RESUMO
BACKGROUND: The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019. METHODS: In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-µg doses of the BNT162b2 vaccine were randomly assigned to receive 30 µg or 60 µg of BNT162b2, 30 µg or 60 µg of monovalent B.1.1.529 (omicron) BA.1-adapted BNT162b2 (monovalent BA.1), or 30 µg (15 µg of BNT162b2 + 15 µg of monovalent BA.1) or 60 µg (30 µg of BNT162b2 + 30 µg of monovalent BA.1) of BA.1-adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 µg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants. RESULTS: A total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 µg and 60 µg) and monovalent BA.1 (60 µg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 µg), with NT50 geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 µg) were also noninferior to BNT162b2 (30 µg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain, with NT50 GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4-BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-µg bivalent BA.1 than with 30-µg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 µg). Adverse events were more common in the 30-µg monovalent-BA.1 (8.5%) and 60-µg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%). CONCLUSIONS: The candidate monovalent or bivalent omicron BA.1-adapted vaccines had a safety profile similar to that of BNT162b2 (30 µg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.).
Assuntos
Vacina BNT162 , COVID-19 , SARS-CoV-2 , Vacinas Combinadas , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacina BNT162/efeitos adversos , Vacina BNT162/imunologia , Vacina BNT162/uso terapêutico , COVID-19/genética , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Vacinação , Vacinas Combinadas/uso terapêutico , Pessoa de Meia-IdadeRESUMO
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 µg of BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-µg dose) to 3.5-fold (50-µg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.
Assuntos
Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Células Th1/imunologia , Vacinas Virais/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/prevenção & controle , Citocinas/imunologia , Feminino , Alemanha , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Células Th1/citologia , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Adulto JovemRESUMO
Implementation of conjugate vaccine technology revolutionized the ability to effectively elicit long-lasting immune responses to bacterial capsular polysaccharides. Although expansion of conjugate vaccine serotype coverage is designed to target residual disease burden to pneumococcal serotypes not contained in earlier vaccine versions, details of polysaccharide Ag structure, heterogeneity, and epitope structure components contributing to vaccine-mediated immunity are not always clear. Analysis of Streptococcus pneumoniae serotype 12F polysaccharide by two-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry revealed a partial substitution of N-acetyl-galactosamine by the keto sugar 2-acetamido-2,6-dideoxy-xylo-hexos-4-ulose (Sug) in up to 25% of the repeat units. This substitution was not described in previous published structures for 12F. Screening a series of contemporary 12F strains isolated from humans (n = 17) identified Sug incorporation at varying levels in all strains examined. Thus, partial Sug substitution in S. pneumoniae serotype 12F may have always been present but is now detectable by state-of-the-art analytical techniques. During the steps of conjugation, the serotype 12F Sug epitope is modified by reduction, and both polysaccharide PPSV23 and conjugate PCV20 vaccines contain 12F Ags with little to no Sug epitope. Both PCV20 and PPSV23 vaccines were evaluated for protection against circulating 12F strains with varying amounts of Sug in their repeat unit based on an opsonophagocytic killing assay involving HL-60 cells and rabbit complement. Both vaccines elicited human-derived neutralizing Abs against serotype 12F, independent of Sug level between â¼2 and 25 mol%. These findings suggest that the newly identified serotype 12F Sug epitope is likely not an essential epitope for vaccine-elicited protection.
Assuntos
Imunogenicidade da Vacina , Streptococcus pneumoniae , Humanos , Sorogrupo , Vacinas Conjugadas , Espectroscopia de Ressonância MagnéticaRESUMO
BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have significantly reduced pneumococcal disease, but disease from non-PCV serotypes remains. The safety, tolerability, and immunogenicity of a 20-valent PCV (PCV20) were evaluated. METHODS: This pivotal phase 3, randomized, double-blind study enrolled adults into 3 age groups (≥60, 50-59, and 18-49 years) at US and Swedish sites. Participants were randomized to receive 1 PCV20 or 13-valent PCV (PCV13) dose. After 1 month, participants aged ≥60 years also received 1 dose of saline or 23-valent polysaccharide vaccine (PPSV23). Safety assessments included local reactions, systemic events, adverse events, serious adverse events, and newly diagnosed chronic medical conditions. Opsonophagocytic activity geometric mean titers 1 month after PCV20 were compared with 13 matched serotypes after PCV13 and 7 additional serotypes after PPSV23 in participants aged ≥60 years; noninferiority was declared if the lower bound of the 2-sided 95% confidence interval for the opsonophagocytic activity geometric mean titer ratio (ratio of PCV20/saline to PCV13/PPSV23 group) was >0.5. PCV20-elicited immune responses in younger participants were also bridged to those in 60-64-year-olds. RESULTS: The severity and frequency of prompted local reactions and systemic events were similar after PCV20 or PCV13; no safety concerns were identified. Primary immunogenicity objectives were met, with immune responses after PCV20 noninferior to 13 matched serotypes after PCV13 and to 6 additional PPSV23 serotypes in participants aged ≥60 years; serotype 8 missed the statistical noninferiority criterion. PCV20 induced robust responses to all 20 vaccine serotypes across age groups. CONCLUSIONS: PCV20 was safe and well tolerated, with immunogenicity comparable to that of PCV13 or PPSV23. PCV20 is anticipated to expand protection against pneumococcal disease in adults. CLINICAL TRIALS REGISTRATION: NCT03760146.
Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Adolescente , Adulto , Anticorpos Antibacterianos , Método Duplo-Cego , Humanos , Imunogenicidade da Vacina , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Solução Salina , Sorogrupo , Vacinas ConjugadasRESUMO
BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have significantly decreased pneumococcal disease worldwide; however, expanding serotype coverage may further reduce disease burden. A 20-valent PCV (PCV20) containing capsular polysaccharide conjugates of serotypes present in the 13-valent PCV (PCV13) and 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) is currently in development. This phase 2 study evaluated safety, tolerability, and immunogenicity of PCV20 in adults without prior pneumococcal vaccination. METHODS: In this randomized, active-controlled, double-blinded trial, 444 adults 60 through 64 years of age were randomized to receive either a single dose of PCV20 followed 1 month later by saline placebo or a single dose of PCV13 followed 1 month later by 23-valent polysaccharide vaccine. Local injection site reactions, select systemic symptoms, and adverse events (AEs) were recorded. Immunogenicity was assessed by measuring serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month after each vaccination. RESULTS: Local reaction and systemic event rates were similar after vaccination with PCV20 or PCV13; no serious vaccine-related AEs were reported. In the PCV20 group, functional immune responses as measured by OPA were robust for all 20 serotypes included in the vaccine, with geometric mean fold rises from baseline ranging from 6.0 to 113.4. CONCLUSIONS: PCV20 was well tolerated in adults 60 to 64 years of age, with a safety profile consistent with historical experience of PCVs in this age group. Substantial OPA responses were elicited against all serotypes. Results demonstrate the potential for PCV20 to expand pneumococcal disease protection. CLINICAL TRIALS REGISTRATION: NCT03313037.
Assuntos
Anticorpos Antibacterianos , Infecções Pneumocócicas , Método Duplo-Cego , Humanos , Imunogenicidade da Vacina , Pessoa de Meia-Idade , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , Sorogrupo , Vacinas Conjugadas/efeitos adversosRESUMO
BACKGROUND: Group B streptococcus (GBS) causes serious diseases in newborn infants, often resulting in lifelong neurologic impairments or death. Prophylactic vaccination of pregnant women prior to delivery could provide comprehensive protection, as early onset and late-onset disease and maternal complications potentially could be addressed. METHODS: Capsular polysaccharide conjugate vaccine GBS6 was designed using surveillance data yielded by whole-genome sequencing of a global collection of recently recovered GBS isolates responsible for invasive neonatal GBS disease. Capsular polysaccharides were isolated, oxidized using sodium periodate, and conjugated to CRM197 by reductive amination in dimethyl sulfoxide. Immune responses in mice and rhesus macaques were measured in a multiplex Luminex immunoglobulin G (IgG) assay and opsonophagocytic activity assays. RESULTS: The optimized conjugates were immunogenic, alone and in combination, in mice and rhesus macaques, inducing IgG antibodies that mediated opsonophagocytic killing. Active immunization of murine dams with GBS6 prior to mating resulted in serotype-specific protection of pups from a lethal challenge with GBS. Protection following passive administration of serotype-specific IgG monoclonal antibodies to dams demonstrated conclusively that anticapsular polysaccharide IgG alone is sufficient for protection. CONCLUSIONS: The findings support the ongoing clinical evaluation of maternal GBS6 vaccination as a potential alternative method to prevent GBS disease in infants.
Assuntos
Animais Recém-Nascidos/imunologia , Imunidade Materno-Adquirida/imunologia , Polissacarídeos Bacterianos/imunologia , Infecções Estreptocócicas/imunologia , Vacinas Estreptocócicas/imunologia , Streptococcus/imunologia , Vacinas Conjugadas/imunologia , Animais , Animais Recém-Nascidos/microbiologia , Anticorpos Antibacterianos/imunologia , Feminino , Imunização/métodos , Imunoglobulina G/imunologia , Macaca mulatta/imunologia , Macaca mulatta/microbiologia , Camundongos , Sorogrupo , Infecções Estreptocócicas/microbiologia , Vacinação/métodosRESUMO
BACKGROUND: A 20-valent pneumococcal conjugate vaccine (PCV20), containing 13-valent PCV (PCV13) components and 7 additional polysaccharide conjugates, was developed to extend protection for pneumococcal disease. This phase 3 study assessed the safety and immunogenicity of PCV20 in children. METHODS: In this single-arm study, children (≥15 months-<18 years of age) received 1 dose of PCV20. Children <5 years of age had ≥3 prior doses of PCV13; children ≥5 years were recruited regardless of previous PCV receipt. Serotype-specific IgG concentrations and opsonophagocytic activity (OPA) titers were measured before and 1 month after PCV20. Local reactions and systemic events, adverse events (AEs), serious AEs, and newly diagnosed chronic medical conditions were collected. RESULTS: Of 839 enrolled participants, 831 (>99%) were vaccinated, and 819 (>97%) completed all study visits. Local reactions and systemic events were mostly mild to moderate in severity. No serious AEs were considered PCV20-related. IgG geometric mean fold rises (GMFRs) from before to 1 month after PCV20 ranged from 27.9-1847.7 (7 additional serotypes) and 2.9-44.9 (PCV13 serotypes) in children <5 years of age, and 10.5-187.7 (7 additional serotypes) and 4.3-127.9 (PCV13 serotypes) in children ≥5 years old. OPA GMFRs from before to 1 month after PCV20 ranged from 12.4-983.6 to 2.8-52.9 in children <5 years of age and from 11.5-499.0 to 5.3-147.9 in children ≥5 years of age. CONCLUSIONS: Among children ≥15 months through <18 years of age, PCV20 was well tolerated and induced robust responses to all 20 serotypes, supporting the use of PCV20 in children.
Assuntos
Anticorpos Antibacterianos , Imunoglobulina G , Infecções Pneumocócicas , Vacinas Pneumocócicas , Vacinas Conjugadas , Humanos , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/administração & dosagem , Lactente , Feminino , Masculino , Pré-Escolar , Anticorpos Antibacterianos/sangue , Adolescente , Criança , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/administração & dosagem , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/imunologia , Imunoglobulina G/sangue , Imunogenicidade da Vacina , Streptococcus pneumoniae/imunologia , SorogrupoRESUMO
BACKGROUND: The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend pneumococcal disease protection beyond 13-valent PCV (PCV13). METHODS: This phase 3, double-blind study conducted in the United States/Puerto Rico evaluated PCV20 safety and immunogenicity. Healthy infants were randomized to receive a 4-dose series of PCV20 or PCV13 at 2, 4, 6 and 12-15 months old. Objectives included demonstrating noninferiority (NI) of PCV20 to PCV13 immunoglobulin G (IgG) geometric mean concentrations after doses 3 and 4 and percentages of participants with predefined IgG concentrations after dose 3, with 7 additional PCV20 serotypes compared with the lowest result among vaccine serotypes in the PCV13 group. Safety assessments included local reactions, systemic events, adverse events, serious adverse events and newly diagnosed chronic medical conditions. RESULTS: Overall, 1991 participants were vaccinated (PCV20, n = 1001; PCV13, n = 990). For IgG geometric mean concentrations 1 month after both doses 3 and 4, all 20 serotypes met NI criteria (geometric mean ratio lower 2-sided 95% confidence interval > 0.5). For percentages of participants with predefined IgG concentrations after dose 3, NI (percentage differences lower 2-sided 95% confidence interval > -10%) was met for 8/13 matched serotypes and 6/7 additional serotypes; 4 serotypes missed the statistical NI criterion by small margins. PCV20 also elicited functional and boosting responses to all 20 serotypes. The safety profile of PCV20 was similar to PCV13. CONCLUSION: A 4-dose series of PVC20 was well tolerated and elicited robust serotype-specific immune responses expected to help protect infants and young children against pneumococcal disease due to the 20 vaccine serotypes. Clinical trial registration: NCT04382326.
Assuntos
Anticorpos Antibacterianos , Imunoglobulina G , Infecções Pneumocócicas , Vacinas Pneumocócicas , Streptococcus pneumoniae , Vacinas Conjugadas , Humanos , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Lactente , Método Duplo-Cego , Masculino , Feminino , Anticorpos Antibacterianos/sangue , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/imunologia , Imunoglobulina G/sangue , Streptococcus pneumoniae/imunologia , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Imunogenicidade da Vacina , Estados Unidos , Sorogrupo , Voluntários SaudáveisRESUMO
BACKGROUND: Pneumococcal infections are associated with high disease burden in older individuals in Japan, South Korea, and Taiwan. The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend protection beyond earlier pneumococcal vaccines. METHODS: This phase 3 randomized, double-blind study investigated the safety and immunogenicity of PCV20 in participantsâ¯≥â¯60â¯years of age from Japan, South Korea, and Taiwan. Participants were randomized to receive PCV20 or 13-valent pneumococcal conjugate vaccine (PCV13). One month after vaccination, PCV20 recipients received a saline injection and PCV13 recipients received 23-valent polysaccharide vaccine (PPSV23). Primary immunogenicity objectives were to demonstrate noninferiority of PCV20 to PCV13 (13 matched serotypes) or PPSV23 (7 additional serotypes) for serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1â¯month after vaccination with PCV20, PCV13, or PPSV23. Noninferiority for each serotype was declared if the lower bound of the 2-sided 95% CI for OPA geometric mean ratio (GMR) wasâ¯>â¯0.5. Safety endpoints included local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Overall, 1421⬠participants were vaccinated (median age [range]: 65 [60-85] years). PCV20 was noninferior to PCV13 for all 13 matched serotypes and to PPSV23 for 6 of 7 additional serotypes. Although statistical noninferiority was missed for serotype 8 (lower bound of the 2-sided 95% CI for OPA GMRâ¯=â¯0.5, thus not meeting the statistical noninferiority criterion ofâ¯>â¯0.5), secondary immunogenicity endpoints for serotype 8 were supportive of a robust immune response. The incidence of AEs and the frequency and severity of local reactions and systemic events were generally similar after PCV20 and PCV13. No safety concerns were identified. CONCLUSION: PCV20 generated robust immune responses to all vaccine serotypes in older adults in Japan, South Korea, and Taiwan. The safety and tolerability profile was similar to PCV13. PCV20 is expected to help protect against all 20 vaccine serotypes. NCT04875533.
Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Humanos , Idoso , Vacinas Conjugadas/efeitos adversos , Japão , Taiwan , Anticorpos Antibacterianos , Infecções Pneumocócicas/epidemiologia , Vacinas Pneumocócicas/efeitos adversos , Método Duplo-Cego , República da Coreia , Imunogenicidade da VacinaRESUMO
The 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on 19-23 June 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with these NEW Regulations" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication (Part 2) covers the recommendations on Biomarkers, IVD/CDx, LBA and Cell-Based Assays. Part 1A (Mass Spectrometry Assays and Regulated Bioanalysis/BMV), P1B (Regulatory Inputs) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 9 and 7 (2024), respectively.
Assuntos
Biomarcadores , Terapia Baseada em Transplante de Células e Tecidos , Vacinas , Humanos , Biomarcadores/análise , Vacinas/imunologia , Citometria de Fluxo , Bioensaio/métodos , União Europeia , BrancosRESUMO
Staphylococcus aureus and other staphylococci cause severe human disease, and there are currently no vaccines available. We evaluated whether manganese transport protein C (MntC), which is conserved across the staphylococcal species group, could confer protection against S. aureus and Staphylococcus epidermidis. In vivo analysis of S. aureus MntC expression revealed that expression occurs very early during the infectious cycle. Active immunization with MntC was effective at reducing the bacterial load associated with S. aureus and S. epidermidis infection in an acute murine bacteremia model. Anti-MntC monoclonal antibodies have been identified that can bind S. aureus and S. epidermidis cells and are protective in an infant rat passive protection model and induce neutrophil respiratory burst activity. This is the first description of a protein that has the potential to provide protection across the staphylococcal species group.
Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Proteínas de Membrana/imunologia , Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/imunologia , Staphylococcus aureus/imunologia , Staphylococcus epidermidis/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Bacteriemia/imunologia , Bacteriemia/prevenção & controle , Bacteriemia/terapia , Carga Bacteriana , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Modelos Animais de Doenças , Feminino , Imunização Passiva , Proteínas de Membrana/genética , Camundongos , Coelhos , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/terapia , Vacinas Antiestafilocócicas/administração & dosagem , Vacinas Antiestafilocócicas/genética , Resultado do TratamentoRESUMO
AIM: Pneumococcal conjugate vaccines (PCV13, PCV15, PCV20) effectively target the capsular polysaccharides of the most common disease-causing Streptococcus pneumoniae serotypes. In this short communication, we analyzed healthy participants who received PCV13 and PCV15 vaccines as part of a recently concluded exploratory clinical trial and report antibody responses to the 13 shared serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) as well as functional OPA responses to serotype 3. METHODS: Sera from 87 adult participants (18 through 49 years of age) randomized to receive either PCV13 or PCV15 were collected (n = 46 or n = 41, respectively), from 17 study centers in the US. IgG concentrations of the 13 shared serotypes and serotype 3-specific OPA titers were analyzed before and 1 month after vaccination using internally validated assays. RESULTS: At 1 month after vaccination, IgG GMCs of the 13 shared serotypes in PCV13 were similar to those for PCV15. Specifically, serotype 3 OPA GMTs and 95% CIs were similar 1 month after vaccination for PCV13 (62.9 [48.9, 80.9]) and PCV15 (71.1 [50.9, 99.2]). CONCLUSION: In healthy participants who received either PCV13 or PCV15, similar serotype-specific responses were observed between all shared serotypes when a uniform validated internal assay was used. Of note, data from this study suggest that both vaccines induce similar functional antibody responses against pneumococcal serotype 3.
Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Adulto , Humanos , Anticorpos Antibacterianos , Imunoglobulina G , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Sorogrupo , Vacinas Conjugadas , Adolescente , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Group A streptococci (GAS) are a major cause of pharyngitis in children. Recently, there were severe GAS outbreaks. The aims of this study were to assess pharyngeal colonization prevalence in healthy children, to assess different diagnostic definitions for GAS pharyngitis and to estimate incidence rates for these infections. METHODS: A 2-year longitudinal study was conducted in healthy children in the United States. Pharyngeal swabs were cultured every 3 months for GAS colonization. Serum antistreptolysin O, antideoxyribonuclease B (DNaseB) and antistreptococcal C5a peptidase (SCP) antibody titers were assessed at baseline. When participants developed a sore throat, pharyngeal swabs were collected for rapid antigen detection test (RADT) and culture, and antibody titers were determined in serum samples. A range of case definitions were used for GAS pharyngitis. RESULTS: A total of 422 children 3-12 years old were enrolled (140, 141 and 141 were 3-5, 6-9 and 10-12 years of age, respectively). The overall prevalence of GAS colonization during the study was 48%. Baseline antistreptolysin O, anti-DNaseB and anti-SCP antibody titers were higher for children older than 5 years. The incidence of GAS pharyngitis per 100 person-years was 15.9 for RADT/culture-proven and 4.6 for serologically confirmed pharyngitis. CONCLUSIONS: GAS throat colonization and pharyngitis were frequent in children 3-12 years old. The case definition employed impacted the measured incidence of GAS pharyngitis, with higher rates detected using RADT/culture-based definitions. These data suggest that case definition is important and that young children are exposed to GAS, which may inform plans for vaccine development and implementation.
Assuntos
Faringite , Infecções Estreptocócicas , Criança , Humanos , Pré-Escolar , Estudos Longitudinais , Antiestreptolisina , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/diagnóstico , Sensibilidade e Especificidade , Streptococcus pyogenes , Faringite/epidemiologia , Faringite/diagnósticoRESUMO
The 16th Workshop on Recent Issues in Bioanalysis (16th WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on LBA, Biomarkers/CDx and Cytometry. Part 1 (Mass Spectrometry and ICH M10) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 15 of Bioanalysis, issues 16 and 14 (2023), respectively.
Assuntos
Bioensaio , Relatório de Pesquisa , Citometria de Fluxo/métodos , Ligantes , Biomarcadores/análise , Bioensaio/métodosRESUMO
Protection conferred by pneumococcal polysaccharide conjugate vaccines (PCVs) is associated with PCV-induced antibodies against vaccine-covered serotypes that exhibit functional opsonophagocytic activity (OPA). Structural similarity between capsular polysaccharides of closely related serotypes may result in induction of cross-reactive antibodies with or without a cross-functional activity against a serotype not covered by a PCV, with the former providing an additional protective clinical benefit. Serotypes 15B, 15A, and 15C, in the serogroup 15, are among the most prevalent Streptococcus pneumoniae serotypes associated with invasive pneumococcal disease following the implementation of a 13-valent PCV; in addition, 15B contributes significantly to acute otitis media. Serological discrimination between closely related serotypes such as 15B and 15C is complicated; here, we implemented an algorithm to quickly differentiate 15B from its closely related serotypes 15C and 15A directly from whole-genome sequencing data. In addition, molecular dynamics simulations of serotypes 15A, 15B, and 15C polysaccharides demonstrated that while 15B and 15C polysaccharides assume rigid branched conformation, 15A polysaccharide assumes a flexible linear conformation. A serotype 15B conjugate, included in a 20-valent PCV (PCV20), induced cross-functional OPA serum antibody responses against the structurally similar serotype 15C but not against serotype 15A, both not included in PCV20. In PCV20-vaccinated adults (18-49 years), robust OPA antibody titers were detected against both serotypes 15B (the geometric mean titer [GMT] of 19,334) and 15C (GMTs of 1692 and 2747 for strains PFE344340 and PFE1160, respectively), but were negligible against serotype 15A (GMTs of 10 and 30 for strains PFE593551 and PFE647449, respectively). Cross-functional 15B/C responses were also confirmed using sera from a larger group of older adults (60-64 years).
Assuntos
Infecções Pneumocócicas , Streptococcus pneumoniae , Idoso , Anticorpos Antibacterianos , Humanos , Imunidade , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Polissacarídeos , Sorogrupo , Vacinas ConjugadasRESUMO
Expanding serotype coverage of pneumococcal conjugate vaccines (PCVs) to target prevailing disease-causing serotypes could further reduce disease burden. To address this need, 2 different PCVs have been investigated: a 20-valent PCV (PCV20; includes the 13 serotypes in the 13-valent PCV [PCV13] plus 7 additional serotypes [8, 10A, 11A, 12F, 15B, 22F, 33F]) and a complementary 7-valent PCV (cPCV7; contains only the 7 additional serotypes). This phase 1b, randomized, controlled, double-blind study evaluated PCV20 and cPCV7 safety and immunogenicity in healthy Japanese adults 18-49 years of age residing in the United States for ≤5 years. Participants (n = 104) were randomized equally to receive a single dose of PCV20, cPCV7, or PCV13. Immunogenicity was assessed at baseline and 1 month after vaccination using serotype-specific opsonophagocytic activity (OPA) titers and serotype-specific immunoglobulin G (IgG) concentrations. Prompted local reactions and systemic events; adverse events (AEs); and serious AEs and newly diagnosed chronic disease were assessed 14 days, through 1 month, and upto 6 months following vaccination, respectively. OPA immune responses were robust for all 20 serotypes in the PCV20 group and for the 7 serotypes in the cPCV7 group 1 month after vaccination. IgG immune response showed similar trends. Injection site pain and muscle pain were the most common local reaction and systemic event; the majority were mild or moderate in severity. Few AEs and no severe AEs, serious AEs, or safety-related withdrawals were reported. Taken together, administration of PCV20 or cPCV7 in Japanese adults was well tolerated and induced robust serotype-specific functional immune responses. NCT03642847.
Assuntos
Infecções Pneumocócicas , Vacinas Pneumocócicas , Adulto , Anticorpos Antibacterianos , Pré-Escolar , Humanos , Japão , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , Sorogrupo , Estados Unidos , Vacinas ConjugadasRESUMO
A Staphylococcus aureus four-antigen vaccine (SA4Ag) was designed for the prevention of invasive disease in surgical patients. The vaccine is composed of capsular polysaccharide type 5 and type 8 CRM197 conjugates, a clumping factor A mutant (Y338A-ClfA) and manganese transporter subunit C (MntC). S. aureus pathogenicity is characterized by an ability to rapidly adapt to the host environment during infection, which can progress from a local infection to sepsis and invasion of distant organs. To test the protective capacity of the SA4Ag vaccine against progressive disease stages of an invasive S. aureus infection, a deep tissue infection mouse model, a bacteremia mouse model, a pyelonephritis model, and a rat model of infectious endocarditis were utilized. SA4Ag vaccination significantly reduced the bacterial burden in deep tissue infection, in bacteremia, and in the pyelonephritis model. Complete prevention of infection was demonstrated in a clinically relevant endocarditis model. Unfortunately, these positive preclinical findings with SA4Ag did not prove the clinical utility of SA4Ag in the prevention of surgery-associated invasive S. aureus infection.
RESUMO
A maternal Group B Streptococcus (GBS) six-valent polysaccharide conjugate vaccine (GBS6) is being developed to protect neonates and infants up to 3 months of age through passive transfer of antibodies from the mother to the infant. Fertility and developmental toxicity studies were conducted in female Sprague Dawley rats and New Zealand White rabbits with GBS6 (20 µg capsular polysaccharide/serotype formulated with or without AlPO4 , the highest clinical dose). Females were administered the full human dose of the GBS6 formulation intramuscularly twice prior to mating and twice during gestation, to ensure that high antibody levels were maintained throughout gestation and lactation. Approximately, half of the rats and rabbits were evaluated at the end of gestation, and the remainder were evaluated at the end of lactation. Maternal blood for GBS6 serology, to measure antibody titers to the GBS6 antigens, was collected prior to the first dose, prior to mating, and at each necropsy. Blood for serology was also collected from offspring at the end of gestation and lactation. In both species, there was no evidence of vaccine-related effects on fertility, embryo-fetal development, or postnatal development of the offspring, supporting regulatory guidance that single-species evaluation would have been sufficient. Functional serum antibodies to all six serotypes in the vaccine were confirmed in maternal animals and functional serum antibodies to one or more of the six serotypes was also confirmed in some rat offspring and most of the rabbit offspring. The results of these studies supported the safety of GBS6 vaccine administration to pregnant women.
Assuntos
Imunização , Streptococcus agalactiae , Animais , Feminino , Fertilidade , Humanos , Polissacarídeos , Gravidez , Coelhos , Ratos , Ratos Sprague-Dawley , Vacinas Conjugadas/toxicidadeRESUMO
INTRODUCTION: Introduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20. METHODS: This phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18-49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28-42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated. RESULTS: Equivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups. CONCLUSIONS: Three different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).