RESUMO
Cervical cancer is caused by human papillomavirus (HPV) infection, which is preventable by HPV vaccines. In Japan, the HPV vaccination rate has remained extremely low due to the concerns for alleged neuropsychological symptoms or "diverse symptoms" following injections of two HPV vaccines, Cervarix and Gardasil, in HPV vaccine lawsuits. In the lawsuits, the attorneys' group has used several manuscripts proposing that aluminum (Al) adjuvant contained in HPV vaccines causes an immune-mediated disease, called macrophagic myofasciitis (MMF), as well as pathology in the central nervous system (CNS). We scientifically evaluated these manuscripts describing the "Al adjuvant-induced pathologies," particularly MMF. Although MMF patients have been reported to develop clinical symptoms/signs in various organs, including the CNS, muscle biopsy of the patients and animal experiments demonstrated that MMF pathology was localized only at the injected muscle. No muscle pathology which characterizes MMF was observed in any other muscles; thus, the systemic and neurological signs of MMF cases were irrelevant to localized MMF pathology. We evaluated that MMF-like pathology was induced as a local inflammatory response following vaccinations; MMF pathology was not the cause of systemic inflammation or "diverse symptoms." Lastly, MMF cases have been reported after vaccinations with Al-hydroxide-containing vaccines exclusively. As Al-hydroxide is a component of Cervarix, but not Gardasil, "diverse symptoms" following two HPV vaccinations in Japan cannot be explained by MMF. Our evaluation would help readers understand the validity of the manuscripts on the role of Al adjuvants or MMF for the alleged "diverse symptoms."
Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Animais , Humanos , Alumínio/efeitos adversos , Infecções por Papillomavirus/prevenção & controle , Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Vacinas contra Papillomavirus/efeitos adversosRESUMO
Bronchial asthma is a chronic lung disorder, that affects an estimated 262 million people worldwide, thereby, causing a large socio-economic burden. Drug molecules from natural sources have exhibited a good promise in providing an alternative therapy in many chronic ailments. Solasodine, a glycoalkaloid has received an immense interest due to its large pharmacological and industrial value, however, its usefulness in asthma control has not been investigated till date. In this work, solasodine was tested for its ability to reverse several characteristics of bronchial asthma induced by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide in experimental rats. Treating asthmatic animals with solasodine (1 mg/kg b.w. or 10 mg/kg b.w.) or dexamethasone (2.5 mg/kg b.w.) reversed OVA-induced airway hyperresponsiveness, infiltration of inflammatory cells and histamine levels in the airways. Furthermore, as compared to OVA-control rats, allergen-induced elevated levels of IgE, nitrites, nitric oxide, and pro-inflammatory mediators, including TNF-α, IL-1ß, LTD-4, and Th2-cytokines, particularly, IL-4, IL-5 were remarkably reduced in both bronchoalveolar lavage fluid and blood. These findings are supported by significant protection offered by various treatments against OVA-induced airway inflammation and mast cell degranulation in mesenteric tissues. Further, In-silico molecular docking studies performed to determine inhibitory potential of solasodine at IL-4 and IL-5, demonstrated strong affinity of phytocompound for these receptors than observed with antagonists previously reported. Results of current study imply that solasodine has therapeutic promise in allergic asthma, presumably due to its ability to prevent mast cell degranulation and consequent generation of histamine and Th2-associated cytokines in airways.
Assuntos
Asma , Interleucina-5 , Alérgenos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar , Citocinas/uso terapêutico , Dexametasona/efeitos adversos , Modelos Animais de Doenças , Histamina/uso terapêutico , Humanos , Imunidade , Imunoglobulina E , Interleucina-4 , Interleucina-5/efeitos adversos , Pulmão , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Óxido Nítrico/uso terapêutico , Nitritos , Ovalbumina , Ratos , Alcaloides de Solanáceas , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV), a major cause of illness and death in infants worldwide, could be prevented by vaccination during pregnancy. The efficacy, immunogenicity, and safety of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine in pregnant women and their infants are uncertain. METHODS: In a phase 2b trial, we randomly assigned pregnant women, at 24 through 36 weeks' gestation, to receive either 120 or 240 µg of RSVpreF vaccine (with or without aluminum hydroxide) or placebo. The trial included safety end points and immunogenicity end points that, in this interim analysis, included 50% titers of RSV A, B, and combined A/B neutralizing antibodies in maternal serum at delivery and in umbilical-cord blood, as well as maternal-to-infant transplacental transfer ratios. RESULTS: This planned interim analysis included 406 women and 403 infants; 327 women (80.5%) received RSVpreF vaccine. Most postvaccination reactions were mild to moderate; the incidence of local reactions was higher among women who received RSVpreF vaccine containing aluminum hydroxide than among those who received RSVpreF vaccine without aluminum hydroxide. The incidences of adverse events in the women and infants were similar in the vaccine and placebo groups; the type and frequency of these events were consistent with the background incidences among pregnant women and infants. The geometric mean ratios of 50% neutralizing titers between the infants of vaccine recipients and those of placebo recipients ranged from 9.7 to 11.7 among those with RSV A neutralizing antibodies and from 13.6 to 16.8 among those with RSV B neutralizing antibodies. Transplacental neutralizing antibody transfer ratios ranged from 1.41 to 2.10 and were higher with nonaluminum formulations than with aluminum formulations. Across the range of assessed gestational ages, infants of women who were immunized had similar titers in umbilical-cord blood and similar transplacental transfer ratios. CONCLUSIONS: RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns. (Funded by Pfizer; ClinicalTrials.gov number, NCT04032093.).
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Proteínas Virais de Fusão , Hidróxido de Alumínio/efeitos adversos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Feminino , Humanos , Lactente , Gravidez , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Vírus Sincicial Respiratório Humano/imunologia , Vacinação , Proteínas Virais de Fusão/imunologiaRESUMO
Aluminium (Al) hydroxide use as adjuvant induces local formation of long-lasting subcutaneous granulomas in sheep. Macrophages within these granulomas have been identified as a new small ruminant lentivirus (SRLV) replication site in naturally infected animals. Diagnosis of Al hydroxide-induced granulomas in sheep is mostly based on postmortem observations but little information is available on in vivo detection. Computed tomography (CT) is used for studying these reactions in other animal species. To determine if CT could be a tool for in vivo diagnosis and research of subcutaneous Al hydroxide-induced granulomas in sheep. A retrospective survey on thoracic CT scans was performed on 46 adult sheep. Analysis included absence or presence, number and location of subcutaneous nodules. Thoracic CT scans and pathological studies were prescribed to two further sheep. Single or multiple subcutaneous nodules were detected in 26 (56.52%) sheep. One or two nodules per animal were most often observed (36.95%). Size ranged between 1.5 and 4.5 cm. Pre-contrast two-dimensional (2D) CT images showed focal or multifocal increases in subcutaneous tissue thickness. Post-contrast 2D CT images revealed hypointense areas in the centre. Histopathology indicated the presence of granulomas composed by a large number of activated macrophages, surrounding a central core of necrosis. Large intracytoplasmic Al-positive aggregates were demonstrated by lumogallion staining. CT is a useful tool to detect subcutaneous Al hydroxide-induced granulomas in vivo in sheep. CT provides a diagnostic and research tool that can be very useful in future works in Al hydroxide-induced pathology, SRLV infection, or both.
Assuntos
Hidróxido de Alumínio , Doenças dos Ovinos , Hidróxido de Alumínio/efeitos adversos , Animais , Granuloma/induzido quimicamente , Granuloma/diagnóstico por imagem , Granuloma/veterinária , Lentivirus , Estudos Retrospectivos , Ruminantes , Ovinos , Doenças dos Ovinos/induzido quimicamente , Doenças dos Ovinos/diagnóstico por imagem , Tomografia , Tomografia Computadorizada por Raios X/veterináriaAssuntos
Composição de Medicamentos/ética , Vacinas contra Papillomavirus/efeitos adversos , Sociedades Científicas/ética , Vacinas Combinadas/efeitos adversos , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Ensaios Clínicos como Assunto/ética , Composição de Medicamentos/estatística & dados numéricos , Humanos , Jornalismo Médico/normas , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Placebos/administração & dosagem , Segurança , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologiaAssuntos
Hidróxido de Alumínio/efeitos adversos , Composição de Medicamentos/métodos , Vacinas contra Papillomavirus/efeitos adversos , Fosfatos/efeitos adversos , Placebos/normas , Vacinas Combinadas/efeitos adversos , Hidróxido de Alumínio/administração & dosagem , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/normas , Humanos , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Fosfatos/administração & dosagem , Placebos/administração & dosagem , Sociedades Científicas/normas , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologiaRESUMO
OBJECTIVE: The 13C-urea breath test (UBT) is the most widely used non-invasive diagnostic test for Helicobacter pylori. Debate continues to surround the possible interference of antacid intake on its result. This study aims to confirm the non-interference of almagate in the determination of H. pylori by UBT. PATIENTS AND METHODS: Observational, multicentre study in adult patients treated with almagate in whom a UBT (TAUKIT®) was indicated. When the UBT result was negative, use of almagate was stopped for 30 days and the UBT was repeated. When the result was positive, no further determinations were made. The primary endpoint was the percentage of patients who, having had a negative result in the first breath test, were positive in the second after having stopped taking almagate (UBT false negatives, possibly attributable to almagate). RESULTS: Of the 167 evaluable patients, 59% were female, average age was 49 and 97% had gastrointestinal symptoms. The result of the first UBT was negative in 71% of cases. Of these, in the second UBT test after stopping the almagate, the negative result was confirmed in 97.5%. Out of the total number of cases evaluated, the rate of false negatives was 1.8%. CONCLUSIONS: Taking almagate has minimal or no interference in the result of UBT for the diagnosis of H. pylori infection. It can therefore be used in the weeks prior to a UBT.
Assuntos
Hidróxido de Alumínio/administração & dosagem , Antiácidos/administração & dosagem , Testes Respiratórios/métodos , Carbonatos/administração & dosagem , Infecções por Helicobacter/diagnóstico , Helicobacter pylori , Hidróxido de Magnésio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Antiácidos/efeitos adversos , Testes Respiratórios/estatística & dados numéricos , Isótopos de Carbono , Carbonatos/efeitos adversos , Dispepsia/tratamento farmacológico , Reações Falso-Negativas , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Hidróxido de Magnésio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Espanha , Fatores de Tempo , UreiaRESUMO
BACKGROUND: Shigella remains in the top four pathogens responsible for moderate to severe diarrhoea in children below 5 years of age. The shigella O-specific polysaccharide (O-SP) is a promising vaccine target. We developed a conjugate vaccine prototype incorporating a unique well defined synthetic oligosaccharide hapten, chemically designed for optimal antigenic, conformational, structural, and functional mimicry of the O-SP from Shigella flexneri 2a (SF2a). We aimed to assess the safety, tolerability, and immunogenicity of this original synthetic oligosaccharide-based vaccine candidate, SF2a-TT15, conceived to drive the antibody response towards the key protective determinants of the native lipopolysaccharide antigen, in a first-in-human phase 1 study. METHODS: We did a first-in-human, dose-escalating, single-blind, observer-masked, randomised, placebo-controlled study at the Clinical Research Center of Tel Aviv Sourasky Medical Center (Israel). Participants were healthy adults aged 18-45 years with low titres of serum SF2a-specific IgG antibodies. 64 eligible participants were assigned to one of two cohorts. 32 participants in each of the two cohorts were randomly assigned via computer-generated algorithm in a stepwise manner to receive the 2 µg (cohort 1) and 10 µg oligosaccharide dose (cohort 2) of the SF2a-TT15 vaccine candidate non-adjuvanted or adjuvanted with aluminium hydroxide (alum) or matching placebos. The vaccine was administered as three single intramuscular injections into the arm, 28 days apart. The primary outcome was the incidence and severity of adverse events, which were assessed in the intention-to-treat safety population analysis including all participants who were randomly assigned and received at least one vaccine or placebo injection. The immunogenicity endpoints were secondary outcomes and were analysed in all participants who were randomly assigned, received all of the assigned injections before the time of the immunogenicity assessment, and provided blood samples for immunological follow-up (per-protocol immunogenicity analysis). The study is registered with ClinicalStudies.gov, NCT02797236 and is completed. FINDINGS: Of 203 volunteers initially screened, 64 participants were enrolled between Sept 20, 2016, and Sept 26, 2017. In each of the two cohorts, 12 participants received the adjuvanted vaccine, 12 received the non-adjuvanted vaccine and eight received the matching placebo (four each). The SF2a-TT15 glycoconjugate was well tolerated at both doses. No serious or severe adverse events occurred. Overall, seven (88%) of eight to 12 (100%) of 12 in each group of volunteers had one adverse event or more after receiving the study agents with the majority of adverse events, 300 (98%) of 307, considered mild in intensity. Of the seven adverse events defined as moderate in severity, one (nausea) was suspected to be related to the vaccine candidate. At all post-immunisation days and for both oligosaccharide doses, whether adjuvanted or not, SF2a-TT15 induced significantly higher serum IgG anti-SF2a lipopolysaccharide geometric mean titres (GMTs) as compared with baseline or with the corresponding GMTs in placebo recipients (p<0·01). After one injection, the non-adjuvanted 10 µg oligosaccharide dose induced a 27-times increase in IgG GMT (5080 vs 189) and the non-adjuvanted 2 µg oligosaccharide dose induced a five-times increase (1411 vs 283), compared with baseline. Alum enhanced the specific IgG response at 2 µg oligosaccharide dose after the third injection (GMTs 3200 vs 1176, p=0.045). INTERPRETATION: SF2a-TT15 was safe and well tolerated and induced high titres of anti-SF2a LPS IgG antibodies. These results support further evaluation of this original synthetic oligosaccharide-protein conjugate vaccine candidate for safety, immunogenicity, and protective efficacy in target populations. FUNDING: The European Union Seventh Framework Programme.
Assuntos
Disenteria Bacilar/prevenção & controle , Imunogenicidade da Vacina , Vacinas contra Shigella/efeitos adversos , Shigella flexneri/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Hidróxido de Alumínio/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Relação Dose-Resposta Imunológica , Disenteria Bacilar/imunologia , Disenteria Bacilar/microbiologia , Feminino , Voluntários Saudáveis , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Antígenos O/genética , Antígenos O/imunologia , Vacinas contra Shigella/administração & dosagem , Vacinas contra Shigella/genética , Vacinas contra Shigella/imunologia , Método Simples-Cego , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/genética , Vacinas Conjugadas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Adulto JovemRESUMO
Aluminum (Al)-based salts are widely used adjuvants in ruminants and other species to strengthen the immune response elicited against vaccine antigen(s). However, they can lead to the formation of long-lasting granulomas composed of abundant activated macrophages. Small ruminant lentiviruses (SRLV) are widely distributed macrophage-tropic retroviruses that cause persistent infections in sheep and goats. Infected monocytes/macrophages and dendritic cells establish an inflammatory microenvironment that eventually leads to clinical manifestations. The aim of this work was to study the effect of Al-induced granulomas in the replication and pathogenesis of SRLV. Eleven adult, naturally SRLV-infected sheep showing clinical arthritis were distributed in vaccine (n = 6), adjuvant-only (n = 3), and control (n = 2) groups and inoculated with commercial Al-based vaccines, Al hydroxide adjuvant alone, or phosphate-buffered saline, respectively. In vitro studies demonstrated viral replication in Al-induced granulomas in 5 out of 10 sheep. Immunohistochemistry (IHC) evinced granular, intracytoplasmic SRLV presence in macrophages within granulomas. Viral sequences obtained from granulomas, blood monocytes, and other tissues were highly similar in most animals, suggesting virus circulation among body compartments. However, notable differences between isolated strains in granulomas and other tissues in specific animals were also noted. Interestingly, the B2 subtype was the most commonly found SRLV genotype, reaching a wider body distribution than previously described. Recombination events between genotypes B2 and A3 along the gag region were identified in two sheep. Our results indicate that Al-hydroxide-derived granulomas may represent an ideal compartment for SRLV replication, perhaps altering natural SRLV infection by providing a new, suitable target tissue.IMPORTANCE Granulomas are inflammation-derived structures elicited by foreign bodies or certain infections. Aluminum adjuvants included in vaccines induce granulomas in many species. In sheep, these are persistent and consist of activated macrophages. Small ruminant lentiviruses (SRLV), which are macrophage-tropic lentiviruses, cause a chronic wasting disease affecting animal welfare and production. Here, we studied the occurrence of SRLV in postvaccination granulomas retrieved from naturally infected ewes after vaccination or inoculation with aluminum only. SRLV infection was confirmed in granulomas by identification of viral proteins, genomic fragments, and enzymatic activity. The infecting SRLV strain, previously found exclusively in carpal joints, reached the central nervous system, suggesting that occurrence of SRLV in postvaccination granulomas may broaden tissue tropism. SRLV recombination was detected in inoculated animals, a rare event in sheep lentiviruses. Potentially, virus-host interactions within granulomas may modify viral pathogenesis and lead to more widespread infection.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Vírus da Artrite-Encefalite Caprina/fisiologia , Granuloma/veterinária , Infecções por Lentivirus/veterinária , Doenças dos Ovinos/virologia , Replicação Viral/efeitos dos fármacos , Animais , Vírus da Artrite-Encefalite Caprina/classificação , Vírus da Artrite-Encefalite Caprina/efeitos dos fármacos , Vírus da Artrite-Encefalite Caprina/isolamento & purificação , Genótipo , Granuloma/induzido quimicamente , Granuloma/virologia , Infecções por Lentivirus/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Filogenia , Recombinação Genética , Ovinos , Doenças dos Ovinos/induzido quimicamente , Tropismo ViralRESUMO
Importance: A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed. Objective: To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China. Interventions: In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 µg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 µg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]). Design, Setting, and Participants: Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020. Main Outcomes and Measures: The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups. Conclusions and Relevance: In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.
Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Imunogenicidade da Vacina , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/genética , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/imunologia , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Humanos , Injeções Intramusculares , Masculino , Pneumonia Viral/imunologia , Propiolactona , SARS-CoV-2 , Vacinas de Produtos Inativados/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Adulto JovemRESUMO
Aluminium hydroxide is a well-known adjuvant used in vaccines. Although it can enhance an adaptive immune response to a co-administered antigen, it causes adverse effects, including macrophagic myofasciitis (MMF), subcutaneous pseudolymphoma, and drug hypersensitivity. The object of this study is to demonstrate pediatric cases of aluminium hydroxide-induced diseases focusing on its rarity, under-recognition, and distinctive pathology. Seven child patients with biopsy-proven MMF were retrieved from the Seoul National University Hospital (SNUH) pathology archives from 2015 to 2019. The medical records and immunisation history were reviewed, and a full pathological muscle examination was carried out. The mean age was 1.7 years (8.9-40 months), who had records of vaccination against hepatitis B, hepatitis A, and tetanus toxoid on the quadriceps muscle. The chief complaints were muscle weakness (n = 6), delayed motor milestones (n = 6), instability, dysarthria, and involuntary movement (n = 1), swallowing difficulty (n = 1), high myopia (n = 1), and palpable subcutaneous nodules with skin papules (n = 1). Muscle biopsy showed MMF (n = 6) and pseudolymphoma (n = 1) with pathognomic basophilic large macrophage infiltration, which had distinctive spiculated inclusions on electron microscopy. The intracytoplasmic aluminium was positive for PAS and Morin stains. Distinctive pathology and ultrastructure suggested an association with aluminium hydroxide-containing vaccines. To avoid misdiagnosis and mistreatment, we must further investigate this uncommon condition, and pharmaceutical companies should attempt to formulate better adjuvants that do not cause such adverse effects.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Fasciite/induzido quimicamente , Miosite/induzido quimicamente , Pseudolinfoma/induzido quimicamente , Vacinação/efeitos adversos , Vacinas Virais/efeitos adversos , Pré-Escolar , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Fasciite/diagnóstico , Fasciite/imunologia , Feminino , Hepatite A/imunologia , Hepatite A/prevenção & controle , Hepatite A/virologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite B/virologia , Humanos , Lactente , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/diagnóstico , Debilidade Muscular/imunologia , Miosite/diagnóstico , Miosite/imunologia , Pseudolinfoma/diagnóstico , Pseudolinfoma/imunologia , Tela Subcutânea , Tétano/imunologia , Tétano/prevenção & controle , Tétano/virologia , Vacinas Virais/administração & dosagemAssuntos
Adjuvantes Imunológicos/efeitos adversos , Cloreto de Alumínio/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Celulite (Flegmão)/induzido quimicamente , Eosinofilia/induzido quimicamente , Celulite (Flegmão)/sangue , Celulite (Flegmão)/patologia , Criança , Eosinofilia/sangue , Eosinofilia/patologia , Feminino , Vacinas contra Hepatite B/efeitos adversos , Vacinas contra Hepatite B/química , Humanos , Masculino , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/química , Testes do Emplastro , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/químicaRESUMO
Sheep health management strategies often include the use of aluminum (Al)-containing vaccines. These products were associated with the appearance of the ovine autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), which included an array of ethological changes in the affected animals. The aim of this pilot study was to investigate cognitive and behavioral changes in sheep subjected to a protocol of repetitive inoculation with Al-containing products. Twenty-one lambs were assigned to three groups (nâ¯=â¯7 each): Control, Adjuvant-only, and Vaccine. Vaccine group was inoculated with commercial Al- hydroxide containing vaccines; Adjuvant-only group received the equivalent dose of Al only (Alhydrogel®), and Control group received Phosphate-buffered saline. Sixteen inoculations were administered within a 349-day period. Ethological changes were studied in late summer (7 inoculations) and mid-winter (16 inoculations). Animals in Vaccine and Adjuvant-only groups exhibited individual and social behavioral changes. Affiliative interactions were significantly reduced, and aggressive interactions and stereotypies increased significantly. They also exhibited a significant increase in excitatory behavior and compulsive eating. There were increased levels of stress biomarkers in these two groups. In general, changes were more pronounced in the Vaccine group than they were in the Adjuvant-only group. Some changes were already significant in summer, after seven inoculations only. This study is the first to describe behavioral changes in sheep after having received repetitive injections of Al-containing products, and may explain some of the clinical signs observed in ovine ASIA syndrome.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Doenças Autoimunes/veterinária , Cognição/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Doenças dos Ovinos/etiologia , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/fisiopatologia , Ovinos , Doenças dos Ovinos/fisiopatologia , Comportamento Social , Vacinas/administração & dosagem , Vacinas/efeitos adversos , Vacinas/químicaRESUMO
BACKGROUND: A dose-sparing inactivated polio vaccine (IPV-Al), obtained by adsorption of inactivated virus to an aluminium hydroxide adjuvant, can help mitigate global supply and the cost constraints of IPV. The objective of this trial was to demonstrate the non-inferiority of IPV-Al to standard IPV. METHODS: This phase 3, observer-blinded, randomised, controlled trial was conducted at 5 investigational sites in the Philippines. Infants not previously vaccinated with any polio vaccines were randomised to receive three IPV-Al (nâ¯=â¯502) or IPV vaccinations (nâ¯=â¯500) at 6, 10 and 14â¯weeks of age plus a booster vaccination at 9â¯months. The primary endpoint was type-specific seroconversion, defined as an antibody titre ≥4-fold higher than the estimated maternal antibody titre and a titre ≥8, one month after the primary vaccination series. RESULTS: Seroconversion rates following primary vaccination with IPV-Al (483 infants in the per-protocol analysis set) or IPV (478 infants) were: polio type 1, 97.1% versus 99.0%; type 2, 94.2% versus 99.0%; and type 3, 98.3% versus 99.6%. IPV-Al was non-inferior to IPV, as the lower 95% confidence limits of the treatment differences were above the predefined -10%-point limit: type 1, -1.85% (-3.85; -0.05); type 2, -4.75% (-7.28; -2.52); type 3, -1.24 (-2.84; 0.13). The booster effect (geometric mean titre (GMT) post-booster / GMT pre-booster) was: type 1, 63 versus 43; type 2, 54 versus 47; type 3, 112 versus 80. IPV-Al was well tolerated with a safety profile comparable to that of IPV. Serious adverse events were recorded for 29 infants (5.8%, 37 events) in the IPV-Al group compared to 28 (5.6%, 48 events) in the IPV group. CONCLUSION: Non-inferiority of IPV-Al to IPV with respect to seroconversion was confirmed and a robust booster response was demonstrated. Both vaccines had a similar safety profile. ClinicalTrials.gov identifier: NCT03032419.
Assuntos
Hidróxido de Alumínio/administração & dosagem , Imunogenicidade da Vacina , Poliomielite/epidemiologia , Poliomielite/prevenção & controle , Vacina Antipólio de Vírus Inativado/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Hidróxido de Alumínio/imunologia , Feminino , Humanos , Imunogenicidade da Vacina/efeitos dos fármacos , Imunogenicidade da Vacina/imunologia , Lactente , Masculino , Filipinas/epidemiologia , Poliomielite/imunologia , Vacina Antipólio de Vírus Inativado/efeitos adversos , Vacina Antipólio de Vírus Inativado/imunologia , Método Simples-CegoRESUMO
BACKGROUND: The burden of human papillomavirus (HPV) diseases is high in Latin America. HPV vaccines licensed from 2006 onwards offer protection against most HPV-related cancers, especially when introduced into national immunization programs. Barriers to optimal vaccine uptake are, however, lowering the impact of adolescent HPV vaccination programs. Immunization of children might overcome these barriers and be a strategy of choice for some countries. METHODS: This multicenter phase III randomized, controlled, single-blind study (NCT01627561) was conducted in Colombia, Mexico and Panama to assess safety and immunogenicity of 2-dose vaccination with AS04-adjuvanted HPV-16/18 vaccine in girls 4-6 years of age. We report safety outcomes and anti-HPV-16/18 antibody titers measured by enzyme-linked immunosorbent assay in HPV-vaccinated girls that were followed over a 36-month period. RESULTS: Over 36 months (ie, 30 months after the second vaccine dose), among 74 girls included in the HPV group, 1 serious adverse event unrelated to vaccination has been reported. No withdrawal because of (serious) adverse events has been reported. At month 36, all girls in the per-protocol-cohort were still seropositive for anti-HPV-16 and anti-HPV-18 with geometric mean concentrations of 1680.6 and 536.4 enzyme-linked immunosorbent assay units/mL, respectively. CONCLUSIONS: The AS04-adjuvanted HPV-16/18 vaccine administered according to a 2-dose schedule to girls 4-6 years of age induced a high and sustained immunologic response with an acceptable safety profile during the 30 months following vaccination.
Assuntos
Hidróxido de Alumínio/efeitos adversos , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Hidróxido de Alumínio/administração & dosagem , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Ensaios Clínicos Fase III como Assunto , Colômbia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Seguimentos , Humanos , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , México , Panamá , Vacinas contra Papillomavirus/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-CegoRESUMO
BACKGROUND: The alginate-antacid Gaviscon Double Action (Gaviscon DA) has a combined acid-neutralizing and reflux-suppressing action. Response to treatment in a symptomatic gastro-oesophageal reflux disease (GERD) population has not yet been tested in a large-scale clinical study. AIM: The aim of this study was to assess the efficacy and safety of Gaviscon DA compared with matched placebo tablets in the reduction of upper gastrointestinal symptoms in patients with GERD. PARTICIPANTS AND METHODS: In this multicentre, randomized, double-blind, placebo-controlled study, adults with GERD symptoms (N=424) received Gaviscon DA or placebo tablets for 7 days. The primary endpoint was a clinically important reduction of at least 1.5 points in the Reflux Disease Questionnaire (RDQ) GERD dimension (combined heartburn/regurgitation) between baseline and the end of the treatment. Secondary endpoints included the change in RDQ score from baseline for individual RDQ dimensions and Overall Treatment Evaluation. RESULTS: A significantly greater proportion of patients treated with Gaviscon DA met the primary endpoint compared with placebo (47.8 vs. 33.2%, respectively, P=0.0031; odds ratio: 1.85, 95% confidence interval: 1.23-2.78). A significant treatment effect was also observed for heartburn, regurgitation and dyspepsia individually. Patients in the Gaviscon DA group rated their overall treatment response greater than patients in the placebo group [mean Overall Treatment Evaluation (SD): 3.2 (3.08) vs. 2.2 (3.34); P<0.001]. No notable differences in the incidence of adverse events were observed between treatments. CONCLUSION: The alginate-antacid combination, Gaviscon DA, is an effective and well-tolerated treatment to reduce reflux symptoms and associated dyspepsia in symptomatic GERD patients.
Assuntos
Alginatos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , Antiácidos/administração & dosagem , Refluxo Gastroesofágico/tratamento farmacológico , Azia/tratamento farmacológico , Ácido Silícico/administração & dosagem , Bicarbonato de Sódio/administração & dosagem , Administração Oral , Adulto , Idoso , Alginatos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Antiácidos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Europa (Continente) , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Azia/diagnóstico , Azia/fisiopatologia , Humanos , Masculino , Mastigação , Pessoa de Meia-Idade , Satisfação do Paciente , Indução de Remissão , Ácido Silícico/efeitos adversos , Bicarbonato de Sódio/efeitos adversos , Inquéritos e Questionários , Comprimidos , Fatores de Tempo , Resultado do TratamentoRESUMO
A 4-year-old boy presented with erythematous vesicular plaques, ulceration, edema, and pruritus on the left foot and ankle 10 days after receiving the tetanus, diphtheria, pertussis, and polio; measles, mumps, rubella, and varicella; and hepatitis A/B vaccines. Biopsy showed eosinophilic infiltrates and flame figures, suggesting Wells syndrome. Patch testing showed a 1+ reaction to neomycin and aluminum hydroxide, with a recall reaction of Wells syndrome of the feet bilaterally. We report a rare case of pediatric Wells syndrome triggered by nonthimerosal vaccine components confirmed by patch testing.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/efeitos adversos , Antibacterianos/efeitos adversos , Celulite (Flegmão)/diagnóstico , Eosinofilia/diagnóstico , Neomicina/efeitos adversos , Vacinação/efeitos adversos , Celulite (Flegmão)/etiologia , Pré-Escolar , Eosinofilia/etiologia , Glucocorticoides/uso terapêutico , Humanos , Masculino , Testes do Emplastro/métodos , Pele/patologiaRESUMO
Approximately 5% of the healthy adult population respond inadequately to the commercial recombinant hepatitis B vaccines. As the recombinant vaccines all have an aluminium-based adjuvant, we tried to enhance the immune response by adding a cytokine-based adjuvant. This new adjuvant AI20, containing 20 µg recombinant human IL-2 attached to 20 µg aluminium hydroxide, was added to HBVaxPro©-10 µg (HBAI20). In a double-blind randomized controlled trial (RCT), 24 naïve subjects were randomized to receive either HBAI20 or commercial HBVaxPro©-10 µg vaccine. In an open-label study, 10 nonresponders received HBAI20 vaccine. All participants received 3 vaccinations (0, 1 and 6 months). In the RCT, the occurrence of any adverse events or severe events was similar between the trial arms. At month 7, all naïve participants were seroprotected; moreover, 92% in the HBAI20 group had protective antibodies 10 days after the second vaccination vs 58% in the HBVaxPro©-10 µg group, P = .16. In the open-label study, no serious adverse events were noted. The HBAI20 vaccine was able to elicit protective anti-HBs titres in 90% of nonresponders, 1 month after the third vaccination. According to these results, the new HBAI20 vaccine seems safe, well-tolerated and may promote more rapid protection against hepatitis B infection.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Vacinas contra Hepatite B/efeitos adversos , Vacinas contra Hepatite B/imunologia , Hepatite B/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Vacinas contra Hepatite B/administração & dosagem , Humanos , Esquemas de Imunização , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The burden of cervical cancer caused by human papillomavirus (HPV) is high in Latin America. The suboptimal HPV vaccination coverage in adolescents could be improved by pediatric immunization. HPV vaccination has not yet been reported in girls <9 years of age. METHODS: This ongoing phase III, controlled, randomized, single-blind, multicenter study conducted in Colombia, Mexico and Panama (NCT01627561) evaluated the safety and immunogenicity of AS04-HPV-16/18 vaccine in 4-6-year-old girls. Healthy girls (randomized 1:1) received either 2 doses of AS04-HPV-16/18 vaccine (HPV group, N=74) or 1 dose of each measles-mumps-rubella and diphtheria-tetanus-acellular-pertussis vaccines (control group, N=74) 6 months apart. We report the safety and serum anti-HPV-16 and anti-HPV-18 antibodies (measured by enzyme-linked immunosorbent assay) up to 6 months postvaccination, that is, month (M) 12. RESULTS: Injection site pain was the most frequently reported solicited local symptom in HPV vaccinees. The incidence of other solicited and unsolicited symptoms after each vaccination was similar between the HPV and control group. Until M12, 1 girl in the HPV group and 2 in the control group reported serious adverse events; all serious adverse events were assessed as unrelated to study vaccines. No potential immune-mediated diseases were identified. All girls seroconverted for both antigens after 2 doses of AS04-HPV-16/18. In initially seronegative girls, anti-HPV-16 geometric mean concentrations were 20080.0 enzyme-linked immunosorbent assay units (EU)/mL at M7 and 3246.5 EU/mL at M12; anti-HPV-18 geometric mean concentrations were 10621.8 EU/mL at M7 and 1216.6 EU/mL at M12. CONCLUSIONS: Two-dose vaccination with AS04-HPV-16/18 was well tolerated and induced adequate antibody responses in 4-6-year-old girls.
Assuntos
Hidróxido de Alumínio/efeitos adversos , Hidróxido de Alumínio/imunologia , Lipídeo A/análogos & derivados , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Hidróxido de Alumínio/administração & dosagem , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Colômbia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Voluntários Saudáveis , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Esquemas de Imunização , Incidência , Lipídeo A/administração & dosagem , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , México , Panamá , Vacinas contra Papillomavirus/administração & dosagem , Método Simples-CegoRESUMO
Patients with macrophagic myofasciitis (MMF) present with diffuse arthromyalgias, chronic fatigue, and cognitive disorder. Representative features of MMF-associated cognitive dysfunction include attentional dysfunction, dysexecutive syndrome, visual memory deficit and left ear extinction. Our study aims to reevaluate the neuropsychological profile of MMF. 105 unselected consecutive MMF patients were subjected to a neuropsychological battery of screen short term and long-term memory, executive functions, attentional abilities, instrumental functions and dichotic listening. From these results, patients were classified in four different groups: Subsymptomatic patients (n=41) with performance above pathological threshold (-1.65 SD) in all tests; Fronto-subcortical patients (n=31) who showed pathological results at executive functions and selective attention tests; Papezian patients (n=24) who showed pathological results in storage, recognition and consolidation functions for episodic verbal memory, in addition to fronto-subcortical dysfunction; and Extinction patients (n=9) who had a left ear extinction at dichotic listening test in association to fronto-subcortical and papezian dysfunction. In addition, inter-test analysis showed that patients with apparently normal cognitive functions (Subsymptomatic group) performed significantly worse to attention tests compared to others. In conclusion, our study shows that (i) most patients have specific cognitive deficits; (ii) all patients with cognitive deficit have impairment of executive functions and selective attention; (iii) patients without measurable cognitive deficits display significant weakness in attention; (iv) episodic memory impairment affects verbal, but not visual, memory; (v) none of the patients show an instrumental dysfunction.