified in subjects who spontaneously cleared infection and different antigens associated with C. trachomatis-related sequelae, such as TFI. These data suggest that novel and unique C. trachomatis T cell antigens identified in individuals with effective immune responses can be considered as targets for vaccine development, and by excluding antigens associated with deleterious sequelae, immune-mediated pathologies may be circumvented.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Chlamydia/inmunología , Chlamydia trachomatis/inmunología , Infecciones del Sistema Genital/inmunología , Adolescente , Adulto , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Infecciones por Chlamydia/microbiología , Chlamydia trachomatis/genética , Epítopos de Linfocito T/inmunología , Femenino , Humanos , Inmunidad Celular , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad , Proteómica , Infecciones del Sistema Genital/microbiología , Adulto JovenRESUMEN
UNLABELLED: Rotavirus gastroenteritis is one of the leading causes of diarrhea in Indian children less than 2 years of age. The 116E rotavirus strain was developed as part of the Indo-US Vaccine Action Program and has undergone efficacy trials. This paper reports the efficacy and additional safety data in children up to 2 years of age. In a double-blind placebo controlled multicenter trial, 6799 infants aged 6-7 weeks were randomized to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. The primary outcome was severe (≥11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. We randomly assigned 4532 and 2267 subjects to receive vaccine and placebo, respectively, with over 96% subjects receiving all three doses of the vaccine or placebo. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. The overall incidence of severe RVGE per 100 person years was 1.3 in the vaccine group and 2.9 in the placebo recipients. Vaccine efficacy against severe rotavirus gastroenteritis in children up to 2 years of age was 55.1% (95% CI 39.9 to 66.4; p<0.0001); vaccine efficacy in the second year of life of 48.9% (95% CI 17.4 to 68.4; p=0.0056) was only marginally less than in the first year of life [56.3% (95% CI 36.7 to 69.9; p<0.0001)]. The number of infants needed to be immunized to prevent one episode of severe RVGE in the first 2 years of life was 40 (95% CI 28.0 to 63.0) and for RVGE of any severity, it was 21 (95% CI 16.0 to 32.0). Serious adverse events were observed at the same rates in the two groups. None of the eight intussusception events occurred within 30 days of a vaccine dose and all were reported only after the third dose. The sustained efficacy of the 116E in the second year of life is reassuring. CLINICAL TRIAL REGISTRY: The trial is registered with Clinical Trial Registry-India (# CTRI/2010/091/000102) and Clinicaltrials.gov (# NCT01305109).
Asunto(s)
Gastroenteritis/prevención & control , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , Animales , Bovinos , Método Doble Ciego , Gastroenteritis/virología , Humanos , Esquemas de Inmunización , India , Lactante , Intususcepción/inducido químicamente , Virus Reordenados , Rotavirus , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/efectos adversosRESUMEN
BACKGROUND: Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE). METHODS: Healthy adults 18-49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135 µg or 45 µg, or rHA 45 µg, 15 µg, 7.5 µg or 3.8 µg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42. RESULTS: 392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50-70% of rHA+GLA/SE recipients and 4-9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% and 15% in the unadjuvanted 135 µg and 45 µg groups, and 82%, 75%, 66%, and 72% in those receiving 45 µg, 15 µg, 7.5 µg, or 3.8 µg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45 µg, 15 µg, 7.5 µg, or 3.8 µg with GLA/SE groups, respectively. CONCLUSIONS: rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control.
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Adyuvantes Inmunológicos/efectos adversos , Emulsiones/efectos adversos , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/inmunología , Lípido A/efectos adversos , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Adulto , Animales , Anticuerpos Antivirales/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Emulsiones/administración & dosificación , Femenino , Voluntarios Sanos , Pruebas de Inhibición de Hemaglutinación , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Vacunas contra la Influenza/administración & dosificación , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Adulto JovenRESUMEN
Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's κ ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans.
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Vacunas contra el Carbunco/inmunología , Vacunas contra el Carbunco/uso terapéutico , Carbunco/mortalidad , Carbunco/prevención & control , Anticuerpos Antibacterianos/inmunología , Aerosoles , Animales , Carbunco/inmunología , Macaca mulatta , ConejosRESUMEN
BACKGROUND: Acute lower respiratory tract infections (ALRTI) are a leading cause of childhood mortality, but there are few data on disease costs in developing countries. OBJECTIVES: This study's purpose was to analyse ALRTI's costs-of-illness and economic burden in urban South African children. METHODS: ALRTI costs-of-illness (expressed in US$ 2010) at a tertiary hospital were measured using a micro-costing approach nested within a clinical trial. Demographic, epidemiological and data on use of health resources were integrated with costs-of-illness to estimate the economic burden of ALRTI in urban South African children aged <5 years. RESULTS: 745 children experiencing 858 ALRTI episodes were studied. 338 (39.4%), 513 (59.8%) and 7 (0.8%) episodes were managed in short-stay, paediatric ward and intensive care settings, respectively. Mean lengths of stay in short-stay, paediatric ward and intensive care (ICU) were 1.4, 8.1 and 14.4 days, respectively. The societal costs-of-illness per ALRTI episode managed in short-stay and paediatric ward settings, respectively, were US$266 (95% CI 245-286) and 1287 (95% CI 1174-1401) in HIV-infected patients, and US$257 (95% CI 247-267) and 1032 (95% CI 931-1133) in HIV-uninfected patients. Family costs were not collected in ICUs. ICU direct medical costs were US$5968 (95% CI 4025-8056) in HIV-uninfected patients and US$7849 in one HIV-infected patient. Under-5 children experienced an estimated 424,220 episodes annually of ALRTI. ALRTI treatment cost the public health system an estimated US$28,975,000 while an additional US$539,000 of costs were borne by families. CONCLUSION: ALRTIs in children <5 years impose a heavy economic burden on families and the South African public health-care system.
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Costo de Enfermedad , Costos de la Atención en Salud , Infecciones del Sistema Respiratorio/economía , Enfermedad Aguda , Preescolar , Países en Desarrollo/economía , Familia , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/economía , Recursos en Salud/economía , Humanos , Lactante , Recién Nacido , Unidades de Cuidados Intensivos/economía , Masculino , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/etiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/administración & dosificación , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/terapia , Sudáfrica/epidemiología , Resultado del Tratamiento , Población UrbanaRESUMEN
BACKGROUND: Development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production is a high priority. We conducted this study to determine the protective efficacy a recombinant, baculovirus-expressed seasonal trivalent influenza virus hemagglutinin (rHA0) vaccine (FluBlok(®)). METHODS: Healthy adult subjects at 24 centers across the US were randomly assigned to receive a single injection of saline placebo (2304 subjects), or trivalent FluBlok containing 45 mcg of each rHA0 component (2344 subjects). Serum samples for assessment of immune responses by hemagglutination-inhibition (HAI) were taken from a subset of subjects before and 28 days after immunization. Subjects were followed during the 2007-2008 influenza season and combined nasal and throat swabs for virus isolation were obtained from subjects reporting influenza-like illness. RESULTS: Rates of local and systemic side effects were low, and the rates of systemic side effects were similar in the vaccine and placebo groups. HAI antibody responses were seen in 78%, 81%, and 52% of FluBlok recipients to the H1, H3, and B components, respectively. FluBlok was 44.6% (95% CI, 18.8%, 62.6%) effective in preventing culture-confirmed influenza meeting the CDC influenza-like illness case definition despite significant antigenic mismatch between the vaccine antigens and circulating viruses. CONCLUSIONS: Trivalent rHA0 vaccine was safe, immunogenic and effective in the prevention of culture confirmed influenza illness, including protection against drift variants.
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Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Femenino , Estudios de Seguimiento , Pruebas de Inhibición de Hemaglutinación , Humanos , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/efectos adversos , Masculino , Persona de Mediana Edad , Nariz/virología , Orthomyxoviridae/aislamiento & purificación , Faringe/virología , Placebos/administración & dosificación , Estados Unidos , Vacunación/métodos , Adulto JovenRESUMEN
The identification of immune correlates of protection is becoming increasingly important in order to derive a quantitative assessment of the benefit conferred by vaccination in clinical trials. The use of immune correlates of protection as an indirect measure of clinical efficacy is essential to achieve regulatory approval for vaccines for which clinical efficacy cannot be tested directly, for example, biodefence vaccines. The correlates apply to the specific vaccine formulation being developed; in general, if a statistically significant correlation is found between a measurable immunological readout and survival in authentic animal models of human infection, the same immunological readout can be defined and applied as a surrogate marker of protection in clinical studies. The surrogate markers of protection can then be used to predict the protective efficacy of a candidate vaccine in humans. This review summarizes some of the immune correlates data reported for biodefence vaccines as well as some of the analytical approaches that can be applied in order to predict clinical efficacy.
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Biomarcadores , Bioterrorismo , Control de Enfermedades Transmisibles/métodos , Modelos Estadísticos , Vacunas/inmunología , Animales , Humanos , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
A previously developed statistical model relates vaccine immune responses to protection against pertussis disease in a household contact setting. Before this model can be used to predict the risk of disease based on immune responses, it must be validated to demonstrate reliable predictions. The model is shown here to be validated in terms of statistical criteria (Prentice surrogacy measures) as well as predictive capability in an independent efficacy trial (meta-analysis). Additionally, the model is used to predict efficacy from two recent immunogenicity trials comparing a 5-component acellular pertussis pentavalent combination vaccine with separate administration of its vaccine components. The model predicted similar protective efficacy rates: 82% after three doses and 83% after four doses. Follow-up of these subjects the model also predicted sustained and comparable efficacy for the combination and separate vaccines (75%) up to the pre-school booster age.
Asunto(s)
Modelos Inmunológicos , Vacuna contra la Tos Ferina/inmunología , Tos Ferina/prevención & control , Humanos , Modelos EstadísticosRESUMEN
Estimates of minimum protective antibody concentrations for vaccine preventable diseases are of critical importance in assessing whether new vaccines will be as effective as those for which clinical efficacy was shown directly. We describe a method for correlating pneumococcal anticapsular antibody responses of infants immunized with pneumococcal conjugate (PnC) vaccine (Prevenar) with clinical protection from invasive pneumococcal disease (IPD). Data from three double blind controlled trials in Northern Californian, American Indian and South African infants were pooled in a meta-analysis to derive a protective concentration of 0.35 microg/ml for anticapsular antibodies to the 7 serotypes in Prevenar. This concentration has been recommended by a WHO Working Group as applicable on a global basis for assessing the efficacy of future pneumococcal conjugate vaccines. The WHO Working Groups anticipated that modifications in antibody assays for pneumococcal anticapsular antibodies would occur. The principles for determining whether such assay modifications should change the protective concentration are outlined. These principles were applied to an improvement in the ELISA for anticapsular antibodies, i.e. absorption with 22F pneumococcal polysaccharide, which increases the specificity of the assay for vaccine serotype anticapsular antibodies by removing non-specific antibodies. Using sera from infants in the pivotal efficacy trial in Northern California Kaiser Permanente (NCKP), 22F absorption resulted in minimal declines in pneumococcal antibody in Prevenar immunized infants but significant declines in unimmunized controls. Recalculation of the protective concentration after 22F absorption resulted in only a small decline from 0.35 microg/ml to 0.32 microg/ml. These data support retaining the 0.35 microg/ml minimum protective concentration recommended by WHO for assessing the efficacy of pneumococcal conjugate vaccines in infants.
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Anticuerpos Antibacterianos/sangre , Especificidad de Anticuerpos , Cápsulas Bacterianas/inmunología , Vacunas Meningococicas , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas , Vacunas Conjugadas , California , Método Doble Ciego , Vacuna Neumocócica Conjugada Heptavalente , Humanos , Inmunoglobulina G/sangre , Indígenas Norteamericanos , Lactante , Vacunas Meningococicas/administración & dosificación , Vacunas Meningococicas/inmunología , Vacunas Neumococicas/administración & dosificación , Vacunas Neumococicas/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto , Sudáfrica , Streptococcus pneumoniae/inmunología , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/inmunologíaRESUMEN
BACKGROUND: Pneumococcal conjugate vaccines are important for the prevention of serious illness and death among infants. Factors associated with pneumococcal conjugate vaccine immunogenicity have not been explored. METHODS: Children <24 months of age received 2, 3, or 4 doses of 7-valent pneumococcal conjugate vaccine (PnCRM7) or control vaccine depending on age at enrollment. Serum samples were tested for serotype-specific antibodies by enzyme-linked immunosorbant assay. Multiple linear regression was used to determine predictors of immunogenicity. RESULTS: Among 315 PnCRM7-vaccinated subjects and 295 control subjects enrolled at <7 months of age, geometric mean concentrations (GMCs) of antibodies were significantly higher after dose 3 than after dose 2 for all serotypes except type 4. The proportion of subjects with antibody concentrations > or =5.0 micro g/mL was higher for all serotypes, but the proportion with concentrations > or =0.35 micro g/mL was higher only for types 6B and 23F. Three-dose and 2-dose regimens for those 7-11 and 12-23 months of age, respectively, were highly immunogenic. Increased maternal antibody concentrations were associated with reduced responses to dose 1 and 3 but not to dose 4 of PnCRM7. CONCLUSIONS: Maternal antibody is associated with a reduced infant response to PnCRM7 but does not interfere with immune memory. In infants, a third priming dose increases the antibody GMC and the proportion achieving an antibody concentration > or =5.0 micro g/mL but has little impact on the proportion achieving a concentration > or =0.35 micro g/mL.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Vacunas Meningococicas/inmunología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/inmunología , Factores de Edad , Lactancia Materna , Ensayo de Inmunoadsorción Enzimática , Femenino , Vacuna Neumocócica Conjugada Heptavalente , Humanos , Inmunidad Materno-Adquirida , Esquemas de Inmunización , Inmunización Secundaria , Indígenas Norteamericanos , Lactante , Modelos Lineales , Masculino , Vacunas Meningococicas/administración & dosificación , Vacunas Neumococicas/administración & dosificación , Streptococcus pneumoniae/inmunología , Estados UnidosRESUMEN
BACKGROUND: Immunization with pneumococcal conjugate vaccines (PCVs) reduces nasopharyngeal colonization by Streptococcus pneumoniae. We attempted to correlate postvaccination serum serotype-specific pneumococcal anticapsular immunoglobulin (Ig) G concentrations with new acquisitions of vaccine-type (VT) serotypes and the VT-related serotype 6A. METHODS: A total of 132 day care center attendees aged 12-35 months received a 9-valent PCV (PnCRM9) and were followed for 2 years for new nasopharyngeal acquisitions of S. pneumoniae. A total of 132 control subjects received a meningococcus type C conjugate vaccine. Serum serotype-specific pneumococcal anticapsular IgG concentrations were determined at 1 month after complete immunization. RESULTS: A logistic regression model of the probability of having a new acquisition of S. pneumoniae (for serotypes 9V, 14, 19F, and 23F) as a function of the IgG concentration showed a negative coefficient, indicating that higher IgG concentrations led to a decreasing probability of having a new acquisition, and achieved statistical significance for serotypes 14 and 19F. Similarly, a new acquisition of serotype 6A was shown to be significantly inversely related to the anti-6B IgG concentration. An effect of the IgG concentration on duration of carriage was not demonstrated. CONCLUSION: The magnitude of herd protection against S. pneumoniae provided by a PCV may depend on the magnitude of IgG concentrations.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Vacunas Bacterianas/inmunología , Inmunoglobulina G/sangre , Nasofaringe/microbiología , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Guarderías Infantiles , Preescolar , Femenino , Humanos , Lactante , Masculino , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/transmisión , Probabilidad , Análisis de Regresión , SerotipificaciónRESUMEN
Clinical trials necessary for the development of new treatment often require testing of multiple endpoints for equivalence or noninferiority relative to an existing effective standard therapy. An example is a vaccine study with multiple antibody measurements in sera of subjects receiving a combination vaccine such as a pneumococcal vaccine, which contains many different serotypes of the pneumococcal organism. This article describes testing methods for the demonstration of simultaneous marginal equivalence or noninferiority of two treatments on each component of the response vector that follows a multivariate normal distribution. Systematic simulation studies are conducted to evaluate the performance of the testing method and to examine under what conditions the power is substantially different if the multiple endpoints are assumed to be independent when they are actually strongly correlated. Data from an illustrative example are used to describe how the study power can be evaluated in the design of the trials.
Asunto(s)
Interpretación Estadística de Datos , Determinación de Punto Final/estadística & datos numéricos , Vacunas/uso terapéutico , Algoritmos , Anticuerpos/análisis , Ensayos Clínicos como Asunto , Simulación por Computador , Humanos , Proyectos de InvestigaciónRESUMEN
The World Health Organization (WHO) is undertaking a series of consultations on serological criteria for the evaluation and licensure of new formulations/combinations or different vaccination schedules of pneumococcal conjugate vaccines. The lack of a definitive serological correlate of protection and the multiplicity of antigens involved, especially since the clinical efficacy of most of the individual serotypes represented in the only licensed vaccine has not been established, are hindering the formulation of criteria for licensure of new formulations or combinations of the vaccine. This report analyses the various options with their relative merits and drawbacks and provides preliminary recommendations as guidance to regulatory agencies in evaluating these vaccines for the purposes of licensure. More detailed recommendations for production and control of pneumococcal conjugate vaccines, including criteria for evaluation for licensure, are currently being drafted.