A short report on highlights of world-wide development of RIX4414: an European experience.
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Administration, Oral↗
Biomedical subjects
T Vesikari
Publications and source records attributed to T Vesikari.
Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation.
AIMS/HYPOTHESIS: We have previously observed an inverse correlation between the incidence of type 1 diabetes and enterovirus infections in the background population. The aim of this study was to analyse whether maternal enterovirus antibody status, which reflects both the frequency of enterovirus infections and the protection conferred by the mother on the offspring, also correlates with the incidence of type 1 diabetes. METHODS: Maternal enterovirus antibodies were analysed from serum samples taken from pregnant women between 1983 and 2001 in Finland and Sweden using enzyme immunoassay and neutralisation assays. Comparable samples were also taken between 1999 and 2001 in countries with a lower incidence of diabetes (Estonia, Germany, Hungary, Israel, Lithuania, Russia). RESULTS: A clear decrease was observed in maternal enterovirus antibody levels over the past 20 years (p<0.0001). The frequency of enterovirus antibodies was higher in countries with a low or intermediate incidence of type 1 diabetes compared with high-incidence countries (p<0.0001). CONCLUSIONS/INTERPRETATION: These findings are in line with our previous observations supporting the hypothesis that a low frequency of enterovirus infection in the background population increases the susceptibility of young children to the diabetogenic effect of enteroviruses.
Antibodies, Viral↗
Safety and immunogenicity of RIX4414 live attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants.
A live attenuated human rotavirus (HRV) vaccine, strain RIX4414, was tested sequentially in adults, previously infected toddlers, and previously uninfected infants. A single dose was given to adults and toddlers and found well tolerated. Next, a dose ranging (three different viral concentrations) safety and immunogenicity study was conducted in rotavirus IgA antibody negative infants (N= 192), who received two doses of RIX4414 vaccine or placebo at 2 and 4 months of age. No side effects were seen after vaccination. Specifically, administration of RIX4414 vaccine was not temporally associated with fever, diarrhea, or increase in liver transaminases. Rotavirus IgA seroconversion ranged from 50 to 88% after one dose and from 73 to 96% after two doses, depending on vaccine titer. After the first dose, on days 7-9 post vaccination, between 38 and 60% of the infants shed the vaccine virus, whereas after the second dose only 0 to 13% of the vaccinees shed the vaccine virus. It is concluded that RIX4414 strain HRV vaccine is virtually non-reactogenic and, at high titer, highly immunogenic in susceptible infants.
Adolescent↗
Screening of rotavirus and adenovirus infections during prolonged hospitalization in a neonatal unit.
UNLABELLED: Rotavirus and adenovirus infections in 308 infants hospitalized for longer than 1 wk, and cases with necrotizing enterocolitis, were screened in a neonatal unit during a 15 mo period, covering two rotavirus epidemics in the community. Altogether, 1020 stool samples were collected weekly until hospital discharge, and in necrotizing enterocolitis cases at the onset of symptoms, and tested for rotavirus and adenovirus by means of enzyme-linked immunosorbent assay. The positive samples were further analysed by polymerase chain reaction. Enzyme-linked immunosorbent assay revealed five adenovirus-positive cases, which were tested negative by polymerase chain reaction. Out of 16 necrotizing enterocolitis cases, one was adenovirus- and another rotavirus positive when tested by polymerase chain reaction, the latter having a concomitant Candida albicans septicaemia. CONCLUSION: Routine rotavirus and adenovirus screening in hospitalized neonates seems to be unnecessary. Viral diagnostic examinations should be considered in patients with necrotizing enterocolitis.
Adenoviridae Infections↗
Effect of rotavirus vaccine on Sapporo virus gastroenteritis in Finnish infants.
BACKGROUND: Sapporo-like viruses (SLVs) occur worldwide, but there is limited information about the SLV-associated gastroenteritis outside Japan. METHODS: Stool specimens from 1,432 episodes of gastroenteritis that occurred in children between 2 months and 2 years of age during a rotavirus vaccine trial (776 episodes in placebo-vaccinated and 656 in rotavirus-vaccinated infants) were examined for SLVs using a reverse transcription-PCR assay. The reverse transcription-PCR took advantage of new primers specific for Sapporo virus genetic clusters I, II and III; SV/SV82 (SV/Sapporo virus 82); SV/Lond92 (SV/ London 92); and SV/PV (Parkville virus). RESULTS: SLVs were detected in association with 132 (9.2%) of all episodes; in 80 (5.6%) episodes SLV was the only gastroenteritis virus detected. The epidemic season of SLVs peaked from March to May concurrently with rotaviruses and astroviruses and overlapping withNorwalk-like viruses. Clinically SLV gastroenteritis was characterized by a mild diarrheal disease, being sharply different from the Norwalk-like virus-associated "winter vomiting disease." Rotavirus vaccination did not have any effect on the number of SLV episodes, but the intensity and duration of SLV-associated diarrhea were reduced in rotavirus-vaccinated children compared with placebo-vaccinated children (P = 0.0008). CONCLUSIONS: SLVs are common causative agents of acute gastroenteritis in young Finnish children. SLV disease is characterized by diarrhea, which is usually mild but can be severe. By an unknown mechanism rotavirus vaccine seems to reduce the severity of SLV-associated diarrhea.
Caliciviridae Infections↗
Human caliciviruses in acute gastroenteritis of young children in the community.
Episodes of acute gastroenteritis in prospectively followed children between 2 months and 2 years of age were examined for rotaviruses, enteric adenoviruses, astroviruses, and human caliciviruses, including both Norwalk-like viruses (NLVs) and Sapporo-like viruses (SLVs), using PCR and reverse transcription (RT)-PCR assays. A virus was identified in 60% (502/832) of all episodes and in 85% of the moderately severe or severe episodes. Human caliciviruses were as common as rotaviruses, both being detected in 29% of the cases. NLVs accounted for a 20% etiologic share of all cases; the clinical picture was a moderately severe disease with vomiting as a predominant symptom. SLVs were detected in 9% of the cases, the clinical picture being a mild diarrheal disease. Astroviruses were found in 10% and enteric adenoviruses in 6% of the cases. Diagnosis with PCR and RT-PCR methods increases the detection of all gastroenteritis viruses, particularly human caliciviruses. As a group, human caliciviruses are common causative agents of gastroenteritis in children <2 years of age in Finland, and, of these, NLVs cause more severe disease than SLVs.
Acute Disease↗
[Antiviral agents and the practicing physician].
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2-Aminopurine↗
Rotaviruses detected by reverse transcription polymerase chain reaction in acute gastroenteritis during a trial of rhesus-human reassortant rotavirus tetravalent vaccine: implications for vaccine efficacy analysis.
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.
Acute Disease↗
Cytokine determinations and rapid diagnosis of early onset neonatal septicaemia.
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C-Reactive Protein↗
Human astrovirus-associated gastroenteritis in children under 2 years of age followed prospectively during a rotavirus vaccine trial.
This study evaluated the clinical significance of human astrovirus-associated gastroenteritis in young children in the community. Placebo- (n = 1207) and rhesus rotavirus tetravalent (RRV-TV) vaccine- (n = 1191) recipient children were followed from 2 mo to 2 y of age. Stool specimens from 1528 episodes of acute gastroenteritis (805 in the placebo group and 723 in the RRV-TV vaccine group) were tested for astrovirus with a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay and positive results were confirmed by Southern hybridization using probes specific for astrovirus serotypes 1 and 2. Astroviruses were detected in 144 (9%) episodes of gastroenteritis; 92% of the findings were serotype 1 and 6% were serotype 2. The astrovirus peak season was in winter. Of the 102 children who had gastroenteritis with astrovirus as the only diarrhoea virus in the stools, 72% had watery diarrhoea, 59% had vomiting, 26% had fever, 5% needed oral rehydration and 3% were hospitalized. Overall, the clinical severity of astrovirus gastroenteritis was much lower than that of rotavirus gastroenteritis. RRV-TV rotavirus vaccine did not protect against astrovirus gastroenteritis. It is concluded that astroviruses are common causative agents in acute gastroenteritis in young children, but the symptoms of astrovirus gastroenteritis are usually mild and the illness is therefore only of minor clinical significance.
Acute Disease↗
Effect of rhesus rotavirus vaccine on enteric adenovirus--associated diarrhea in children.
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Adenovirus Infections, Human↗
Human calicivirus-associated sporadic gastroenteritis in Finnish children less than two years of age followed prospectively during a rotavirus vaccine trial.
BACKGROUND: Human caliciviruses (HuCV) cause outbreaks of gastroenteritis, but their role in sporadic diarrhea in young children is not well-established. METHODS: Children (n = 2398) participating in a trial of oral rhesus-human reassortant rotavirus tetravalent (RRV-TV) vaccine were evaluated from 2 months to 2 years of age. Stool specimens from 1477 episodes of acute gastroenteritis (788 in a placebo and 689 in a RRV-TV vaccine recipient group) were tested for human calicivirus (HuCV) by reverse transcriptase-PCR with the use of broadly reactive primers, and positive results were confirmed by Southern hybridization with probes specific for main genetic clusters of Genogroups I and II of HuCV. RESULTS: HuCV were detected in 158 (20%) and 155 (22%) cases of gastroenteritis in the placebo and RRV-TV vaccine groups, respectively. According to hybridization results, 8% of HuCV were of Genogroup I and 92% were of Genogroup II. The peak season of HuCV gastroenteritis was from November to February. Of the 148 patients with pure HuCV infection in the placebo group, 89% had vomiting, 79% had watery diarrhea, 21% had fever, 28% needed oral rehydration and 1.4% were hospitalized. The diarrhea in HuCV gastroenteritis was much less severe than that in rotavirus gastroenteritis, but vomiting was equally severe. There was no effect of RRV-TV vaccine on the frequency or clinical severity of HuCV gastroenteritis. CONCLUSION: HuCVs are second in frequency to rotaviruses as causative agents in acute gastroenteritis in young children in the community.
Caliciviridae↗
Rotavirus vaccine studies in Europe.
Following the discovery and recognition of rotavirus as an important human enteropathogen, work towards the development of rotavirus vaccines was begun in the USA and Europe. The first candidate rotavirus vaccine was launched by SmithKline-RIT, Belgium, and studied in clinical trials in Finland, Yugoslavia, Italy, Switzerland, Austria and the UK. Efficacy trials in Finland of RIT 4237 strain live oral bovine rotavirus vaccine resulted in some fundamental findings about rotavirus immunity in humans: protection against disease rather than infection; better protection against severe than mild disease and heterotypic rather than homotypic protection. Another bovine rotavirus vaccine, strain WC-3, was studied briefly in France. Also studies of rhesus rotavirus vaccine were started early in Europe, and efficacy studies were carried out in Finland and Sweden. Recently, rhesus-human re-assortant tetravalent (RRV-TV) rotavirus vaccine was tested in a field trial in Finland this study was pivotal for the registration of the vaccine in the USA and European Union countries. Despite extensive experience with rotavirus vaccines in Europe, the need for such vaccines in many European countries still requires further assessment.
Animals↗
Rotavirus gastroenteritis in Finland: burden of disease and epidemiological features.
The burden of disease attributable to childhood rotavirus infection in Finland was assessed from data on hospital admissions for acute gastroenteritis and from reported virological diagnoses of rotavirus from 1985 to 1995. The mean number of hospitalizations (3584 annually in children under 5 y of age) corresponded to approximately 5.6% of the birth cohort. Rotavirus was estimated to be responsible for 54% of cases; accordingly, 3% of all children in Finland are hospitalized for rotavirus diarrhoea. The monthly distribution of hospitalizations for acute diarrhoea showed a similar pattern as monthly diagnoses of rotavirus, with a long epidemic period starting as early as November or December and lasting until June or even July. The prevalent rotavirus G-type throughout the study period was G1, which was detected in over 60% of the cases; however, in the season 1988-89 G4 was the prominent type. Improved case management has led to a shorter duration of hospital stay (3.3 d in 1985 vs. 2.3 d in 1995), but otherwise these was no significant trend for rotavirus gastroenteritis over the years. These findings underscore the need to control rotavirus gastroenteritis with a specific intervention, notably rotavirus vaccination.
Acute Disease↗
Serological evaluation of herpes simplex virus type 1 and type 2 infections in pregnancy.
OBJECTIVE: Serological evaluation of herpes simplex virus infections during pregnancy. METHODS: 2991 serum samples were obtained during 1st, 2nd, and 3rd trimester from 997 pregnant women. Baculovirus expressed glycoproteins gG1 (HSV-1) and gG2 (HSV-2) were used as antigens in ELISA for HSV-1 and HSV-2 IgG and IgA antibodies. RESULTS: The prevalence of HSV-1 gG1 antibodies was 70% and that of HSV-2 gG2 antibodies 16%. Among susceptible women we found five (0.6%) cases with serological evidence of primary HSV-2 infection during pregnancy. Evidence of active HSV-1 infection was found in nine (0.9%) cases. Decline of HSV-2 gG2 IgG antibody levels during pregnancy was pronounced compared with HSV-1 gG1 IgG antibody levels (p < 0.01); also the proportion of seroreversions was considerably higher among HSV-2 seropositives (25%) than among HSV-1 seropositives (3%) (p < 0.001). CONCLUSIONS: HSV-2 gG2 IgG antibodies were readily distinguished from HSV-1 gG1 IgG antibodies by the glycoprotein gG ELISAs. Serological assays for gG2 antibodies should guard against the decline of specific antibodies during pregnancy.
Adult↗
Rotavirus vaccines: development and use for the prevention of diarrhoeal disease.
Rotavirus causes annually 600 000 deaths of young children worldwide, mainly in developing countries. The burden of rotavirus disease is significant also in developed countries and has not diminished with improved hygiene. Natural protective immunity against severe rotavirus disease is built up during the first 2-3 years of life. Likewise, studies with live attenuated oral rotavirus vaccines have shown that the majority of severe episodes of rotavirus diarrhoea are preventable by oral immunization. Candidate rotavirus vaccines were first developed by tissue culture adaptation and attenuation of bovine and rhesus rotaviruses, both of which share the inner core VP6 group antigen with human group A rotaviruses. Subsequently, such heterologous rotaviruses were improved for use as human vaccines by reassortment with human rotaviruses; the resulting reassortants express human rotavirus VP7 surface antigens. A rhesus-human reassortant tetravalent (RRV-TV) rotavirus vaccine was licensed in the USA in 1998, and is recommended for universal immunization of healthy children; licensure in Europe is also imminent. In Finland, this vaccine has prevented 90% of severe episodes of rotavirus gastroenteritis. Protective efficacy of RRV-TV vaccine in developing countries is lower and a more intensive immunization schedule may be needed. Several other candidate rotavirus vaccines, including bovine-human reassortants, are being investigated.
Animals↗
Concurrent administration of rhesus rotavirus tetravalent (RRV-TV) vaccine with pentavalent diphtheria-pertussis-tetanus-Haemophilus influenzae beta-inactivated polio and hepatitis B vaccines.
To investigate the incorporation of oral rhesus-human reassortant rotavirus tetravalent (RRV-TV) vaccine into a routine immunization programme, RRV-TV or oral placebo was coadministered with a pentavalent diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae b (Hib)-inactivated polio vaccine and hepatitis B vaccine following a 3-4-5-mo schedule in a double-blind trial involving 249 infants. Seroconversion rates after 3 doses of rotavirus vaccine were 80% for rotavirus immunoglobulin A (IgA) and 93% for RRV neutralizing antibodies. Rotavirus vaccine did not interfere with the immune responses to diphtheria, tetanus, pertussis, Hib, poliovirus 1, 2 and 3, or hepatitis B. Following the first, second and third doses of vaccine, fever >38 degrees C on the day of vaccination was seen in 31%, 24% and 24%, respectively, with no difference between RRV-TV- and placebo-vaccinated children. This fever was presumably due to the whole-cell pertussis vaccine. Those vaccinees who received concomitant RRV-TV vaccine had another peak of fever around d 4 after the first dose, when 25% of them had fever >38 degrees C and 3% >39 degrees C. It is concluded that RRV-TV rotavirus vaccine can be given concurrently with other childhood immunizations following a 3-4-5-mo vaccination schedule. However, febrile reactions to RRV-TV rotavirus vaccine are common when the first dose is given at the age of 3 mo.
Antibody Formation↗
Humoral and cell-mediated immune responses in humans to the NSP4 enterotoxin of rotavirus.
Rotavirus nonstructural protein NSP4 has recently been suggested to function as a viral enterotoxin and play a role in the pathophysiological mechanism whereby rotaviruses induce diarrhea. The ability of rotavirus NSP4 to stimulate a humoral immune response was examined in naturally infected children and adults, rotavirus vaccinated children, as well as a cellular immune response in adults. In this study, 10 of 10 naturally infected children and 9 of 10 rotavirus-vaccinated children showed a weak humoral IgG immune response to recombinant NSP4 (rNSP4) and/or a synthetic peptide corresponding to residues 114-134 of NSP4. Modest serum IgG antibody responses were detected in 20 of 20 adults. A cellular immune response to rNSP4 and/or NSP4(114-134) were detected in 8 of 10 adults measured either as a T-cell proliferative response (7 of 10), an increased production of IL-2 (6 of 10), or increased production of interferon-gamma (8 of 10). These results indicate that NSP4 induces a humoral immune response in humans and show for the first time that NSP4 stimulates a cellular immune response, possibly including cytolytic T-cells.
Adult↗