Reactogenicity and immunogenicity of a high-titer rhesus rotavirus-based quadrivalent rotavirus vaccine.

We evaluated the reactogenicity and antigenicity of a quadrivalent rotavirus vaccine composed of serotype 3 rhesus rotavirus (RRV) and three single-gene-substitution reassortants of RRV and human strain D (D x RRV, serotype 1), DS1 (DS1 x RRV, serotype 2), or ST3 (ST3 x RRV, serotype 4) in a double-masked study with 302 infants in Caracas, Venezuela. Three doses of the quadrivalent vaccine composed of either 10(5) PFU (low titer) or 10(6) PFU (high titer) of each component were administered to 99 and 101 infants, respectively, at 4-week intervals starting at the second month of age; 102 infants received a placebo. Postvaccination reactions were monitored by home visits every other day during the week postvaccination. The vaccine was associated with the occurrence of mild, short-lived febrile episodes in 26 and 23% of the recipients after the first doses of high- or low-titer vaccine, respectively, in comparison with 13% of the infants receiving the placebo. Febrile reactions occurred less frequently in vaccinees after the second or third dose than after the initial dose. The vaccine was not significantly associated with diarrhea or any additional symptom or sign. Serum specimens obtained shortly before the first, 4 weeks after the first, and 4 weeks after the third dose of vaccine or placebo were tested by an immunoglobulin A enzyme-linked immunosorbent assay and by neutralization assays. Seroresponses occurred significantly more often after 3 doses than after a single dose of either vaccine. Immunoglobulin A responses were observed in 80 and 79% of the infants after 3 doses of high- or low-titer vaccine, respectively. Most of the infants tested developed a neutralization response to RRV after 3 doses of the high- (90%) or low-(88%) titer vaccine. Neutralization response rates to human rotavirus serotypes 1 to 4 after 3 doses were similar in both vaccine and 87 of 90 receiving the high-titer vaccine developed seroresponses, as detected by any of the assays employed. The study indicates that 3 doses of quadrivalent vaccine at a titer of 10(6) PFU of each component offered no advantage over the lower-titer preparation for use in efficacy trials.     

Reactions to and antigenicity of two human-rhesus rotavirus reassortant vaccine candidates of serotypes 1 and 2 in Venezuelan infants.

The reactions to and antigenicity of two human-rhesus rotavirus (RRV) reassortants (human rotavirus strain D x RRV and human rotavirus strain DS1 x RRV) with the VP7 neutralization specificity of a serotype 1 or serotype 2 rotavirus were evaluated in a placebo-controlled double-blind trial in 116 1- to 5-month-old infants in Caracas, Venezuela. The children were randomly divided into five groups to receive orally the following inocula: (i) 10(4) PFU of D x RRV reassortant; (ii) 10(4) PFU of DS1 x RRV reassortant; (iii) 10(4) PFU of RRV; (iv) 5 x 10(3) PFU of D x RRV and 5 x 10(3) PFU of RRV; and (v) placebo. The children were examined daily for 7 days following vaccine administration; 8 to 26% of the vaccinated infants developed a mild febrile reaction which in most cases lasted only 1 day. Seroresponses to rotavirus were observed in 39 to 65% of the vaccinees by plaque neutralization assay and in 57 to 88% by an immunoglobulin A enzyme-linked immunosorbent assay. Vaccine shedding was detected in 53 to 86% of the vaccinees. Analysis of neutralization antibody responses indicates that the VP4 protein represents an important component of the response induced by the vaccines.     

Intussusception among infants given an oral rotavirus vaccine

BACKGROUND: Intussusception is a form of intestinal obstruction in which a segment of the bowel prolapses into a more distal segment. Our investigation began on May 27, 1999, after nine cases of infants who had intussusception after receiving the tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) were reported to the Vaccine Adverse Event Reporting System. METHODS: In 19 states, we assessed the potential association between RRV-TV and intussusception among infants at least 1 but less than 12 months old. Infants hospitalized between November 1, 1998, and June 30, 1999, were identified by systematic reviews of medical and radiologic records. Each infant with intussusception was matched according to age with four healthy control infants who had been born at the same hospital as the infant with intussusception. Information on vaccinations was verified by the provider. RESULTS: Data were analyzed for 429 infants with intussusception and 1763 matched controls in a case-control analysis as well as for 432 infants with intussusception in a case-series analysis. Seventy-four of the 429 infants with intussusception (17.2 percent) and 226 of the 1763 controls (12.8 percent) had received RRV-TV (P=0.02). An increased risk of intussusception 3 to 14 days after the first dose of RRV-TV was found in the case-control analysis (adjusted odds ratio, 21.7; 95 percent confidence interval, 9.6 to 48.9). In the case-series analysis, the incidence-rate ratio was 29.4 (95 percent confidence interval, 16.1 to 53.6) for days 3 through 14 after a first dose. There was also an increase in the risk of intussusception after the second dose of the vaccine, but it was smaller than the increase in risk after the first dose. Assuming full implementation of a national program of vaccination with RRV-TV, we estimated that 1 case of intussusception attributable to the vaccine would occur for every 4670 to 9474 infants vaccinated. CONCLUSIONS: The strong association between vaccination with RRV-TV and intussusception among otherwise healthy infants supports the existence of a causal relation. Rotavirus vaccines with an improved safety profile are urgently needed.     

Prospective study of diarrheal diseases in Venezuelan children to evaluate the efficacy of rhesus rotavirus vaccine

The efficacy of a rhesus rotavirus vaccine (MMU 18006, serotype 3) against infantile diarrhea was evaluated by active home surveillance of a group of 320 children 1-10 months of age in Caracas, Venezuela. During a 1 year period following oral administration of vaccine or placebo under a double-masked code, over 600 diarrheal episodes were detected. Etiologic studies revealed that heat-stable toxin (ST) producing enterotoxigenic E. coli (ETEC) was the most common diarrheal agent detected (34%) followed by enteropathogenic E. coli (EPEC, 10.9%), heat-labile toxin (LT) producing ETEC (7.6%), rotavirus (6.9%), Cryptosporidium (4.8%) and Campylobacter (1.3%). ST-producing ETEC were also recovered from over 20% of control stool specimens obtained during diarrhea-free periods, whereas EPEC, rotavirus, Cryptosporidium, and Campylobacter were rarely detected in such control specimens. Rotavirus was responsible for about one-half of the more severe cases of diarrhea. Twenty-two of 151 infants who received placebo (14.6%) and eight of 151 receiving a 10(4) PFU dose of vaccine (5.3%) had rotavirus diarrhea during the follow-up period for an efficacy level of 64% against any rotavirus diarrhea. However, vaccine efficacy reached 90% against the more severe cases of rotavirus diarrhea and was noticeably high in the 1-4 month age group. Serotypic analysis of the rotaviruses detected suggests that the resistance induced by the vaccine was type specific since significant protection was only evident against serotype 3 rotaviruses. A 10(3) PFU dose tested initially in 18 children did not appear to protect against rotavirus diarrhea.     

Relative frequencies of rotavirus serotypes 1, 2, 3, and 4 in Venezuelan infants with gastroenteritis.

We have used a recently developed monoclonal antibody enzyme-linked immunosorbent assay (K. Taniguchi, T. Urasawa, Y. Morita, H. B. Greenberg, and S. Urasawa, J. Infect. Dis. 155:1159-1166, 1987) for serotyping rotaviruses recovered from 134 Venezuelan infants over a period of 15 months. One hundred and nine of the specimens were typed with the following distribution: serotype 1, 48%; serotype 2, 16%; serotype 3, 22%; and serotype 4, 14%. Three specimens reacted with two different monoclonal antibodies. In addition, 6 specimens (5%) containing enough outer capsid antigen could not be typed; partial RNA sequence analysis of the glycoprotein gene from three of these six strains failed to reveal sequence differences with prototype strains that could be serotyped with the monoclonal antibodies. Variations in the recovery rates of the different serotypes were observed. Serotypes 2, 3, and 4 predominated at the beginning of the study, and serotype 1 predominated at the end of the study. Diarrheal illness appeared to be more prolonged in infants shedding rotavirus serotypes 1 and 3 than in those shedding serotypes 2 and 4.     

Evaluation of the antigenicity and reactogenicity of varying formulations of the rhesus rotavirus-based quadrivalent and the M37 rotavirus vaccine candidates

Three phase l trials of the rhesus rotavirus (RRV) based quardrivalent vaccine [composed of sero-type 3 (RRV), and serotypes 1 (D × RRV), 2 (DS1 × RRV), and 4 (ST3 × RRV) human rotavirus × RRV reassortants] and the M37 (nursery strain) rotavirus vaccine candidates were conducted in an attempt to find a safe and optimally antigenic formulation. Infants 10-20 weeks old received, in trial I, 1) the quadrivalent vaccine as two separate bivalent doses (1 × 10⁴PFUeachof D × RRV and RRV, followed 4 weeks later by 1 × 10⁴ PFU each of DS1 × RRV and ST3 × RRV) or 2) placebo; in trial II, 1) one dose of quadrivalent vaccine (10⁴ PFU of each component), or 2) two doses of quadrivalent vaccine, or 3) a 10⁴ PFU dose of M37 vaccine, or 4) M37 vaccine followed by the quadrivalent vaccine, or 5) placebo; in trial III, 1) a dose of a higher-titered quadrivalent vaccine (10⁵ PFU of each component), or 2) two doses of higher titered quadrivalent vaccine, or 3) a dose of higher titered M37 vaccine (10⁵ PFU) or 4) two doses of M37 vaccine (10⁵ PFU), or 5) M37 vaccine (10⁵ PFU) followed by the higher titered quadrivalent vaccine, or 6) placebo. A mild, transient fever during the first week post-vaccination was associated with the bivalent or quadrivalent vaccines but not with the M37 vaccine. Fourfold or greater serum IgA ELISA responses to rotavirus were observed in 48-92% of the infants receiving quadrivalent vaccine and in 32-50% of those receiving M37 vaccine. Neutralization seroresponses to human rotaviruses in infants receiving quadrivalent vaccine ranged from 9% (to serotype 3 in recipients of the first dose of bivalent vaccine in trial I) to 68% (to serotype 1 in recipients of two doses of higher titered quadrivalent vaccine in trial III). M37 vaccine induced homologous neutralization responses in 33-78% of the infants and responses to human strains sharing its VP7 (Wa) or VP4 (ST3) serotype in 13-35% of the infants. Overall, both vaccine candidates induced a greater number of antibody responses when two doses or a higher titered preparation was administered. © 1994 Wiley-Liss, Inc.     

Diversity of rotavirus serotypes in Mexican infants with gastroenteritis.

One hundred thirty-two stool specimens from infants with rotavirus gastroenteritis hospitalized in two Mexican cities (Mexico City and Mérida) were examined by serotype- and subgroup-specific enzyme immunoassays. Among them, 38 (29%) were serotype 1, 15 (11%) were serotype 2, 13 (10%) were serotype 3, 22 (17%) were serotype 4, none was serotype 5 or 6, and 44 (33%) could not be serotyped. By subgrouping, 121 specimens were characterized as follows: 24 (18%) were subgroup 1, 97 (74%) were subgroup 2, and none had both subgroup specificities. While serotype 1 rotavirus predominated in the Mexico City area for 4 consecutive years (1984 to 1987), serotype 4 predominated in Mérida during the single epidemic season studied (1985). These data demonstrate that all four primary human rotavirus serotypes circulated in Mexico, with serotype 1 being the most prevalent. The seroneutralization responses of 14 of the 22 patients infected with serotype 4 strains had been previously studied. Of these 14 infants, 11 appeared to have primary infections, as indicated by absence of neutralizing antibodies in the acute-phase sera and their young age (8 months on average) at the time of illness. Seven patients seroresponded to serotypes 1 and 4; two seroresponded to serotypes 1, 3, and 4; three seroresponded to serotype 1; and two had low-level seroresponses to serotype 3 or 4. These data indicate that heterotypic neutralizing antibody responses occur frequently following infection with serotype 4 rotaviruses.     

Immunoglobulin G subclass response to a meningococcal quadrivalent polysaccharide-diphtheria toxoid conjugate vaccine

Changes in the immunoglobulin G1 (IgG1)/IgG2 ratio following vaccination can indicate the activation of cellular control mechanisms typical of a T-cell-dependent response. We examined IgG subclass ratios in 17 healthy adults (26 to 55 years of age) before and 4 to 6 weeks following immunization with a quadrivalent meningococcal-polysaccharide diphtheria toxoid conjugate vaccine against serogroups A, C, Y, and W135. Serologic responses were determined by serum bactericidal antibody assay and serogroup-specific IgG, IgG1, and IgG2 enzyme-linked immunosorbent assay. Prevaccination serogroup A-specific IgG1/IgG2 ratios were <1 for all subjects and differed by subject for C, Y, and W-135. Postvaccination, significant increases in IgG, IgG1, and IgG2, were observed for all serogroups. Serogroup-specific IgG1/IgG2 ratios increased for group A (14/17 subjects, 88%), decreased in more than half of subjects for groups C (9/17, 53%) and W135 (12/17, 71%) and decreased for serogroup Y (16/17, 94%). IgG1/IgG2 ratios differed between individual vaccinees and were similar to the responses of adults who received pneumococcal conjugate vaccines or a monovalent C conjugate vaccine. Further studies on IgG subclasses following meningococcal polysaccharide and conjugate vaccination are needed.     

Molecular epidemiology of rotavirus in black infants in South Africa.

The molecular epidemiology of rotavirus infections in black infants in Ga-Rankuwa, South Africa, was investigated by polyacrylamide gel electrophoresis. Between 1983 and 1986, 14 different RNA electrophoretic patterns were observed for children with acute gastroenteritis. These electrophoretypes showed a sequential pattern of appearance, with a limited number being present at any one time. In contrast, for neonates only one RNA electrophoretype was detected, which persisted for at least 3 years.     

Virological and serological studies of Venezuelan equine encephalomyelitis in humans.

During the 1971 epidemic of Venezuelan equine encephalomyelitis (VEE) in south Texas, 203 suspect VEE cases were evaluated by the Center for Disease Control. Sixty-seven were confirmed as cases of VEE. Laboratory confirmation was accomplished by isolation of VEE virus from a serum specimen taken during the acute illness in 50 (75%) of the confirmed cases. Serological confirmation was obtained in 17 cases (25%). Virus isolations were most often obtained from sera collected during the first 3 days of illness. Peak serum virus titers (algebraic mean, 10(5-7) suckling mouse intracranial 50% lethal doses [SMICLD50] per ml) occurred on day 2 of illness. One-half of the sera from which virus was isolated contained at least 10(5) SMICLD50/ml, which has been shown to be sufficient to infect some vector mosquitoes. Blood from 13 virus-positive VEE cases was obtained 1 and 11 months after illness. Hemagglutination-inhibiting, complement-fixing, and neutralizing antibodies were formed by all 13 patients 1 month after illness. Hemagglutination-inhibiting antibody titers were essentially unchanged 11 months after illness. Complement-fixing antibody was undetectable 11 months after illness in 23% of cases and was detectable at dilutions of 1:8 or 1:6 in 77%. Neutralizing antibody (measured by log neutralization index) was not detectable 1 year after illness in one person (8%); titers had declined from 1.0 to 2.0 in 46%, were unchanged in 39%, and were not tested in one person (8%). No evidence of intrafamilial spread of VEE virus was obtained in either of two illness and antibody surveys. A randomized household illness and antibody survey of 681 Port Isabel residents revealed an inapparent infection ratio of 1:11 and an overall antibody prevalence of 3.2%.     

我国轮状病毒疫苗保护效果的Meta分析

目的 评价我国轮状病毒中疫苗(lanzhou lamb rotavirus vaccine,LLR)的保护效果.方法 在PubMed、Cochrane图书馆、CNKI、SinoMed、万方数据库等数据库中检索相关文献,将有关轮状病毒疫苗保护效果的研究纳入分析.采用软件Stata1 1.0中的Meta分析方法对纳入的文献进行异质性检验,选取固定效应模型(P＞0.1)或随机效应模型(P≤0.1)对文献报道的RR进行合并,求其效应合并值及95％ CI.疫苗保护效果为[(1-RR)×100％].结果 共纳入10篇文献,均为队列研究.LLR对轮状病毒胃肠炎的保护率为72％(95％CI:63％ ～79％);对轮状病毒导致的重症腹泻保护率为70％ (95％CI:40％～85％).结论 接种LLR可降低轮状病毒腹泻的发病,减少重症病例.     

Safety and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine after one or two doses given to infants and toddlers

With the emergence of multiple meningococcal serogroups in different geographic areas, broad vaccine protection from infancy is desirable. One hundred and seventy-five infants received either two doses of a meningococcal quadrivalent (A, C, W-135, Y) conjugate vaccine (MenACWY-CRM) at 6 and 12 months, one dose of MenACWY-CRM at 12 months, or MenC at 12 months and MenACWY-CRM at 18 months. Bactericidal antibody titers using human complement were measured before and 1 month after each dose. Injection-site reactions were reported by 22–45% of participants following MenACWY-CRM given at 6 or 12 months. Similar proportions of subjects had injection-site reactions following two doses of MenACWY-CRM (32–41%) or one dose of MenC (26–44%). The incidence of systemic adverse events was comparable between groups. After two doses of MenACWY-CRM, the percentages of participants reporting hSBA titers ≥8 were 100% for C, W-135, and Y, and 84% for A. Serogroup C titers were more than 10-fold higher after two doses of MenACWY-CRM than after one dose of MenC or MenACWY-CRM at 12 months. Serogroup C titers were comparable following a single dose of MenACWY-CRM or MenC at 12 months. MenACWY-CRM is well tolerated and immunogenic given at 12 months, or two doses at 6 and 12 months of age.