Vaccines against norovirus: state of the art trials in children and adults.

Noroviruses (NoVs), a group of nonenveloped, single-stranded RNA viruses belonging to the Caliciviridae family, are the leading cause worldwide of acute infectious gastroenteritis. Serious and eventual fatal outcomes may be observed in at-risk populations such as the very young or older adults, especially in those with underlying diseases. NoVs are highly infectious, with a low number of virus particles causing infection, and they are highly resistant to environmental conditions. NoVs have multiple routes of transmission including faecal-oral, aerosolized vomitus, person to person and via contaminated surfaces or food and water. NoVs can cause frequent and dramatic outbreaks where people congregate in close quarters such as hospitals, long-term care facilities, cruise liners and military barracks and ships. Of the seven NoV genogroups, human disease is most frequently caused by genogroups I and II, although genogroup IV has also been associated with illness. The absence of reliable, high-yield cell culture systems or animal models has steered the development of vaccines towards nonreplicating recombinant capsid proteins including viruslike particles and the sub-virus-sized P particles. Takeda Vaccines is developing a candidate NoV vaccine formulation based on adjuvanted viruslike particles from the GI.1 genotype and a consensus GII.4 sequence derived from three natural GII.4 variants. Early clinical trial results show good tolerability and robust immune responses to both components. This approach is designed to induce broad protective immune responses in adults and children.

A serologic study of organisms possibly associated with pertussis-like coughing.

OBJECTIVE: To assess the frequency of serologic evidence for an infection with microorganisms other than Bordetella pertussis in children with pertussis-like coughs. METHODS: The study was performed within a protective efficacy trial of an acellular pertussis vaccine. Children who coughed for >7 days and had no laboratory evidence of recent infection with B. pertussis were eligible for the present study. Antibodies to Mycoplasma, Chlamydia, respiratory syncytial virus and influenza viruses A and B were measured by complement fixation, and antibodies to adenovirus and parainfluenza viruses 1, 2 and 3 were measured by enzyme-linked immunosorbent assay (ELISA) in acute and convalescent serum samples. Significant titer rises (4-fold titer rise in complement fixation, 100% increase of units in ELISA) and concentrations of antibodies beyond age-specific reference values were regarded as indicative of recent infection. In some children IgM antibodies to Epstein-Barr virus and to cytomegalovirus were also measured by ELISA. RESULTS: A total of 149 of 1179 (12.6%) children had no laboratory evidence of B. pertussis infection. Serologic evidence for other infections were found in 56% (83 of 149). Adenovirus (33), parainfluenza viruses 1, 2 and 3 (18), Mycoplasma pneumoniae (15) and respiratory syncytial virus (14) were most common. Of this group 48% had been vaccinated against pertussis. CONCLUSION: We present data that a proportion of pertussis-like coughs in children may be caused by adenovirus, parainfluenza viruses, respiratory syncytial virus and Mycoplasma. The differential diagnosis of pertussis-like coughs by laboratory methods should include these infections, especially in vaccinated children.

Arbaprostil's [15(R)-15-methyl PGE2] effects on intrauterine pressure in the nonpregnant and pregnant human female--a report of four clinical trials.

Four clinical trials evaluating arbaprostil's effects on the human uterus are reported. The initial two trials measured intrauterine pressures in nonpregnant and pregnant human females following arbaprostil doses of 10, 25, and/or 50 mcg. No statistical differences were found at any dosage level in either study for average uterine resting pressures, average peak pressures, the number of contractions or Montevideo units. Subsequently, two trials determined the abortifacient potential of arbaprostil in pregnant women during the first trimester. The first utilized total daily doses of 400 and 800 mcgs. while the second used total daily doses of 1200 and 1600 mcgs. Vaginal spotting was noted in one woman receiving 400 mcgs, three receiving 1200 mcgs. and in two receiving 1600 mcgs. One episode of moderate bleeding was seen in the latter study. Based on these studies, arbaprostil exhibits little potential for inducing abortifacient activity at these dosages in these patient populations.

The synchronization of human arm movements to external events.

Previous research revealed the existence of coupling mechanisms (e.g. iso-directionality) at the level of perception and action. The present experiment investigated how the strength of the perception-action coupling affected synchronization performance. Arm movements were to be synchronized with a moving light that traveled back and forth from the left to the right side of a runway. Four experimental conditions were administered representing the orthogonal combination of two viewing conditions (intermittent vs. continuous) and two synchronization modes (in-phase, i.e. arm moving in the same direction as the light vs. anti-phase, i.e. arm moving in the opposite direction). Performance outcome measures, movement kinematics, and relative phase were used to examine the data. The results revealed a better synchronization performance when the arm and light traveled in the same direction (iso-directionality) during the continuous viewing condition. Apparently, the strength of the perception-action coupling has a severe impact on the quality of the synchronization of an arm movement to an external event.

Assessment of nine candidate DTP-vaccines with reduced amount of antigen and/or without adjuvant as a fourth (booster-) dose in the second year of life.

BACKGROUND: The incidence of local reactions to diphtheria-, tetanus and acellular pertussis (DTaP-) vaccines in infants and toddlers increases with each subsequent dose, and entire thigh swellings (ETS) have been reported. Lowering the amount of antigen or of adjuvant may decrease the reactogenicity of DTaP while maintaining a protective immune response. OBJECTIVES: Following priming with three doses of a DTaP vaccine during infancy, the safety, reactogenicity and immunogenicity of nine different candidate DTaP-vaccines with reduced amounts of antigen and/or adjuvant given as fourth (booster) dose were evaluated. METHODS: Study participants were healthy infants aged 15-27 months at the time of booster vaccination. Each participant had received three doses of a DTaP vaccine (Infanrixtrade mark, GlaxoSmithKline, Rixensart, Belgium; "reference DTaP") at age 3, 4, and 5 months as part of a previous clinical trial. More than 20,000 children were eligible for participation in the current study protocol at the time. In a first phase at a University hospital-based vaccination study center, nine sequential cohorts of 63-119 study subjects received one of nine different candidate vaccines. Patients and study personal were blinded with regard to which vaccine was currently in use. Reactogenicity was solicited from parents using diary cards. Blood was drawn prior to and 4 weeks after vaccination and immediately centrifuged. The serum was stored at -20 degrees C until serology was performed by ELISA tests. As soon as the first candidate vaccine with adequate reactogenicity and immunogenicity profile was identified in the first study phase, a second study phase was initiated in parallel, to evaluate the safety and reactogenicity of the respective candidate vaccine in private practices in large cohorts (1613-2095 study subjects per group). RESULTS: In the first study phase, DTaP with no aluminum induced the highest frequency of ETS and fever. All other candidate vaccines caused lower rates of local and general reactions than the reference DTaP. As a general rule, vaccines with less antigen induced fewer reactions, although there was no strict dose-response effect and the difference, e.g. between a one-tenth and a one-fifth DTaP dose (DTaP 1/5; DTaP 1/10) was not clinically relevant. Separate injections of Td and aP caused fewer general reactions than the respective TdaP combination and local reactions were higher at the aP than at the Td injection site. Again, as a general rule, reduced amounts of antigen induced lower antibody concentrations, although all vaccines induced "protective" anti-tetanus and anti-diphtheria antibody responses. A total of 92-100% of children showed seroresponses to pertussis antigens even when vaccinated with reduced amounts of the respective pertussis antigen. Elimination of aluminum from DTaP vaccine induced higher anti-tetanus-antibody concentrations and so did a reduction of the amount of diphtheria antigen. Additional examples for antigen interaction were increased antibody concentrations, observed with injection of Td and aP into different limbs. In the second study phase, all three vaccines evaluated (one with a reduced amount of diphtheria antigen, TdaP; one with reduced amounts of all antigens, tdap; and one with a fifth dose of the reference vaccine (DTaP 1/5)) were safe and had an acceptable reactogenicity profile in a total of 4871 study subjects. CONCLUSIONS: Local reactions due to DTaP booster doses in the second year of life can be reduced by reducing the amount of antigen in the respective vaccine while an adequate immunogenicity is maintained. Aluminum-free vaccines induced ETS and fever most commonly. Any changes in vaccine composition should lead to a full evaluation of the new product.

Spatial interactions during bimanual coordination patterns: the effect of directional compatibility.

Whereas previous bimanual coordination research has predominantly focused on the constraining role of timing, the present study addressed the role of spatial (i.e., directional) constraints during the simultaneous production of equilateral triangles with both upper limbs. In addition to coordination modes in which mirror-image and isodirectional movements were performed (compatible patterns), new modes were tested in which the left limb lagged with respect to the right by one triangle side (non-compatible patterns). This resulted in the experimental manipulation of directional compatibility between the limbs. In addition, triangles with either horizontal or vertical orientations were to be drawn in order to assess the role of static images on movement production. Results supported the important role of directional constraints in bimanual coordination. Furthermore, triangles in vertical orientations (with a vertical symmetry axis, i.e., one apex pointing up) were drawn more successfully than those in horizontal orientations (with a horizontal symmetry axis, i.e., one apex pointing left or right), suggesting that the static aspects of a geometric form may affect movement dynamics. Finally, evidence suggested that cognitive processes related to integration of the submovements into a unified plan mediate the performance of new coordination patterns. The implications of the present finding for clinical populations are discussed

Acellular pertussis diphtheria-tetanus-pertussis vaccine containing separately purified pertussis toxoid, filamentous haemagglutinin and 69 kDa outer membrane protein as a booster in children.

In two double-blind, randomized, comparative studies involving a total of 218 children, an acellular pertussis (DTPa) vaccine containing diphtheria and tetanus toxoids and pertussis components filamentous haemagglutinin (FHA), pertussis toxoid (PT), and 69 kDa outer membrane protein (69 kDa OMP) was administered as a booster to 17-month-old and 5-year-old children with a history of routine whole-cell diphtheria-tetanus-pertussis (DTPw) vaccination. The control groups in these studies received DTPw vaccine. Among 17-month-old toddlers, significantly lower proportions of DTPa vaccine recipients had local pain (7.3%), redness (14.5%) and swelling (9.1%) than DTPw vaccine recipients (23.6%, 30.9% and 23.6%, respectively). A trend toward fewer local reactions was also seen in 5-year-old children vaccinated with DTPa in private practice and public clinics although differences were not statistically significant. Fever (rectal temperature > or = 38 degrees C) was reported more frequently for DTPw vaccine recipients in both age groups. While no differences existed between groups in terms of geometric mean antibody titres (GMTs) prior to booster vaccination, anti-PT antibody GMTs were higher among DTPa vaccine recipients than among DTPw vaccine recipients after booster vaccination. The difference was statistically significant in 5-year-old subjects. Furthermore, significantly higher anti-FHA and anti-69 kDa OMP GMTs were seen in DTPa vaccine recipients in both age groups. In pre-vaccination seropositive subjects and in pre-vaccination seronegative subjects the rate of immune response to pertussis antigens was higher for DTPa than for DTPw vaccine recipients with the exception of the rate of response induced to 69 kDa OMP in 5-year-old children.(ABSTRACT TRUNCATED AT 250 WORDS)

Two trials of an acellular DTP vaccine in comparison with a whole-cell DTP vaccine in infants: evaluation of two PT doses and two vaccination schedules.

The present trials being carried out in Switzerland and Turkey, the reactogenicity and immunogenicity of acellular DTP vaccines containing either 25 micrograms or 8 micrograms of PT and 25 micrograms of FHA were compared with those of a conventional whole-cell DTP vaccine during a primary vaccination course following either a 0-1-2 schedule starting at three months of age (Switzerland) or a 0-2-4 schedule starting at two months of age (Turkey). The whole-cell vaccine was associated with significantly more local reactions than the acellular vaccines; general reactions were also more frequent among whole-cell recipients. The 25 micrograms PT dose vaccine was no more reactogenic than the 8 micrograms PT dose vaccine. There was no evidence of increases in frequencies of local or general reactions from one acellular vaccine dose to the next. The 25 micrograms PT dose acellular DTP vaccine resulted in immune responses to all four antigens (PT, FHA, diphtheria and tetanus toxoids) at least equivalent to those observed with whole-cell vaccination. Significantly lower anti-PT antibody levels were seen with the 8 micrograms PT dose vaccine.

Overview of the clinical development of a diphtheria-tetanus--acellular pertussis vaccine.

A tricomponent acellular pertussis vaccine containing pertussis toxoid, filamentous hemagglutinin, and pertactin combined with diphtheria and tetanus toxoids (DTPa) was developed as a less reactogenic alternative to the traditional whole cell pertussis (DTPw) vaccine. In studies of DTPa as a primary vaccination and as a booster dose in DTPa- or DTPw-primed children, the vaccine was safe, well-tolerated, and highly immunogenic; it was less reactogenic than DTPw but at least as immunogenic. A three-dose primary vaccination sequence with DTPa vaccine in the first 6 months of life protects against pertussis under conditions of high infectious pressure. These results support the licensing of the vaccine for primary and booster vaccination in a growing number of countries. Combined DTPa-based pediatric vaccines are in clinical development.

Immunogenicity and safety of a live attenuated varicella vaccine (Oka/SB Bio) in healthy children.

An Oka strain varicella vaccine developed by SmithKline Beecham Biologicals in the early 1980s is registered for immunization of high-risk groups in nine European countries. Because the preparation must be stored at -20 degrees C, it was reformulated to facilitate its use for general vaccination in healthy children with storage at 2-8 degrees C for 2 years. Studies using production lots of the reformulated vaccine in approximately 1400 healthy children are summarized. During the 42-day follow-up, no vaccine-related serious adverse events were reported. Unsolicited reactogenicity rates were low: 14.2% in children ages 9-36 months (the main target age group for the vaccine). Seroconversion rates were 98.6% after a single dose. Consistent reactogenicity and immunogenicity were observed across vaccine lots. After efficacy is demonstrated in other studies, widespread use of this vaccine will prevent a common and potentially serious childhood illness.

The identification of coordination constraints across planes of motion.

Two dominant coordination constraints have been identified during isofrequency conditions in previous work: the egocentric constraint, i.e., simultaneous activation of homologous muscle groups, and the allocentric constraint, i.e., moving the segments in the same direction in extrinsic space. To verify their generalization, bimanual drawing movements were performed in different planes of motion (transverse, frontal, sagittal, frontal-transverse) according to the in-phase and anti-phase mode along the X- and Y-axes. Convergent findings were obtained across the transverse, frontal, and frontal-transverse planes. The in-phase mode along both axes was performed most accurately/consistently, whereas the anti-phase mode resulted in a deterioration of the coordination pattern and this effect was most pronounced when the latter mode was introduced with respect to both dimensions. For sagittal plane motions, the in-phase mode was again superior but the second most optimal configuration was the anti-phase mode along both axes. This finding was hypothesized to result from the familiarity with the pattern since it resembles cycling behavior. It illustrates how cognitive mapping is superimposed onto the dynamics of interlimb coordination. Overall, these results support the presence of both the egocentric and allocentric constraint during bimanual movement production.

Evaluation of a single-sample serological technique for diagnosing pertussis in unvaccinated children.

This study was performed to evaluate the sensitivity of immunoglobulin (Ig)G and IgA antibodies to pertussis toxin and filamentous hemagglutinin in diagnosing pertussis from a single serum sample. The pertussis group was defined according to the World Health Organization pertussis case definition. The control group coughed for 21 days or more but had no microbiological or serological evidence of Bordetella infection. Both cohorts were divided into infants (< 12 months of age), toddlers (1-4 years) and school children (5-10 years). There were 525 subjects in the pertussis group and 321 in the control group, with an even distribution of genders. IgG and IgA antibodies to pertussis toxin and filamentous hemagglutinin were measured in a standardized enzyme immunoassay. Antibody levels beyond the 95 percentile of the control cohort were regarded as indicative of recent contact, setting the specificity level at 0.95. Acute serum samples drawn between 1 week and 3 weeks after the onset of coughing showed a low sensitivity (2-19%) for diagnosing pertussis. In convalescent samples taken 5-10 weeks after the onset of symptoms, detection of IgG anti-pertussis toxin was the best single test, with a sensitivity of 61%, 65%, and 74% in infants, toddlers and school children, respectively. A combination of IgG anti-pertussis toxin and IgA anti-filamentous hemagglutinin using age-specific reference values had a sensitivity of 81-89% in diagnosing pertussis from a single serum sample taken 5-10 weeks after the beginning of symptoms.

Evaluation of live attenuated varicella vaccine (Oka-RIT strain) and combined varicella and MMR vaccination in 13-17-month-old children.

The Oka-RIT strain of live attenuated varicella vaccine at dose levels 5300 PFU (high titre) and 2000 PFU (low titre) was tested in 13-17-month-old children; 50% of the children received the varicella vaccine alone, and the other 50% received it together with a measles-mumps-rubella (MMR) vaccine. The high titre and low titre varicella vaccines induced 96% and 92% seroconversion rates, respectively. Following combined vaccination with MMR, the corresponding seroconversion rates for varicella were significantly lower at 85% and 72% respectively. Seroconversion rates to measles, mumps and rubella were not affected by the combination of varicella vaccine plus MMR vaccination. Single varicella vaccine at both titre levels was found safe, although 10% of the children had minor skin reactions, possibly attributable to the vaccine. Reactions typically associated with MMR vaccination did not significantly increase after the combined varicella plus MMR vaccination. This study confirmed that the Oka-RIT strain varicella vaccine is safe and immunogenic in healthy young children, but failed to find a totally satisfactory combination for a varicella-MMR vaccine.

Dose-response study of RIT 4237 oral rotavirus vaccine in breast-fed and formula-fed infants.

The RIT 4237 live attenuated bovine rotavirus vaccine was given orally at three dose levels to 75 breast-fed, 40 formula-fed and 24 fasting infants ages 4 to 6 months. Vaccine of 10(8.3) (50% tissue culture-infective doses) (TCID50) per dose gave a neutralizing antibody response in 14 of 14 (100%) formula-fed, in 18 of 26 (69%) breast-fed and in 5 of 8 (63%) fasting infants, or an overall response rate of 77% (37 of 48). The overall response rate to a vaccine of 10(7.2) TCID50 per dose was 61% (33 of 49), or slightly but not significantly lower than that at the higher dose level. On the other hand a vaccine of 10(6.3) TCID50 per dose gave a significantly (P less than 0.01) lower composite response rate of 33% (14 of 42). The overall serologic response rate to the vaccine at the two higher doses was somewhat better (24 of 28, 86%) in formula-fed infants than in breast-fed infants (37 of 52, 71%). However, the response rate of the breast-fed infants can also be considered satisfactory. Thus the current recommendation for use of the RIT 4237 vaccine would be administration of a dose of at least 10(8) TCID50 after feeding with either formula or breast milk.

Response to RIT 4237 oral rotavirus vaccine in breast-fed and formula-fed infants.

Twenty-six full-term newborns (15 males and 11 females) were followed-up from birth to 5 months of age. During the first month of life, all of them were breast-fed. Thereafter those infants whose mothers produced enough milk continued breast-feeding (n = 16) while the remaining (n = 10) changed to an adapted milk formula supplying approximately 2 g/kg/day of protein and 100 Kcal/kg/day. At 4 months of life, all infants were vaccinated with one oral dose of RIT 4237 rotavirus vaccine of bovine origin. Before and one month after the vaccination, total protein immunoglobulin and IgM type antibodies against rotavirus were evaluated in serum. Growth, weight, length, head circumference and nutritional serum parameters were comparable in both groups of infants as well as the immune response to the RIT 4237 vaccine. Moreover, the "take" of RIT 4237 oral rotavirus vaccine was not lowered by the concomitant administration of human breast-milk which is known to contain rotavirus antibodies. Therefore, breast-feeding is probably not a contraindication for vaccination with RIT 4237, which is most important in developing countries where rotavirus infection is common in young infants and results in acute diarrhoea often leading to death.

Combined vaccination with live oral polio vaccine and the bovine rotavirus RIT 4237 strain.

A clinical trial was carried out in 3-month-old infants to assess whether concomitant oral administration of live polio and rotavirus RIT 4237 vaccines would reduce their immunogenicities as a result of mutual interference. One hundred and sixty breast-fed male and female infants were randomly allocated to four study groups to receive in a blind fashion the poliovirus vaccine, the RIT 4237 vaccine, a combination of both vaccines or a placebo preparation. Antibody titres were measured in pre- and postvaccination serum samples by the ELISA test and the neutralizing antibody test (NT) for rotavirus and by the NT for polioviruses types 1 and 3. The percentage of subjects with immune responses to rotavirus in the placebo group was low, indicating the absence of wild rotavirus circulation in the population. Antibody responses against polio types 1 and 3 were found in about a quarter of the infants receiving a placebo because the study was performed during a polio vaccination campaign when vaccine viruses are known to circulate. The results showed that 73% of seroconversion was obtained when RIT 4237 was administered alone and that the responses to polioviruses types 1 and 3 were good. However, simultaneous administration of polio and RIT 4237 vaccines caused a significant reduction of the antibody response to rotavirus but not to polioviruses types 1 and 3.

Antibodies to filamentous hemagglutinin of Bordetella pertussis and protection against whooping cough in schoolchildren.

A pertussis outbreak was studied prospectively in an elementary school with 39 pupils. All had been immunized with at least three doses of Finnish diphtheria-tetanus toxoid-pertussis vaccine. Diagnosis of pertussis was based on culture, polymerase chain reaction results, and EIA serology using filamentous hemagglutinin (FHA), pertussis toxin, and 69-kDa outer membrane protein as antigens. At the first sampling, 21 children had symptoms suggestive of pertussis, and 18 were healthy. Of the latter, 8 remained healthy without any antibiotic treatment and 9 developed clinical pertussis 1-22 days later. One child developed cough later, but this symptom did not meet criteria for pertussis. The mean levels of IgG, IgM, and IgA antibodies to FHA were significantly higher in 8 healthy children than in 9 children who developed pertussis after the first sampling (P < .001, P = .027, and P = .011, respectively). The results show that antibodies to FHA of Bordetella pertussis in immunized schoolchildren correlate with protection against pertussis.