RESUMO
Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, entails significant mortality and morbidity. Disease incidence is highest in infants <1 year and young children globally. In Europe, N. meningitidis serogroup B is responsible for over 50% of overall IMD cases, whereas the majority of IMD cases in Latin America is caused either by serogroup B or C. The development of an effective vaccine against serogroup B has challenged the researchers for over half a century. Serogroup B capsular polysaccharide was an inappropriate vaccine antigen, and the success of outer membrane vesicle (OMV) vaccines was restricted to homologous bacterial strains. Reverse vaccinology led to the development of a 4-component meningococcal vaccine including three novel antigens, and OMVs (4CMenB). Each vaccine component has a different target. 4CMenB has been authorised based on its immunogenicity and safety data because the low disease incidence precluded formal clinical efficacy studies. Human serum bactericidal antibody (hSBA) assay tests functional antibodies in the serum of vaccinated individuals (i.e. the vaccine immunogenicity), and is the accepted correlate of protection. Vaccine strain coverage has been assessed both through hSBA assays and a more conservative method named Meningococcal Antigen Typing System (MATS). Effectiveness data of 4CMenB have been collected in the field since 2013. The vaccine proved effective in outbreak control in North America, and recent data from the introduction of the vaccine in the United Kingdom infant national immunisation programme reveal a vaccine effectiveness of 82.9% for the first two doses, with an acceptable safety profile.
Assuntos
Genoma Bacteriano/genética , Vacinas Meningocócicas/uso terapêutico , Neisseria meningitidis Sorogrupo B/genética , Neisseria meningitidis Sorogrupo B/imunologia , Humanos , Meningite Meningocócica/imunologia , Meningite Meningocócica/prevenção & controle , Infecções Meningocócicas/prevenção & controleRESUMO
Tick-borne encephalitis (TBE) is caused by an arthropod-borne virus, belonging to the family of Flaviviridae. In case of disease, which can lead to neurological sequelae or even fatal outcomes, only symptomatic treatment is available. TBE can be prevented by vaccination. Various primary immunization schedules have been developed. To identify the most suitable schedule, the present randomised, controlled study was designed to provide data on the immune response elicited by four different immunization schedules obtained by ELISA and by neutralization test (NT). A total of 398 healthy subjects aged > or =12 years were randomised to vaccination according to either the rapid schedule (Group R, vaccination on days 0, 7 and 21), the conventional schedule (Group C, vaccination on days 0, 28 and 300), the modified conventional schedule (Group M, vaccination on days 0, 21 and 300) or the accelerated conventional schedule (Group A, vaccination on days 0, 14 and 300). Within 3 weeks (i.e. by day 21) antibody levels were higher in Group R and Group A than in Group M and Group C. Group R and Group C both had higher titres on days 42, 180 and 300, than Group A and Group M. The rapid schedule thus combines the advantages of fast protection and of high titres over the observation period of 300 days.
Assuntos
Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/prevenção & controle , Esquemas de Imunização , Vacinas Virais/administração & dosagem , Adolescente , Adulto , Criança , Encefalite Transmitida por Carrapatos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologiaRESUMO
The influence of steroids on the antibody response to a MF59-adjuvanted influenza vaccine in elderly COPD patients has not been studied previously. In the influenza season 2001/02 (October-February) elderly COPD patients were recruited at 14 doctor's offices and our 250-bed hospital. Patients were stratified into three groups according to current treatment regimen: (a) > 10 mg of prednisolone/day (SS); (b) inhaled steroids (IS); (c) no steroid treatment (control group, CG). All patients were vaccinated with the MF59-adjuvanted influenza vaccine. Antibodies against the influenza strains A/H1N1, A/H3N2, and B were measured at baseline, 4 and 24 weeks after vaccination by hemagglutination inhibition (HI) assay. One-hundred and sixty-two patients completed the study (CG n = 42; IS n = 87; SS n = 33). Mean age was 71.3 years (range 60-89). Twenty-one percent of all patients reported local reactions; no serious adverse events were observed. Four weeks after vaccination, mean geometric HI titres (GMT) for A/H1N1, A/H3N and B increased significantly in all groups (p < or = 0.05). After 24 weeks, GMTs to A/H1N1 and A/H3N2 returned to baseline, while GMTs to type B remained significantly higher than baseline in all groups. Significant differences between the groups as regards GMTs, seroconversion (56-89%) or seroprotection rates (64-93%) were not observed. Systemic steroids did not influence the antibody response towards the MF59-adjuvanted influenza vaccine. We found that the strains included in the vaccine showed varying long-term immunogenicity.
Assuntos
Adjuvantes Imunológicos/farmacologia , Corticosteroides/farmacologia , Vacinas contra Influenza/imunologia , Polissorbatos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Esqualeno/farmacologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/imunologia , VacinaçãoRESUMO
This study investigated the immune response and safety in 430 adults, when boosted more than 3 years after primary or booster TBE immunisation as measured by neutralization test (NT) and ELISA. Tested by NT, the post-booster day 21 geometric mean titer (GMT) was 331 and 142 for the 18-49 and > or =50 years old, respectively. The post-/pre-booster geometric mean titer ratio (GMR) was 2.29 for the 18-49 years old and 3.21 for the > or =50 years old. An at least four-fold increase of neutralizing TBE antibodies was observed in only 26 and 38% of subjects aged 18-49 and > or =50 years, respectively. The booster effect in subjects with only the primary vaccination course prior to study entry clearly depended on the time elapsed since last TBE vaccination with an estimated annual decline rate of 15%. In subjects with at least one additional booster vaccination virtually no antibody decline was observed. This study clearly indicates that (1) adults may be effectively and safely boosted with a different TBE vaccine and (2) following four immunisations protective antibodies can be detected far beyond a period of 3 years, thus, strongly supporting the reconsideration of currently recommended booster intervals.
Assuntos
Encefalite Transmitida por Carrapatos/prevenção & controle , Imunização Secundária , Vacinas Virais/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunização Secundária/efeitos adversos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Fatores de Tempo , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversosAssuntos
Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/prevenção & controle , Vacinas Virais , Adolescente , Adulto , Fatores Etários , Química Farmacêutica , Criança , Encefalite Transmitida por Carrapatos/imunologia , Alemanha , Humanos , Segurança , Fatores de Tempo , Vacinação , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Vacinas Virais/química , Vacinas Virais/imunologiaRESUMO
A total of 3,559 children aged 1-11 years were enrolled in two clinical studies to evaluate immunogenicity and safety of a new pediatric tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer. Immunogenicity was evaluated in the rapid immunization schedule (Days 0, 7, and 21) from sera collected at baseline and on Day 42 post-immunization by in vitro TBE virus neutralization test. All subjects analyzed achieved levels of TBE antibodies to fulfil the definition of seroconversion or a four-fold increase in antibody titres from baseline. The frequency of solicited post-immunization reactions ranged from 1 to 32% for reported local reactions and from 1 to 14% for systemic reactions. Overall, this can be regarded as expected for an inactivated, aluminium-adjuvanted, TBE vaccine. There was no indication for any new safety issues. An acceptably low number of febrile reactions above 38 degrees C with the highest frequency after first immunization (i.e. 15% and 5% in children aged 1-2 and 3-11 years, respectively), mainly below 39 degrees C, was reported. The results of both studies clearly show that TBE vaccination with this new TBE vaccine formulation can be achieved with a high degree of safety in children from 1 to 11 years of age.
Assuntos
Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/prevenção & controle , Vacinas Virais/imunologia , Anticorpos Antivirais/análise , Anticorpos Antivirais/biossíntese , Química Farmacêutica , Criança , Pré-Escolar , Encefalite Transmitida por Carrapatos/imunologia , Excipientes , Feminino , Humanos , Lactente , Masculino , Método Simples-Cego , Vacinas Virais/efeitos adversos , Vacinas Virais/químicaRESUMO
BACKGROUND: The aim of this study was to investigate the safety of the split-product influenza vaccine Begrivac(R), containing the recommended virus strains for the influenza season 1998/99. PATIENTS: Eighty-three children aged 6 months - 12 years were enrolled in the study. METHODS: Adverse events (AEs) were reported for up to 21 days after the last immunization. A hemagglutination assay was performed of blood samples taken before and after vaccination. RESULTS: Only mild (40 %) to moderate and mainly local reactions (redness, swelling, induration and pain) were reported. Seroprotection after the first immunisation was reached against influenza strain A (H1N1) in 75 % of the vaccinees, against strain A (H3N2) in 83 % and against strain B in 33 %. After the second immunisation, 96 % of the population achieved seroprotection against A (H1N1), 100 % against A (H3N2) and 96 % against B. CONCLUSIONS: The influenza split vaccine is safe and effective in children.
Assuntos
Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Lactente , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Masculino , Estudos ProspectivosRESUMO
The aim of this study was to evaluate the effectiveness of the influenza vaccine used at the Proelmed Medical Center, Poland during the influenza season 1998-1999. The study randomised patients attending the Proelmed Medical Center, Poland to receive influenza vaccination or not. Volunteers were monitored for the following 6 months by interviews at which systemic and local symptoms were recorded. 193 volunteers were randomised to receive influenza vaccine and 206 to the control group. In the vaccinated group, 7 cases (3.7%) of influenza were recorded, compared to 59 cases (28.6%) in the unvaccinated group. Respiratory disease other than influenza occurred in 29.5% of the vaccinated group and 34.5% of the unvaccinated group. Vaccinated patients had a total of 62 days off sick due to influenza, compared to 467 days for the unvaccinated patients. No unexpected adverse events were reported. The influenza vaccine used is highly efficacious in protecting against influenza infection leading to absenteeism from work, and has a good safety profile.
Assuntos
Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Qualidade de Produtos para o Consumidor , Tolerância a Medicamentos , Humanos , Influenza Humana/epidemiologia , Polônia/epidemiologia , Estações do AnoRESUMO
UNLABELLED: BACKGROUND, METHOD: Given the worldwide distribution of infection and the mobility of large parts of the population immunizations against tetanus, diphtheria and polio remain a challenge. This is especially true for adolescents and adults since antibodies tend to wane once immunized children enter adolescence and adulthood. A new combination vaccine against tetanus, diphtheria and polio (Td-IPV) for booster immunizations was subjected to a randomized, controlled and single-blind trial. Non-inferiority had to be demonstrated with regard to efficacy (immunogenicity) and safety in comparison to separate Td and IPV injections. RESULTS: Almost 500 subjects from community practices and occupational/immunization clinics took part. Antibody titres were equivalent for all antigens. Local and systemic reactions were equal or even less marked in the intervention group. CONCLUSION: From a public health perspective the new vaccine can make an important contribution to ensure adequate protection against tetanus, diphtheria and polio in adolescent and adult populations.
Assuntos
Toxoide Diftérico/imunologia , Difteria/prevenção & controle , Poliomielite/prevenção & controle , Vacina Antipólio de Vírus Inativado/imunologia , Toxoide Tetânico/imunologia , Tétano/prevenção & controle , Adolescente , Adulto , Idoso , Formação de Anticorpos/imunologia , Difteria/imunologia , Toxoide Diftérico/administração & dosagem , Toxoide Diftérico/efeitos adversos , Feminino , Humanos , Imunização Secundária , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Poliomielite/imunologia , Vacina Antipólio de Vírus Inativado/administração & dosagem , Vacina Antipólio de Vírus Inativado/efeitos adversos , Método Simples-Cego , Tétano/imunologia , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/efeitos adversos , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/efeitos adversos , Vacinas Combinadas/imunologiaRESUMO
Although the introduction of tissue culture vaccines for rabies has dramatically improved the immunogenicity and safety of rabies vaccines, they are often prohibitively expensive for developing countries. To examine whether smaller doses of these vaccines could be used, we tested the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) on 211 patients in Thailand with World Health Organization (WHO) category II and III exposures to rabies. The patients presented at two Thai hospitals and were randomized into three groups. Patients in Group 1 received 0.1 ml PCECV intradermally at two sites on days 0, 3, 7, and at one site on days 30 and 90. Group 2 was treated similarly, except that purified Vero cell rabies vaccine (PVRV) was used instead of PCECV. Group 3 received 1.0 ml PCECV intramuscularly on days 0, 3, 7, 14, 30 and 90. After 0, 3, 7, 14, 30 and 90 days serum was collected from the subjects and the geometric mean titres (GMTs) of rabies virus neutralizing antibody determined. After 14 days the GMT of 59 patients vaccinated intradermally with PCECV was equivalent to that of patients who received PVRV. Adverse reactions were more frequent in patients who received vaccines intradermally, indicating the reactions were associated with the route of injection, rather than the vaccine per se. We conclude that PCECV is a safe and highly immunogenic vaccine for postexposure rabies vaccination when administered intradermally in 0.1-ml doses using the two-site method ("2,2,2,0,1,1") recommended by WHO.
Assuntos
Anticorpos Antivirais/biossíntese , Imunização Secundária , Vacina Antirrábica/imunologia , Raiva/imunologia , Raiva/prevenção & controle , Adolescente , Adulto , Idoso , Animais , Embrião de Galinha , Criança , Pré-Escolar , Chlorocebus aethiops , Esquema de Medicação , Feminino , Humanos , Injeções Intradérmicas , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Vacina Antirrábica/administração & dosagem , Vacina Antirrábica/efeitos adversos , Tailândia , Células VeroRESUMO
OBJECTIVE: To investigate the immunogenicity of and tolerance towards the preservative-free inactivated influenza vaccine Begrivac. METHODS: In this prospective, single-centre, non-controlled study, efficacy was evaluated by the change in influenza antibody titre from baseline to 21 days following vaccination. The safety variables included post-injection reactions and adverse events. Blood samples were taken on day 21 and the antibody titre assayed by haemagglutination inhibition test. RESULTS: All three of the European efficacy requirements for influenza vaccines are satisfied by the new preservative-free vaccine described in this report. The mean geometric increase in titre and the proportion of vaccination responders were greater in patients of the adult group than in the elderly. Thus for strain A/Beijing/262/95 66% of subjects seroconverted and 28% showed a significant increase in antibody titre (total 94%), compared to a total of 45 patients (76%) in the elderly group. For strain A/Sydney/5/97 the corresponding figures were total 55 (90%) adult and 47 (80%) elderly, and for B/Beijing/184/93 46 (75%) adult and 31 (53%) elderly. Sixty four subjects (53%) reported adverse events, mainly local reactions at the injection site such as pain, erythema and induration, and systemic reactions such as headache and fatigue. CONCLUSIONS: The absence of preservative in this novel vaccine preparation does not have any detectable impact on its efficacy or safety and tolerability profile.
Assuntos
Vacinas contra Influenza/farmacologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/biossíntese , Tolerância a Medicamentos , Eritema/etiologia , Feminino , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Conservantes Farmacêuticos/administração & dosagem , Estudos Prospectivos , Segurança , Timerosal/administração & dosagem , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/farmacologiaRESUMO
The equivalence and interchangeability of Purified Chick Embryo Cell Culture Rabies Vaccine (PCECV) to Human Diploid Cell Culture Rabies Vaccine (HDCV) and the immunogenicity of a reduced post-exposure regimen with PCECV was investigated. Statistical analyses revealed no difference (P=0.05) between the geometric mean titers (GMT) on day 49 of subjects that received PCECV or HDCV. In Year 2, subjects were boosted with one or two dose(s) of PCECV. No significant difference (P=0.05) was detected between the GMT of the two groups on days 7 and 365 post-booster. Subjects that received HDCV initially developed an adequate anamnestic response to PCECV. On day 21 post-booster, the GMT of subjects that received two boosters was higher (151.6 IU/ml) than those that received one booster (120.9 IU/ml). However, this difference may not be clinically significant.
Assuntos
Vacina Antirrábica/administração & dosagem , Adulto , Animais , Células Cultivadas , Embrião de Galinha , Diploide , Feminino , Humanos , Esquemas de Imunização , Imunização Secundária , Masculino , Vacina Antirrábica/imunologiaRESUMO
In a prospective, controlled, randomized, multicenter study the immunogenicity of a single (day 0) and two (day 0, 28) booster vaccination against diphtheria were compared in subjects who had received their last diphtheria vaccination more than 10 years ago. Both short-term and long-term immunogenicity was assessed by determining diphtheria antitoxin levels four weeks after vaccination and after one and two years. 102 subjects received the first booster vaccination, and 83 were vaccinated twice. Prior to the first vaccination 27% of the subjects had a diphtheria antitoxin level below 0.01 I.U./ml; after the first booster only 5% were unprotected. The second booster did not show a significant effect, however, in 1 of the 5 subjects who were still unprotected after the first booster the second elicited an antitoxin level of more than 0.01 I.U./ml. After one and two years 7% and 8% of the subjects had diphtheria antitoxin level below 0.01 I.U./ml. A serological effect of a second booster vaccination four weeks after the first one could not be demonstrated neither after one nor after two years.
Assuntos
Antitoxina Diftérica/sangue , Toxoide Diftérico/imunologia , Difteria/prevenção & controle , Imunização Secundária , Adolescente , Adulto , Difteria/imunologia , Toxoide Diftérico/administração & dosagem , Feminino , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosAssuntos
Vacina contra Difteria e Tétano/administração & dosagem , Difteria/prevenção & controle , Poliomielite/prevenção & controle , Vacinas contra Poliovirus/administração & dosagem , Tétano/prevenção & controle , Adolescente , Adulto , Formação de Anticorpos/imunologia , Criança , Difteria/etiologia , Vacina contra Difteria e Tétano/imunologia , Humanos , Programas de Imunização , Poliomielite/imunologia , Vacinas contra Poliovirus/imunologia , Tétano/imunologia , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologiaRESUMO
In a prospective, controlled, randomized, multicenter study the immunogenicity and tolerance of a single vaccination (day 0) and two (day 0, 28) booster vaccinations against diphtheria were compared in subjects who had received their last diphtheria vaccination more than 10 years ago. 415 subjects received the first booster vaccination, and 203 were vaccinated twice. The geometric mean diphtheria antitoxin concentration after the first booster (day 28) was 2.354 I.U./ml, and after the second booster (day 56) 2.238 I.U./ml. Prior to the first vaccination 48.9% of the subjects had a diphtheria antitoxin level below 0.1 I.U./m; after the first and second boosters 95.4% and 97.5% of subjects, respectively, showed a level of at least 0.1 I.U./ml. A clear serological effect of a second booster 4 weeks after the first one could not be demonstrated.
Assuntos
Toxoide Diftérico/administração & dosagem , Difteria/prevenção & controle , Imunização Secundária/tendências , Adolescente , Adulto , Difteria/imunologia , Toxoide Diftérico/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Pulmonary emphysema is very uncommon in children in the first decade of life. The few cases documented in the literature were all due to alpha1-antitrypsin deficiency. We present the case of a 6-year-old white boy with chronic cough and dyspnea on exertion. Lung biopsy showed panacinar type emphysema with patent airways and diffuse hyperplasia of pulmonary neuroendocrine cells revealed after immunostaining for bombesin, a peptide produced by these cells. We speculate that idiopathic diffuse hyperplasia of bombesin-producing pulmonary neuroendocrine cells may contribute to the pathogenesis of unusual COPD in childhood.
Assuntos
Pulmão/patologia , Sistemas Neurossecretores/patologia , Enfisema Pulmonar/patologia , Bombesina/análise , Criança , Tosse/etiologia , Dispneia/etiologia , Humanos , Hiperplasia , Pulmão/química , Masculino , Sistemas Neurossecretores/química , Enfisema Pulmonar/complicações , Enfisema Pulmonar/etiologia , alfa 1-Antitripsina/análiseRESUMO
Salivary SIgA antibodies against RS virus were studied in 105 children during the first year of life. The infants were divided into groups according to their risk of atopy. At birth 13 neonates showed measurable amounts of SIgA to RS virus. In another 26 children specific antibodies were detected but in concentrations too low for quantitative analysis. During the first year of life this increased to 29 antibody-positive samples with measurable amounts of antibody and 39 with concentrations too low for quantitative determination. At this time 8 children of the high risk group had developed symptoms of allergy. None of these children had measurable amounts of SIgA anti-RSV in their saliva. In comparison, 10 of the remaining 26 high risk infants without symptoms of allergy did have such antibodies. Atopic infants had significantly more respiratory infections during the first year of life than nonatopic infants. The avidity of SIgA anti-RSV in neonatal samples was significantly higher than avidity determined in breast milk SIgA but comparable to the avidity of serum IgG. During the first year of life a continuing decrease of salivary SIgA avidity was observed.
Assuntos
Anticorpos Antivirais/análise , Hipersensibilidade Imediata/imunologia , Imunoglobulina A Secretora/análise , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/imunologia , Afinidade de Anticorpos , Feminino , Sangue Fetal/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Masculino , Infecções Respiratórias/microbiologia , Saliva/imunologiaAssuntos
Anticorpos Antivirais/análise , Bovinos/imunologia , Imunoglobulina A Secretora/análise , Imunoglobulina M/análise , Proteínas do Leite/imunologia , Leite Humano/imunologia , Vírus Sinciciais Respiratórios/imunologia , Saliva/imunologia , Animais , Humanos , Hipersensibilidade Imediata/imunologia , Lactente , Recém-NascidoRESUMO
As part of an epidemiological study that aims to characterize chemically the mutation(s) in transthyretin (TTR) related to familial amyloidotic polyneuropathy (FAP) of different ethnic origins, studies were carried out on TTR from two FAP kindreds of Italian origin. Two different criteria were employed in the characterization of TTR from these kindreds: (1) immunoblotting of cyanogen bromide fragments for screening of TTR(Met30) and (2) isoelectric focusing. TTR(Met30) was not detected but other substitutions were demonstrated using isoelectric focusing techniques. One of the variants found is a basic TTR variant. The substitutions occurring in the variant TTRs of these two kindreds are not known and are presently under study.