Evaluation of a bivalent (CVD 103-HgR/CVD 111) live oral cholera vaccine in adult volunteers from the United States and Peru. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia: rationale and design. A Randomized, Placebo-Controlled Trial of the Bivalent Killed, Whole-Cell, Oral Cholera Vaccine in Adults and Children in a Cholera Endemic Area in Kolkata, India Safety and Allele-Specific Immunogenicity of a Malaria Vaccine in Malian Adults: Results of a Phase I Randomized Trial A mass vaccination campaign targeting adults and children to prevent typhoid fever in Hechi; Expanding the use of Vi polysaccharide vaccine in Southeast China: A cluster-randomized trial Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. Evaluation of Safety, Immunogenicity and Efficacy of an Attenuated Rotavirus Vaccine, RIX4414: A Randomized, Placebo-Controlled Trial in Latin American Infants Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial Efficacy of a Low-Cost, Inactivated Whole-Cell Oral Cholera Vaccine: Results from 3 Years of Follow-Up of a Randomized, Controlled Trial Randomised vaccine trial of single dose of killed Leishmania major plus BCG against anthroponotic cutaneous leishmaniasis in Bam, Iran Immunogenicity and Safety of Two Different Haemophilus influenzae Type b Conjugate Vaccines in Korean Infants A randomised, double-blind, controlled trial of a killed L. major vaccine plus BCG against zoonotic cutaneous leishmaniasis in Iran. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. Methodological issues arising from systematic reviews of the evidence of safety of vaccines. Autoclaved Leishmania major vaccine for prevention of visceral leishmaniasis: a randomised, double-blind, BCG-controlled trial in Sudan Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique. Safety and immunogenicity of tetravalent pneumococcal vaccines containing 6B, 14, 19F and 23F polysaccharides conjugated to either tetanus toxoid or diphtheria toxoid in young infants and their boosterability by native polysaccharide antigens. Preliminary assessment of the safety and immunogenicity of live oral cholera vaccine strain CVD 103-HgR in healthy Thai adults. Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial. Leishmanization: use of an old method for evaluation of candidate vaccines against leishmaniasis. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. Phase 1 Study of a Combination AMA1 Blood Stage Malaria Vaccine in Malian Children Safety and elicitation of humoral and cellular responses in colombian malaria-naive volunteers by a Plasmodium vivax circumsporozoite protein-derived synthetic vaccine. A local reaction at or near injection site: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belém, Brazil. Immunogenicity and safety of four different doses of Haemophilus influenzae type b-tetanus toxoid conjugated vaccine, combined with diphtheria-tetanus-pertussis vaccine (DTP-Hib), in Indonesian infants. Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate vaccine [corrected] for prevention of pneumonia and meningitis in Gambian infants. Safety and immunogenicity of tetravalent rhesus-based rotavirus vaccine in Bangladesh Safety and immunogenicity of pneumococcal conjugate vaccine in combination with diphtheria, tetanus toxoid, pertussis and Haemophilus influenzae type b conjugate vaccine Safety and immunogenicity of Haemophilus influenzae type B vaccine given in combination with DTwP at 6, 10 and 14 weeks of age. Safety, Reactogenicity, and Immunogenicity of Human Rotavirus Vaccine RIX4414 in Human Immunodeficiency Virus-positive Infants in South Africa 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 Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans.
To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1 , a single-dose , oral cholera vaccine was developed by combining two live , attenuated vaccine strains , CVD 103-HgR ( classical , Inaba ) and CVD 111 ( El Tor , Ogawa ) . The vaccines were formulated in a double-chamber sachet ; one chamber contained lyophilized bacteria , and the other contained buffer . In the first study , 23 U.S. adult volunteers received CVD 103-HgR at 10(8 ) CFU plus CVD 111 at 10(8 ) , 10(7 ) , or 10(6 ) CFU , CVD 111 alone at 10(7 ) CFU , or placebo . In the second study , 275 Peruvian adults were r and omized to receive CVD 103-HgR at 10(9 ) CFU plus CVD 111 at 10(9 ) or 10(8 ) CFU , CVD 111 alone at 10(9 ) CFU , CVD 103-HgR alone at 10(9 ) CFU , or placebo . Three of 15 U.S. volunteers who received CVD 111 at 10(7 ) or 10(8 ) CFU developed mild diarrhea , compared to none of 4 who received CVD 111 at 10(6 ) CFU and 1 of 4 who received placebo . Twelve ( 63 % ) of 19 vaccine recipients shed the El Tor vaccine strain . All but one volunteer developed significant Ogawa and Inaba vibriocidal antibody titers . Volunteers who received CVD 111 at 10(7 ) CFU had geometric mean Ogawa titers four to five times higher than those of volunteers who received the lower dose . In the second study , all dosage regimens were well tolerated in Peruvians . About 20 % of volunteers who received CVD 111 at the high dose excreted the El Tor organism , compared to 7 % in the low-dose group . CVD 111 was detected in the stools of two placebo recipients , neither of whom had symptoms or seroconverted . In all vaccine groups , 69 to 76 % developed fourfold rises in Inaba vibriocidal antibodies . Among those who received the bivalent vaccine , 53 to 75 % also developed significant rises in Ogawa vibriocidal antibodies . We conclude that it is feasible to produce a single-dose , oral bivalent vaccine that is safe and immunogenic against both biotypes ( El Tor and classical ) and both serotypes ( Inaba and Ogawa ) of cholera for population s in both developed and developing parts of the world BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic , generally well tolerated , and effective against HPV-16 or HPV-18 infections , and associated precancerous lesions in an event-triggered interim analysis of the phase III r and omised , double-blind , controlled PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . We now assess the vaccine efficacy in the final event-driven analysis . METHODS Women ( 15 - 25 years ) were vaccinated at months 0 , 1 , and 6 . Analyses were done in the according-to- protocol cohort for efficacy ( ATP-E ; vaccine , n=8093 ; control , n=8069 ) , total vaccinated cohort ( TVC , included all women receiving at least one vaccine dose , regardless of their baseline HPV status ; represents the general population , including those who are sexually active ; vaccine , n=9319 ; control , n=9325 ) , and TVC-naive ( no evidence of oncogenic HPV infection at baseline ; represents women before sexual debut ; vaccine , n=5822 ; control , n=5819 ) . The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2 + ( CIN2 + ) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline , and DNA negative at baseline and month 6 for the corresponding type ( ATP-E ) . This trial is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Mean follow-up was 34.9 months ( SD 6.4 ) after the third dose . Vaccine efficacy against CIN2 + associated with HPV-16/18 was 92.9 % ( 96.1 % CI 79.9 - 98.3 ) in the primary analysis and 98.1 % ( 88.4 - 100 ) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types ( ATP-E cohort ) . Vaccine efficacy against CIN2 + irrespective of HPV DNA in lesions was 30.4 % ( 16.4 - 42.1 ) in the TVC and 70.2 % ( 54.7 - 80.9 ) in the TVC-naive . Corresponding values against CIN3 + were 33.4 % ( 9.1 - 51.5 ) in the TVC and 87.0 % ( 54.9 - 97.7 ) in the TVC-naive . Vaccine efficacy against CIN2 + associated with 12 non-vaccine oncogenic types was 54.0 % ( 34.0 - 68.4 ; ATP-E ) . Individual cross-protection against CIN2 + associated with HPV-31 , HPV-33 , and HPV-45 was seen in the TVC . INTERPRETATION The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2 + associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes . FUNDING GlaxoSmithKline Biologicals An oral rhesus-human rotavirus tetravalent ( RRV-TV ) vaccine ( 10(4 ) pfu of rhesus rotavirus [ type G3 ] and of 3 human-rhesus reassortants [ G1 , G2 , and G4 ] ) was evaluated in a field trial in Lima , Peru . At 2 , 3 , and 4 months of age , infants received either a dose of RRV-TV , an initial dose of vaccine followed by a dose of placebo at 3 and 4 months , or a dose of placebo .  Rotavirus-specific IgA responses were detected by ELISA in 75 % of the three-dose vaccine group , 59 % of the one-dose vaccine group ( P = .05 ) , and 24 % of the placebo group ( P < .001 ) : 64 % , 48 % , and 12 % of each group , respectively , had a neutralizing antibody response to at least 1 serotype . Both one and three doses of vaccine failed to induce a significant level of protection against rotavirus diarrhea ; however , they did provide some protection ( range , 35%-66 % ) against more severe rotavirus diarrhea , especially for episodes caused by type G1 Phase-III vaccine efficacy  trials typically employ individually r and omized design s intended to ensure that measurements of vaccine protective efficacy reflect only direct vaccine effects . As a result , decisions about introducing newly licensed vaccines into public health programmes often fail to consider the substantially greater protection that may occur when a vaccine is deployed in public health programmes , due to the combination of direct plus indirect vaccine protective effects . Vaccine total protection can be better evaluated with cluster r and omized trials . Such a design was considered to generate policy relevant data to accelerate the rationale introduction of the licensed typhoid fever Vi polysaccharide ( PS ) vaccine in Asia by the Diseases of the Most Impoverished ( DOMI ) typhoid fever programme . The DOMI 's programme multi-country study is one of the largest cluster r and omized vaccine trials ever mounted in Asia , which includes approximately 200,000 individuals . Its main objective is to determine the effectiveness of a licensed Vi PS vaccine .  The rationale and design of this study are discussed . Preliminary results are presented that determined the final planning of the trial before immunization . Important method ological and practical issues regarding vaccine cluster r and omized design s are illustrated Objectives An effective vaccine against cholera has been used for public health purpose s in Vietnam since the 1990s . This vaccine was reformulated to meet WHO requirements . We assessed the safety and immunogenicity of the reformulated bivalent ( Vibrio cholerae 01 and 0139 ) killed whole cell oral vaccine in a cholera endemic area in Kolkata , India . Design Double-blind , r and omized , placebo controlled trial Setting The trial was conducted in the clinical trial ward of the Infectious Diseases Hospital in Kolkata , India Participants The participants were 101 healthy adults ( males and non-pregnant females ) aged 18–40 years and 100 healthy children ( males and non-pregnant females ) aged 1–17 years . Interventions Participants were r and omized to receive either the bivalent killed whole cell oral cholera vaccine or placebo ( killed oral Escherichia coli K12 ) Outcome Measures For safety : proportion of subjects with adverse events during the duration of study participation . For immunogenicity : Proportion of subjects who had a ≥4-fold rise in serum vibriocidal antibody titers 14 days after the second dose of vaccine or placebo . Results Adverse reactions were observed with similar frequency among vaccine and placebo recipients in both age groups . Among adults 4 % of vaccine and 8 % of placebo recipients and among children 4 % of vaccine and 2 % of placebo recipients had at least one adverse event within 28 days of the first dose of the vaccine . Following immunization , 53 % of adult and 80 % of children vaccinees showed a ≥4 fold rise in serum V. cholerae O1 vibriocidal antibody titers . A less pronounced response to V. cholerae O139 vibriocidal antibody titers post-immunization was noted among vaccinees . Conclusions We found the vaccine to be safe and immunogenic in a cholera-endemic area in India . Trial Registration Clinical Trials.gov Objectives : The objectives were to evaluate the safety , reactogenicity , and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels . Design : We conducted a r and omized , double-blind , controlled phase I clinical trial . Setting : B and iagara , Mali , West Africa , is a rural town with intense seasonal transmission of Plasmodium falciparum malaria . Participants : Forty healthy , malaria-experienced Malian adults aged 18–55 y were enrolled . Interventions : The FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 ( MSP-142 ) from the 3D7 clone of P. falciparum , adjuvanted with AS02A . The control vaccine was a killed rabies virus vaccine ( Imovax ) . Participants were r and omized to receive either FMP1/AS02A or rabies vaccine at 0 , 1 , and 2 mo and were followed for 1 y. Outcome Measures : Solicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-142 and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured . Results : Transient local pain and swelling were more common in the malaria vaccine group than in the control group ( 11/20 versus 3/20 and 10/20 versus 6/20 , respectively ) . MSP-142 antibody levels rose during the malaria transmission season in the control group , but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group . Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-142 alleles and their subunits . Conclusions : FMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones . Anti-MSP-142 antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine Background One of the goals of this study was to learn the coverage , safety and logistics of a mass vaccination campaign against typhoid fever in children and adults using locally produced typhoid Vi polysaccharide ( PS ) and group A meningococcal PS vaccines in southern China . Methods The vaccination campaign targeted 118,588 persons in Hechi , Guangxi Province , aged between 5 to 60 years , in 2003 . The study area was divided into 107 geographic clusters , which were r and omly allocated to receive one of the single-dose parenteral vaccines . All aspects regarding vaccination logistics , feasibility and safety were documented and systematic ally recorded . Results of the logistics , feasibility and safety are reported . Results The campaign lasted 5 weeks and the overall vaccination coverage was 78 % . On average , the 30 vaccine teams gave immunizations on 23 days . Vaccine rates were higher in those aged ≤ 15 years ( 90 % ) than in adolescents and young adults ( 70 % ) . Planned mop-up activities increased the coverage by 17 % . The overall vaccine wastage was 11 % . The cold chain was maintained and documented . 66 individuals reported of adverse events out of all vaccinees , where fever ( 21 % ) , malaise ( 19 % ) and local redness ( 19 % ) were the major symptoms ; no life-threatening event occurred . Three needle-sharp events were reported . Conclusion The mass immunization proved feasible and safe , and vaccine coverage was high . Emphasis should be placed on : injection safety measures , community involvement and incorporation of mop-up strategies into any vaccination campaign . School-based and all-age Vi mass immunizations programs are potentially important public health strategies for prevention of typhoid fever in high-risk population s in southern China 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 . 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 BACKGROUND Pneumonia is estimated to cause 2 million deaths every year in children . Streptococcus pneumoniae is the most important cause of severe pneumonia . We aim ed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children . METHODS We undertook a r and omised , placebo-controlled , double-blind trial in eastern Gambia . Children age 6 - 51 weeks were r and omly allocated three doses of either pneumococcal conjugate vaccine ( n=8718 ) or placebo ( 8719 ) , with intervals of at least 25 days between doses . Our primary outcome was first episode of radiological pneumonia . Secondary endpoints were clinical or severe clinical pneumonia , invasive pneumococcal disease , and all-cause admissions . Analyses were per protocol and intention to treat . FINDINGS 529 children assigned vaccine and 568 allocated  placebo were not included in the per- protocol analysis . Results of per- protocol and intention-to-treat analyses were similar . By per- protocol analysis , 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo . Pneumococcal vaccine efficacy was 37 % ( 95 % CI 27 - 45 ) against first episode of radiological pneumonia . First episodes of clinical pneumonia were reduced overall by 7 % ( 95 % CI 1 - 12 ) . Efficacy of the conjugate vaccine was 77 % ( 51 - 90 ) against invasive pneumococcal disease caused by vaccine serotypes , 50 % ( 21 - 69 ) against disease caused by all serotypes , and 15 % ( 7 - 21 ) against all-cause admissions . We also found an efficacy of 16 % ( 3 - 28 ) against mortality . 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo . INTERPRETATION In this rural African setting , pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease , and can substantially reduce admissions and improve child survival . Pneumococcal conjugate vaccines should be made available to African infants Background Killed oral cholera vaccines ( OCVs ) have been licensed for use in developing countries , but protection conferred by licensed OCVs beyond two years of follow-up has not been demonstrated in r and omized , clinical trials . Methods /Principal Findings We conducted a cluster-r and omized , placebo-controlled trial of a two-dose regimen of a low-cost killed whole cell OCV in residents 1 year of age and older living in 3,933 clusters in Kolkata , India . The primary endpoint was culture-proven Vibrio cholerae O1 diarrhea episodes severe enough to require treatment in a health care facility . Of the 66,900 fully dosed individuals ( 31,932 vaccinees and 34,968 placebo recipients ) , 38 vaccinees and 128 placebo-recipients developed cholera during three years of follow-up ( protective efficacy 66 % ; one-sided 95%CI lower bound = 53 % , p<0.001 ) . Vaccine protection during the third year of follow-up was 65 % ( one-sided 95%CI lower bound = 44 % , p<0.001 ) . Significant protection was evident in the second year of follow-up in children vaccinated at ages 1–4 years and in the third year in older age groups . Conclusions / Significance The killed whole-cell OCV conferred significant protection that was evident in the second year of follow-up in young children and was sustained for at least three years in older age groups . Continued follow-up will be important to establish the vaccine 's duration of protection . Trial Registration Clinical Trials.gov NCT00289224 BACKGROUND A vaccine consisting of a single dose of whole-cell autoclave-killed Leishmania major ( ALM ) mixed with BCG was assessed in comparison with BCG alone against anthroponotic ( human to human transmission ) cutaneous leishmaniasis in a r and omised double-blind trial in Bam , Iran . METHODS 3637 schoolchildren , aged 6 - 15 years , with no history of cutaneous leishmaniasis and no response to a leishmanin skin test , were r and omly assigned to receive 1 mg ALM mixed with BCG ( n = 1839 ) , or BCG alone ( n = 1798 ) . Safety of the vaccine and the incidence of confirmed cases of cutaneous leishmaniasis were followed up for 2 years . FINDINGS Side-effects were those usually associated with BCG vaccination , but tended to persist longer in the ALM + BCG group . After exclusion of four cases occurring within 80 days of vaccination ( one in the ALM + BCG group and three in the BCG group ) , the 2-year incidence of cutaneous leishmaniasis did not differ significantly between vaccine and BCG groups : 2.8 % vs 3.3 % , respectively ( total cases 112 ) . A sex-stratified analysis showed that in boys the vaccine conferred a protective efficacy of 18 % and 78 % for the first and second years , respectively -- a crude 2-year overall protection of 55 % ( 95 % CI 19 - 75 % , p < 0.01 ) . In the first 9 months after vaccination , there was a non-significant excess of cases in the ALM + BCG group ( 25 vs 16 ) , whereas the incidence of cutaneous leishmaniasis thereafter was significantly reduced in the ALM + BCG group ( 27 vs 44 , p < 0.05 ) . INTERPRETATION A single dose of ALM + BCG was safe and more immunogenic than BCG alone , as measured by leishmanin skin test . The exact reason for the apparent protective effect of the vaccine in boys is unknown , and may be a chance finding . However , since boys are more exposed to the infection , which is indicated by higher disease prevalence in boys in this study population , the preferential protective effect in boys may have result ed from a greater booster effect produced by repeated exposure to infected s and flies . Booster injections or alternative adjuvants should be tried to improve the potential efficacy of this vaccine The incidence of invasive diseases , including meningitis caused by Haemophilus influenzae type b ( Hib ) was markedly decreased after routine immunization of Hib vaccine through diverse schedules in many countries . The purpose of this study was to evaluate the immunogenicity and safety of Hib conjugate vaccines in Korean children before the implementation of a national immunization program against Hib in Korea . A multicenter controlled trial was performed on two different Hib vaccines in Korean children . A total of 319 infants were enrolled : 199 infants were immunized with the Hib polysaccharide conjugated to the tetanus toxoid ( PRP-T ) and 120 infants with the Hib polysaccharide conjugated to the outer-membrane protein of Neisseria meningitides ( PRP-OMP ) . Immunogenicity was evaluated by enzyme-linked immunosorbent assay ( ELISA ) and serum bactericidal assay . Both vaccines showed good immunologic responses after primary immunization . After 2 doses of PRP-T or PRP-OMP , 78.9 % and 91.7 % of infants achieved an antibody level of ≥1.0 µg/mL , respectively . Both vaccines were safe and well-tolerated . No serious adverse events were observed . Thus , Hib conjugate vaccines appear to be safe and show good immunogenicity in Korean infants . These results will be important reference data for the implementation of Hib vaccine in the national immunization program of Korea Safety and efficacy of killed ( autoclaved ) L. major promastigotes , ALM , mixed with BCG against zoonotic cutaneous leishmaniasis was tested in healthy volunteers ( n = 2453 ) in a r and omized double blind trial vs. BCG as control . Side-effects were similar in both groups but tended to be slightly more frequent and prolonged in the ALM + BCG group . Leishmanin skin test conversion ( in duration > or = 5 mm ) was significantly greater in the ALM + BCG than in the BCG group ( 36.2 % vs. 7.9 % on day-80 and 33 % vs. 19 % , after 1 year , respectively ) . Cumulative incidence rates for 2 years , were similar in both groups ( 18.0 % vs. 18.5 % ) . However , LST responders on day 80 ( > or = 5 mm ) had a significantly lower incidence ( 35 % ) of CL during the first year than non-responders . A single dose of ALM + BCG is not sufficiently immunogenic to provide a measurable response when compared to BCG alone . A single dose of this vaccine has been shown to be safe with no evidence of an exacerbating response following natural infection ; hence , multiple doses or other adjuvants should be considered to increase its immunogenicity BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the  9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo .  All children received Haemophilus influenzae type b conjugate vaccine .  Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection BACKGROUND The RTS , S/AS01(E ) c and i date malaria vaccine is being developed for immunisation of infants in Africa through the exp and ed programme on immunisation ( EPI ) . 8 month follow-up data have been reported for safety and immunogenicity of RTS , S/AS01(E ) when integrated into the EPI . We report extended follow-up to 19 months , including efficacy results . METHODS We did a r and omised , open-label , phase 2 trial of safety and efficacy of the RTS , S/AS01(E ) c and i date malaria vaccine given with EPI vaccines between April 30 , 2007 , and Oct 7 , 2009 , in Ghana , Tanzania , and Gabon . Eligible children were 6 - 10 weeks of age at first vaccination , without serious acute or chronic illness . All children received the EPI diphtheria , tetanus , pertussis ( inactivated whole-cell ) , and hepatitis-B vaccines , Haemophilus influenzae type b vaccine , and oral polio vaccine at study months 0 , 1 , and 2 , and measles vaccine and yellow fever vaccines at study month 7 . Participants were r and omly assigned ( 1:1:1 ) to receive three doses of RTS , S/AS01(E ) at 6 , 10 , and 14 weeks ( 0 , 1 , 2 month schedule ) or at 6 weeks , 10 weeks , and 9 months ( 0 , 2 , 7 month schedule ) or placebo . R and omisation was according to a predefined block list with a computer-generated r and omisation code . Detection of serious adverse events and malaria was by passive case detection . Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months . This study is registered with Clinical Trials.gov , number NCT00436007 . FINDINGS 511 children were enrolled .  Serious adverse events occurred in 57 participants in the RTS , S/AS01(E ) 0 , 1 , 2 month group ( 34 % , 95 % CI 27 - 41 ) , 47 in the 0 , 1 , 7 month group ( 28 % , 21 - 35 ) , and 49 ( 29 % , 22 - 36 ) in the control group ; none were judged to be related to study vaccination . At month 19 , anticircumsporozoite immune responses were significantly higher in the RTS , S/AS01(E ) groups than in the control group . Vaccine efficacy for the 0 , 1 , 2 month schedule ( 2 weeks after dose three to month 19 , site-adjusted according-to- protocol analysis ) was 53 % ( 95 % CI 26 - 70 ; p=0·0012 ) against first malaria episodes and 59 % ( 36 - 74 ; p=0·0001 ) against all malaria episodes . For the entire study period , ( total vaccinated cohort ) vaccine efficacy against all malaria episodes was higher with the 0 , 1 , 2 month schedule ( 57 % , 95 % CI 33 - 73 ; p=0·0002 ) than with the 0 , 1 , 7 month schedule ( 32 % CI 16 - 45 ; p=0·0003 ) . 1 year after dose three , vaccine efficacy against first malaria episodes was similar for both schedules ( 0 , 1 , 2 month group , 61·6 % [ 95 % CI 35·6 - 77·1 ] , p<0·001 ; 0 , 1 , 7 month group , 63·8 % [ 40·4 - 78·0 ] , p<0·001 , according-to- protocol cohort ) . INTERPRETATION Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine . The 0 , 1 , 2 month vaccine schedule has been selected for phase 3 c and i date vaccine assessment . FUNDING Program for Appropriate Technology in Health Malaria Vaccine Initiative ; GlaxoSmithKline Biologicals Adaptations to the recognized methods of systematic review ing are required when addressing questions about safety , particularly about rare and /or long-term serious adverse events . Conducting a systematic review of vaccine safety requires the implementation of novel strategies for locating studies , the use of experimental instruments to assess the quality of non-r and omized studies , and the employment of pooling methods for non-r and omized data , where appropriate . St and ardizing both the indexing of adverse event data on electronic libraries and their reporting would improve the potential of systematic review s of vaccine to draw accurate conclusions about the safety of a vaccine . BACKGROUND Visceral leishmaniasis is a major cause of morbidity and mortality in the Sudan . Drug treatment is expensive , and drug resistance is becoming increasingly common . Safe , effective , and cheap vaccines are needed . We report the results of a vaccine trial against human visceral leishmaniasis . METHODS We undertook a double-blind r and omised trial to test the safety and efficacy of an autoclaved Leishmania major ( ALM ) promastigote vaccine ( 1 mg per dose ) . Of 5093 volunteers screened , 2306 had negative leishmanin skin tests and reciprocal titres of less than 6400 in the direct agglutination test . They were r and omly assigned two doses of ALM mixed with BCG or BCG alone . Volunteers were followed up for 2 years . The primary endpoint was clinical visceral leishmaniasis or post-kala-azar dermal leishmaniasis . Analyses were by intention to treat . FINDINGS Side-effects were confined to the injection site . The cumulative frequency of visceral leishmaniasis at 2 years did not differ significantly between the group assigned ALM plus BCG and that assigned BCG alone ( 133/1155 [ 11.5 % ] vs 141/1151 [ 12.3 % ] , p=0.6 ) . The vaccine efficacy was 6 % ( 95 % CI -18 to 25 ) . The proportion of individuals showing leishmanin skin conversion was significantly higher in the ALM plus BCG group than in the BCG alone group throughout follow-up ( 303 [ 30 % ] vs 72 [ 7 % ] at 42 days ) . Individuals whose leishmanin test converted after vaccination ( in duration > or = 5 mm ) had a significantly lower frequency of visceral leishmaniasis than non-responders ( 27/375 [ 7.2 % ] vs 210/1660 [ 12.7 % ] , p=0.003 ) . INTERPRETATION We found no evidence that two doses of ALM plus BCG offered significant protective immunity against visceral leishmaniasis compared with BCG alone . Leishmanin skin conversion with an in duration of 5 mm or more in either group was associated with protection from the disease BACKGROUND The development of a malaria vaccine remains a public health priority for sub-Saharan Africa .  RTS , S/AS02A c and i date malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia . However , genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine . OBJECTIVE We carried out a phase I , double-blind r and omized controlled trial in 60 children aged 1 - 4 in Mozambique to evaluate the safety , reactogenicity and immunogenicity of the paediatric vaccine dose ( fixed 25 microg RTS , S in 0.25 ml ) of RTS , S/AS02A , prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population . METHOD Children were r and omized to receive either RTS , S/AS02A or Engerix-B vaccine . Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events ( AEs ) . RESULTS The RTS , S/AS02A was found to be safe and well tolerated . Serious adverse events were balanced between both groups and none was related to vaccination . The frequency of adverse events reported with RTS , S/AS02A was comparable to previous studies in children .  Grade 3 AEs were infrequent ( one case of pain , one of fever in each group and some swelling greater than 20 mm in diameter ) , transient and resolved without sequelae . RTS , S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response BACKGROUND New vaccines against pneumococcal infections in infancy are needed . We assessed in young infants the safety and immunogenicity of two tetravalent vaccines containing pneumococcal 6B , 14 , 19F and 23F polysaccharides conjugated to either tetanus toxoid ( Pnc-T ) or diphtheria toxoid ( Pnc-D ) . METHODS Pnc-T or Pnc-D containing 3 microg of polysaccharide of each of the four pneumococcal polysaccharides or placebo were given intramuscularly in a double blinded fashion ( 25 infants per group ) at 2 , 4 and 6 months of age . At 12 months of age all 75 children were boosted with a 23-valent nonconjugate polysaccharide pneumococcal vaccine .  Serum type-specific anticapsular antibody concentrations were measured at 2 , 4 , 6 , 7 , 12 and 13 months of age . Adverse events occurring within 72 h after each injection were recorded . RESULTS Both Pnc-T and Pnc-D were well-tolerated .  Pnc-T and Pnc-D had higher antibody concentrations compared with placebo after primary immunity ( type 6B , 1.66 , 1.40 and 0.60 microg/ml , respectively ; type 14 , 4.81 , 2.65 and 2.22 microg/ml , respectively ; type 19F , 2.40 , 3.48 and 0.83 microg/ml , respectively ; type 23F , 0.96 , 0.44 and 0.35 microg/ml , respectively ) . Proportions of infants with concentrations above 1.0 microg/ml were also higher in the vaccine recipients than in those given placebo . After booster with the nonconjugate polysaccharide vaccine , both geometric antibody concentration and proportion with concentrations > or = 1.0 microg/ml were significantly higher among either Pnc-T or Pnc-D recipients than among placebo recipients . CONCLUSIONS Both Pnc-T and Pnc-D were well-tolerated , induced serotype-specific anticapsular antibodies and induced immunologic memory A single dose ( 5 x 10(8 ) organisms ) of attenuated A- B+ Vibrio cholerae classical Inaba recombinant vaccine strain CVD 103-HgR or placebo was administered to 24 healthy young Thai adults in a r and omized , placebo-controlled , double-blind trial of safety and immunogenicity . None of the volunteers experienced untoward reactions . The vaccine strain was recovered from 2 of 12 vaccines . The vibriocidal antibody response ( the best immunological correlate of protection ) was good : 11 of 12 vaccinees ( 92 % ) manifested significant serotype-homologous Inaba antibody rises with a peak reciprocal geometric mean titer ( RGMT ) postvaccination of 3,417 ; 9 of 12 exhibited significant serotype-heterologous Ogawa antibody rises ( prevaccination RGMT , 180 ; peak RGMT , 2,874 ) . Nine of 12 vaccinees had significant rises in serum antitoxin . None of the controls exhibited rises in vibriocidal or antitoxic antibody . This preliminary study further confirms the safety and immunogenicity of CVD 103-HgR live oral cholera vaccine and paves the way for larger community studies of this c and i date cholera vaccine CONTEXT Human papillomavirus ( HPV ) vaccine programs may decrease the morbidity and mortality due to cervical cancer seen among women in low-re source countries . However , the 3-dose schedule over a 6-month period is a potential barrier to vaccine introduction in such setting s. OBJECTIVE To determine the immunogenicity and reactogenicity of different dosing schedules of quadrivalent HPV vaccine in adolescent girls in Vietnam . DESIGN , SETTING , AND PARTICIPANTS Open-label , cluster r and omized , noninferiority study ( conducted between October 2007 and January 2010 ) assessing 4 schedules of an HPV vaccine delivered in 21 schools to 903 adolescent girls ( aged 11 - 13 years at enrollment ) living in northwestern Vietnam . INTERVENTION Intramuscular injection of 3 doses of quadrivalent HPV vaccine delivered on a st and ard dosing schedule ( at 0 , 2 , and 6 months ) and 3 alternative dosing schedules ( at 0 , 3 , and 9 months ; at 0 , 6 , and 12 months ; or at 0 , 12 , and 24 months ) . MAIN OUTCOME MEASURES Serum anti-HPV geometric mean titers ( GMT ) measured 1 month after the third dose of the HPV vaccine was administered ; GMT was determined by type-specific competitive immunoassay . Noninferiority of each alternative vaccination dosing schedule was achieved if the lower bound of the multiplicity-adjusted confidence interval ( CI ) of the type-specific GMT ratio for HPV-16 and HPV-18 was greater than 0.5 ( primary outcome ) . Safety outcomes were immediate reactions , local reactions , fever within 7 days after each dose , and serious adverse events up to 30 days following the last dose . RESULTS In the intention-to-treat analysis , 809 girls who received at least 1 HPV vaccine dose had valid serum measurements 1 month after the third dose . After the third dose , the GMTs for those in the st and ard schedule group who received doses at 0 , 2 , and 6 months were 5808.0 ( 95 % CI , 4961.4 - 6799.0 ) for HPV-16 and 1729.9 ( 95 % CI , 1504.0 - 1989.7 ) for HPV-18 ; 5368.5 ( 95 % CI , 4632.4 - 6221.5 ) and 1502.3 ( 95 % CI , 1302.1 - 1733.2 ) , respectively , for those whose received doses at 0 , 3 , and 9 months ; 5716.4 ( 95 % CI , 4876.7 - 6700.6 ) and 1581.5 ( 95 % CI , 1363.4 - 1834.6 ) , respectively , for those who received doses at 0 , 6 , and 12 months ; and 3692.5 ( 95 % CI , 3145.3 - 4334.9 ) and 1335.7 ( 95 % CI , 1191.6 - 1497.3 ) , respectively , for those who received doses at 0 , 12 , and 24 months . Noninferiority criteria were met for the alternative schedule groups that received doses at 0 , 3 , and 9 months ( HPV-16 GMT ratio : 0.92 [ 95 % CI , 0.71 - 1.20 ] ; HPV-18 GMT ratio : 0.87 [ 95 % CI , 0.68 - 1.11 ] ) and at 0 , 6 , and 12 months ( HPV-16 GMT ratio : 0.98 [ 95 % CI , 0.75 - 1.29 ] ; HPV-18 GMT ratio : 0.91 [ 95 % CI , 0.71 - 1.17 ] ) . Prespecified noninferiority criteria were not met for the alternative schedule group that received doses at 0 , 12 , and 24 months ( HPV-16 GMT ratio : 0.64 [ 95 % CI , 0.48 - 0.84 ] ; HPV-18 GMT ratio : 0.77 [ 95 % CI , 0.62 - 0.96 ] ) . Pain at the injection site was the most common adverse event . CONCLUSIONS Among adolescent girls in Vietnam , administration of the HPV vaccine on st and ard and alternative schedules was immunogenic and well tolerated . The use of 2 alternative dosing schedules ( at 0 , 3 , and 9 months and at 0 , 6 , and 12 months ) compared with a st and ard schedule ( at 0 , 2 , and 6 months ) did not result in inferior antibody concentrations . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00524745 To establish the safety and reproducibility of live challenge with Leishmania major , a single frozen stabilate was used in two open , single-arm leishmanization ( LZ ) trials . A total of 42 inoculations in 28 male adult volunteers were followed until complete healing . Lesions induced by LZ are as diverse as natural infection , but much milder . Total protection was seen in 100 % ( 11/11 ) of recovered volunteers . LZ used as live challenge to test vaccine c and i date s reduces the required sample size , is cost effective for surrogate markers studies and will induce protection in the participants who are not protected by c and i date vaccines BACKGROUND Typhoid fever is common in developing countries . The licensed typhoid vaccines confer only about 70 percent immunity , do not protect young children , and are not used for routine vaccination . A newly devised conjugate of the capsular polysaccharide of Salmonella typhi , Vi , bound to nontoxic recombinant Pseudomonas aeruginosa exotoxin A ( rEPA ) , has enhanced immunogenicity in adults and in children 5 to 14 years old and has elicited a booster response in children 2 to 4 years old . METHODS In a double-blind , r and omized trial , we evaluated the safety , immunogenicity , and efficacy of the Vi-rEPA vaccine in children two to five years old in 16 communes in Dong Thap Province , Vietnam . Each of the 11,091 children received two injections six weeks apart of either Vi-rEPA or a saline placebo . Cases of typhoid , diagnosed by the isolation of S. typhi from blood cultures after 3 or more days of fever ( a temperature of 37.5 degrees C or higher ) , were identified by active surveillance over a period of 27 months . We estimated efficacy by comparing the attack rate of typhoid in the vaccine group with that in the placebo group . RESULTS S. typhi was isolated from 4 of the 5525 children who were fully vaccinated with Vi-rEPA and from 47 of the 5566 children who received both injections of placebo ( efficacy , 91.5 percent ; 95 percent confidence interval , 77.1 to 96.6 ; P<0.001 ) . Among the 771 children who received only one injection , there was 1 case of typhoid in the vaccine group and 8 cases in the placebo group . Cases were distributed evenly among all age groups and throughout the study period . No serious adverse reactions were observed . In all 36 children studied four weeks after the second injection of the vaccine , levels of serum IgG Vi antibodies had increased by a factor of 10 or more . CONCLUSIONS The Vi-rEPA conjugate typhoid vaccine is safe and immunogenic and has more than 90 percent efficacy in children two to five years old . The antibody responses and the efficacy suggest that this vaccine should be at least as protective in persons who are more than five years old Background Apical Membrane Antigen-1 ( AMA1 ) is one of the leading blood stage malaria vaccine c and i date s. AMA1-C1/Alhydrogel ® consists of an equal mixture of recombinant AMA1 from FVO and 3D7 clones of P. falciparum , adsorbed onto Alhydrogel ® . A Phase 1 study in semi-immune adults in Mali showed that the vaccine was safe and immunogenic , with higher antibody responses in those who received the 80 µg dose . The aim of this study was to assess the safety and immunogenicity of this vaccine in young children in a malaria endemic area . Design This was a Phase 1 dose escalating study in 36 healthy children aged 2–3 years started in March 2006 in Donéguébougou , Mali . Eighteen children in the first cohort were r and omized 2∶1 to receive either 20 µg AMA1-C1/Alhydrogel ® or Haemophilus influenzae type b Hiberix ® vaccine . Two weeks later 18 children in the second cohort were r and omized 2∶1 to receive either 80 µg AMA1-C1/Alhydrogel ® or Haemophilus influenzae type b Hiberix ® vaccine . Vaccinations were administered on Days 0 and 28 and participants were examined on Days 1 , 2 , 3 , 7 , and 14 after vaccination and then about every two months . Results to Day 154 are reported in this manuscript . Results Of 36 volunteers enrolled , 33 received both vaccinations . There were 9 adverse events related to the vaccination in subjects who received AMA1-C1 vaccine and 7 in those who received Hiberix ® . All were mild to moderate . No vaccine-related serious or grade 3 adverse events were observed . There was no increase in adverse events with increasing dose of vaccine or number of immunizations . In subjects who received the test vaccine , antibodies to AMA1 increased on Day 14 and peaked at Day 42 , with changes from baseline significantly different from subjects who received control vaccine . Conclusion AMA-C1 vaccine is well tolerated and immunogenic in children in this endemic area although the antibody response was short lived . Trial Registration Clinical trials.gov Substantial experimental evidence indicates that the Plasmodium circumsporozoite ( CS ) protein has great potential as a vaccine c and i date . We tested the safety and immunogenicity of vaccines composed of P. vivax CS-derived synthetic peptides .  Sixty-nine healthy , malaria-naive volunteers were r and omized to receive three injections of placebo or synthetic proteins N , R , or C ( 10 , 30 , or 100 microg/dose ) in a double-blinded fashion . Vaccines were well tolerated and no serious adverse events were observed . Peptides N and R elicited humoral responses at all doses ; peptide C elicicted these responses only at doses of 30 and 100 microg . The N peptide at a dose of 100 microg elicited the greatest antibody response . Antibodies to the three peptides recognized P. vivax sporozoites in an immunofluorescent antibody test . Peripheral blood mononuclear cells from most immunized volunteers also produced interferon-gamma upon peptide in vitro stimulation . These vaccines appear safe , well tolerated , and immunogenic in malaria-naive volunteers . Further optimization and development of this vaccine is being attempted to conduct phase II clinical trials The need for developing a case definition and guidelines for a local reaction at or near the injection site , methods for the development of the case definition and guidelines as an adverse event following immunization as well as the rationale for selected decisions about the case definition for a local reaction at or near the injection site are explained in the Preamble section . The case definition is structured in 2 levels of diagnostic certainty : level 1 includes any description of morphological or physiological change at or near the injection site that is described or identified by a healthcare provider . Level 2 is any description of morphological or physiological change at or near injection site that is described by any other person . In Guidelines section , the working group recommends to enable meaningful and st and ardized data collection , analysis , and presentation of information about a local reaction at or near the injection site . However , implementation of all guidelines might not be possible in all setting s. The availability of information may vary depending upon re sources , geographic region , and whether the source of information is a prospect ively design ed clinical trial , a post-marketing surveillance or epidemiologic study , or an individual report of a local reaction at injection site A tetravalent rhesus-human reassortant rotavirus ( RRV-TV ) vaccine ( 4 x 10(4 ) plaque-forming units/dose ) was evaluated for safety , immunogenicity and efficacy in a prospect i ve , r and omized , double-blind , placebo-controlled trial involving 540 Brazilian infants . Doses of vaccine or placebo were given at ages 1 , 3 and 5 months . No significant differences were noted in the occurrence of diarrhoea or vomiting in vaccine and placebo recipients following each dose . Low- grade fever occurred on days 3 - 5 in 2 - 3 % of vaccinees after the first dose , but not after the second or third doses of vaccine . An IgA antibody response to rhesus rotavirus ( RRV ) occurred in 58 % of vaccinees and 33 % of placebo recipients . Neutralizing antibody responses to individual serotypes did not exceed 20 % when measured by fluorescent focus reduction , but exceeded 40 % when assayed by plaque reduction neutralization . There were 91 cases of rotavirus diarrhoea among the 3-dose ( vaccine or placebo ) recipients during two years of follow-up , 36 of them among children given the vaccine . Overall vaccine efficacy was 8 % ( P = 0.005 ) against any diarrhoea and 35 % ( P = 0.03 ) against any rotavirus diarrhoea . Protection during the first year of follow-up , when G serotype 1 rotavirus predominated , was 57 % ( P = 0.008 ) , but fell to 12 % in the second year . Similar results were obtained when analysis was restricted to episodes in which rotavirus was the only identified pathogen . There was a tendency for enhanced protection by vaccine against illness associated with an average of 6 or more stools per day . These results are sufficiently encouraging to warrant further studies of this vaccine in developing countries using a higher dosage in an attempt to improve its immunogenicity and efficacy Widespread use of Haemophilus influenzae type b ( Hib ) conjugated vaccine in industrialized countries has result ed in a dramatic decline in the incidence of invasive Hib diseases , but the vaccine 's cost has prevented its inclusion in basic immunization programs in developing countries . To overcome this problem , combination with diphtheria-tetanus-pertussis ( DTP ) vaccine or reduction in the dose of Hib vaccine has been proposed . To evaluate the immunogenicity and adverse reactions from lower doses of Hib-polyribosylphosphate ( PRP ) conjugated with tetanus toxoid ( PRP-T ) , a double-blind study was conducted in Jakarta , Indonesia , and its suburbs . A total of 1048 infants 6 weeks to 6 months of age received three doses of DTP vaccine combined with the usual 10 microg dose or with a reduced dose of 5 , 2.5 or 1.25 microg of PRP-T at two-monthly intervals . Antibodies were measured prior to the first dose and 4 - 6 weeks following the third dose . Adverse reactions were similar among all four groups . The only significant difference was a higher rate of irritability ( p<0.02 ) and of temperature elevation > 38 degrees C ( p<0.009 ) after doses 1 and 2 in the lowest dose group ( 1.25 microg PRP-T ) compared to the other groups . All participants tested had a 4-fold increase in antibodies against all DTP antigens . In addition , after a fourth booster dose of Hib , 99.6 % of infants produced > or=0.15 microg/ml of antibody to Hib-PRP , and 96.4 % showed levels > or=1.0 microg/ml after primary immunization , level that correlate with short- and long-term immunity , respectively . Antibody titers to the PRP antigen showed no significant differences among dosage groups with the exception of the 5.0 microg group , which had a significantly higher GMC than the 1.25 microg group ( p<0.012 ) . This study demonstrates that primary vaccination with half , one-fourth , or one-eighth of the usual dose of PRP-T , combined with DTP vaccine , produces protective immune responses , and has side effects that are comparable to DTP vaccination alone . In these lower dosages , PRP-T conjugate vaccine can lower vaccine costs to a level that is affordable for infant immunization programs in developing countries BACKGROUND In developing countries , pneumonia and meningitis due to Haemophilus influenzae type b ( Hib ) are common in children under age 12 months and the mortality from meningitis is high . Protein-polysaccharide conjugate vaccines have brought Hib disease under control in industrialised countries . We did a double-blind r and omised trial in The Gambia to assess the efficacy of a Hib conjugate vaccine for the prevention of meningitis , pneumonia , and other invasive diseases due to Hib . METHODS Between March , 1993 , and October , 1995 , 42,848 infants were r and omly allocated the conjugate vaccine Hib polysaccharide tetanus protein ( PRP-T ) mixed with diphtheria-tetanus-pertussis vaccine ( DTP ) , or DTP alone at age 2 months , 3 months , and 4 months . Children who presented with signs of invasive Hib were investigated by blood culture and , where appropriate , by lumbar puncture , chest radiograph , or percutaneous lung aspirate . Children were followed up for between 5 and 36 months . FINDINGS The median ages at which children received the study vaccine were 11 weeks , 18 weeks , and 24 weeks . 83 % of children enrolled received all three doses of vaccine . 17 cases of culture-positive Hib pneumonia , 28 of Hib meningitis , and five of other forms of invasive Hib disease were detected amongst the study children . The efficacy of the vaccine for the prevention of all invasive disease after three doses was 95 % ( PRP-T vaccinees 1 , controls 19 [ 95 % CI 67 - 100 ] ) , for the prevention of Hib pneumonia after two or three doses , 100 % ( vaccinees 0 , controls 10 [ 55 - 100 ] ) , and for the prevention of radiologically defined pneumonia at any time after enrollment , 21.1 % ( PRP-T vaccinees 198 , controls 251 [ 4.6 - 34.9 ] ) . INTERPRETATION PRP-T conjugate Hib vaccine prevented most cases of meningitis and pneumonia due to Hib in Gambian infants . The reduction in the overall incidence of radiologically defined pneumonia in PRP-T vaccinees suggests that about 20 % of episodes of pneumonia in young Gambian children are due to Hib . The introduction of Hib vaccines into developing countries should substantially reduce childhood mortality due to pneumonia and meningitis Background . Rotavirus is the most common cause of severe gastroenteritis among children worldwide . Objectives . To compare the safety , immunogenicity and shedding patterns of rhesus rotavirus (RRV)-tetravalent vaccine vs. placebo among infants in rural Bangladesh . Methods . A double blinded , placebo-controlled trial was conducted in which infants ( n = 120 ) were r and omly assigned to receive three doses of either vaccine or placebo administered at ∼6 , 10 and 14 weeks of age together with routine immunizations . Data on possible adverse effects of vaccinations were collected daily for 7 days after each dose . Stool sample s were collected after each dose , and serum sample s were obtained before the first and after the third vaccination . Results . Fever ( ≥38 ° C ) , as measured by study assistants , was noted more frequently among vaccinees ( 15 % ) than among placebo recipients ( 2 % ) during the 7 days after vaccination but was not reported more frequently by parents of vaccinees vs. placebo recipients . Overall 87 % of vaccinees had an antibody response ( measured by IgA or anti-RRV-neutralizing antibodies ) after vaccination compared with 32 % of placebo recipients . Rates of seroconversion were higher among subjects with lower levels of prevaccination antibodies and those who shed rotavirus after vaccination . Vaccine strain viruses were detected in stools from placebo vaccine recipients who had evidence of IgA seroconversion . Conclusions . In this population RRV-tetravalent vaccine was comparably immunogenic and safe as in trials conducted in developed countries , where this vaccine has been proved effective in preventing severe rotavirus diarrhea . These data support continued evaluation of rotavirus vaccines in developing countries Background . Pneumococcal polysaccharide/protein conjugate vaccines ( PnCV ) are immunogenic and effective in infancy . However , an addition to the nine currently recommended vaccine injections during the first year of life of African children may be a deterrent to participation in a PnCV program . Thus we have evaluated the safety and immunogenicity of a 9-valent PnCV ( Wyeth Lederle Pediatrics and Vaccines ) mixed with diphtheria , tetanus toxoid , cell pertussis and Haemophilus influenzae type b ( TETRAMUNE ) . Methods . Healthy Gambian infants were r and omized at the age of 2 months to receive three doses 1 month apart of either ( 1 ) placebo reconstituted in TETRAMUNE in the right thigh ( control ) or ( 2 ) PnCV in the left thigh and TETRAMUNE in the right thigh ( separate ) or ( 3 ) PnCV reconstituted in TETRAMUNE as a single injection in the right thigh ( combined ) . The vaccines were given together with routine Exp and ed Program on Immunization vaccines . Adverse reactions were recorded after vaccination , and antibody concentrations were measured by enzyme-linked immunosorbent assays . Results . Local in duration and tenderness were observed more commonly at the site of injection of TETRAMUNE than at the site of injection with PnCV after each dose of vaccination . Swelling at the site of injection was encountered more frequently at the site of administration of TETRAMUNE than at the site of administration PnCV ( P < 0.00001 for Doses 1 and 2 and P < 0.0009 for Dose 3 ) . Swelling at the site of administration of TETRAMUNE mixed with PnCV was comparable with that observed for TETRAMUNE alone . Although most mothers reported that the babies “ felt hot ” 24 h after each injection , febrile reactions ( temperature , ≥38 ° C ) were infrequent and resolved with antipyretics . Geometric mean titer for anti-polyribosylribitol phosphate antibody was 11.6 & mgr;g/ml [ 95 % confidence limits ( 95 % CI ) , 9.2 , 14.6 ] in the control group and comparable with 13.3 & mgr;g/ml ( 95 % CI 11.0 , 16.0 ) in the combined group and significantly higher at 17.9 & mgr;g/ml ( 95 % CI 14.7 , 21.9;P = 0.01 ) in the separate group . Geometric mean concentrations of serotype-specific pneumococcal antibodies were higher in the combined group than the separate group for all nine serotypes . Antibody responses to diphtheria and pertussis antigens were similar in all groups . Anti-tetanus toxoid antibody concentrations were lowest in the combined group ( 6.66 IU/ml , 95 % CI 5.77 , 7.68 in the control group ; 5.15 IU/ml , 95 % CI 4.39 , 6.03 in the combined group;P = 0.02 ) . However , all vaccinees achieved protective antibody values . Conclusion . The combination of TETRAMUNE and PnCV is safe and immunogenic OBJECTIVE To assess the immunogenicity and reactogenicity of a tetanus conjugate Haemophilus influenzae type b vaccine ( Act-Hib ) when extemporaneously mixed and administered as a DTwP-Hib combination using an  Indian DTwP vaccine ( BE DTwP ) in comparison with a licensed DTwP-Hib combination vaccine . METHODS 378 healthy infants were enrolled and r and omly allocated to receive either three doses , at 6 , 10 and 14 weeks of age , of Act-Hib in combination with BE DTwP ( Group A , n = 160 ) , TetrAct-Hib ( Group B , n = 160 ) , or BE DTwP and Act-Hib as separate injections ( Group C , n = 58 ) . Sera collected before the first dose and one month after the third dose were tested for antibodies to vaccine antigens . Safety was determined using parental diary cards . RESULTS Anti-Hib antibody concentrations indicative of short-term protection ( > 0.15 g/ml ) were elicited in all but one subject in Group A ( 99.3 % ) , and all subjects in Groups B and C. The concentration of 1 g/ml , considered to provide long-term protection , was achieved in 96.7 % , 100 % and 98.2 % of the infants in Groups A , B and C , respectively . All children displayed satisfactory responses to the three DTwP component antigens , TetrAct-Hib eliciting higher titers against diphtheria and tetanus than BE DTwP. No vaccine-associated serious adverse events occurred . The BE DTwP vaccine was associated with more reports of fever than TetrAct-Hib , but most symptoms were regarded as mild and all resolved without sequelae . CONCLUSIONS Combining Act-Hib and a local DTwP vaccine did not affect the anti-Hib response . In countries where DTwP vaccine available for use in the EPI program is manufactured by a local or other developing country manufacturer , mixing it with lyophilised Act-Hib is a reasonable option though the immunogenicity may have to be documented before routine use . However , use of TetrAct-Hib combination vaccine would be preferable in view of its lower reactogenicity and superior immunogenicity with respect to diphtheria and tetanus Background : Rotavirus and human immunodeficiency virus ( HIV ) infections are a cause of great public health concern in developing countries . The current study evaluated the safety , reactogenicity , and immunogenicity of RIX4414 vaccine in asymptomatic or mildly symptomatic ( clinical stages I and II according to WHO classification ) HIV-infected South African infants . Methods : A total of 100 HIV-positive infants aged 6 to 10 weeks enrolled in this double-blind , 1:1 r and omized , placebo-controlled study were allocated into 2 groups to receive 3 doses of RIX4414 vaccine/placebo according to a 0- , 1- , and 2-month schedule . Routine vaccines were concomitantly administered . Solicited and unsolicited symptoms were recorded for 15 and 31 days after each dose , respectively . Serious adverse events were recorded throughout the study period . Serum antirotavirus IgA concentrations ( enzyme-linked immunosorbent assay , cut-off ≥20 U/mL ) and the immunodeficiency status were determined at screening and 2 months post-Dose 3 . Stool sample s were analyzed for rotavirus using enzyme-linked immunosorbent assay at predetermined points and during diarrhea episodes . Results : All symptoms ( solicited and unsolicited ) occurred at a similar frequency in both groups . Six fatal serious adverse events in RIX4414 and 9 in placebo groups were reported . At 2 months post-Dose 3 , the seroconversion rates were 57.1 % ( 95 % CI : 34–78.2 ) in RIX4414 and 18.2 % ( 95 % CI : 5.2–40.3 ) in the placebo group . The mean absolute CD4 + cell count , CD4 + percentage , and HIV-1 viral load were comparable in both groups at screening and 2 months post-Dose 3 . Rotavirus shedding peaked at Day 7 after Dose 1 of RIX4414 with prolonged shedding was observed in 1 infant only . Conclusions : Three doses of RIX4414 vaccine was tolerated well by the South African HIV-positive infants . A satisfactory immune response was mounted without aggravating their immunologic or HIV condition 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 Group A meningococci are the source of major epidemics of meningitis in Africa . An affordable , highly immunogenic meningococcal A conjugate vaccine is needed . METHODS We conducted two studies in Africa to evaluate a new MenA conjugate vaccine ( PsA-TT ) . In study A , 601 children , 12 to 23 months of age , were r and omly assigned to receive PsA-TT , a quadrivalent polysaccharide reference vaccine ( PsACWY ) , or a control vaccine ( Haemophilus influenzae type b conjugate vaccine [ Hib-TT ] ) . Ten months later , these children underwent another round of r and omization within each group to receive a full dose of PsA-TT , a one-fifth dose of PsACWY , or a full dose of Hib-TT , with 589 of the original participants receiving a booster dose . In study B , 900 subjects between 2 and 29 years of age were r and omly assigned to receive PsA-TT or PsACWY .  Safety and reactogenicity were evaluated , and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody ( SBA ) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay . RESULTS In study A , 96.0 % of the subjects in the PsA-TT group and 63.7 % of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline ; in study B , 78.2 % of the subjects in the PsA-TT group and 46.2 % of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline . The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3 , respectively , than they were in the PsACWY groups ( P<0.001 ) . In study A , the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine . Safety profiles were similar across vaccine groups , although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and in duration at the vaccination site . Adverse events were consistent with age-specific morbidity in the study areas ; no serious vaccine-related adverse events were reported . CONCLUSIONS The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine . ( Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation ; Controlled-Trials.com numbers , IS RCT N78147026 and IS RCT N87739946 . )
With more vaccines becoming available worldwide , vaccine research is on the rise in developing countries .