Statistical modeling alongside observational data predicts long-term immunogenicity of one dose and two doses of pediatric hepatitis A vaccine in the Mendoza province of Argentina.

BACKGROUND: Follow-up for anti-hepatitis A (HA) antibody persistence up to 10 years was conducted after implementation of universal vaccination against HA virus (HAV) in Mendoza, Argentina. Based on these data, statistical modeling was used to predict the antibody persistence to 30 years. METHODS: A non-interventional study evaluated long-term immunogenicity (geometric mean concentrations [GMCs] and seroprotection rate) following routine vaccination with 1 dose (Group 1: N = 436) or 2 doses (Group 2: N = 108) of HA vaccine. Associated statistical modeling based on a Bayesian approach of mixed effects models on log transformed titers evaluated three models (linear, piecewise linear, and exponential decay, with and without a natural boosting effect). RESULTS: From the initial cohort, 9 participants (Group 1) and 1 participant (Group 2) showed antibody titers below the seroprotective threshold and received a booster. At Year 10, 190 (Group 1) and 51 (Group 2) participants remained in the study without a booster dose and all were seroprotected. Regarding statistical modeling, the piecewise linear model showed the best fit and demonstrated high and similar seroprotection for each schedule up to 30 years (89% [1-dose schedule], 85% [2-dose schedule]). The 2-dose schedule showed higher GMC (95% CI) than the 1-dose schedule (Year 10: 352 [271-456] versus 78 [69.8-87.6] mIU/mL) and Year 30 (predicted) (37 [13-97] versus 19 [11-34] mIU/mL). Natural boosting had little impact on predicted seroprotection rates at 30 years for the 1-dose schedule (89% [0.8-0.96] and 84% [0.73-0.94] with and without a natural booster, respectively). CONCLUSIONS: Long-term persistence of anti-HAV antibodies was observed up to 10 years with 1-dose and 2-dose vaccine schedules, supporting booster flexibility. Statistical modeling predicted good persistence of seroprotection for each schedule up to 30 years. Natural boosting had a limited impact on seroprotection rate predictions, enabling extrapolation of these results to non-endemic settings for traveler vaccination.

Five-year follow-up of immune response after one or two doses of inactivated hepatitis A vaccine given at 1 year of age in the Mendoza Province of Argentina.

Our study was conducted to further investigate the single-dose approach of hepatitis A vaccination, while providing supportive data on the flexibility of booster administration. Participants received at least one dose of Avaxim 80U Pediatric at 11-23 months of age, and they will be followed for 10 years. We report here the fourth and fifth years after the first vaccination. Group assignment was based on whether the children received 1 dose and no booster during the study (Group 1) or 2 doses and no further booster (Group 2). Anti-HAV antibody concentrations were assessed at each annual visit. Of the 546 initial participants, 441 (80.8%) and 412 (75.5%) were followed up 4 and 5 years after vaccination, respectively. Of the 411 subjects evaluable at Year 5, 318 had received one vaccine dose and 85 had received two. Seroprotection rates were still high in Group 1 (99.7%) and in Group 2 (100%) 5 years after one or two doses of Avaxim 80U Pediatric, correspondingly. Anti-HAV geometric mean concentrations decreased in both groups compared to what they were 3 years after vaccination, while remaining well above the 10 mIU/mL threshold 5 years after vaccination. The highest concentrations were found in the children who received 2 vaccine doses. Hepatitis A humoral immunity induced by a single dose of inactivated hepatitis A vaccine can persist for at least 5 years in a paediatric population. The study results also support recommendations in favour of a flexible time window for booster vaccination.

Surveillance for rotavirus in Argentina.

Group A rotaviruses are the major cause of severe gastroenteritis in young children worldwide. Because rotavirus vaccination appeared imminent, a nationwide surveillance program was organized between October 1996 and October 1998 in the largest Argentine cities. Surveillance for disease burden, rotavirus detection, and rotavirus typing was undertaken at nine locations. Results showed rotavirus to be associated with 42% of diarrhea admissions. Although the prevalent G types changed from year to year, common G types were found in 96% of the cases and were usually associated with common P types. Uncommon G types, G9 and G5, were found at low prevalence and uncommon G/P combinations occurred at almost every study site. These data suggest that a rotavirus vaccine could substantially decrease the rotavirus disease burden in Argentina, but that introduction of a vaccine should be accompanied by a concurrent surveillance system.

Genomic and antigenic variation among rotavirus strains circulating in a large city of Argentina.

Knowledge of the antigenic diversity of rotaviruses circulating in a region should be acquired before introducing a rotavirus vaccine. In a collection of 151 rotavirus-positive samples from Mendoza, Argentina, strain diversity was evaluated utilizing G-typing monoclonal antibodies (MAbs), reverse-transcriptase-polymerase chain reaction (RT-PCR) G and P typing, and electropherotyping (PAGE). The G type of 137 (91%) specimens was determined. Typing MAb reactivity with the homologous type ranged from 25-94%. For the seven G1 MAbs utilized, 28 patterns of reactivity among 68 G1 strains occurred. For the 48 G2 strains, six patterns of reactivity occurred utilizing three G2-specific MAbs. Of the 92 samples G- and P-typed by reverse-transcriptase-polymerase chain reaction, 89% had single G/P combinations: eight G1[P4], one G1[P6], twelve G1[P8], 58 G2 [P4], and two G2 [P6]. Nine samples had more than one G type with a single P type, one sample had two P types associated with one G type, and one sample contained multiple G and P types. Twenty-nine PAGE patterns occurred for all G types, but differences of antigenic reaction did not predict differences in migration of gene segments 7, 8, and 9. For three specimens showing discordant results between G type by enzyme-linked immunosorbent assay (EIA) and RT-PCR, we observed unexpected electropherotypes. Complementary evaluation by RT-PCR and MAb-based EIA with multiple typing MAbs revealed genetic and antigenic diversity of circulating rotaviruses, including extensive intratypic variation of the G1 and G2 neutralization antigens, in Mendoza during a single season of rotavirus activity.

Diarrhea and enteric emerging viruses in HIV-infected patients.

To evaluate the prevalence of enteric viruses and their possible association with diarrhea, 244 stool samples were collected from HIV-infected and uninfected patients with or without diarrhea (subgroups I-a, Ib, II-a, and II-b, respectively). Subjects were screened by polyacrylamide gel electrophoresis, latex agglutination, and enzyme immunoassays for rotaviruses, adenoviruses, picobirnaviruses, and astroviruses. Enteric viruses were found significantly more often in specimens from HIV patients (20%) than in specimens from uninfected HIV patients (0%) (p < 0.05). Picobirnavirus was detected in 14.63% of 82 HIV-infected patients with diarrhea, but it was detected neither in those without diarrhea (0%) (p < 0.05) nor in the groups of uninfected HIV subjects (0%) (p < 0.05). Nor could astrovirus (subgroups I-a [4.00%] versus subgroup I-b [5.26%],p > 0.05) or enteric adenovirus (subgroup I-a [1.22%] versus subgroup I-b [0%], p > 0.05) be linked to the diarrhea disorder in HIV-infected patients. Rotaviruses were not detected in any of the clinical subgroups studied. Enteric viruses were detected in 15 of 93 (16.13%) of the HIV-infected patients with CD4+ T cell count <200/microl and 3 of 19 (15.79%) of those HIV-infected individuals with a CD4+ T cell count 200-499/microl, showing no significant difference (p > 0.05). According to our data, unusual enteric viruses such as picobirnavirus, astrovirus, and enteric adenovirus occur in HIV-infected population in Córdoba, Argentina. However, only picobirnaviruses could be significantly associated with diarrhea in these patients.

[Rotavirus laboratory network: results after one year of observation]. / Red de laboratorios de Rotavirus: resultados del primer año de vigilancia.

Rotavirus is the most common cause of severe diarrhea in children and it has been estimated that in Argentina Rotavirus is responsible for 21,000 hospitalizations, 85,000 medical attentions and an annual medical cost of US$ 27 millions. Given that a Rotavirus vaccine is about to be approved, a laboratory network based surveillance system was organized. Herein, we present the results after one year of study. Severe diarrhea was responsible for 9% of pediatric hospitalizations and rotavirus was detected in 42.1% of the diarrhea cases. We estimated that Rotavirus causes 3.8% of pediatric hospitalizations. The number of diarrhea and Rotavirus diarrhea hospitalizations was greater during the first year of life (62% and 71.3%, respectively). The number of diarrhea hospitalizations during the December-May semester was significantly higher than the rest of the year. A Rotavirus diarrhea peak was detected between April and June. These results indicate that Rotavirus is the most important etiological agent of severe diarrhea in Argentine children and show the importance of performing Rotavirus diagnosis in every pediatric hospital. The additional costs will be compensated by many benefits such as better use of antibiotics, improved nosocomial spread control, better handling of hospital beds and of laboratory resources and of the hospitalized patient.

Red de laboratorios de Rotavirus: resultados del primer año de vigilancia / Rotavirus laboratory network: results after one year experience

Rotavirus es el principal agente productor de diarrea infantil y se ha estimado que provoca en Argentina 21.000 hospitalizaciones, 85.000 atenciones ambulatorias, y un costo mayor a los 27 millones de dolares anuales. Ante la inminente aprobación de una vacuna contra este patógeno se organizó un Sistema de Vigilancia Epidemiológica en base a una Red de laboratorios. Se presentan los resultados obtenidos luego del primer año de funcionamiento de esta Red. Se encontró que el 9 por ciento de la internación pediátrica es debido a diarrea aguda, y rotavirus se halló en el 42,1 por ciento de los casos estudiados. Se estimó que rotavirus provoca el 3,8 por ciento de las internaciones pediátricas. La internación por diarrea y la internación asociada a diarrea por rotavirus fue mayor en el primer año de vida (62 por ciento y 71,3 por ciento respectivamente). En el semestre de diciembre a mayo el número de internaciones por diarrea fue significativamente mayor que en el semestre restante. Se detectó un pico de diarreas por rotavirus entre abril y junio en las distintas Unidades centinelas. Estos resultados señalan a los rotavirus como el principal agente etiológico de la gastroenteritis infantil aguda en nuestro país y avalan la necesidad de incorporar su diagnóstico en todos los hospitales pediátricos. Los costos adicionales serán ampliamente superados por los beneficios relacionados con elmejor manejo de las camas hospitalarias, los recursos del laboratorio, y el paciente internado por diarrea, el uso correcto de antibióticos, y el control de la diseminación intrahospitalaria de rotavirus

Characterization of a novel human calicivirus that may be a naturally occurring recombinant.

We identified a Norwalk-like calicivirus (CV) whose genome likely was derived from naturally occurring recombination. This strain (Arg320) was detected by the EIA developed against recombinant Mexico virus (rMxV) capsids, but the viral RNA polymerase sequence was closer to Lordsdale virus, in a separate genetic cluster of Norwalk-like viruses. A 3.3 kb cDNA from the RNA polymerase region to the 3' end of the genome of Arg320 was cloned and sequenced. The sequence demonstrated that the capsid region of Arg320 shared 95% amino acid identity with MxV, but 68% identity with Lordsdale virus, while the RNA polymerase region shared 95% identity with Lordsdale virus, but 87% identity with MxV. Pair-wise sequence comparisons identified a potential recombination site at the polymerase/capsid junction. This is the first example of a naturally occurring recombinant in the CV family. Further studies to search for and characterize other strains may be necessary for understanding the genetic diversity of the family.

Anticipating rotavirus vaccines: review of epidemiologic studies of rotavirus diarrhea in Argentina.

Rotavirus is the most common cause of severe diarrhea in children worldwide, and vaccines currently being field-tested could be available for childhood immunization in several years. To assess the rotavirus disease burden in Argentina and the value of future national surveillance for the disease, we reviewed available data on rotavirus detections reported by published and unpublished studies conducted in nine Argentine cities and by a multicenter study. Data from these studies indicated that rotavirus was detected in 20% of 5,226 specimens (within a range of 6% to 54% for different studies) from children hospitalized for diarrhea and in 9% of 6,587 specimens (within a range of 5% to 22% for different studies) from children who were outpatients, members of mixed populations (hospitalized patients and outpatients), or survey subjects in community-based studies. The hospital data showed that while rotavirus was detected throughout the year, a peak occurred during the winter months (May-July) when up to half of the children with diarrhea were found positive for rotavirus. Attempted serotyping of 294 rotavirus-positive specimens for G-protein by three laboratories was successful in 230 cases (78%); the resulting data indicated that serotype G1 was the most common (being present in 60% of the successfully serotyped specimens), followed by G2 (in 20%), G4 (in 14%), and G3 (in 5%). Based on national data for Argentina, we estimate that in 1991 there were roughly 84,500 rotavirus-associated outpatient visits (1 for every 8 births) and 21,000 hospitalizations averaging 4 days in length (1 for every 31 births), all of which entailed direct medical costs estimated at US$ 27.7 million. These preliminary data show that the rotavirus disease burden in Argentine children is extensive and could be decreased by a safe and effective vaccine. Further surveillance is needed to improve our understanding of the epidemiology and distribution of rotavirus strains in Argentina, to more accurately assess the cost-effectiveness of a rotavirus vaccine program, and to indicate what methods might best be used to monitor such a program's impact.

[Characterization of antigenic types of circulating rotaviruses in Mendoza, Argentina based on typing of the external VP7 capsid protein]. / Caracterización de tipos antigenícos de rotavirus circulantes en Mendoza, Argentina en base a tipificación de la proteina de la capside externa VP7.

Rotavirus is one of the most common etiologic agents of acute diarrhea in childhood. Understanding the immunologic mechanisms involved in rotavirus diseases, including knowledge on seasonal and geographic antigenic variations may be crucial for vaccine development. A monoclonal antibody based ELISA specific for antigenic domains on the outer capsid protein VP7 has been developed and used widely in the past years. We studied the rotavirus VP7-serotype epidemiology causing diarrhea in children who consulted at two main hospitals of Mendoza, Argentina over a 20 month period. A total of 227 cases of diarrhea were identified, 45 of which (20%) were rotavirus positive. We're able to serotype 43 viruses (96%), 42 VP7-type 1 and one VP7-type 3. The VP7-type 3 was detected towards the end of the second year, possibly representing a new incoming VP7-type. Three electropherotype patterns were identified, two corresponding to VP7-type epidemiology in Mendoza, Argentina seems to be characterized by a relatively homogeneous pattern of circulation with a strong predominance of VP7-type 1 viruses, at least during the 20 month period studied, in contrast to what has been reported in larger, more cosmopolitan cities like Buenos Aires.

Caracterización de tipos antigenícos de rotavirus circulantes en Mendoza, Argentina, en base a tipificación de la proteína de la capside externa VP7 / Characterization of antigenic types of circulating rotavirus in Mendoza, Argentina with base to typing of external VP7 capsid protein

El rotavirus es uno de los agentes etiológicos más comunes de la diarrea aguda de la infancia. La compresión de los mecanismos inmunológicos involucrados en las enfermedades por rotavirus incluso el conocimiento de las variaciones antigénicas, estacionales y geográficas pueden ser cruciales para el desarrollo de la vacuna. Un anticuerpo monoclonal, basado en ELISA, específico para el dominio antigénico sobre la cápside exterior proteica VP7, ha sido desarrollado y usado ampliamente durante los últimos años. Estudiamos la epidemiología del rotavirus VP7, causante de diarrea en niños que consultaron en los dos hospitales principales de Mendoza, Argentina, durante un período de 20 meses. Fueron identificados 227 casos de diarrea, 45 de los cuales (20 por ciento) fueron rotavirus positivas. Pudimos determinar el serotipo de 43 virus (96 por ciento), 42 tipo VP7 y 1 tipo VP7-3. Este último fue detectado hacia el final del segundo año representando posiblemente un tipo VP7 nuevo, que llegaba. Se identificaron 3 patrones electroforéticos, dos correspondientes a la epidemia de tipo VP7 en Mendoza, parecían caracterizados por un patrón relativamente homogéneo de circulación con fuerte predominancia del virus VP7-tipo 1,por lo menos durante el período estudiado de 20 meses, en contraste con lo que se ha informado en ciudades más grandes y cosmopolitas, tales como Buenos Aires