RESUMO
BACKGROUND: RotaShield, a vaccine intended to prevent severe rotavirus diarrhea, was withdrawn in July 1999, 9 months after it became available in the United States, because of a temporal association with intussusception events that occurred in vaccinated infants. We explore here the effect of age on the risk of intussusception. METHODS: We reanalyzed a case-control database of the Centers for Disease Control and Prevention by use of a 21-day window, to define vaccine-associated events. We obtained data on vaccine use from the National Immunization Survey and estimated the age-stratified background incidence of intussusception by use of Healthcare Cost and Utilization Project data. We combined these data to estimate how absolute risk varies with age and to model the projected population-attributable risk associated with 3 different vaccination schedules. RESULTS: We found that the incidence of intussusception associated with the first dose of vaccine increased with age. Infants > or = 90 days old accounted for 80% of cases of intussusception associated with a first dose but had received only 38% of first doses. Modeling of the recommended schedule of vaccination at ages 2, 4, and 6 months projected 1 intussusception event/11,000-16,000 vaccine recipients; modeling of a 2-dose schedule beginning in the neonatal period projected 1 intussusception event/38,000-59,000 vaccine recipients. CONCLUSIONS: The practice of initiating immunization after age 90 days, which we call "catch-up" vaccination, contributed disproportionately to the occurrence of intussusception associated with the use of RotaShield. A fully implemented 2-dose vaccination schedule begun during the neonatal period would lead to, at most, a 7% increase in the incidence of intussusception above the annual background incidence.
Assuntos
Intussuscepção/etiologia , Vírus Reordenados , Vacinas contra Rotavirus/efeitos adversos , Vacinação , Fatores Etários , Estudos de Casos e Controles , Pré-Escolar , Esquema de Medicação , Humanos , Incidência , Lactente , Recém-Nascido , Intussuscepção/epidemiologia , Fatores de Risco , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/genética , Estados Unidos/epidemiologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/genéticaRESUMO
A rapid and reliable method for the identification of five clinically relevant G genotypes (G1 to G4 and G9) of human rotaviruses based on oligonucleotide microarray hybridization has been developed. The genotype-specific oligonucleotides immobilized on the surface of glass slides were selected to bind to the multiple target regions within the VP7 gene that are highly conserved among individual rotavirus genotypes. Rotavirus cDNA was amplified in a PCR with primers common to all group A rotaviruses. A second round of nested PCR amplification was performed in the presence of indodicarbocyanine-dCTP and another pair of degenerate primers also broadly specific for all genotypes. The use of one primer containing 5'-biotin allowed us to prepare fluorescently labeled single-stranded hybridization probe by binding of another strand to magnetic beads. The identification of rotavirus genotype was based on hybridization with several individual genotype-specific oligonucleotides. This approach combines the high sensitivity of PCR with the selectivity of DNA-DNA hybridization. The specificity of oligonucleotide microchip hybridization was evaluated by testing 20 coded rotavirus isolates from different geographic areas for which genotypes were previously determined by conventional methods. Analysis of the coded specimens showed that this microarray-based method is capable of unambiguous identification of all rotavirus strains. Because of the presence of random mutations, each individual virus isolate produced a unique hybridization pattern capable of distinguishing different isolates of the same genotype and, therefore, subgenotype differentiation. This strain information indicates one of several advantages that microarray technology has over conventional PCR techniques.
Assuntos
Antígenos Virais , Proteínas do Capsídeo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Rotavirus/genética , Rotavirus/isolamento & purificação , Sequência de Bases , Capsídeo/genética , Primers do DNA/genética , DNA Viral/genética , DNA Viral/isolamento & purificação , Desenho de Fármacos , Genes Virais , Genótipo , Humanos , Técnicas de Sonda Molecular , Mutação , Sondas de Oligonucleotídeos/genética , Rotavirus/classificação , Especificidade da Espécie , Virologia/métodosRESUMO
The safety and immunogenicity of an orally administered, live rotavirus vaccine comprised of four strains, each with a titer of 10(5.3) or 10(5.8) pfu, and each having 10 genes from the UK bovine strain and the VP7 gene from human rotavirus serotype 1, 2, 3, or 4, were evaluated in adults, young children and infants in randomized, double-blind phase 1 trials. Three doses of rotavirus vaccine or placebo given with childhood immunizations to infants at 2, 4, and 6 months of age were well tolerated and did not inhibit antibody responses to childhood vaccines which included DTP, Hib, hepatitis B and OPV. Serum rotavirus antibody responses were detected in 12 of 20 infants after 1 dose, and in 19/19 of the vaccinees after three doses. Neutralizing antibody responses were detected more often against the bovine rotavirus UK strain (95%) than to human rotavirus VP7 serotypes 1 (37%), 2 (32%), 3 (32%) or 4 (32%). The efficacy of this quadrivalent rotavirus vaccine needs to be evaluated further.
Assuntos
Proteínas do Capsídeo , Vacinas contra Rotavirus/imunologia , Rotavirus/imunologia , Adolescente , Adulto , Animais , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Cápsulas Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Bordetella pertussis/imunologia , Capsídeo/imunologia , Bovinos , Criança , Pré-Escolar , Corynebacterium diphtheriae/imunologia , Diarreia Infantil/microbiologia , Diarreia Infantil/virologia , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Fezes/virologia , Vacinas Anti-Haemophilus/administração & dosagem , Haemophilus influenzae/imunologia , Humanos , Imunoglobulina A/biossíntese , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Vacina Antipólio Oral/administração & dosagem , Polissacarídeos Bacterianos/administração & dosagem , Rotavirus/classificação , Rotavirus/isolamento & purificação , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/efeitos adversos , Segurança , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
The importance of rotaviruses (RVs) as the single most important cause of severe diarrhoea of infants and young children is well recognized. At NIH, we developed a quadrivalent (tetravalent [TV]) vaccine to protect against the four epidemiologically important RV serotypes. It is comprised of live attenuated rhesus RV (RRV), a VP7 serotype G3 strain (the 'Jennerian' approach), and three reassortant RVs, each containing 10 RRV genes and one human RV gene that codes for the major outer protein, VP7, that determines serotype G1, G2 or G4 specificity (the 'modified Jennerian' approach). The vaccine was safe and effective against severe diarrhoea in a major prelicensure collaborative effort of phase III trials. In February 1998 and again in June 1998, the Advisory Committee on Immunization Practices (ACIP) recommended routine immunization with three oral doses at 2, 4 and 6 months of age. The tetravalent vaccine (RotaShield) was licensed in the USA by the FDA in August 1998. In July 1999, after about 1.5 million doses had been given, the CDC recommended suspending administration of the vaccine because post-licensure surveillance of adverse events had suggested an association with intussusception. After further investigation by CDC, in October 1999, the ACIP withdrew its recommendation concluding that '...intussusception occurs with significantly increased frequency in the first 1-2 weeks after vaccination with RRV-TV, particularly following the first dose'. The implications of these developments from a practical, epidemiological, analytical and ethical perspective are discussed.
Assuntos
Diarreia/imunologia , Diarreia/prevenção & controle , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia , Criança , Contraindicações , Países em Desenvolvimento , Diarreia/virologia , Ética Clínica , Humanos , Lactente , Licenciamento , Risco , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/administração & dosagem , Estados Unidos , Vacinação/efeitos adversos , Vacinação/normas , Vacinação/tendências , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaAssuntos
Anticorpos Antivirais/sangue , Hepatite Viral Humana/história , Citomegalovirus/imunologia , Anticorpos Anti-Hepatite A , Anticorpos Anti-Hepatite/sangue , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Hepatite Viral Humana/sangue , Hepatite Viral Humana/virologia , Herpesvirus Humano 4/imunologia , História do Século XX , Humanos , Microscopia Imunoeletrônica , Reação TransfusionalRESUMO
This report describes the results of additional analyses of the trial carried out with the rhesus rotavirus-based quadrivalent vaccine in Venezuela. In the present study, we re-examined the data from this previous rotavirus vaccine trial to assess the statistical interaction between vaccine efficacy and (i) the duration of efficacy into the second year of life, (ii) socioeconomic conditions, and (iii) rotavirus seasonality. We found that among Venezuelan children, the rotavirus vaccine confers protection against severe diarrhea during the first 2 years of life independently of socioeconomic conditions and seasonality.
Assuntos
Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Rotavirus/imunologia , Vacinas Virais/farmacologia , Fatores Etários , Animais , Diarreia/epidemiologia , Diarreia/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Lactente , Macaca mulatta , Masculino , Estações do Ano , Fatores Socioeconômicos , Venezuela/epidemiologiaRESUMO
The development and implementation of safe and effective vaccines to prevent the enormous health burden of rotavirus-associated disease is a global public health goal. Human rotaviruses, the major aetiological agents of severe infantile diarrhoea worldwide, display surprisingly diverse and complex serotypic specificities. Ten VP7 serotypes and 7 VP4 serotypes have so far been detected. An increasing number of observations, obtained from analyses of (i) natural rotavirus infections in infants and young children, (ii) experimental rotavirus infections in laboratory animals, and (iii) extensive rotavirus vaccine field trials performed in different populations of various parts of the world, appears to support the concept that serotype-specific antibodies to rotaviruses play an important role in protection against rotavirus-associated illnesses. Thus, the first licensed rotavirus vaccine (RRV-based quadrivalent vaccine) was designed to cover the epidemiologically important VP7 serotype 1, 2, 3, and 4.
Assuntos
Diarreia Infantil/epidemiologia , Infecções por Rotavirus/epidemiologia , Vacinas contra Rotavirus , Rotavirus/classificação , Anticorpos Antivirais/imunologia , Criança , Pré-Escolar , Diarreia Infantil/imunologia , Diarreia Infantil/prevenção & controle , Epitopos/análise , Epitopos/imunologia , Feminino , Genótipo , Humanos , Imunização , Lactente , Recém-Nascido , Masculino , Rotavirus/genética , Rotavirus/imunologia , Rotavirus/isolamento & purificação , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , SorotipagemRESUMO
In 1972, a 27-nm virus-like particle was discovered by use of immune electron microscopy (IEM) in an infectious stool filtrate derived from an outbreak of gastroenteritis in an elementary school in Norwalk, Ohio. IEM enabled the direct visualization of antigen-antibody interaction, as the particles were aggregated and coated by specific antibodies. This allowed the recognition and identification of a 27-nm virus-like particle that did not have a distinctive morphology, was low-titered, and was among the smallest viruses known. Serum antibody responses to the 27-nm particle were demonstrated in key individuals infected under natural or experimental conditions; this and other evidence suggested that this virus-like particle was the etiologic agent of the Norwalk gastroenteritis outbreak. The fastidious 27-nm Norwalk virus is now considered to be the prototype strain of a group of noncultivatable viruses that are important etiologic agents of epidemic gastroenteritis in adults and older children.
Assuntos
Vírus Norwalk/isolamento & purificação , Gastroenterite/etiologia , Humanos , Microscopia Imunoeletrônica , Técnicas de Cultura de Órgãos , Vírion/isolamento & purificaçãoRESUMO
BACKGROUND: Rotaviruses are routinely diagnosed by detection of rotavirus antigen in stools using an enzyme immunoassay (EIA). A sensitive method, like reverse transcription polymerase chain reaction (RT-PCR), may reveal more rotaviruses, but the clinical significance of such findings is not well established. OBJECTIVES: To study whether RT-PCR can detect more episodes of rotavirus-associated gastroenteritis than EIA and to determine how rotavirus RT-PCR findings might change efficacy analysis of a rotavirus vaccine trial, in which the outcome measure was rotavirus gastroenteritis diagnosis with EIA. STUDY DESIGN: We applied RT-PCR for detection of rotaviruses in gastroenteritis episodes encountered in an efficacy trial of rhesus-human reassortant rotavirus tetravalent (RRV-TV) vaccine, in a total of 2398 infants. During a follow-up, covering two rotavirus epidemic seasons, 256 cases of rotavirus associated gastroenteritis were detected by EIA; 226 were in the primary efficacy analysis period that included children who had received three doses of vaccine or placebo. RESULTS: With RT-PCR, 84 (33%) more cases of rotavirus gastroenteritis were diagnosed than with EIA, 65 of these were in the primary efficacy analysis period. Clinically, cases of rotavirus gastroenteritis diagnosed by RT-PCR were much milder (median severity score 6 on a 20-point scale) than those diagnosed by EIA (median score 11), P < 0.0001. RT-PCR revealed proportionally more G2 and G4 rotaviruses than EIA. G1 rotaviruses detected by RT-PCR were almost equally divided between RRV-TV (25) vaccine and placebo (28) groups, whereas an apparent vaccine protective effect was seen in the distribution of G2 (one in the RRV-TV and eight in the placebo group) and G4 rotaviruses (six in the RRV-TV and 14 in the placebo group). CONCLUSION: RT-PCR is a useful tool in the diagnosis of rotavirus gastroenteritis, particularly for cases associated with other than the epidemiologically dominant G-type. Application of RT-PCR contributes to the overall appraisal of performance of rotavirus vaccine.
Assuntos
Diarreia Infantil/virologia , Gastroenterite/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Vacinas contra Rotavirus , Rotavirus/isolamento & purificação , Vacinas Virais/imunologia , Doença Aguda , Diarreia Infantil/imunologia , Diarreia Infantil/fisiopatologia , Método Duplo-Cego , Seguimentos , Gastroenterite/imunologia , Gastroenterite/fisiopatologia , Humanos , Lactente , Rotavirus/genética , Rotavirus/imunologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Vacinas AtenuadasRESUMO
Live rotavirus vaccine candidates representing VP7 serotypes 1, 2, 3 or 4 derived by reassortment between bovine UK rotavirus and human rotavirus strains D, DS-1, P or ST3 were evaluated for safety and immunogenicity in adults, children and infants. Infection was defined by evidence of rotavirus shed in stools or a 4-fold or greater increase in serum rotavirus-specific IgA or IgG ELISA or plaque reduction neutralization antibody. A single oral dose (10(5.3) or 10(5.8) pfu) of reassortant virus was well tolerated and infected most infants: 10/20 (50%) by D x UK; 9/11 (82%) by DS-1 x UK; 8/10 (80%) by P x UK and 13/14 (93%) by ST3 x UK. All 14 infants given two doses of D x UK were infected. These findings demonstrating satisfactory levels of attenuation, safety, infectivity and immunogenicity of each reassortant in infants warrant additional studies of a candidate vaccine containing these four strains.
Assuntos
Antígenos Virais , Proteínas do Capsídeo , Capsídeo/imunologia , Rotavirus/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Adolescente , Adulto , Alanina Transaminase/sangue , Animais , Anticorpos Antivirais/sangue , Bovinos , Pré-Escolar , Humanos , Imunização Secundária , Lactente , Pessoa de Meia-Idade , Sorotipagem , Vacinação , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Virais/efeitos adversosRESUMO
The vervet monkey rotavirus SA11, a prototype strain of group A rotaviruses, has been shown to possess VP7 serotype 3 specificity but its neutralization specificity with regard to the other outer capsid protein VP4 has not been elucidated. We thus determined its VP4 specificity by two-way cross-neutralization with guinea pig antiserum prepared with a single gene substitution reassortant that had only the VP4-encoding gene from the simian rotavirus SA11 strain and remaining ten genes from human rotavirus DS-1 strain (G serotype 2). The SA11 VP4 was related antigenically in a one-way fashion to rhesus monkey rotavirus MMU18006 VP4 (a P5B strain) and marginally to human and canine rotavirus VP4s with P serotype 5A specificity. In addition, the SA11 VP4 was shown to be distinct antigenically from those of other known P serotypes (1-4, and 6-11) as well as those of uncharacterized equine, lapine, and avian rotavirus strains. The SA11 VP4 is thus proposed for classification as a P5B serotype.
Assuntos
Antígenos Virais , Proteínas do Capsídeo , Capsídeo/imunologia , Chlorocebus aethiops/virologia , Rotavirus/classificação , Animais , Bovinos , Cães , Cobaias , Humanos , Soros Imunes/imunologia , SorotipagemRESUMO
BACKGROUND: Rotaviruses are the principal known etiologic agents of severe diarrhea among infants and young children worldwide. Although a rhesus rotavirus-based quadrivalent vaccine is highly effective in preventing severe diarrhea in developed countries, in developing countries its efficacy has been less impressive. We thus conducted a catchment study in Venezuela to assess the efficacy of the vaccine against dehydrating diarrhea. METHODS: In this randomized, double-blind, placebo-controlled trial, 2207 infants received three oral doses of the quadrivalent rotavirus vaccine (4x10(5) plaque-forming units per dose) or placebo at about two, three, and four months of age. During approximately 19 to 20 months of passive surveillance, episodes of gastroenteritis were evaluated at the hospital. RESULTS: The vaccine was safe, although 15 percent of the vaccinated infants had febrile episodes (rectal temperature, > or =38.1 degrees C) during the six days after the first dose, as compared with 7 percent of the controls (P<0.001). However, the vaccine gave 88 percent protection against severe diarrhea caused by rotavirus and 75 percent protection against dehydration, and produced a 70 percent reduction in hospital admissions. Overall, the efficacy of the vaccine against a first episode of rotavirus diarrhea was 48 percent. Horizontal transmission of vaccine virus was demonstrated in 15 percent of the vaccine recipients and 13 percent of the placebo recipients with rotavirus-positive diarrhea. CONCLUSIONS: In this study in a developing country, the quadrivalent rhesus rotavirus-based vaccine induced a high level of protection against severe diarrheal illness caused by rotavirus.
Assuntos
Diarreia Infantil/prevenção & controle , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus , Vacinas Virais , Anticorpos Antivirais/sangue , Desidratação/etiologia , Desidratação/prevenção & controle , Países em Desenvolvimento , Diarreia Infantil/complicações , Diarreia Infantil/virologia , Transmissão de Doença Infecciosa , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Lactente , Masculino , Rotavirus/classificação , Rotavirus/imunologia , Infecções por Rotavirus/complicações , Infecções por Rotavirus/transmissão , Venezuela , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologiaRESUMO
The Norwalk and Hawaii viruses are antigenically distinct members of the family Caliciviridae and are considered to be important etiologic agents of epidemic gastroenteritis, with most studies focusing on the role of Norwalk virus. To further investigate the importance of Hawaii virus, Hawaii virus-like particles (VLPs) were produced by expression of its capsid protein in the baculovirus system and these VLPs were used as the antigen in an enzyme-linked immunosorbent assay that was efficient in the detection of a serologic response to Hawaii virus. The ready availability of Hawaii VLPs should enable larger-scale epidemiological studies to further elucidate the importance of this agent.
Assuntos
Antígenos Virais/genética , Caliciviridae/genética , Capsídeo/genética , Antígenos Virais/biossíntese , Antígenos Virais/química , Capsídeo/biossíntese , Capsídeo/química , Humanos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genéticaRESUMO
Previously, four human x bovine rotavirus reassortant candidate vaccines, each of which derived ten genes from bovine rotavirus UK strain and only the outer capsid protein VP7-gene from human rotavirus strain D (G serotype 1), DS-1 (G serotype 2), P (G serotype 3), or ST3 (G serotype 4), were developed [Midthun et al., (1985): Journal of Virology 53:949-954; (1986): Journal of Clinical Microbiology 24:822-826]. Such human x bovine reassortant vaccines should theoretically provide antigenic coverage for the four epidemiologically most important VP7(G) serotypes 1, 2, 3, and 4. In an attempt to increase the antigenicity of VP7-based human x animal reassortant rotavirus vaccines which derive a single VP7-encoding gene from the human strain and the remaining ten genes from the animal strain, we generated double gene substitution reassortants. This was done by incorporating another protective antigen (VP4) of an epidemiologically important human rotavirus by crossing human rotavirus Wa strain (P serotype 1A), with each of the human x bovine single VP7-gene substitution rotavirus reassortants. In this way four separate double gene substitution rotavirus reassortants were generated. Each of these reassortants bears the VP4-encoding gene from human rotavirus Wa strain, the VP7-encoding gene from human rotavirus strain D, DS-1, P, or ST3, and the remaining nine genes from bovine rotavirus strain UK. The safety, antigenicity, and protective efficacy of individual components as well as combinations of strains are currently under evaluation.
Assuntos
Antígenos Virais/imunologia , Proteínas do Capsídeo , Capsídeo/imunologia , Rotavirus/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , Antígenos Virais/genética , Capsídeo/genética , Bovinos , Linhagem Celular , Chlorocebus aethiops , Genes Virais , Cobaias , Humanos , Rotavirus/genéticaRESUMO
The most extensively explored strategy for rotavirus vaccination has been the Jennerian approach, which uses an antigenically related rotavirus strain from an animal host as the immunogen to induce protection against the 4 epidemiologically important group A rotavirus VP7 serotypes. Because this approach has shown limited efficacy, a modified Jennerian approach was developed with the goal of achieving broader antigenic coverage. Four VP7 serotypes were incorporated into a quadrivalent vaccine comprised of three rhesus-human rotavirus reassortants, each with 10 rhesus rotavirus genes and 1 human rotavirus gene that encodes VP7 serotype 1, 2, or 4 specificity; the rhesus rotavirus itself provides coverage for VP7 serotype 3. This approach appears quite promising for preventing severe rotavirus diarrhea, including those episodes that lead to dehydration. Additional strategies under development stress the role not only of human rotavirus VP7 but also of human rotavirus VP4, the other outer capsid protein that also induces neutralizing antibodies.
Assuntos
Antígenos Virais , Proteínas do Capsídeo , Diarreia/prevenção & controle , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus , Rotavirus/imunologia , Vacinas Virais , Animais , Capsídeo/imunologia , Pré-Escolar , Ensaios Clínicos como Assunto , Diarreia/virologia , Humanos , Lactente , Recém-Nascido , Macaca mulatta , Vacinas AtenuadasRESUMO
Rotavirus vaccine development has focused on the delivery of live attenuated rotavirus strains by the oral route. The initial "Jennerian" approach involving bovine (RIT4237, WC3) or rhesus (RRV) rotavirus vaccine candidates showed that these vaccines were safe, well tolerated, and immunogenic but induced highly variable rates of protection against rotavirus diarrhea. The goal of a rotavirus vaccine is to prevent severe illness that can lead to dehydration in infants and young children in both developed and developing countries. These studies led to the concept that a multivalent vaccine that represented each of the four epidemiologically important VP7 serotypes might be necessary to induce protection in young infants, the target population for vaccination. Human-animal rotavirus reassortants whose gene encoding VP7 was derived from their human rotavirus parent but whose remaining genes were derived from the animal rotavirus parent were developed as vaccine candidates. The greatest experience with a multivalent vaccine to date has been gained with the quadrivalent preparation containing RRV (VP7 serotype 3) and human-RRV reassortants of VP7 serotype 1, 2, and 4 specificity. Preliminary efficacy trial results in the United States have been promising, whereas a study in Peru has shown only limited protection. Human-bovine reassortant vaccines, including a candidate that contains the VP4 gene of a human rotavirus (VP4 serotype 1A), are also being studied.
Assuntos
Infecções por Rotavirus/prevenção & controle , Rotavirus/genética , Rotavirus/imunologia , Vacinação/métodos , Animais , Bovinos , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Macaca mulatta , Proteínas Recombinantes/imunologia , Rotavirus/química , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/imunologia , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/análise , Vacinas Atenuadas/imunologia , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/análise , Vacinas Sintéticas/imunologia , Proteínas Virais/imunologiaRESUMO
Comparisons in rotavirus neutralizing-antibody responses were made with sera collected from vaccinated infants. The methods were a plaque reduction assay and a new enzyme-linked immunosorbent assay-based neutralization assay. Agreement of 94% was found in detecting at least fourfold seroresponses, and correlation coefficients between titers obtained by the two methods showed excellent agreement, indicating that either could be used reliably.
Assuntos
Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Testes de Neutralização/métodos , Rotavirus/imunologia , Ensaio de Placa Viral/métodos , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática/estatística & dados numéricos , Estudos de Avaliação como Assunto , Humanos , Lactente , Testes de Neutralização/estatística & dados numéricos , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Vacinas Sintéticas/farmacologia , Ensaio de Placa Viral/estatística & dados numéricos , Vacinas Virais/farmacologiaRESUMO
In a four cell trial, a single 10(4) plaque-forming unit dose of rhesus rotavirus (RRV) vaccine (serotype G3), a human rotavirus-rhesus rotavirus reassortant vaccine with serotype G1 specificity, a similar vaccine with serotype G2 specificity, or a placebo was administered with buffer orally at 2 months of age to 800 Peruvian infants. Only the RRV vaccine was associated with a febrile response (< 38 degrees C) that occurred in 9% of the infants on day 4 after vaccination. Diarrhea or other side-effects were not associated with administration of vaccine. Vaccine strains were shed by only 12-18% of the infants as determined by examination of a single stool specimen obtained on days 4 or 5 after vaccination. Fifty per cent of vaccines developed an IgA ELISA seroresponse; however, a serotype-specific seroresponse by plaque reduction neutralization was demonstrated in < 20% of the participants against each of the three candidate vaccine strains. Vaccine efficacy was evaluated by twice-weekly home surveillance for diarrheal diseases during 24 months post-immunization. Rotavirus diarrheal episodes were identified by ELISA. Only the RRV vaccine had a significant protective efficacy (29%, p = 0.03, chi-square test) against rotavirus diarrhea. Analysis of vaccine efficacy against rotavirus episodes of any severity in which no other enteropathogen was isolated showed a trend towards higher vaccine efficacy. In addition, a similar trend was observed in rotavirus-only episodes in which there was some degree of dehydration or when health services were utilized. Serotype G1 or G2 rotavirus strains were most prevalent during surveillance. Neither serotype G1 or serotype G2 vaccines were protective against serotype 1 or 2 rotavirus diarrhea, respectively. The serotype G2 vaccine was 84% protective against serotype 1 and 2 dehydrating rotavirus diarrhea in the small numbers of individuals evaluated. We conclude that one dose of 10(4) p.f.u. of the RRV, serotype G1, or serotype G2 rotavirus vaccine failed to induce either an adequate serotype-specific seroresponse or serotype-specific protection in children immunized at 2 months of age. Only the RRV vaccine induced a low level of protection against rotavirus diarrhea mainly of serotype G1 specificity. Future studies need to explore whether higher vaccine dose and/or more than one dose would increase the immunogenicity and efficacy of the rotavirus vaccine, especially in developing countries with a high level of baseline rotavirus antibodies.
Assuntos
Diarreia Infantil/prevenção & controle , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus , Rotavirus , Vacinas Virais/administração & dosagem , Método Duplo-Cego , Humanos , Lactente , PeruRESUMO
Diarrheal illnesses in humans have been recognized since antiquity. Such illnesses continue to take a great toll of lives, with a disproportionately high mortality in infants and young children in developing countries. Bacteriologic and parasitologic advances made during the past century led to the discovery of the etiology of some of the diarrheal illnesses, but the etiology of the major portion remained unknown. It was assumed that viruses caused most of these illnesses because: (i) bacteria were recovered from only a small proportion of episodes, and (ii) bacteria-free filtrates were found to induce gastroenteritis in adult volunteer studies. However, an etiologic agent could not be recovered despite the "golden age" of virology in the 1950's and 1960's when tissue culture technology enabled the discovery of numerous cultivatable enteric viruses, none of which emerged as an important etiologic agent of gastroenteritis. The discoveries of the Norwalk virus in 1972, and of rotaviruses in 1973, both without the benefit of in vitro tissue culture systems, ushered in a new era in the study of the etiology of viral gastroenteritis. The Norwalk virus was found to be an important cause of non-bacterial epidemic gastroenteritis in adults and older children, and rotaviruses were shown to be the single most important etiologic agents of severe diarrheal illnesses of infants and young children in both developed and developing countries. With the major advances in the study of rotaviruses, there is a high degree of optimism that in the not-too-distant future, a rotavirus vaccine will be available. In addition, the recent molecular biologic advances in the study of the Norwalk and Norwalk-like viruses, now firmly established as caliviviruses, represent a major new horizon in the study of these viruses.
Assuntos
Diarreia/virologia , Gastroenterite/virologia , Vírus Norwalk , Rotavirus , Diarreia/história , Gastroenterite/história , História do Século XX , Humanos , Vírus Norwalk/genética , Vírus Norwalk/fisiologia , Rotavirus/imunologia , Rotavirus/fisiologia , Rotavirus/ultraestruturaRESUMO
Rotaviruses, members of the Reoviridae family, are major etiologic agents of acute nonbacterial gastroenteritis of the young in a wide variety of mammalian and avian species, including humans. The need for effective immunoprophylaxis against rotaviral gastroenteritis has stimulated interest in the biochemical, molecular, genetic, and clinical aspects of these agents with the aim of developing safe and effective vaccines. Because neutralizing antibodies appear to play an important role in protection against many viral diseases, rotavirus antigens that induce neutralizing antibodies have played a central role in research and development of a rotavirus vaccine. The VP7 glycoprotein and VP4 spike protein that constitute the outer capsid of a complete rotavirus particle have been shown to be independent neutralization antigens. Since type specificity of the outer capsid proteins of a rotavirus appears to play an important role in protection against disease in experimental animal models, continued efforts have been made for classification and typing of neutralization specificities on the VP7 or VP4 capsid protein. Based on a criterion of > 20-fold differences between the homologous and heterologous reciprocal neutralizing antibody titers, fourteen VP7 (G) serotypes have been established. Studies are underway to characterize and classify the VP4 (P) serotypes among the strains that exhibit the fourteen different G serotypes. Attempts to classify the VP4 serotypes based on the same criterion (i.e., > 20-fold antibody differences) that is applied to classification of VP7 serotypes are in progress. This standard of > 20-fold antibody differences can be applied with hyperimmune serum raised to a reassortant possessing the VP4 encoding gene (and an unrelated VP7 encoding gene). Genotypes can provide leads towards classification but the serotype of a strain should be based on neutralization.