Immune Status of Infants Fed Soy-Based Formulas With or Without Added Nucleotides for 1 Year: Part 1: Vaccine Responses, and Morbidity Significant Correlation Between the Infant Gut Microbiome and Rotavirus Vaccine Response in Rural Ghana Interference of oral poliovirus vaccine on RIT 4237 oral rotavirus vaccine Human neonatal rotavirus vaccine (RV3-BB) targets rotavirus from birth The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants. Rotavirus-Specific Immunoglobulin A Responses Are Impaired and Serve as a Suboptimal Correlate of Protection Among Infants in Bangladesh Seroefficacy of Vi Polysaccharide–Tetanus Toxoid Typhoid Conjugate Vaccine (Typbar TCV) An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants. Effect of human rotavirus vaccine on severe diarrhea in African infants. Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial. Effect of a mixture of micronutrients, but not of bovine colostrum concentrate, on immune function parameters in healthy volunteers: a randomized placebo-controlled study Albendazole treatment of children with ascariasis enhances the vibriocidal antibody response to the live attenuated oral cholera vaccine CVD 103-HgR. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. Supplementation with zinc, but not vitamin A, improves seroconversion to vibriocidal antibody in children given an oral cholera vaccine. Evaluation of Safety, Immunogenicity and Efficacy of an Attenuated Rotavirus Vaccine, RIX4414: A Randomized, Placebo-Controlled Trial in Latin American Infants Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5-9-year-old Indonesian children Immunologic response to oral cholera vaccination in a crossover study: a novel placebo effect. Evaluation of RIX4414, a live, attenuated rotavirus vaccine, in a randomized, double-blind, placebo-controlled phase 2 trial involving 2464 Singaporean infants. Oral Iodine Supplementation Does Not Reduce Neutralizing-Antibody Responses to Oral Poliovirus Vaccine 919 Impact of enterovirus and other enteric pathogens on oral polio and rotavirus vaccine performance in Bangladeshi infants Effect of Antihelminthic Treatment on Vaccine Immunogenicity to a Seasonal Influenza Vaccine in Primary School Children in Gabon: A Randomized Placebo-Controlled Trial Immunogenicity, safety and protective efficacy of one dose of the rhesus rotavirus vaccine and serotype 1 and 2 human-rhesus rotavirus reassortants in children from Lima, Peru. Transplacental rotavirus IgG interferes with immune response to live oral rotavirus vaccine ORV-116E in Indian infants. Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Probiotic bacteria stimulate
virus–specific neutralizing antibodies
following a booster polio vaccination Evaluation of a probiotics, Bifidobacterium breve BBG-01, for enhancement of immunogenicity of an oral inactivated cholera vaccine and safety: a randomized, double-blind, placebo-controlled trial in Bangladeshi children under 5 years of age. Effect of administration of 200,000 IU of vitamin A to women within 24 hrs after delivery on response to PPV administered to the newborn. LARGE-SCALE FIELD TRIAL OF TY21A LIVE ORAL TYPHOID VACCINE IN ENTERIC-COATED CAPSULE FORMULATION Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. Combined vaccination with live oral polio vaccine and the bovine rotavirus RIT 4237 strain. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial Evaluation of immune responses to an oral typhoid vaccine, Ty21a, in children from 2 to 5 years of age in Bangladesh. Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial. A comparison of heterogeneity variance estimators in combining results of studies. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial Impact of Withholding Breastfeeding at the Time of Vaccination on the Immunogenicity of Oral Rotavirus Vaccine—A Randomized Trial
Background Immunologic development of soy-fed infants has not been extensively studied . Early studies of soy flour – based formulas showed decreased immunoglobulin production when soy protein intake was limited . However , there were no significant differences in rotavirus vaccine responses between breast-fed and soy protein isolate – based formula-fed infants .  Nucleotides added to milk-based formula benefit infant immune status , but reports of the immunologic effects of adding nucleotides to soy-based formula are not available . This study evaluated immune status and morbidity of infants fed soy protein isolate formulas with and without added nucleotides for 1 year . Methods Newborn , term infants enrolled in a masked 12-month feeding trial were assigned r and omly to groups fed soy formula with or without added nucleotides ( n = 94 , n = 92 ) . A nonr and omized human milk/formula cohort ( n = 81 ) was concurrently enrolled . Recommended immunizations were administered at 2 , 4 , and 6 months . Immune status was determined from antibody responses to Haemophilus influenzae type b , tetanus , diphtheria , and poliovirus vaccines at 6 , 7 , and 12 months . Parents and physicians reported morbidity data . Results All vaccine responses were within normal ranges . No response differences were observed between infants fed soy formula and those fed nucleotide-supplemented soy . However , antibody to H. influenzae type b at 7 and 12 months was higher in infants fed nucleotide-supplemented soy than in infants fed human milk/formula ( P = 0.007 , P = 0.008 , respectively ) . Human milk/formula-fed infants had higher poliovirus neutralizing antibody at 12 months than did soy-fed infants ( P = 0.016 ) . Morbidity analyses showed that only physician-reported diarrhea was different among groups ( groups fed human milk/formula had less diarrhea than did soy groups , P = 0.011 ) . Conclusions Term infants fed soy protein isolate – based formulas  have normal immune development as measured by antibody responses to childhood immunizations Background . Rotavirus ( RV ) is the leading cause of diarrhea-related death in children worldwide and 95 % of RV-associated deaths occur in Africa and Asia where RV vaccines ( RVVs ) have lower efficacy . We hypothesize that differences in intestinal microbiome composition correlate with the decreased RVV efficacy observed in poor setting s. Methods . We conducted a nested , case-control study comparing prevaccination , fecal microbiome compositions between 6-week old , matched RVV responders and nonresponders in rural Ghana . These infants ' microbiomes were then compared with 154 age-matched , healthy Dutch infants ' microbiomes , assumed to be RVV responders .  Fecal microbiome analysis was performed in all groups using the Human Intestinal Tract Chip . Results . We analyzed findings in 78 Ghanaian infants , including 39 RVV responder and nonresponder pairs . The overall microbiome composition was significantly different between RVV responders and nonresponders ( FDR , 0.12 ) , and Ghanaian responders were more similar to Dutch infants than nonresponders ( P = .002 ) . RVV response correlated with an increased abundance of Streptococcus bovis and a decreased abundance of the Bacteroidetes phylum in comparisons between both Ghanaian RVV responders and nonresponders ( FDR , 0.008 vs 0.003 ) and Dutch infants and Ghanaian nonresponders ( FDR , 0.002 vs 0.009 ) . Conclusions . The intestinal microbiome composition correlates significantly with RVV immunogenicity and may contribute to the diminished RVV immunogenicity observed in developing countries A vaccination trial , performed on 86 3-month-old infants , has shown that the ability of the RIT 4237 live attenuated rotavirus strain to induce seroconversion is dramatically reduced when administered with live poliovirus vaccine . In a subsequent trial performed on 93 infants the attempt to overcome the poliovirus interference by administering two doses of associated vaccines was unsuccessful . No interference by the RIT 4237 strain on live attenuated polioviruses was observed Background A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine . Methods We conducted a r and omized , double‐blind , placebo‐controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine ( RV3‐BB ) in preventing rotavirus gastroenteritis . Healthy newborns received three doses of RV3‐BB , administered according to a neonatal schedule ( 0 to 5 days , 8 weeks , and 14 weeks of age ) or an infant schedule ( 8 weeks , 14 weeks , and 18 weeks of age ) , or placebo . The primary analysis was conducted in the per‐ protocol population , which included only participants who received all four doses of vaccine or placebo within the visit windows , with secondary analyses performed in the intention‐to‐treat population , which included all participants who underwent r and omization . Results Among the 1513 participants in the per‐ protocol population , severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6 % of the participants in the placebo group ( 28 of 504 babies ) , in 1.4 % in the neonatal‐schedule vaccine group ( 7 of 498 ) , and in 2.7 % in the infant‐schedule vaccine group ( 14 of 511 ) . This result ed in a vaccine efficacy of 75 % ( 95 % confidence interval [ CI ] , 44 to 91 ) in the neonatal‐schedule group ( P<0.001 ) , 51 % ( 95 % CI , 7 to 76 ) in the infant‐schedule group ( P=0.03 ) , and 63 % ( 95 % CI , 34 to 80 ) in the neonatal‐schedule and infant‐schedule groups combined ( combined vaccine group ) ( P<0.001 ) . Similar results were observed in the intention‐to‐treat analysis ( 1649 participants ) ; the vaccine efficacy was 68 % ( 95 % CI , 35 to 86 ) in the neonatal‐schedule group ( P=0.001 ) , 52 % ( 95 % CI , 11 to 76 ) in the infant‐schedule group ( P=0.02 ) , and 60 % ( 95 % CI , 31 to 76 ) in the combined vaccine group ( P<0.001 ) . Vaccine response , as evidence d by serum immune response or shedding of RV3‐BB in the stool , occurred in 78 of 83 participants ( 94 % ) in the neonatal‐schedule group and in 83 of 84 participants ( 99 % ) in the infant‐schedule group . The incidence of adverse events was similar across the groups . No episodes of intussusception occurred within the 21‐day risk period after administration of any dose of vaccine or placebo , and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant‐schedule group . Conclusions RV3‐BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia . ( Funded by the Bill and Melinda Gates Foundation and others ; Australian New Zeal and Clinical Trials Registry number , ACTRN12612001282875 . BACKGROUND Oral poliovirus vaccine is less immunogenic and effective in low-income countries than in high-income countries , similarly to other oral vaccines . The high prevalence of intestinal pathogens and associated environmental enteropathy has been proposed to explain this problem . Because administration of an antibiotic has the potential to resolve environmental enteropathy and clear bacterial pathogens , we aim ed to assess whether antibiotics would improve oral poliovirus vaccine immunogenicity . METHODS We did a double-blind , r and omised , placebo-controlled trial of the effect of azithromycin on the immunogenicity of serotype-3 monovalent oral poliovirus vaccine given to healthy infants living in 14 blocks of Vellore district , India . Infants were eligible to participate if they were 6 - 11 months old , available for the study duration , and lacked serum neutralising antibodies to serotype-3 poliovirus . Infants were r and omly assigned ( 1:1 ) at enrolment to receive oral 10 mg/kg azithromycin or placebo once daily for 3 days , followed by serotype-3 monovalent oral poliovirus vaccine on day 14 . The primary outcome was detection of serum neutralising antibodies to serotype-3 poliovirus at a dilution of one in eight or more on day 35 and was assessed in the per- protocol population ( ie , all those who received azithromycin or placebo , oral poliovirus vaccine , and provided a blood sample according to the study protocol ) . Safety outcomes were assessed in all infants enrolled in the study . The trial is registered with the Clinical Trials Registry India , number CTRI/2014/05/004588 . FINDINGS Between Aug 5 , 2014 , and March 21 , 2015 , 754 infants were r and omly assigned : 376 to receive azithromycin and 378 to placebo . Of these , 348 ( 93 % ) of 376 in the azithromycin group and 357 ( 94 % ) of 378 infants in the placebo group completed the study per protocol . In the azithromycin group , 175 ( 50 % ) seroconverted to serotype-3 poliovirus compared with 192 ( 54 % ) in the placebo group ( risk ratio 0·94 , 95 % CI 0·81 - 1·08 ; p=0·366 ) . Azithromycin  reduced faecal biomarkers of environmental enteropathy ( calprotectin , myeloperoxidase , α1-antitrypsin ) and the prevalence of bacterial but not viral or eukaryotic pathogens . Viral pathogens were associated with lower seroconversion . Three serious adverse events were reported ( two in the azithromycin group and one in the placebo group ) , but none was considered related to the study interventions . INTERPRETATION Azithromycin did not improve the immunogenicity of oral poliovirus vaccine despite reducing biomarkers of environmental enteropathy and the prevalence of pathogenic intestinal bacteria . Viral interference and innate antiviral immune mechanisms might be more important determinants of the immunogenicity of live-virus oral vaccines . FUNDING Bill & Melinda Gates Foundation Abstract Background Rotavirus (RV)–specific immunoglobulin A ( IgA ) responses following oral RV vaccination are impaired in low-income countries , where the utility of RV-IgA as a correlate of protection ( CoP ) remains unclear . In a monovalent oral RV vaccine ( Rotarix ) efficacy trial among infants in Dhaka , Bangladesh , we identified factors associated with poor RV-IgA responses and explored the utility of RV-IgA as a CoP. Methods Infants were r and omized to receive Rotarix or no Rotarix at 10 and 17 weeks of life and followed with active diarrheal surveillance .  RV-IgA concentration , seroconversion , and seropositivity were determined at 18 weeks of life and analyzed for correlation(s ) with rotavirus diarrhea ( RVD ) and for contribution to Rotarix vaccine effect . Results Among vaccinated infants , overall RV-IgA geometric mean concentration was 21 U/mL ; only 27 % seroconverted and 32 % were seropositive after vaccination . Increased RV-specific maternal antibodies significantly impaired immunogenicity . Seroconversion was associated with reduced risk of RVD through 1 year of life , but RV-IgA seropositivity only explained 7.8 % of the vaccine effect demonstrated by the clinical endpoint ( RVD ) . Conclusions RV-IgA responses were low among infants in Bangladesh and were significantly impaired by maternal antibodies . RV-IgA is a suboptimal CoP in this setting ; an improved CoP for RV in low-income countries is needed . Clinical Trials Registration NCT01375647 Background Salmonella Typhi is the major cause of enteric fever in lower-income countries . New conjugate vaccines show promise as public health interventions , but there are no efficacy data available from endemic areas . Methods Data were obtained from a previously published phase 3 r and omized controlled trial comparing Vi polysaccharide-tetanus toxoid conjugate vaccine ( Vi-TT ) with Vi polysaccharide vaccine ( Vi-PS )  in participants aged 2 - 45 years . An additional open-label arm administered Vi-TT to children aged 6 - 23 months . The proportion of participants with presumed clinical or sub clinical infection ( " seroincidence " ) was determined using mixture models and compared using relative risks ( RRs ) . Results Of 387 participants , 81 ( 21 % ) were classified as having presumed typhoid infection during the 2-year postvaccination period . Seroincidence was lower in participants r and omized to Vi-TT rather than Vi-PS among those aged 2 - 45 years ( RR , 0.372 ; 95 % confidence interval [ CI ] , .235-.588 ; P < .001 ) and those aged 2 - 15 years ( RR , 0.424 ; 95 % CI , .231-.778 ; P = .004 ) . There was no difference in seroincidence for Vi-TT between those aged 2 - 45 years and those aged 6 - 23 months ( RR , 1.073 ; 95 % CI , .563 - 2.046 ; P = .83 ) . Vaccine seroefficacy was 85 % ( 95 % CI , 80%-88 % ) . Conclusion This is the first field estimate of the seroefficacy of a Vi-TT vaccine and shows that Typbar TCV substantially reduces the number of serologically defined clinical or sub clinical infections in infants , children , and adults . These results support the recent World Health Organization recommendations for deployment of typhoid conjugate vaccines in high-burden areas BACKGROUND Dietary selenium intakes in many countries , including the United Kingdom , are lower than international recommendations . No functional consequences of these lower intakes have been recognized , although experimental studies suggest that they might contribute to reduced immune function , increased cancer incidence , and increased susceptibility to viral disease . OBJECTIVE The objective was to assess whether administration of small selenium supplements to otherwise healthy UK subjects leads to functional changes in immune status and the rates of clearance and mutation of a picornavirus : live attenuated polio vaccine . DESIGN Twenty-two adult UK subjects with relatively low plasma selenium concentrations ( < 1.2 micromol/L , approximately 60 % of those screened ) received 50 or 100 microg Se ( as sodium selenite ) or placebo daily for 15 wk in a double-blind study . All subjects received an oral live attenuated poliomyelitis vaccine after 6 wk and enriched stable (74)Se intravenously 3 wk later . RESULTS Selenium supplementation increased plasma selenium concentrations , the body exchangeable selenium pool ( measured by using (74)Se ) , and lymphocyte phospholipid and cytosolic glutathione peroxidase activities . Selenium supplements augmented the cellular immune response through an increased production of interferon gamma and other cytokines , an earlier peak T cell proliferation , and an increase in T helper cells . Humoral immune responses were unaffected . Selenium-supplemented subjects also showed more rapid clearance of the poliovirus , and the poliovirus reverse transcriptase-polymerase chain reaction products recovered from the feces of the supplemented subjects contained a lower number of mutations . CONCLUSIONS The data indicate that these subjects had a functional selenium deficit with suboptimal immune status and a deficit in viral h and ling . They also suggest that the additional 100 microg Se/d may be insufficient to support optimal function BACKGROUND Strategies are needed to improve oral rotavirus vaccine ( RV ) , which provides suboptimal protection in developing countries . Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function . METHODS Infants 5weeks old living in urban Vellore , India were enrolled in a r and omized , double-blind , placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc ( 5 mg ) , probiotic ( 1010Lactobacillus rhamnosus GG ) or placebo on the immunogenicity of two doses of RV ( Rotarix ® , GlaxoSmithKline Biologicals ) given at 6 and 10weeks of age . Infants were eligible for participation if healthy , available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose . The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration . RESULTS The study took place during July 2012 to February 2013 . 620 infants were r and omized equally between study arms and 551 ( 88.9 % ) completed per protocol . Seroconversion was recorded in 54/137 ( 39.4 % ) , 42/136 ( 30.9 % ) , 40/143 ( 28.0 % ) , and 37/135 ( 27.4 % ) infants receiving ( 1 ) probiotic and zinc , ( 2 ) probiotic and placebo , ( 3 ) placebo and zinc , ( 4 ) two placebos  . Seroconversion showed a modest improvement among infants receiving probiotic ( difference between groups 1 , 2 and 3 , 4 was 7.5 % ( 97.5 % Confidence Interval ( CI ) : -1.4 % , 16.2 % ) , p=0.066 ) but not zinc ( difference between groups 1 , 3 and 2 , 4 was 4.4 % ( 97.5 % CI : -4.4 % , 13.2 % ) , p=0.272 ) . 16 serious adverse events were recorded , none related to study interventions . CONCLUSIONS Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India . A modest effect of combined supplementation deserves further investigation . TRIAL REGISTRATION The trial was registered in India ( CTRI/2012/05/002677 ) BACKGROUND Rotavirus is the most common cause of severe gastroenteritis among young children worldwide . Data are needed to assess the efficacy of the rotavirus vaccine in African children . METHODS We conducted a r and omized , placebo-controlled , multicenter trial in South Africa ( 3166 infants ; 64.1 % of the total ) and Malawi ( 1773 infants ; 35.9 % of the total ) to evaluate the efficacy of a live , oral rotavirus vaccine in preventing severe rotavirus gastroenteritis . Healthy infants were r and omly assigned in a 1:1:1 ratio to receive two doses of vaccine ( in addition to one dose of placebo ) or three doses of vaccine - the pooled vaccine group - or three doses of placebo at 6 , 10 , and 14 weeks of age . Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were grade d with the use of the Vesikari scale . RESULTS A total of 4939 infants were enrolled and r and omly assigned to one of the three groups ; 1647 infants received two doses of the vaccine , 1651 infants received three doses of the vaccine , and 1641 received placebo . Of the 4417 infants included in the per- protocol efficacy analysis , severe rotavirus gastroenteritis occurred in 4.9 % of the infants in the placebo group and in 1.9 % of those in the pooled vaccine group ( vaccine efficacy , 61.2 % ; 95 % confidence interval , 44.0 to 73.2 ) . Vaccine efficacy was lower in Malawi than in South Africa ( 49.4 % vs. 76.9 % ) ; however , the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa ( 6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year ) . Efficacy against all-cause severe gastroenteritis was 30.2 % . At least one serious adverse event was reported in 9.7 % of the infants in the pooled vaccine group and in 11.5 % of the infants in the placebo group . CONCLUSIONS Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life . ( Clinical Trials.gov number , NCT00241644 . ) BACKGROUND Despite the success of rotavirus vaccines , suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation . A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth . METHODS This phase 2a r and omised , double-blind , three-arm , placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zeal and between Jan 13 , 2012 , and April 17 , 2014 . Healthy , full-term ( ≥36 weeks gestation ) babies , who weighed at least 2500 g , and were 0 - 5 days old at the time of r and omisation were r and omly assigned ( 1:1:1 ; computer-generated ; telephone central allocation ) according to a concealed block r and omisation schedule to oral RV3-BB vaccine with the first dose given at 0 - 5 days after birth ( neonatal schedule ) , to vaccine with the first dose given at about 8 weeks after birth ( infant schedule ) , or to placebo . The primary endpoint was cumulative vaccine take ( serum immune response or stool shedding of vaccine virus after any dose ) after three doses . The immunogenicity analysis included all r and omised participants with available outcome data . This trial is registered with the Australian New Zeal and Clinical Trials Registry , ACTRN12611001212943 . FINDINGS 95 eligible participants were r and omised , of whom 89 were included in the primary analysis .  A cumulative vaccine take was detected in 27 ( 90 % ) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four ( 13 % ) of 32 participants in the placebo group ( difference in proportions 0·78 , 95 % CI 0·55 - 0·88 ; p<0·0001 ) . 25 ( 93 % ) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight ( 25 % ) of 32 participants in the placebo group ( difference in proportions 0·68 , 0·44 - 0·81 ; p<0·0001 ) . A serum IgA response was detected in 19 ( 63 % ) of 30 participants and 20 ( 74 % ) of 27 participants , and stool shedding of RV3-BB was detected in 21 ( 70 % ) of 30 participants and 21 ( 78 % ) of 27 participants in the neonatal and infant schedule groups , respectively . The frequency of solicited and unsolicited adverse events was similar across the treatment groups . RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo . INTERPRETATION RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule . A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines . FUNDING Australian National Health and Medical Research Council , the New Zeal and Health Research Council , and the Murdoch Childrens Research Institute Background Supplementation of nutritional deficiencies helps to improve immune function and resistance to infections in malnourished subjects . However , the suggested benefits of dietary supplementation for immune function in healthy well nourished subjects is less clear . Among the food constituents frequently associated with beneficial effects on immune function are micronutrients such as vitamin C , vitamin E , β-carotene and zinc , and colostrum . This study was design ed to investigate the effects these ingredients on immune function markers in healthy volunteers . Methods In a double-blind , r and omized , parallel , 2 * 2 , placebo-controlled intervention study one hundred thirty-eight healthy volunteers aged 40–80 y ( average 57 ± 10 y ) received one of the following treatments : ( 1 ) bovine colostrum concentrate 1.2 g/d ( equivalent to ~500 mg/d immunoglobulins ) , ( 2 ) micronutrient mix of 288 mg vitamin E , 375 mg vitamin C , 12 mg β-carotene and 15 mg zinc/day , ( 3 ) combination of colostrum and micronutrient mix , or ( 4 ) placebo .  Several immune function parameters were assessed after 6 and 10 weeks . Data were analyzed by analysis of variance . Groups were combined to test micronutrient treatment versus no micronutrient treatment , and colostrum treatment versus no colostrum treatment . Results Overall , consumption of the micronutrient mix significantly enhanced delayed-type hypersensitivity ( DTH ) responses ( p < 0.05 ) . Adjusted covariance analysis showed a positive association between DTH and age . Separate analysis of younger and older age groups indicated that it was the older population that benefited from micronutrient consumption . The other immune function parameters including responses to systemic tetanus and oral typhoid vaccination , phagocytosis , oxidative burst , lymphocyte proliferation and lymphocyte subset distribution were neither affected by the consumption of micronutrients nor by the consumption of bovine colostrum concentrate . Conclusion Consumption of bovine colostrum had no effect on any of the immune parameters assessed . The micronutrient mix enhanced cellular immunity as measured by DTH , with an increased effect by incremental age , but did not affect any of the other immune parameters measured . Although correlations between decreased DTH and enhanced risk of certain infection have been reported , it remains unclear whether and enhanced DTH response actually improves immune defense . The present data suggests that improvement of immune parameters in a population with a generally good immune and nutritional status is limited and that improvement of immune function in this population may be difficult Because concurrent infections with geohelminth parasites might impair the immune response to oral vaccines , we studied the vibriocidal antibody response to the oral cholera vaccine CVD 103-HgR in children infected with Ascaris lumbricoides and investigated the effect of albendazole pretreatment on the postvaccination response . Children with ascariasis were r and omized to receive either 2 sequential doses of 400 mg of albendazole or placebo . After the second dose , CVD 103-HgR was given , and serum vibriocidal antibody levels were measured before and 10 days after vaccination . Postvaccination rates of seroconversion were greater in the treatment group that received albendazole ( P=.06 ) . Significantly greater rates of seroconversion and geometric mean titer were observed in the albendazole group in subjects with non-O ABO blood groups . A significant association was observed between vibriocidal seroconversion rates and treatment group , suggesting that A. lumbricoides infections impair the immune response to oral cholera vaccine , particularly in subjects of non-O blood groups When tested under conditions of moderate transmission of typhoid fever , a liquid formulation of the oral typhoid fever vaccine Ty21a had a protective efficacy of 96 % in Egypt , and an enteric coated capsule formulation had an efficacy of 67 % in Chile . We compared the two formulations under conditions of intense transmission of typhoid fever in Indonesia in a r and omised , double-blind trial . 20,543 subjects ( age range 3 - 44 years ) received either three doses of enteric coated capsules containing placebo or live Ty21a , or three doses of lyophilised placebo or live Ty21a reconstituted with phosphate buffer . During 30 months of follow-up , the rate of blood-culture-positive typhoid fever among controls was 810/100,000 per year . Rates of typhoid fever were 379/100,000 per year for subjects who received the liquid formulation of vaccine and 468/100,000 per year for subjects who received enteric coated capsules . The protective efficacies of the liquid and enteric coated formulations were 53 % and 42 % , respectively . Neither formulation protected against infection with Salmonella paratyphi A. No major side-effects were noted , but the overall incidence of side-effects was greater in the vaccine groups . Under conditions of intense transmission , Ty21a protected against typhoid fever ; however , because Ty21a will not protect all individuals , there is a need for additional approaches to prevent the disease BACKGROUND The safety and efficacy of an attenuated G1P[8 ] human rotavirus ( HRV ) vaccine were tested in a r and omized , double-blind , phase 3 trial . METHODS We studied 63,225 healthy infants from 11 Latin American countries and Finl and who received two oral doses of either the HRV vaccine ( 31,673 infants ) or placebo ( 31,552 infants ) at approximately two months and four months of age . Severe gastroenteritis episodes were identified by active surveillance . The severity of disease was grade d with the use of the 20-point Vesikari scale . Vaccine efficacy was evaluated in a subgroup of 20,169 infants ( 10,159 vaccinees and 10,010 placebo recipients ) . RESULTS The efficacy of the vaccine against severe rotavirus gastroenteritis and against rotavirus-associated hospitalization was 85 percent ( P<0.001 for the comparison with placebo ) and reached 100 percent against more severe rotavirus gastroenteritis . Hospitalization for diarrhea of any cause was reduced by 42 percent ( 95 percent confidence interval , 29 to 53 percent ; P<0.001 ) . During the 31-day window after each dose , six vaccine recipients and seven placebo recipients had definite intussusception ( difference in risk , -0.32 per 10,000 infants ; 95 percent confidence interval , -2.91 to 2.18 ; P=0.78 ) . CONCLUSIONS Two oral doses of the live attenuated G1P[8 ] HRV vaccine were highly efficacious in protecting infants against severe rotavirus gastroenteritis , significantly reduced the rate of severe gastroenteritis from any cause , and were not associated with an increased risk of intussusception . ( Clinical Trials.gov numbers , NCT00139347 and NCT00263666 . To investigate whether micronutrient supplementation could improve the vibriocidal antibody response of children to a killed oral cholera vaccine , 2 - 5-year-old children were r and omly assigned to receive vitamin A and zinc ( AZ group ) , vitamin A and a placebo ( A group ) , zinc and a placebo ( Z group ) , or both placebos ( P group ) . All children received 2 doses of the vaccine . The number of children who had a > or = 4-fold increase in vibriocidal antibody was significantly greater in the AZ group than in the P group ( P = .025-.028 ) . Factorial analysis suggested that the proportion of children with a > or = 4-fold increase in vibriocidal antibody titer was significantly greater in the zinc-supplemented groups than in the groups that did not receive zinc ( P = .013-.048 ) and that vitamin A supplementation did not have a significant effect . Thus , supplementation with zinc improves seroconversion to vibriocidal antibody and , hence , has the potential to improve the efficacy of oral cholera vaccine in children Background : A live attenuated monovalent rotavirus vaccine RIX4414 was developed with a human strain of G1P1A P[8 ] specificity to reduce the rotavirus burden in children . Methods : A double blind , r and omized , placebo-controlled study evaluated the efficacy , immunogenicity , safety and reactogenicity of 2 oral doses of RIX4414 ( 104.7 , 105.2 or 105.8 focus-forming units ) at 2 and 4 months coadministered with routine vaccinations and oral poliovirus vaccine given for study purpose s at least 14 days apart . The 2155 infants ( 1618 vaccine/537 placebo ) enrolled in Brazil , Mexico and Venezuela were followed until 1 year of age . Results : Antirotavirus IgA seroconversion rates 2 months after dose 2 ranged between 61 % ( 10 4.7 ffu group ) and 65 % ( 105.8 ffu group ) , and most of the infants had seroprotective levels of antibodies to coadministered routine vaccinations . The reactogenicity profile of RIX4414 was similar to that of the placebo , and no vaccination-related serious adverse events were reported . Protective efficacy against severe and any rotavirus gastroenteritis from 15 days post-dose 2 was highest in the 105.8 ffu group [ 86 % ; 95 % confidence interval ( 95 % CI ) , 63–96 % and 70 % ( 95 % CI 46–84 % ) , P < 0.001 , 2-sided Fisher 's exact test ] . The efficacy against hospitalization was 79 % ( 95 % CI 48–92 % ) for pooled vaccine groups . Multiple rotavirus serotypes [ G1 ( 50 % ) , G9 ( 40 % ) , G2 , G3 and G4 ] were identified from gastroenteritis stools ( enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction ) during the study period . For severe gastroenteritis caused by G9 serotypes , the protection reached 77 % ( 95 % CI 18–96 % ) in the 105.8 ffu group , providing proof of concept that the monovalent G1P1A P[8 ] human rotavirus vaccine elicits cross-protection against the G9 strain . A reduction in any and severe rotavirus gastroenteritis was already observed at post-dose 1 ( period : day of dose 1 to 14 days post-dose 2 ) in vaccinees compared with placebo recipients . Conclusions : Two doses of RIX4414 are highly efficacious , providing cross-protection ( G1 and G9 strains , prevalent during this study ) and early protection against any and severe rotavirus gastroenteritis and hospitalization to infants in Latin America Oral vaccines offer great promise as public-health measures to prevent disease in less-developed countries . CVD 103-HgR , a genetically engineered , attenuated , Vibrio cholerae O1 strain has proved effective in industrialised countries . We have assessed the safety , immunogenicity , and excretion of this live cholera vaccine in children in north Jakarta , Indonesia . 412 children aged 5 - 9 years received single doses of 5 x 10(6 ) , 5 x 10(7 ) , 5 x 10(8 ) , 5 x 10(9 ) , or 1 x 10(10 ) colony forming units ( CFU ) of CVD 103-HgR or placebo ( 5 x 10(8 ) inactivated Escherichia coli K-12 ) with buffer . All doses were well tolerated . The 5 x 10(8 ) CFU dose , which is highly immunogenic in subjects in industrialised countries ( greater than 90 % seroconversion ) , elicited seroconversions of vibriocidal antibody in only 16 % of Indonesian children . By contrast , a single 5 x 10(9 ) CFU dose of vaccine result ed in high rates ( 75 % and 87 % ) of seroconversion with two different batches of vaccine . A batch prepared with a centrifugation step gave significantly higher geometric mean titres ( 16-fold increase over baseline ) than did a batch in which there was a filtration step between fermentation and lyophilisation ( 10-fold increase over baseline ) . At a 5 x 10(9 ) CFU dose , CVD 103-HgR is well tolerated and highly immunogenic in Indonesian children and should therefore be further investigated for use as a one-dose live oral cholera vaccine in developing countries The authors conducted a two-period crossover study of the reactogenicity and immunogenicity of live oral cholera vaccine CVD 103-HgR  among US university students . Subjects ingested 5 x 10(8 ) colony forming units of either killed Escherichia coli K12 placebo or vaccine , followed by the opposite treatment one week later . Surprisingly , the dynamics of the immunologic response were influenced by prior ingestion of placebo . Subjects who received placebo first showed stronger vibriocidal antibody responses 2 weeks after vaccination compared with subjects who received vaccine first ; this same pattern was seen for antitoxin titers . The authors suggest that ingestion of E. coli K12 one week prior to immunization boosts the immunologic response to vaccine by an unknown mechanism . Future crossover studies that examine immunologic outcomes might be design ed to explore the ubiquity of such an effect BACKGROUND At present , no rotavirus vaccine is commercially available for use worldwide . Hence , a live , attenuated monovalent vaccine was developed with human strain RIX4414 ( G1P1A P[8 ] specificity ) . Vaccination trials involving infants are ongoing in developed and developing countries . METHODS This study was a r and omized , double-blind , placebo-controlled trial conducted at pediatric hospitals and polyclinics in Singapore for the evaluation of the immunogenicity , reactogenicity , and efficacy of 2 oral doses of RIX4414 . In total , 2464 healthy infants ( who were 11 - 17 weeks old when the first dose was administered , which is in accordance with the local immunization schedule ) were enrolled to receive RIX4414 at 3 concentrations of virus ( 10(4.7 ) , 10(5.2 ) , or 10(6.1 ) focus-forming units ) or placebo at 1-month intervals , concomitantly with routinely administered infant vaccines . RESULTS The RIX4414 vaccine was highly immunogenic , and virtually all vaccine recipients ( 98%-100 % ) experienced " vaccine take " ( i.e. , a combined immunogenicity end point based on seroconversion and /or shedding of RIX4414 in postvaccination stool sample s ) after receipt of 2 doses at all 3 dosage levels . Depending on the virus concentration , the anti-rotavirus IgA seroconversion rate varied from 76 % ( 95 % confidence interval [ CI ] , 68%-83 % ) to 91 % ( 95 % CI , 85%-95 % ) . Two doses of RIX4414 were well tolerated , with no increase in high fever , severe diarrhea , or vomiting after either dose or with increased viral concentration , compared with placebo . There was no observed interference with routine vaccinations of infants when RIX4414 was coadministered . The calculated efficacy of RIX4414 against rotavirus gastroenteritis was 82 % ( P = .046 ) ; however , this result was considered to be of limited conclusive value because of the low number of rotavirus gastroenteritis episodes identified during the follow-up period . CONCLUSIONS The live , attenuated rotavirus vaccine ( RIX4414 ) was well tolerated and highly immunogenic in Singaporean infants . The immunogenicity of routinely administered infant vaccines was not impaired by concomitant administration of RIX4414 vaccine Iodine deficiency is a major cause of impaired mental development , goitre , and cretinism in many parts of the world . Because existing immunization programmes can be used to deliver oral iodized oil ( OIO ) to infants at risk , it was important to know whether OIO could adversely affect the antibody response to vaccines , such as trivalent oral poliovirus vaccine ( OPV ) . A r and omized , double-blind , placebo-controlled clinical trial was conducted in Subang , West Java , Indonesia , in which 617 eight-week-old infants received either OIO or a placebo ( poppy-seed oil ) during a routine visit for their first dose of OPV as part of the Exp and ed Programme on Immunization ( EPI ) . The infants received two boosters of OPV at 4-week intervals after the first dose , and were followed up when 6 months old . Neutralizing antibody titres to poliovirus serotypes 1 , 2 , and 3 were compared in serum sample s that were taken from 478 of these infants just before the first dose of OPV and at 6 months . It was found that oral iodized oil did not reduce the antibody responses to any of the three serotypes of OPV . These results indicate that oral iodine may safely be delivered to infants at the same time as oral poliovirus vaccine according to current EPI immunization schedules Highlights • Oral vaccines exhibit poor performance in low-income setting s.• Enterovirus and Campylobacter carriage are associated with lower OPV immunogenicity.• Enterovirus carriage is associated with lower Rotarix immunogenicity and efficacy Background Helminth infections are a major public health problem , especially in the tropics . Infected individuals have an altered immune response with evidence that antibody response to vaccination is impaired . Hence , treatment of helminth infections before vaccination may be a simple intervention to improve vaccine immunogenicity . In the present study we investigated whether a single-dose antihelminthic treatment influences antibody responses to a seasonal influenza vaccine in primary school children living in Gabon , Central Africa . Methods In this placebo-controlled double-blind trial conducted in Gabon the effect of a single-dose antihelminthic treatment with 400 mg albendazole versus a placebo one month prior to immunization with a seasonal influenza vaccine was investigated . Antiviral antibody titers against all three vaccine strains were assessed by haemagglutination inhibition ( HI ) test at baseline ( Day 0 ; vaccination ) and four weeks ( Day 28 ) as well as 12 weeks ( Day 84 ) following vaccination . Vaccine-specific memory B-cell response was measured at Day 0 and Day 84 by vaccine-specific Enzyme-linked Immunospot ( ELISpot ) assay . The trial is registered with the Pan African Clinical Trials Registry ( PACTR ) ( PACTR201303000434188 ) . Results 98 school children aged 6–10 years were r and omly allocated to receive either antihelminthic treatment or placebo and were vaccinated one month after the treatment . The  prevalence of helminths at baseline was 21 %  . Vaccine-specific HI titers against at least one of the three vaccine strains increased at Day 28 and Day 84 in all participants . HI titers against both influenza A strains as well as memory B-cell response were modestly higher in the antihelminthic treated group compared to the placebo group but the difference was not statistically significant . Total but not specific IgA was elevated in the antihelminthic treated group compared to the control group at Day 28 . Conclusion In our setting antihelminthic treatment had no significant effect on influenza vaccine immunogenicity . A trend towards better antiviral and vaccine immunogenicity in the antihelminthic treated group encourages studies to be conducted with alternative treatment schedules or in population s with a higher helminth burden 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 c and i date 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 The lower immune response and efficacy of live oral rotavirus ( RV ) vaccines tested in developing countries may be due in part to high levels of pre-existing RV antibodies transferred to the infant from mother via the placenta . The c and i date RV vaccine strain 116E was isolated from a newborn indicating that it might grow well even in the presence of this transplacental rotavirus antibody . Since the immune response to this vaccine among infants in the Indian subcontinent has been greater than that of the commercially licensed vaccines , we question ed whether this might be due to the ability of RV 116E to grow well in infants despite the presence of maternal RV antibody . To this end , we tested pre-immunization sera from Indian infants enrolled in a phase Ia/IIb trial of c and i date RV vaccine ORV-116E  for transplacental RV IgG to see whether it affected the immune responses and seroconversion to the vaccine . We found that the high titers of transplacental RV IgG diminished the immune responses of  infants to ORV-116E vaccine . However , the vaccine was able to overcome the inhibitory effect of this RV IgG in a dose-dependent manner . This report clearly demonstrates the interference of maternal antibody on RV vaccine immunogenicity in infants in a field study as well as the ability of ORV-116E to overcome this interference when used at a higher dose In a search for new strategies to improve oral vaccination , the effect of orally administered Lactobacillus casei strain GG ( LGG ) in conjunction with D x RRV rhesus-human reassortant live oral rotavirus vaccine was tested in 2 - 5-month-old infants . Infants who received LGG showed an increased response with regard to rotavirus-specific IgM secreting cells , measured using an ELISPOT technique , on day 8 after vaccination . In infants receiving LGG or placebo , respectively , a rotavirus IgM seroconversion was detected in 26/27 ( 96 % ) , versus 23/27 ( 85 % ) cases ( p = 0.15 ) and rotavirus IgA seroconversion was detected in 26/28 ( 93 % ) versus 20/27 ( 74 % ) cases ( p = 0.05 ) . These findings suggest that LGG has an immunostimulating effect on oral rotavirus vaccination . The clinical significance of LGG-enhanced immune responses to oral vaccines should be further evaluated Summary Background Orally ingested probiotic bacteria may modulate the immune response and increase antibody titers against enteric infections by bacteria or viruses . Even though positive effects of probiotics on respiratory tract infections have been reported , overall only few studies have examined effects on virus infections concerning organs other than the gastrointestinal tract . Aim of the study It was the aim of the study to investigate whether and how probiotics affect the immune response to a st and ardized enterovirus challenge ( polio ) and infections not limited to the gastrointestinal tract in healthy adults . Methods In a r and omized , controlled and double – blind study 64 volunteers consumed for 5 weeks chemically acidified clotted milk without bacteria or with 1010/serving Lactobacillus rhamnosus GG or Lactobacillus acidophilus CRL431 added . In the second week subjects were vaccinated orally against polio 1 , 2 and 3 . Polio virus neutralizing serum activity , the primary parameter , was determined by the st and ard neutralization test ( WHO ) before and three times after vaccination . Polio – specific IgA , IgG and IgM were detected by ELISAs . Results Probiotics increased poliovirus neutralizing antibody titers ( NT ) and affected the formation of poliovirus – specific IgA and IgG in serum . The maximum increase after immunization was about 2 , 2.2 , or 4–fold higher , respectively , for NT , IgG or , IgA , in volunteers consuming probiotics instead of placebo . No consistent difference was noted between bacterial strains . Conclusions Probiotics induce an immunologic response that may provide enhanced systemic protection of cells from virus infections by increasing production of virus neutralizing antibodies To evaluate the probiotic , Bifidobacterium breve strain Yakult ( BBG-01 ) , for safety and enhancement of immunogenicity in an oral inactivated cholera vaccine , a r and omized double-blind placebo-controlled study was performed . Bangladeshi children under 5-year-old received BBG-01 or placebo for 4 weeks with two doses of oral cholera vaccine .  Serum/fecal antibodies and fecal bacterial flora in the study participants were monitored . All adverse events were mild and transient and had no significant difference between the two groups . Immunological responses were similar comparing the two groups . A negative correlation between Bifidobacterium and Enterobacteriaceae in the probiotic group suggests a possible involvement of BBG-01 in alteration of the enteric bacterial flora . In conclusion , BBG-01 is well tolerated by Bangladeshi children although the post vaccinal immunostimulatory effect of BBG-01 was not evident OBJECTIVE To explore the effect of maternal supplementation of vitamin A on the immune response to oral polio vaccine  in breastfed infants . DESIGN R and omized controlled trial . SETTING Hospital based . METHODS One hundred mothers having uncomplicated deliveries r and omly received either 200,000 IU vitamin A orally ( Experimental ) or placebo ( Control ) . All the newborns were given a dose of oral polio vaccine within 72 hours after birth and were breastfed . Type specific neutralizing antibodies to polio viruses in test sera diluted from 1:4 to 1:512 and serum retinol levels were determined from the cord blood and at the age of 6 weeks . Breast milk retinol levels were determined at 3 , 10 , 30 , 45 and 90 days of lactation . RESULTS Seroconversion to OPV and geometric means of antibody titers to the three types of polio viruses were comparable between the groups of infants belonging to the experimental and control mothers . Breast milk retinol levels were significantly higher in the experimental group upto 45 - 90 days of lactation . Majority of the infants at birth had serum retinol levels < 15 micrograms/dl which improved significantly by 6 weeks irrespective of the maternal supplementation status . CONCLUSIONS Maternal vitamin A supplementation soon after delivery improves vitamin A intakes of breastfed infants during the first 3 months and has no interference with the seroconversion to a neonatal dose of OPV . OPV administered to newborn in turn has no adverse effect on the vitamin A status of the breastfed infants Three doses , given within one week , of Ty21a attenuated Salmonella typhi oral vaccine in an enteric-coated formulation provided 67 % efficacy for at least 3 years in a r and omised , placebo-controlled field trial involving 109,000 schoolchildren in Santiago , Chile . Increasing the interval between doses to twenty-one days did not enhance protection . Significantly less protection followed administration of vaccine in gelatin capsules with sodium bicarbonate . Ty21a provides the same level of protection as the heat/phenol-inactivated whole cell parenteral vaccine but differs in not causing adverse reactions .  Ty21a may now be regarded as a practical public health tool BACKGROUND Rotavirus is a leading cause of childhood gastroenteritis and death worldwide . METHODS We studied healthy infants approximately 6 to 12 weeks old who were r and omly assigned to receive three oral doses of  live pentavalent human-bovine ( WC3 strain ) reassortant rotavirus vaccine containing human serotypes G1 , G2 , G3 , G4 , and P[8 ] or placebo at 4-to-10-week intervals in a blinded fashion . Active surveillance was used to identify subjects with serious adverse and other events . RESULTS The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events . Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose ( relative risk , 1.6 ; 95 percent confidence interval , 0.4 to 6.4 ) . The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent ( 95 percent confidence interval , 91.2 to 96.6 percent ) . In a nested sub study , efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent ( 95 percent confidence interval , 66.8 to 79.9 percent ) ; efficacy against severe gastroenteritis was 98.0 percent ( 95 percent confidence interval , 88.3 to 100 percent ) . The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent ( 95 percent confidence interval , 73.9 to 92.5 percent ) . CONCLUSIONS This vaccine was efficacious in preventing rotavirus gastroenteritis , decreasing severe disease and health care contacts . The risk of intussusception was similar in vaccine and placebo recipients . ( Clinical Trials.gov number , NCT00090233 . 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 r and omly 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 sample s 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 BACKGROUND Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries , but no efficacy studies have been done in developing countries in Asia . We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam . METHODS In this multicentre , double-blind , placebo-controlled trial , undertaken in rural Matlab , Bangladesh , and urban and periurban Nha Trang , Vietnam , infants aged 4 - 12 weeks without symptoms of gastrointestinal disorders were r and omly assigned ( 1:1 ) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks , 10 weeks , and 14 weeks of age , in conjunction with routine infant vaccines including oral poliovirus vaccine . R and omisation was done by computer-generated r and omisation sequence in blocks of six . Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent re collection . The primary endpoint was severe rotavirus gastroenteritis ( Vesikari score > or=11 ) arising 14 days or more after the third dose of placebo or vaccine to end of study ( March 31 , 2009 ; around 21 months of age ) . Analysis was per protocol ; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis . This study is registered with Clinical Trials.gov , number NCT00362648 . FINDINGS 2036 infants were r and omly assigned to receive pentavalent rotavirus vaccine ( n=1018 ) or placebo ( n=1018 ) . 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per- protocol analysis . Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days ( IQR 480 - 575 ) . 38 cases of severe rotavirus gastroenteritis ( Vesikari score > or=11 ) were reported during more than 1197 person-years of follow up in the vaccine group , compared with 71 cases in more than 1156 person years in the placebo group , result ing in a vaccine efficacy of 48.3 % ( 95 % CI 22.3 - 66.1 ) against severe disease ( p=0.0005 for efficacy > 0 % ) during nearly 2 years of follow-up . 25 ( 2.5 % ) of 1017 infants assigned to receive vaccine and 20 ( 2.0 % ) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose . The most frequent serious adverse event was pneumonia ( vaccine 12 [ 1.2 % ] ; placebo 15 [ 1.5 % ] ) . INTERPRETATION In infants in developing countries in Asia , pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis , and our results support exp and ed WHO recommendations to promote its global use . FUNDING PATH ( GAVI Alliance grant ) and Merck Young children are very susceptible to typhoid fever , emphasizing the need for vaccination in under five age groups . The parenteral Vi polysaccharide vaccine is not immunogenic in children under 2 years and the oral Ty21a vaccine ( Vivotif ) available in capsular formulation is only recommended for those over 5 years . We studied immune responses to a liquid formulation of Ty21a in children 2 - 5 years of age . Since children in developing countries are in general hypo responsive to oral vaccines , the study was design ed to determine if anti-helminthic treatment prior to vaccination , improves responses . In a pilot study in 20 children aged 4 - 5 years , the immune responses in plasma and in antibody in lymphocyte secretions ( ALS ) to the enteric coated capsule formulation of Ty21a was found to be comparable to a liquid formulation ( P>0.05 ) . Based on this , children ( n=252 ) aged ≥ 2-<3 years and ≥3-<5 years were r and omized to receive a liquid formulation of Ty21a with and without previous anti-helminthic treatment . The vaccine was well tolerated with only a few mild adverse events recorded in < 1 % of the children . De-worming did not improve immune responses and both age groups developed 32 - 71 % IgA , IgG , and IgM responses in plasma and 63 - 86 % IgA responses in ALS and stool specimens to a membrane preparation ( MP ) of Ty21a . An early MP specific proliferative T cell response was also seen . We recommend that safety and efficacy studies with a liquid formulation of the vaccine are carried out in children under five , including those less than two years of age to determine if Ty21a is protective in these age groups and applicable as a public health tool for controlling typhoid fever in high prevalence areas of typhoid fever including Bangladesh BACKGROUND Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income setting s. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines . We assessed the safety and immunogenicity of the P2-VP8-P[8 ] subunit rotavirus vaccine at different doses in South African toddlers and infants . METHODS This double-blind , r and omised , placebo-controlled , dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers ( aged 2 to <3 years ) and term infants ( aged 6 to < 8 weeks , without previous rotavirus vaccination ) . Block r and omisation ( computer-generated , electronic allocation ) was used to assign eligible toddlers ( in a 6:1 ratio ) and infants ( in a 3:1 ratio ) in each dose cohort ( 10 μg , followed by 30 μg , then 60 μg if doses tolerated ) to parenteral P2-VP8-P[8 ] subunit rotavirus or placebo injection . The two highest tolerated doses were then assessed in an exp and ed cohort ( in a 1:1:1 ratio ) . Parents of participants and clinical , data , and laboratory staff were masked to treatment assignment . P2-VP8-P[8 ] vaccine versus placebo was assessed first in toddlers ( single injection ) and then in infants ( three injections 4 weeks apart ) . The primary safety endpoints were local and systemic reactions within 7 days after each injection , adverse events within 28 days after each injection , and all serious adverse events , assessed in toddlers and infants who received at least one dose . In infants receiving all study injections , primary immunogenicity endpoints were anti-P2-VP8-P[8 ] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection . This trial is registered at Clinical Trials.gov , number NCT02109484 . FINDINGS Between March 17 , 2014 , and Sept 29 , 2014 , 42 toddlers ( 36 to vaccine and six to placebo ) and 48 infants ( 36 to vaccine and 12 to placebo ) were enrolled in the dose-escalation phase , in which the 30 μg and 60 μg doses where found to be the highest tolerated doses . A further 114 infants were enrolled in the exp and ed cohort between Nov 3 , 2014 , and March 20 , 2015 , and all 162 infants ( 12 assigned to 10 μg , 50 to 30 μg , 50 to 60 μg , and 50 to placebo ) were included in the safety analysis . Serum IgA seroresponses were observed in 38 ( 81 % , 95 % CI 67 - 91 ) of 47 infants in the 30 μg group and 32 ( 68 % , 53 - 81 ) of 47 in the 60 μg group , compared with nine ( 20 % , 10 - 35 ) of 45 in the placebo group ; adjusted IgG seroresponses were seen in 46 ( 98 % , 89 - 100 ) of 47 infants in the 30 μg group and 47 ( 100 % ; 92 - 100 ) of 47 in the 60 μg group , compared with four ( 9 % , 2·5 - 21 ) of 45 in the placebo group ; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 ( 85 % , 72 - 94 ) of 47 infants in both the 30 μg and 60 μg groups , compared with three ( 7 % , 1·4 - 18 ) of 45 participants in the placebo group . Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo . Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups . Eight serious adverse events ( one with placebo , two with 30 μg , and five with 60 μg ) occurred in seven infants within 28 days of any study injection , none of which were deemed related to study treatment . INTERPRETATION The parenteral P2-VP8-P[8 ] vaccine was well tolerated and immunogenic in infants , providing a novel approach to vaccination against rotavirus disease . On the basis of these results , a phase 1/2 trial of a trivalent P2-VP8 ( P[4 ] , P[6 ] , and P[8 ] ) subunit vaccine is underway at three sites in South Africa . FUNDING Bill & Melinda Gates Foundation For r and om effects meta- analysis , seven different estimators of the heterogeneity variance are compared and assessed using a simulation study . The seven estimators are the variance component type estimator ( VC ) , the method of moments estimator ( MM ) , the maximum likelihood estimator ( ML ) , the restricted maximum likelihood estimator ( REML ) , the empirical Bayes estimator ( EB ) , the model error variance type estimator ( MV ) , and a variation of the MV estimator ( MVvc ) . The performance of the estimators is compared in terms of both bias and mean squared error , using Monte Carlo simulation . The results show that the REML and especially the ML and MM estimators are not accurate , having large biases unless the true heterogeneity variance is small . The VC estimator tends to overestimate the heterogeneity variance in general , but is quite accurate when the number of studies is large . The MV estimator is not a good estimator when the heterogeneity variance is small to moderate , but it is reasonably accurate when the heterogeneity variance is large . The MVvc estimator is an improved estimator compared to the MV estimator , especially for small to moderate values of the heterogeneity variance . The two estimators MVvc and EB are found to be the most accurate in general , particularly when the heterogeneity variance is moderate to large BACKGROUND Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa . Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries , we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana , Kenya , and Mali between April , 2007 , and March , 2009 . METHODS In our multicentre , double-blind , placebo-controlled trial , undertaken in rural areas of Ghana and Kenya and an urban area of Mali , we r and omly assigned infants aged 4 - 12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks , 10 weeks , and 14 weeks of age . Infants with HIV infection were not excluded . R and omisation was done by computer-generated r and omisation sequence in blocks of six . We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospect ively by clinicians . The primary endpoint was severe rotavirus gastroenteritis ( Vesikari score > or=11 ) , detected by enzyme immunoassay , arising 14 days or more after the third dose of placebo or vaccine to end of study ( March 31 , 2009 ; around 21 months of age ) . Analysis was per protocol ; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis . This study is registered with Clinical Trials.gov , number NCT00362648 . FINDINGS 5468 infants were r and omly assigned to receive pentavalent rotavirus vaccine ( n=2733 ) or placebo ( n=2735 ) . 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per- protocol analysis . 79 cases of severe rotavirus gastroenteritis were reported in 2610.6 person-years in the vaccine group , compared with 129 cases in 2585.9 person-years in the placebo group , result ing in a vaccine efficacy against severe rotavirus gastroenteritis of 39.3 % ( 95 % CI 19.1 - 54.7 , p=0.0003 for efficacy > 0 % ) . Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given . 42 ( 1.5 % ) of 2723 infants assigned to receive vaccine and 45 ( 1.7 % ) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose . The most frequent serious adverse event was gastroenteritis ( vaccine 17 [ 0.6 % ] ; placebo 17 [ 0.6 % ] ) . INTERPRETATION Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years . We support WHO 's recommendation for adoption of rotavirus vaccine into national exp and ed programmes on immunisation in Africa . FUNDING PATH ( GAVI Alliance grant ) and Merck Background Breast milk contains anti-rotavirus IgA antibodies and other innate immune factors that inhibit rotavirus replication in vitro . These factors could diminish the immunogenicity of oral rotavirus vaccines , particularly if breastfeeding occurs close to the time of vaccine administration . Methods Between April 2011 and November 2012 , we conducted an open label , r and omized trial to compare the immunogenicity of Rotarix ( RV1 ) in infants whose breastfeeding was withheld one hour before through one hour after vaccination with that in infants breastfed at the time of vaccination . The trial was conducted in the peri-urban area of Ibrahim Hyderi in Karachi , Pakistan . Both groups received three doses of RV1 at 6 , 10 and 14 weeks of age . Seroconversion ( anti-rotavirus IgA antibodies ≥20 U/mL in subjects seronegative at 6 weeks of age ) following three vaccine doses ( 6 , 10 and 14 weeks ) was determined at 18 weeks of age ( primary objective ) and seroconversion following two doses ( 6 and 10 weeks ) was determined at 14 weeks of age ( secondary objective ) . Results Four hundred eligible infants were r and omly assigned in a 1:1 ratio between the withholding breastfeeding and immediate breastfeeding arms . Overall , 353 ( 88.3 % ) infants completed the study according to protocol ; 181 in the withholding breastfeeding group and 172 in the immediate breastfeeding group . After three RV1 doses , anti-rotavirus IgA antibody seroconversion was 28.2 % ( 95 % CI : 22.1 ; 35.1 ) in the withholding arm and 37.8 % ( 95 % CI : 30.9 ; 45.2 ) in the immediate breastfeeding arm ( difference : -9.6 % [ 95 % CI : -19.2 ; 0.2 ] p=0.07 ) . After two doses of RV1 , seroconversion was 16.6 % ( 95 % CI : 11.9 ; 22.7 ) in the withholding arm and 29.1 % ( 95 % CI : 22.8 , 36.3 ) in the immediate breastfeeding arm ( difference : -12.5 % [ 95 % CI : -21.2,-3.8 ] p=0.005 ) . Conclusions Withholding breastfeeding around the time of RV1 vaccine administration did not lead to increased anti-rotavirus IgA seroconversion compared with that seen with a breastfeed at the time of vaccination . On the contrary , IgA seroconversion in infants immediately breastfed tended to be higher than in those withheld from a feeding . Our findings suggest that breastfeeding should be continued adlib around the time of rotavirus vaccination and withholding breastfeeding at that time is unlikely to improve the vaccine immunogenicity . Trial Registration Clinical Trials.gov
BACKGROUND Oral vaccines underperform in low-income and middle-income countries compared with in high-income countries .
Whether interventions can improve oral vaccine performance is uncertain .