[The evaluation of the reactogenicity, harmlessness and prophylactic efficacy of Grippol trivalent polymer-subunit influenza vaccine administered to schoolchildren]. [The immunogenic properties and prophylactic efficacy of a live polyvalent influenza vaccine in children 5 to 14 years old]. [The comparative characteristics of the safety, immunogenic activity and prophylactic potency of the adult and children types of live influenza vaccine in schoolchildren aged 7-14 years]. Immunogenicity and efficacy of Russian live attenuated and US inactivated influenza vaccines used alone and in combination in nursing home residents. Efficacy and Safety of 1 and 2 Doses of Live Attenuated Influenza Vaccine in Vaccine-Naive Children Effectiveness of influenza vaccine in health care professionals: a randomized trial. Impact of influenza vaccination on civilian aircrew illness and absenteeism. Evaluation of an attenuated, cold-recombinant influenza B virus vaccine. The effectiveness of influenza vaccine against influenza a (H3N2) virus infections in nursing homes in Niigata, Japan, during the 1998-1999 and 1999-2000 seasons. A dictionary of epidemiology [Evaluation of the safety, reactogenicity and antigenic activity of inactivated chromatographic influenza vaccine in school children]. Prevention of symptomatic seasonal influenza in 2005-2006 by inactivated and live attenuated vaccines. Responses to one or two doses of a deoxycholate subunit influenza vaccine in a primed population. Effectiveness of Inactivated Influenza Vaccine for Prevention of Otitis Media in Children Evaluation of monovalent influenza vaccine in a retirement community during the epidemic of 1965-66. Safety, Efficacy, and Effectiveness of Cold-Adapted Influenza Vaccine-Trivalent Against Community-Acquired, Culture-Confirmed Influenza in Young Children Attending Day Care Immunogenicity of 1967 polyvalent and 1968 Hong Kong influenza vaccines. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. Clinical efficacy of cell culture–derived and egg‐derived inactivated subunit influenza vaccines in healthy adults. Do hospital employees benefit from the influenza vaccine? Efficacy of intranasal virosomal influenza vaccine in the prevention of recurrent acute otitis media in children. Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination An integrated, multistudy analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years Field trial of live attenuated influenza A/B ("Alice"/R-75) vaccine. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. [Influence of multiplicity of immunizations of children with inactivated influenza vaccine on immune response and the effectiveness of protection]. Efficacy and Safety of a Live Attenuated, Cold-Adapted Influenza Vaccine, Trivalent Against Culture-Confirmed Influenza in Young Children in Asia Clinical and epidemiological evaluation of a live, cold-adapted influenza vaccine for 3-14-year-olds. Efficacy of inactivated split-virus influenza vaccine against culture-confirmed influenza in healthy adults: a prospective, randomized, placebo-controlled trial. Efficacy of live attenuated and inactivated influenza vaccines in schoolchildren and their unvaccinated contacts in Novgorod, Russia. Efficacy of sequential annual vaccination with inactivated influenza virus vaccine. Trials of aqueous killed influenza vaccine in Canada, 1968-69. Evaluation of a neuraminidase-specific influenza A virus vaccine in children: antibody responses and effects on two successive outbreaks of natural infection. Influenza vaccine in healthy preschool children. Field trial with human and equine influenza vaccines in children: protection and antibody titres. Is influenza vaccination cost effective for healthy people between ages 65 and 74 years? A randomised controlled trial. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. [The results of state trials of inactivated influenza vaccines for children]. The effectiveness of vaccination against influenza in healthy, working adults. Quantitative Synthesis in Systematic Reviews The Efficacy of Live Attenuated Influenza Vaccine Against Influenza-associated Acute Otitis Media in Children Studies of the 1996-1997 inactivated influenza vaccine among children attending day care: immunologic response, protection against infection, and clinical effectiveness. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: A randomized controlled trial. Evaluation in children of cold-adapted influenza B live attenuated intranasal vaccine prepared by reassortment between wild-type B/Ann Arbor/1/86 and cold-adapted B/Leningrad/14/55 viruses. [A comparative study of the inoculation properties of live recombinant and inactivated influenza vaccines made from strain A/Philippines/2/82 (H3N2) in 8- to 15-year-old children]. Controlled trial of inactivated influenza vaccine containing the a-Hong Kong strain during an outbreak of influenza due to the a-England-42-72 strain. Correlated studies of a recombinant influenza-virus vaccine. IV. Protection against naturally occurring influenza in military trainees. Influenza A virus vaccines containing purified recombinant H3 hemagglutinin are well tolerated and induce protective immune responses in healthy adults. Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period. Live attenuated and inactivated influenza vaccine in school-age children. Influenza immunization: field trial on a university campus. Comparison of Serology and Reactogenicity between Influenza Subunit Vaccines and Whole Virus or Split Vaccines Use of influenza A virus vaccines in seronegative children: live cold-adapted versus inactivated whole virus. Comparison of live attenuated and inactivated influenza vaccines in schoolchildren in Russia: I. Safety and efficacy in two Moscow schools, 1987/88. [A comparative study of live and inactivated influenza vaccines: the organization of the observation and the results of a study of their reactogenicity and immunogenicity]. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience Class-specific antibody responses in school children vaccinated with an A/Brazil/11/78 (H1N1)-like recombinant influenza virus prepared from the A/Leningrad/134/57 paediatric cold-adapted donor strain. A controlled trial of inactivated monovalent influenza A vaccines in general practice. Study of live recombinant cold-adapted influenza bivalent vaccine of type A for use in children: an epidemiological control trial. Comparison of heterotypic protection against influenza A/Taiwan/86 (H1N1) by attenuated and inactivated vaccines to A/Chile/83-like viruses. [Basic results of a committee trial of the new vaccine Grippovac SE-AZh]. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. [Results of coded trials of the activity of the trivalent subunit influenza vaccine Grippovak in Moscow kindergartens in December 1983 through the 1st quarter of 1984]. [The investigation of the safety, genetic stability and immunogenicity of live influenza vaccine for adults in vaccination of 3-6 years old children]. [A comparative study of the protective properties of live recombinant and inactivated influenza vaccines made from strain A/Philippines/2/82 (H3N2) in 8- to 15-year-old children]. An evaluation of influenza immunization: influence of route of administration and vaccine strain. [Effectiveness of an influenza vaccine in a working population in Colombia]. Comparison of US inactivated split-virus and Russian live attenuated, cold-adapted trivalent influenza vaccines in Russian schoolchildren. Effective protection against influenza after vaccination with subunit vaccine. Correlation of Cellular Immune Responses with Protection against Culture-Confirmed Influenza Virus in Young Children Comparative efficacy of inactivated and live attenuated influenza vaccines. Incompletely matched influenza vaccine still provides protection in frail elderly. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons
Vaccine " Grippol "-- has been developed at the State Research Center -- Institute of Immunology . The preparation belongs to new generation vaccines and is a trivalent polymer-subunit vaccine containing the sterile conjugate of influenza virus surface proteins , types A and B , bound with copolymer polyoxidonium . The administration of " Grippol " to children of school age ( 6 - 18 years ) demonstrated low reactogenicity of the vaccine , its safety and sufficient prophylactic effectiveness . During observations on total morbidity ( with the exception of influenza and acute respiratory diseases ) no side effects produced by " Grippol " were registered . At the same time the fact that the morbidity rate of upper respiratory tract disease in the group of children immunized with the vaccine decreased in comparison with the control group ( by 2.4 times ) can not be disregarded Production lots of a live influenza vaccine made of strains A/47/T ( N1H1 ) , A/47/6/2 ( H3N2 ) , and B/60/32 were used for vaccination of 3663 children aged from 5 to 14 years inoculated twice with monovaccines , a trivaccine made of the above strains , or placebo . Both mono- and polyvaccine were practically areactogenic . An average per cent of subjects with a significant rise in antibody titres to the respective three antigens was 60 % . The efficacy of the vaccination was 31.0 - 42.8 % for monopreparations and 36.3 % for the trivaccine . The studies showed the possibility and expedience of using for children the live influenza vaccine in the form of a polyvalent preparation including current influenza type A and B viruses In Russia for prevention of influenza in children , aged from 3 to 14 years , the children 's live influenza vaccine ( LIV ) , based upon A/Leningrad/134/47/57(H2N2 ) master strain ( LIVI ) is used . The need for double immunization appears to be one out of the faulties of this preparation . The study was aim ed to comparing the safety , immunogenic activity and prevention of influenza by  LIV for adults ( LIVII ) ( A/Leningrad/134/17/57(H2N2 master strain ) and LIVI in children aged from 7 to 17 years under similar administration schedule . The safety , the preventive efficacy , humoral and secretory immunity were studied . In total 2486 persons , including 539 children , twice inoculated with LIVI , 971 persons once inoculated with LIVII , and 840 treated by placebo were obserbed . From the data of the clinical observations during 7 days after immunization both vaccines appeared to be low reactogenic . The LIVII advantages in induction of the humoral and secretory antibodies in comparison with children 's vaccine had been revealed . Both vaccines were highly efficacious , the efficiency of both preparations was more pronounced after serologic correction of the diagnosis . The results obtained permit to recommend the single immunization by the variant of LIV at the base on A/Leningrad/134/17/57/(H2N2 ) master strain for prevention of influenza in school children The immunogenicity and efficacy of Russian live attenuated and US inactivated trivalent influenza vaccines administered alone or in three different combinations were evaluated in a r and omized , placebo-controlled , double-blinded study of 614 elderly or chronically ill nursing home residents in St. Petersburg , Russia during the 1996 - 97 influenza season .  Postvaccination serum antibody responses were more frequent among individuals administered the combination vaccines than among those vaccinated with live or inactivated vaccine alone . Only individuals who received live vaccine , alone or in combination with inactivated vaccine , achieved significant postvaccination increases in virus-specific nasal IgA. Efficacy in preventing laboratory-confirmed influenza in vaccinated versus nonvaccinated individuals was 67 % ( 95%CI , 36 - 81 % ) for recipients of a combination of the vaccines compared with 51 % ( 95%CI , -17 - 79 % ) for recipients of live vaccine alone and 50 % ( 95%CI , -26 - 80 % ) for recipients of inactivated vaccine alone . These results suggest that administration of a combination of influenza vaccines may provide a strategy for improved influenza vaccination of elderly people Background : We investigated the efficacy and safety of 1 versus 2 doses of live attenuated influenza vaccine ( LAIV ) in influenza vaccine – naive children aged 6 to < 36 months . Patients / Methods : Subjects were r and omized to 1 of 4 regimens in year 1 : 2 doses LAIV , 1 dose LAIV , excipient placebo , or saline placebo . In year 2 , LAIV recipients were to receive 1 dose of LAIV and placebo recipients were to receive saline placebo . Because of an unintended treatment allocation error in year 2 , 1 block of subjects who were r and omized to LAIV received saline placebo and 1 block who were r and omized to placebo received LAIV . Results : In year 1 , vaccine efficacy versus placebo among recipients of 2 and 1 doses of LAIV was 73.5 % and 57.7 % , respectively , against antigenically similar strains . In year 2 , absolute efficacy of a single dose of LAIV was 73.6 % and 65.2 % , respectively , in recipients of 2 and 1 doses of LAIV in year 1 . Year 2 efficacy was 57.0 % in subjects who received 2 doses of LAIV in year 1 and placebo in year 2 . Safety and tolerability of LAIV were consistent with previous studies . Reactogenicity was similar between placebo groups . Seroconversion rates were significantly higher in the 2-dose versus the 1-dose LAIV group in year 1 and in both LAIV groups versus placebo in years 1 and 2 . Conclusions : One dose of LAIV provided clinical ly significant protection against influenza in young children previously unvaccinated against influenza ; 2 doses provided additional protection . Protection after 2 doses in year 1 persisted through a second season without revaccination . LAIV excipients were not a major contributor to reactogenicity . These benefits provide support for increased use of LAIV in children ≥2 years of age CONTEXT Data are limited and conflicting regarding the effectiveness of influenza vaccine in health care professionals . OBJECTIVE To determine the effectiveness of trivalent influenza vaccine in reducing infection , illness , and absence from work in young , healthy health care professionals . DESIGN R and omized , prospect i ve , double-blind , controlled trial over 3 consecutive years , from 1992 - 1993 to 1994 - 1995 . SETTING Two large teaching hospitals in Baltimore , Md. PARTICIPANTS Two hundred sixty-four hospital-based health care professionals without chronic medical problems were recruited ; 49 participated for 2 seasons ; 24 participated for 3 seasons . The mean age was 28.4 years , 75 % were resident physicians , and 57 % were women . INTERVENTION Participants were r and omly assigned to receive either an influenza vaccine or a control ( meningococcal vaccine , pneumococcal vaccine , or placebo ) . Serum sample s for antibody assays were collected at the time of vaccination , 1 month after vaccination , and at the end of the influenza season . Active weekly surveillance for illness was conducted during each influenza epidemic period . MAIN OUTCOME MEASURES Serologically defined influenza infection ( 4-fold increase in hemagglutination-inhibiting antibodies ) , days of febrile respiratory illness , and days absent from work . RESULTS We conducted 359 person-winters of serologic surveillance ( 99.4 % follow-up ) and 4746 person-weeks of illness surveillance ( 100 % follow-up ) . Twenty-four(13.4 % ) of 179 control subjects and 3 ( 1.7 % ) of 180 influenza vaccine recipients had serologic evidence of influenza type A or B infection during the study period . Vaccine efficacy against serologically defined infection was 88 % for influenza A ( 95 % confidence interval [ CI ] , 47%-97 % ; P=.001 ) and 89 % for influenza B ( 95 % CI , 14%-99 % ; P=.03 ) . Among influenza vaccinees , cumulative days of reported febrile respiratory illness were 28.7 per 100 subjects compared with 40.6 per 100 subjects in controls ( P=.57 ) and days of absence were 9.9 per 100 subjects vs 21.1 per 100 subjects in controls ( P=.41 ) . CONCLUSIONS Influenza vaccine is effective in preventing infection by influenza A and B in health care professionals and may reduce reported days of work absence and febrile respiratory illness . These data support a policy of annual influenza vaccination of health care professionals BACKGROUND Approximately 10 % of the general population worldwide acquires influenza infection every year . Airline crews run a particularly high risk of contracting influenza and influenza-like viruses because they come in contact with hundreds of potentially infected individuals every day . Respiratory diseases are the most frequent cause of absenteeism among flight crews in airline companies . Several studies have shown the efficacy of influenza vaccination in the workplace of healthy , working adults leading to increased productivity and lower absenteeism . We conducted a double blind , r and omized , placebo-controlled study on flight crews of an airline company in order to determine the safety and efficacy of a trivalent inactivated influenza vaccine in reducing illness and absences from work . METHODS The 813 healthy members of a Brazilian airline company were r and omly assigned to receive injections of either an influenza vaccine or a placebo , with a follow-up period of 7 mo after vaccination . Primary outcomes included influenza-like illness episodes and absenteeism from work due to such episodes . RESULTS Demographic characteristics were similar in the two groups . No significant side-effects occurred in either group . Compared to the placebo group , individuals receiving the vaccine showed 39.5 % fewer episodes of flu-like illness ( p < 0.001 ) and 26 % fewer days of work lost ( p = 0.03 ) . The vaccinated group developed 33 % fewer episodes of any severe flu-like illness ( p < 0.01 ) . CONCLUSION The data indicates that influenza vaccination is safe in airline flight crews and may produce health-related benefits including reduced absenteeism A live , attenuated influenza B virus vaccine was evaluated in a group of students . The virus , cold-recombinant ( CR ) 7 , was produced by recombining the attenuated cold-adapted parent , B/Ann Arbor/1/66 , with a wild strain , B/Hong Kong/8/73 . In ferrets , the wild strain produced histopathologic lesions in the lungs , whereas the CR strain and the attenuated parent did not . A total of 306 individuals was inoculated intranasally with either the CR virus or a placebo . After inoculation , only one symptom was significantly more common in the vaccinees than in the control subjects . That symptom , sore throat , occurred briefly in 26 % of the vaccine recipients and in 10.5 % of the placebo recipients . An outbreak of influenza B occurred three months after vaccination . When serologic infection rates in the two groups were compared , it was found that the vaccine had been significantly effective ( P less than 0.01 ) in preventing infection OBJECTIVE To evaluate the effectiveness of influenza vaccines against  influenza-like illness ( ILI ) among nursing home residents . DESIGN Prospect i ve , nonr and omized , cohort study . SETTING Nine nursing homes during the 1998 - 1999 influenza season and 11 nursing homes during the 1999 - 2000 influenza season in Niigata Prefecture , Japan . PARTICIPANTS Six hundred ninety-nine residents and 440 healthcare workers ( HCWs ) during the first season , and 930 residents and 517 HCWs during the second season , with vaccination rates ranging from 0 % to 97.7 % . RESULTS Overall , ILI decreased from 24.3 % during the 1998 - 1999 season to 8.8 % during the 1999 - 2000 season . Multivariate analysis adjusted for several factors , including gender , age , underlying diseases , and resident and HCW vaccination rates , failed to demonstrate clear individual protection of residents ( relative risk [ RR ] , 1.42 ; P = .2 for the first season ; RR , 0.95 ; P = .9 for the second season ) . However , vaccination rates of 60 % or greater for residents and HCWs reduced the risk of ILI , and also could prevent outbreaks during the 2 seasons . Highly impaired activities of daily living and chronic respiratory diseases were significantly associated with increased ILI . CONCLUSIONS A high vaccination rate for both residents and HCWs may reduce the risk of ILI and institutional outbreaks in nursing homes When the first edition of A Dictionary of Epidemiology was launched in 1983 , its principal aim was to facilitate communication among health professionals . The field was relatively young and comprised complex interdisciplinary relations ranging from the biomedical sciences to statistics and the social sciences . The International Epidemiological Association ( IEA ) co-sponsored the project with the aim of developing certain st and ards for teaching , research reports and communication of epidemiological findings to the public . This is a well-known history : John M Last , the emeritus professor of epidemiology and community medicine from the University of Ottawa , Canada , was appointed as the editor of A Dictionary ... , and kept ahead of the task during the subsequent decades . The original slim pocket book grew substantially with each re-edit , keeping pace with the remarkable developments in the discipline . When the fourth edition was launched in 2001 , John Last told me with a smile that he would die soon , supposedly to increase the value of the signature he had just h and written in my book . Fortunately , he did not , and his love for dictionary-making allowed him to produce his A Dictionary of Public Health , and to collaborate in the recently launched fifth edition of A Dictionary ... , now edited by Miquel Porta , professor of preventive medicine and public health from the Universitat Autònoma de Barcelona , senior scientist of the Institut Municipal d’Investigació Mèdica in Barcelona , Spain , and collaborator in the previous editions . If he had to limit his professional bookcase to a single volume , Professor Charles du V Florey , the former president of the IEA , would choose to keep A Dictionary .... I argue that anybody among us — epidemiologists and would-be epidemiologists ( hopefully with a larger shelf)—should also have a copy of this book at h and for frequent consultation . The collective effort gathered in its making is impressive . Miquel Porta has built over the previously crafted editions , and has relied on the support of a wide network of professionals to up date each entry and to exp and the selection of subjects . The Journal of Epidemiology and Community Health joined the initiative by publishing a call for su bmi ssions . Items already selected from the previous edition have been revised and up date d ; several new items have been added . As a result , the fifth edition of A Dictionary ... performs normative and informative functions : you will be informed on important matters and instructed on how to proceed in the epidemiological field . Readers with different needs and anxieties with knowledge will find straightforward writing , authoritative definitions and pertinent bibliographical references . How to differentiate a rate from a ratio , incidence from prevalence , confounding from intervening variables , type I from type II error ? How to appraise emerging themes in the epidemiological literature such as genetic polymorphisms and Bayesian statistics ? Key method ological issues such as meta- analysis , multilevel analysis and regression models : the list solely enrols a small sample of possible search es . The selection of issues was broad in scope ; intelligent and synthetic writing contemplated from the easier to the more intricate subjects . You may want to up date conceptual and method ological issues relevant to your teaching and research activities , to resolve doubts or to confirm an impression . You may want to check on terminology , fulfil curiosities or learn about topics unrelated to your preferential themes . You may be a professional applied to other health specialities , an undergraduate or a high school student . Several users will meet their needs by consulting A Dictionary ... ; even those who aim lessly scan the text may find some valuable insight . While it will not resolve all your needs in the epidemiological field , it surely provides enough substance to build on — a very good start or ammunition for more comprehensive search es . Miquel Porta dealt with the challenge of preparing reader-friendly texts on a wide range of subjects , which will satisfy both a beginner and an experienced epidemiologist . He seems to have transposed Occam ’s razor ( see the correspondent entry : ‘ ‘ the philosophical principle of parsimony ... assumptions to explain a phenomenon must not be multiplied beyond necessity ... ’ ’ ) to the writing of the book . If I may indulge in selftestimony , I found my teenage daughter consulting the book and it motivated a conversation on subjects so dear to me .... Arousing the interest of the young for a speciality admittedly perceived as difficult by adolescents ; as goes the popular saying , this is priceless ! ‘ ‘ Epidemiology is the study of the occurrence and distribution of healthrelated states or events in specified population s , including the study of the determinants influencing such states , and the application of this knowledge to control the health problems ’ ’ . The definition has matured over the years and presents slight modifications from its previous formulation in the fourth edition . The entry for ‘ ‘ Epidemiology ’ ’ exp and s the conceptualisation of terms comprised in the definition and includes historical aspects . In subsequent years , this definition will be the benchmark of the discipline , until Miquel Porta and his collaborators eventually prepare a further edition to meet the new needs that the future may bring forth . I dare to guess that the prospect i ve sixth edition of A Dictionary ... will have an online dynamic interface interacting with the hard copy . I also dare to guess that it will include a new entry for A Dictionary of Epidemiology , whose importance to the professional field will surely have earned it To evaluate the safety , reactogenicity and immunogenicity of inactivated chromatographic influenza vaccine A(H3N2 ) produced by the Pasteur Research Institute of Epidemiology and Microbiology in Leningrad , children aged 7 - 15 years received the vaccine intradermally in doses of 114 - 228 IU , and 152 children received placebo .  In this study inactivated influenza vaccine introduced parenterally to children aged 11 - 15 years in a dose of 228 IU proved to be nonreactogenic . The reactogenicity index of the preparation injected in a dose of 114 IU to children aged 7 - 10 years was 0.6 % . Immunization in a single injection was accompanied by significant seroconversions in 87.5%-96.0 % of children with the highly pronounced growth of antibody titers ( 21.1 - 34.6 times ) . The complex of clinico-laboratory tests showed the safety of this preparation for both age groups BACKGROUND The efficacy of influenza vaccines may vary annually . In 2004 - 2005 , when antigenically drifted viruses were circulating , a r and omized , placebo-controlled trial involving healthy adults showed that inactivated vaccine appeared to be efficacious , whereas live attenuated vaccine appeared to be less so . METHODS In 2005 - 2006 , we continued our trial , examining the absolute and relative efficacies of the live attenuated and inactivated vaccines in preventing laboratory-confirmed symptomatic influenza . RESULTS A total of 2058 persons were vaccinated in October and November 2005 . Study wide influenza activity was prolonged but of low intensity ; type A ( H3N2 ) virus was circulating , which was antigenically similar to the vaccine strain . The absolute efficacy of the inactivated vaccine was 16 % ( 95 % confidence interval [ CI ] , -171 % to 70 % ) for the virus identification end point ( virus isolation in cell culture or identification through polymerase chain reaction ) and 54 % ( 95 % CI , 4%-77 % ) for the primary end point ( virus isolation or increase in serum antibody titer ) . The absolute efficacies of the live attenuated vaccine  for these end points were 8 % ( 95 % CI , -194 % to 67 % ) and 43 % ( 95 % CI , -15 % to 71 % ) , respectively . CONCLUSIONS With serologic end points included , efficacy was demonstrated for the inactivated vaccine in a year with low influenza attack rates . The efficacy of the live attenuated vaccine was slightly less than that of the inactivated vaccine , but not statistically greater than that of the placebo A trial with a trivalent influenza subunit vaccine prepared with sodium deoxycholate was carried out in 88 volunteers between May and November 1981 . Each haemagglutinin antigen was present at 7 micrograms per dose . Fourfold or greater haemagglutination inhibition antibody ( HI ) responses to the H1N1 virus A/Brazil/11/78 occurred in 70 % of volunteers following a single dose . For the H3N2 virus A/Bangkok/1/79 and B/Singapore/222/79 these figures were 52 and 11 % , respectively . No increase in the antibody titre was noted to any of the antigens following a second vaccination dose . Antibody levels remained relatively constant six months after vaccination . A response to B/Singapore/222/79 , comparable with the HI response for the influenza A antigens , was noted when serum titres were estimated by a plaque reduction procedure . No neuraminidase inhibition antibody could be detected in response to either A/Brazil/11/78 or A/Bangkok/1/79 . No reactions specifically attributable to the vaccine occurred after either injection . A lower HI response to A/Brazil/11/78 was noted in volunteers 52 years of age and older , who also showed less evidence of earlier priming to this virus . Levels of nasal wash neutralizing antibodies to A/Brazil/11/78 were proportional to those detected in sera by HI tests , but were present in smaller amounts Objective : The objective of this study was to evaluate the effectiveness of inactivated influenza vaccine in preventing acute otitis media ( AOM ) and otitis media with effusion ( OME ) in children aged 6 to 60 months who attend day care . Study Design : This prospect i ve , single-blind study was conducted in 8 day care centers in Ankara , Turkey . One hundred nineteen ( 61 vaccinated and 58 unvaccinated against influenza ) healthy children were examined at study entry and at 6-week intervals for 6 months by the same 2 otorhinolaryngologists who were blinded about the vaccination status of the children . The frequency of AOM and OME is compared between the 2 groups and the effect of influenza season on frequency of episodes was evaluated . Based on national influenza laboratory data , the influenza season was determined to be the period between December 15 , 2003 , and January 31 , 2004 . Result : The frequencies of AOM , OME and total otitis media episodes in vaccinated children were 2.3 % , 22.8 % and 25.2 % , respectively , and these frequencies were 5.2 % , 31.1 % and 36.3 % in the unvaccinated group . The difference was statistically significant ( P < 0.01 ) . This difference was especially prominent in the influenza season ( P < 0.05 ) . Conclusion : Influenza vaccine is effective in reducing AOM and OME episodes in 6- to 60-month-old day care children , especially during influenza season Monovalent adjuvant and aqueous influenza vaccines were evaluated in a retirement community from 1964 to 1966 . In the second year of investigation , an epidemic of A2 influenza provided opportunity to study the protective value of immunization . Vaccine efficacy was shown to be related to the pattern of vaccination . Individuals who had received single doses of A2 vaccine in both years of the study were considerably better protected than those who had received  vaccine  in only one of the years . The rate of febrile illnesses in the former group was more than 90 % below that of vaccinated control . Those given one dose were only about half as well protected . Monovalent adjuvant A2 vaccine given more than a year before the outbreak appeared to protect as well as , if not slightly better than , monovalent aqueous vaccine administered several months before the epidemic OBJECTIVE . The goal was to evaluate the safety , tolerability , and efficacy of an investigational , refrigerator-stable formulation of live attenuated influenza vaccine ( cold-adapted influenza vaccine-trivalent ) against culture-confirmed influenza , acute otitis media , and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons . METHODS . Children 6 to < 36 months of age who were attending day care were assigned r and omly in year 1 to receive 2 doses of vaccine or placebo intranasally , 35 ± 7 days apart . In year 2 , subjects received 1 dose of the same treatment as in year 1 . RESULTS . A total of 1616 subjects ( vaccine : 951 subjects ; placebo : 665 subjects ) in year 1 and 1090 subjects ( vaccine : 640 subjects ; placebo : 450 subjects ) in year 2 were able to be evaluated for efficacy . The mean age at first vaccination was 23.4 ± 7.9 months . In year 1 , the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4 % ; efficacy was 91.8 % against A/H1N1 and 72.6 % against B. In year 2 , the overall efficacy was 88.7 % ; efficacy was 90.0 % against H1N1 , 90.3 % against A/H3N2 , and 81.7 % against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6 % in year 1 and 97.0 % in year 2 . Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent ( 82.3 % ) than placebo ( 75.4 % ) . CONCLUSIONS . Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care Influenza A2 vaccine containing 300 chick-cell agglutination ( CCA ) units per dose of the Hong Kong variant provided a high degree of protection during an outbreak of respiratory illnesses in military personnel in December 1968 and January 1969 . This inactivated chicken embryo-propagated virus vaccine stimulated hemagglutination-inhibition antibody responses that were equivalent to natural infection . Polyvalent vaccine , 1967 formula , was not without some contribution in preventing disease in those who did not receive Hong Kong influenza vaccine .  Influenza A2 comprised 56 % of all respiratory illnesses during the outbreak . Virus was isolated in rhesus monkey kidney cultures from pharyngeal washings of a third of the individuals with serologic evidence of infection by influenza A2 BACKGROUND The efficacy of influenza vaccines may decline during years when the circulating viruses have antigenically drifted from those included in the vaccine . METHODS We carried out a r and omized , double-blind , placebo-controlled trial of inactivated and live attenuated influenza vaccines in healthy adults during the 2004 - 2005 influenza season and estimated both absolute and relative efficacies . RESULTS A total of 1247 persons were vaccinated between October and December 2004 . Influenza activity in Michigan began in January 2005 with the circulation of an antigenically drifted type A ( H3N2 ) virus , the A/California/07/2004-like strain , and of type B viruses from two lineages . The absolute efficacy of the inactivated vaccine against both types of virus was 77 % ( 95 % confidence interval [ CI ] , 37 to 92 ) as measured by isolating the virus in cell culture , 75 % ( 95 % CI , 42 to 90 ) as measured by either isolating the virus in cell culture or identifying it through real-time polymerase chain reaction , and 67 % ( 95 % CI , 16 to 87 ) as measured by either isolating the virus or observing a rise in the serum antibody titer . The absolute efficacies of the live attenuated vaccine were 57 % ( 95 % CI , -3 to 82 ) , 48 % ( 95 % CI , -7 to 74 ) , and 30 % ( 95 % CI , -57 to 67 ) , respectively . The difference in efficacy between the two vaccines appeared to be related mainly to reduced protection of the live attenuated vaccine against type B viruses . CONCLUSIONS In the 2004 - 2005 season , in which most circulating viruses were dissimilar to those included in the vaccine , the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic illnesses from influenza in healthy adults . The live attenuated vaccine also prevented influenza illnesses but was less efficacious . ( Clinical Trials.gov number , NCT00133523 . BACKGROUND More efficient methods are needed to manufacture influenza vaccines . This trial compared the efficacy of cell culture-derived influenza vaccine ( CCIV ) and egg-derived trivalent inactivated vaccine ( TIV ) with placebo against laboratory-confirmed influenza illness in healthy adults in the United States , Finl and , and Pol and during the 2007 - 2008 influenza season . METHODS A total of 11,404 study participants aged 18 - 49 years were r and omized equally to receive CCIV ( Optaflu ; n = 3828 ) , TIV ( Agrippal ; n = 3676 ) , or placebo ( n = 3900 ) . Each participant was observed during a 6-month study surveillance period . Nasal and throat swabs for virus isolation and characterization were collected from all patients with influenza-like illness . Vaccine immunogenicity was evaluated in a subset of 1045 participants . RESULTS Efficacy of CCIV and TIV against vaccine-like ( 83.8 % [ 1-sided 97.5 % confidence interval [ CI ] lower limit , 61.0 % ] and 78.4 % [ 1-sided 97.5 % CI lower limit , 52.1 % ] , respectively ) and all circulating influenza virus strains ( 69.5 % [ 1-sided 97.5 % CI lower limit , 55.0 % ] and 63.0 % [ 1-sided 97.5 % lower limit , 46.7 % ] , respectively ) exceeded the Center for Biologics Evaluation and Research efficacy criteria . Immunogenicity of both vaccines exceeded the Center for Biologics Evaluation and Research licensing criteria . Both vaccines were well tolerated , with similar safety profiles . Most solicited reactions were mild to moderate in severity and transient . No vaccination-related serious adverse events were reported ; no withdrawals result ed from vaccine-related adverse events . CONCLUSIONS Both CCIV and TIV were effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains , were well tolerated , and had good safety profiles . Both vaccines can be considered for annual influenza vaccination campaigns . CLINICAL TRIALS REGISTRATION NCT00630331 Although current guidelines target hospital employees who contact high-risk patients as a high priority for influenza immunization , there are few data to support or refute this recommendation . Therefore , the authors enrolled 179 hospital employees in a r and omized double-blind  placebo-controlled  clinical trial during the 1985–1986 influenza season .  Influenza immunization was performed without serious adverse reactions and there was no increase in absenteeism attributable to the vaccination . Among those who developed clinical influenza , there was a trend toward fewer days of illness in the vaccinated group compared with the placebo group ( 6.0 vs. 8.0 , p=0.07 ) . There were no statistically significant differences between subjects receiving influenza vaccine and those receiving the placebo when comparing incidences of influenza-like illness , severities of illness , and sick absenteeism .  Influenza immunization of hospital employees was performed at minimal cost and risk but provided little benefit , most likely because of an unexpected drift of the prevalent influenza strain away from the vaccine type To evaluate the efficacy of an intranasal , inactivated , virosomal subunit influenza vaccine for prevention of new episodes of acute otitis media ( AOM ) in children with recurrent AOM , 133 children aged 1 - 5 years were r and omized to receive the vaccine  ( n=67 ) or  no vaccination  ( n=66 ) . During a 6-month period , 24 ( 35.8 % ) vaccine recipients had 32 episodes of AOM ; 42 ( 63.6 % ) control subjects had 64 episodes . The overall efficacy of vaccination in preventing AOM was 43.7 % ( 95 % confidence interval , 18.6 - 61.1 ; P=.002 ) . Children vaccinated before influenza season had a significantly better outcome than did those vaccinated after the onset of influenza season . The cumulative duration of middle ear effusion was significantly less in vaccinated children than in control subjects . Data suggest that the intranasal virosomal influenza vaccine might be considered among the options for the prevention of AOM in children < 5 years old with recurrent AOM Background Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine ( TIV ) against culture-confirmed influenza A and /or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic . Methods 6203 subjects were r and omized to receive TIV ( N = 4137 ) or placebo ( N = 2066 ) . The sample size was based on an assumed attack rate of 4 % which provided 90 % power to reject the hypothesis that vaccine efficacy ( VE ) was ≥ 45 % . Cases of influenza like illness ( defined as fever ( oral temperature ≥37.8 ° C ) plus cough and /or sore throat ) were identified both by active ( biweekly phone contact ) and passive ( self reporting ) surveillance and nasal and throat swabs were collected from subjects for viral culture . Results TIV was well tolerated and induced a good immune response . The 2005/2006 influenza season was exceptionally mild in the study area , as it was throughout Europe , and only 46 culture-confirmed cases were found in the study cohort ( 10 influenza A and 36 influenza B ) . Furthermore among the B isolates , 35 were identified as B/Hong Kong 330/2001-like ( B/Victoria/2/87 lineage ) which is antigenically unrelated to the vaccine B strain ( B/Yamagata/16/88 lineage ) . The attack rate in the vaccine group ( 0.7 % ) was not statistically significantly different from the attack rate in the placebo group ( 0.9 % ) . Conclusion Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy . This experience illustrates the challenge of conducting a prospect i ve influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance . Trial Registration Clinical trial registery : NCT00197223 Background R and omized evidence for vaccine immunogenicity and safety is urgently needed in the setting of p and emics with new emerging infectious agents . We carried out an observational survey to evaluate how many r and omized controlled trials testing 2009 H1N1 vaccines were published among those registered , and what was the time lag from their start to publication and from their completion to publication . Methods PubMed , EMBASE and 9 clinical trial registries were search ed for eligible r and omized controlled trials . The units of the analysis were single r and omized trials on any individual receiving influenza vaccines  in any setting . Results 73 eligible trials were identified that had been registered in 2009–2010 . By June 30 , 2011 only 21 ( 29 % ) of these trials had been published , representing 38 % of the r and omized sample size ( 19905 of 52765 ) . Trials starting later were published less rapidly ( hazard ratio 0.42 per month ; 95 % Confidence Interval : 0.27 to 0.64 ; p<0.001 ) . Similarly , trials completed later were published less rapidly ( hazard ratio 0.43 per month ; 95 % CI : 0.27 to 0.67 ; p<0.001 ) . R and omized controlled trials were completed promptly ( median , 5 months from start to completion ) , but only a minority were subsequently published . Conclusions Most registered r and omized trials on vaccines for the H1N1 p and emic are not published in the peer- review ed literature Please cite this paper as : Ambrose et al. ( 2011 ) An integrated , multi study analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years . Influenza and Other Respiratory Viruses 5(6 ) , 389–397 . Background Trivalent , Ann Arbor strain , live attenuated influenza vaccine ( LAIV ) is approved in several countries for use in eligible children aged ≥2 years . Objective To describe the safety of Ann Arbor strain LAIV in children aged 2–17 years . Methods An integrated analysis of r and omized , controlled trials of LAIV . Results A total of 4245 and 10 693 children received ≥1 dose of  LAIV in year 1 of 6 trivalent inactivated influenza vaccine (TIV)‐controlled and 14 placebo‐controlled studies , respectively ; 3212 children were revaccinated in year 2 of 4 placebo‐controlled studies . Compared with placebo for days 0–10 post‐vaccination , LAIV recipients exhibited increased runny/stuffy nose ( + 7 % ) , headache ( + 7 % ) , and tiredness/decreased activity ( + 2 % ) after dose 1 ; and a higher rate of decreased appetite ( + 4 % ) after year 2 revaccination . Compared with TIV , only runny/stuffy nose was increased ( dose 1 , + 12 % ; dose 2 , + 4 % ) . Compared with initial vaccination , LAIV reactogenicity was lower after dose 2 in year 1 and revaccination in year 2 . Unsolicited adverse events ( AEs ) increased with LAIV in some comparisons were headache , nasal congestion/rhinorrhea , rhinitis , and pyrexia ; ear pain and lower respiratory illness were decreased . There was no evidence of an increase in any potential vaccine‐related serious AE in LAIV recipients . Among children aged 2–17 years and specifically aged 24–35 months , there was no evidence that lower respiratory illness or wheezing illness occurred at a higher rate in LAIV recipients . Conclusion This analysis supports the safety of Ann Arbor strain LAIV in children aged 2–17 years and provides a consensus assessment of events expected after vaccination The reactogenicity , immunogenicity and protection effecacy of a serum inhibitor-resistant live attenuated influenza A/B ( " Alice"/R-75 ) vaccine was determined in a group of health young volunteers . The influenza A component was derived from A/Engl and /42/72 ( H3N2 ) strain , and the B component from B/Hong Kong/5/72 strain .  Sixty-eight subjects had hemagglutination inhibition ( HAI ) antibody titers to influenza A hemagglutinin ( HA ) antigen of less than or equal to 1:8 ( " low A " group ) and 75 had similarly low antibody titers to B HA antigen ( " low B " group ) . Two inocula given 14 days apart consisted of vaccine in two doses ( VV ) ; one dose of vaccine followed by placebo ( VP ) ; or two doses of placebo ( PP ) . The reactogenicity of the vaccine was low , with approximately 25 % of subjects in both the immunized and placebo categories having symptoms mainly of respiratory nature . The A component of the vaccine was immunogenic with 90.9 % of the subjects in the low A group VV category showing seroconversion . By contrast , only 20 % of VV subjects in the low B group seroconverted to B antigen . The vaccine afforded significant protection againndergone a slight antigenic drift . There was no difference in protection afforded either by one or two doses of the vaccine . Thus the overall protection efficacy following at least one dose of the vaccine was 80.0 % ( p = .01 ) , and in the low A group subjects it was 85.5 % ( p = .01 ) BACKGROUND Influenzavirus vaccine is used infrequently in healthy children , even though the rates of influenza in this group are high . We conducted a multicenter , double-blind , placebo-controlled trial of a live attenuated , cold-adapted , trivalent influenzavirus vaccine in children 15 to 71 months old . METHODS Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray , and 1314 were assigned to receive two doses approximately 60 days apart . The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time . The subjects were monitored with viral cultures for influenza during the subsequent influenza season . A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions . RESULTS The intranasal vaccine was accepted and well tolerated . Among children who were initially seronegative , antibody titers increased by a factor of four in 61 to 96 percent , depending on the influenza strain . Culture-positive influenza was significantly less common in the vaccine group ( 14 cases among 1070 subjects ) than the placebo group ( 95 cases among 532 subjects ) . The vaccine efficacy was 93 percent ( 95 percent confidence interval , 88 to 96 percent ) against culture-confirmed influenza . Both the one-dose regimen ( 89 percent efficacy ) and the two-dose regimen ( 94 percent efficacy ) were efficacious , and the vaccine was efficacious against both strains of influenza circulating in 1996 - 1997 , A(H3N2 ) and B. The vaccinated children had significantly fewer febrile illnesses , including 30 percent fewer episodes of febrile otitis media ( 95 percent confidence interval , 18 to 45 percent ; P<0.001 ) . CONCLUSIONS A live attenuated , cold-adapted influenzavirus vaccine was safe , immunogenic , and effective against influenza A(H3N2 ) and B in healthy children The formation of immunity and epidemiological effectiveness of inactivated influenza vaccines  in children , regularly immunized against influenza for three years , were evaluated . The study revealed that a year after each immunization the number of children having antibodies in liters regarded as protective decreased 2 - 2.5 times . At the periods of epidemics morbidity rate among the vaccines dynamically decreased in these years 1.3 , 2.0 and 2.8 times . Considering that a year after the second immunization a high immune stratum ( 60 - 78 % ) was retained in the group under study , we propose that annual immunization of the same children be limited by a period of three years , followed by an interval of one year Background : This study was design ed to evaluate the efficacy and safety of cold-adapted influenza vaccine , trivalent ( CAIV-T ) against culture-confirmed influenza in children 12 to < 36 months of age during 2 consecutive influenza seasons at multiple sites in Asia . Methods : In year 1 , 3174 children 12 to < 36 months of age were r and omized to receive 2 doses of CAIV-T ( n = 1900 ) or placebo ( n = 1274 ) intranasally ≥28 days apart . In year 2 , 2947 subjects were rer and omized to receive 1 dose of CAIV-T or placebo . Results : Mean age at enrollment was 23.5 ± 7.4 months . In year 1 , efficacy of CAIV-T compared with placebo was 72.9 % [ 95 % confidence interval ( CI ) : 62.8–80.5 % ] against antigenically similar influenza subtypes , and 70.1 % ( 95 % CI : 60.9–77.3 % ) against any strain . In year 2 , revaccination with CAIV-T demonstrated significant efficacy against antigenically similar ( 84.3 % ; 95 % CI : 70.1–92.4 % ) and any ( 64.2 % ; 95 % CI : 44.2–77.3 % ) influenza strains . In year 1 , fever , runny nose/nasal congestion , decreased activity and appetite , and use of fever medication were more frequent with CAIV-T after dose 1 . Runny nose/nasal congestion after dose 2 ( year 1 ) and dose 3 ( year 2 ) and use of fever medication after dose 3 ( year 2 ) were the only other events reported significantly more frequently in CAIV-T recipients . Conclusions : CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia Reported is a study of live , cold-adapted ( CA ) reassortant mono- , di- , and trivalent influenza type A and B vaccines in a series of controlled clinical and epidemiological investigations involving nearly 130 000 children aged 3 - 15 years . The results of clinical , immunological , and morbidity investigations of the vaccinees and a control group over 6-months ' follow-up indicated that the vaccines were completely attenuated by the children . Transient febrile reactions occurred in < 1 % of the children after vaccination , including double seronegative individuals with low antibody titres . The type A reisolates examined were genetically stable . The reassortants did not suppress each other after simultaneous inoculation of children and stimulated antibody response to influenza virus strains A1 , A3 , and B. The incidence of influenza-like diseases was approximately 30 - 40 % lower among the vaccinated group than among the control group . The study demonstrates , for the first time , the efficacy of CA vaccine  against infections caused by influenza B virus BACKGROUND A new trivalent inactivated split-virus influenza vaccine ( TIV ) was recently introduced in the United States . We assessed the efficacy of TIV against culture-confirmed influenza A and /or B. METHODS In this double-blind trial conducted from September 2006 to May 2007 in the Czech Republic and Finl and , participants aged 18 - 64 years were r and omized to receive 1 dose of TIV ( n = 5103 ) or placebo ( n = 2549 ) . Influenza-like illnesses ( ILI ) ( defined as at least 1 systemic symptom [ fever { oral temperature , > or = 37.8 degrees C } and /or myalgia ] and at least 1 respiratory symptom [ cough and /or sore throat ] ) were identified by both active ( biweekly phone contact ) and passive surveillance . Nasal and throat swab specimens were collected for viral culture . RESULTS The attack rate for culture-confirmed ILI was 3.2 % in the placebo group , with most strains identified as influenza A ( all except 1 were H3N2 ) matching the vaccine strain . There were 6 cases of influenza B , all of which were of a different lineage ( Yamagata ) than the vaccine strain . Vaccine efficacy against culture-confirmed influenza A and /or B due to strains antigenically matched to the vaccine was 66.9 % ( 95 % confidence interval [ CI ] , 51.9%-77.4 % ; P < .001 ) and to any strain was 61.6 % ( 95 % CI , 46.0%-72.8 % ; P < .001 ) . CONCLUSION TIV is efficacious against culture-confirmed influenza in healthy adults . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00363870 Children aged 7 - 14 years in Novgorod , Russia , were given Russian live cold-adapted or inactivated influenza vaccines or placebo over a 2-year period . Schools were r and omly assigned as a whole to one of the preparations . In the first year , the vaccines were bivalent , containing types A ( H3N2 ) and A ( H1N1 ) components . In the second year , the vaccines also contained a type B component . In the first year , all viruses isolated were type A ( H3N2 ) ; in the second , about three-quarters of the isolates were type B and the rest type A ( H1N1 ) . During both years , the vaccines protected the vaccinated children . Where significant differences existed , the live attenuated vaccine was more protective than the inactivated . Vaccination rates in schools in which live attenuated vaccines had been used were inversely related to illness rates of staff and unvaccinated children , suggesting that viral transmission had been reduced by the vaccine Inactivated influenza virus vaccine  efficacy after annual revaccination has been reported to be less than that after first vaccination in boarding school children . We prospect ively examined the immunogenicity and efficacy of this vaccine in healthy 30- to 60-year-old volunteers in Houston , Texas , over two epidemic seasons ( 1983 - 1985 ) encompassing outbreaks due to influenza A ( H3N2 and H1N1 ) and influenza B viruses . A placebo group that had never ( or not in recent years ) received inactivated influenza virus vaccine , a group that received the vaccine for the first time ( first vac ) , and a group given two or more recent vaccinations ( multivac ) were evaluated in a double-blind fashion each year . Vaccination induced higher frequencies of rise in serum antibody titer to vaccine components in first vac than in multivac volunteers , but mean postvaccination titers were similar . Clinical and virologic evaluations of illnesses during both epidemics and of influenza infections diagnosed serologically over the epidemic seasons revealed no overall reduction in illness from that in the placebo group for either vaccine group ; modest reductions in influenza infection-related illness that were significant only for the multivac group against A/H3N2-related illness ( 55 % ; p less than 0.04 ) ; reduction in moderate-to-severe lower respiratory and /or systemic illness due to influenza for multivac ( 73 % , p less than 0.025 ) but not first vac ( 15 % , p greater than 0.10 ) volunteers during the A/H3N2 epidemic ; reduction in influenza virus shedding in the multivac ( 54 % , p less than 0.05 ) but not the first vac ( 16 % , p greater than 0.10 ) group when compared with the placebo group for both years ; and overall 63 - 81 % reductions in documented infections with each influenza virus for both vaccine groups with the exception of A/H1N1 for the first vac group ( 24 % , p greater than 0.10 ) and type B for the multivac group ( 58 % , p = 0.067 ) . Vaccine efficacy was only modest in these studies , but in contrast to the earlier report in boarding school children , efficacy appeared to be somewhat greater after repeated annual vaccination than after first administration The appearance of the p and emic A/Hong Kong/1/68 ( H3N2 ) influenzavirus strain provided an opportunity for a clinical field trial of influenza vaccines in Canada during the winter of 1968 - 69 . As by November 1968 there were reports of influenza B activity and as supplies of A2/HK/68 vaccines were limited , it was decided to make a series of strictly r and omized double-blind trials comparing A2/HK/68 vaccines not only with B/Mass/66 vaccines but also with a bivalent vaccine that was already in production and contained B/Mass/66 and A2/Mtl/68 , the latter a strain isolated in Canada during January 1968 . In 4 trials , a total of 13 729 military personnel and 4 795 primary schoolchildren were vaccinated .  Reported vaccine reactions were less than 0.1 % with zonally-purified vaccines and 2.6 % with the " st and ard " aqueous killed bivalent vaccine .  Three children had serious reactions . Surveillance detected an outbreak of influenza in the first two trials on the military . The 3 vaccines containing A2 strains gave similar clinical protection conservatively estimated at 42 - 55 % but probably about 80 % . The effectiveness of the A2/Mtl/68 vaccine , which was in production before the Hong Kong variant had been isolated , was unexpected . In the absence of a vaccine specific to a new p and emic strain , it should not be assumed that a vaccine made from another recent strain could not be useful Three groups of children were immunized with an inactivated Port Chalmers ( H3ChN2Ch ) influenza vaccine ( group A ) , a neuraminidase-specific ( Heq1N2Ch ) influenza vaccine ( group B ) , or a placebo . Immunization induced seroconversion for H3Ch and N2Ch-specific antibody in group A and for N2Ch antibody in group B. The protective efficacies observed against naturally acquired illness with the Port Chalmers strain of influneza A virus were 68.7 % and 37.4 % in groups A and B , respectively , in comparison to the placebo group , and those against illness produced by the subsequent outbreak of the Victoria strain were 80.0 % and 72.7 % . These data support the role of neuraminidase-specific immunization in protection against influenza . Although the degree of protection after vaccination with the Heq1N2Ch vaccine was less than that provided by the biphasic H3ChN2Ch vaccine against the Port Chalmers strain , it appeared to be similar in the two vaccine study groups against the Victoria strain BACKGROUND Studies of  influenza vaccination in healthy children have not definitely answered the question of their efficacy . METHODS We have carried out a r and omized trial in a well selected population of healthy preschool children in Sardinia , Italy . During October 1995 , 344 children aged 1 to 6 years , were r and omly assigned to receive  influenza vaccine  ( n=177 ) or no treatment ( n=167 ) . Two doses of a trivalent subvirion vaccine , containing 15 mg of highly purified surface antigens from the component strains A/Johannesburg/33/94-like , A/Singapore/6/86-like and B/ Beijing/184/ 93-like were administered . Follow-up data were collected from December 1 , 1995 through April 30 , 1996 . RESULTS Seroconversion was documented in 17 out of 17 children . No specific systemic symptoms or severe local reactions were observed after vaccination . Influenza-like episodes , defined by the presence of fever and cough or sore throat that lasted at least 72 hours , occurred in 63 ( 37.7 % ) of unvaccinated children and in 22 ( 12.4 % ) of vaccinated ones . The corresponding reduction in disease incidence was 67 % ( 95 % CI : 0.59 - 0.74 ) . Three episodes of otitis were observed among children in the control group versus zero among vaccinated children ( p=0.07 ) . Mean duration of day care center absenteism was significantly reduced by vaccination ( 2.3 days in unvaccinated and 0.5 day in vaccinated children , p<0.001 ) CONCLUSIONS Influenza vaccine is safe and effective in healthy preschool children . However the favourable implication s of vaccination on disease rate in subsequent years have to be evaluated A placebo-controlled influenza vaccination trial was carried out on 374 children in the winter of 1967 - 68 . The children were r and omly vaccinated with 300 CCA of A2/Engl and /1/1966 , 300 CCA of A/equine 2/Miami/1963 , or with a placebo . During this winter an influenza outbreak occurred , caused by A2/Nederl and /1968 . The A2 vaccine yielded a protection rate of 58 % ( P = 0.02 ) and the A/equine 2 vaccine a rate of 19 % ( P = 0.33 ) . Serological data revealed that all influenza infections occurred in subjects who had a pre-epidemic  haemagglutination inhibition titre  below 150 . The antibody response against various human influenza A2 viruses and against the horse strain ( A/equine 2 ) is discussed The aim of this study was to determine the cost effectiveness of influenza vaccination for healthy people aged 65 - 74 years living in the UK . People without risk factors for influenza ( chronic heart , lung or renal disease , diabetic , immunosuppressed or those living in an institution ) were identified from 20 general practitioner ( GP ) practice s in Liverpool in September 1999 . 729/5875 ( 12.4 % ) eligible individuals were recruited and r and omised to receive either influenza vaccine or placebo ( ratio 3:1 ) , with all participants receiving 23-valent-pneumococcal polysaccharide vaccine unless already administered . The primary analysis was the frequency of influenza as recorded by a GP diagnosis of pneumonia or influenza like illness . In 2000 , the UK vaccination policy was changed with influenza vaccine becoming available for all people aged 65 years and over irrespective of risk . As a consequence of this policy change , the study had to be fundamentally restructured and only results obtained over a one rather than the originally planned two-year r and omised controlled trial framework were used . Results from 1999/2000 demonstrated no significant difference between groups for the primary outcome ( relative risk 0.8 , 95 % CI 0.16 - 4.1 ) . In addition , there were no deaths or hospitalisations for influenza associated respiratory illness in either group . The subsequent analysis , using both national and local sources of evidence , estimated the following cost effectiveness indicators : ( 1 ) incremental NHS cost per GP consultation avoided = 2000 pound sterling ; ( 2 ) incremental NHS cost per hospital admission avoided = 61,000 pound sterling ; ( 3 ) incremental NHS cost per death avoided = 1,900,000 pound sterling and ( 4 ) incremental NHS cost per QALY gained = 304,000 pound sterling . The analysis suggested that influenza vaccination in this population would not be cost effective CONTEXT Influenza virus is a major cause of illness , disruption to daily life , and increased use of health care in all age groups . OBJECTIVE To assess the safety and effectiveness of intranasally administered trivalent , live , attenuated influenza virus ( LAIV ) vaccine for reducing illness , absenteeism , and health care use among healthy , working adults . DESIGN R and omized , double-blind , placebo-controlled trial conducted from September 1997 through March 1998 . SETTING Thirteen centers across the United States . PARTICIPANTS A total of 4561 healthy , working adults aged 18 to 64 years recruited through health insurance plans , at work sites , and from the general population . INTERVENTION Participants were r and omized 2:1 to receive intranasally administered trivalent LAIV vaccine ( n = 3041 ) or placebo ( n = 1520 ) in the fall of 1997 . MAIN OUTCOME MEASURES Episodes of febrile illness , severe febrile illness , febrile upper respiratory tract illness , work loss , and health care use during the peak and total influenza outbreak periods , and adverse events . RESULTS Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods ( 13.2 % for vaccine vs 14.6 % for placebo ; P=.19 ) . However , vaccination significantly reduced the numbers of severe febrile illnesses ( 18.8 % reduction ; 95 % confidence interval [ CI ] , 7.4%-28.8 % ) and febrile upper respiratory tract illnesses ( 23.6 % reduction ; 95 % CI , 12.7%-33.2 % ) . Vaccination also led to fewer days of illness across all illness syndromes ( 22.9 % reduction for febrile illnesses ; 27.3 % reduction for severe febrile illnesses ) , fewer days of work lost ( 17.9 % reduction for severe febrile illnesses ; 28.4 % reduction for febrile upper respiratory tract illnesses ) , and fewer days with health care provider visits ( 24.8 % reduction for severe febrile illnesses ; 40.9 % reduction for febrile upper respiratory tract illnesses ) . Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes . Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination , but serious adverse events between the groups were not significantly different . The match between the type A(H3N2 ) vaccine strain and the predominant circulating virus strain ( A/Sydney/05/97[H3N2 ] ) for the 1997 - 1998 season was poor , suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain . CONCLUSION Intranasal trivalent LAIV vaccine was safe and effective in healthy , working adults in a year in which a drifted influenza A virus predominated Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11 - 14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines . The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A ( H3N2 ) and A ( H1N1 ) hemagglutinins , 3.5 micrograms per 0.2 ml of the preparation each . The studies demonstrated the safety and low reactogenicity of these vaccines , as well as their high antigenic potency . In 1984 during mixed influenza B + A ( H1N1 ) epidemic the preparations produced a pronounced prophylactic effect : the efficacy indices were 1.6 - 1.9 ( p less than 0.001 ) . The results obtained in these studies made it possible to recommend two inactivated influenza vaccines ( chromatographic and centrifugal ) for practical medicine with the aim of protecting children aged 11 years and over from influenza BACKGROUND Although influenza causes substantial morbidity and mortality in all age groups , current recommendations emphasize annual immunization for people at high risk for complications of influenza . We conducted a double-blind , placebo-controlled trial of vaccination against influenza in healthy , working adults . METHODS In the fall of 1994 , we recruited working adults from 18 to 64 years of age from in and around the Minneapolis-St . Paul area and r and omly assigned them to receive either influenza vaccine or placebo injections . The primary study outcomes included upper respiratory illnesses , absenteeism from work because of upper respiratory illnesses , and visits to physicians ' offices for upper respiratory illnesses . The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses . RESULTS We enrolled a total of 849 subjects . Baseline characteristics were similar in the two groups . During the follow-up period , consisting of the 1994 - 1995 influenza season ( December 1 , 1994 , through March 31 , 1995 ) , those who received the vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo ( 105 vs. 140 episodes per 100 subjects , P < 0.001 ) , 43 percent fewer days of sick leave from work due to upper respiratory illness ( 70 vs. 122 days per 100 subjects , P = 0.001 ) , and 44 percent fewer visits to physicians ' offices for upper respiratory illnesses ( 31 vs. 55 visits per 100 subjects , P = 0.004 ) . The cost savings were estimated to be $ 46.85 per person vaccinated . CONCLUSIONS Vaccination against influenza has substantial health-related and economic benefits for healthy , working adults A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis Background : Acute otitis media ( AOM ) is a frequent complication of influenza in young children .  Influenza vaccination is known to protect against AOM by preventing influenza illness . We sought to determine the efficacy of the live attenuated influenza vaccine ( LAIV ) against influenza-associated AOM compared with placebo and trivalent inactivated influenza vaccine ( TIV ) . LAIV is approved for eligible children aged ≥2 years in the United States and in several other countries . Methods : AOM incidence data from 6 r and omized , double-blind , placebo-controlled trials and 2 r and omized , double-blind , TIV-controlled trials in children 6 to 83 months of age were pooled and analyzed . Results : A total of 290 cases of AOM were identified in 24,046 study subjects .  LAIV efficacy against influenza-associated AOM was 85.0 % ( 95 % confidence interval [ CI ] , 78.3%–89.8 % ) compared with placebo and 54.0 % ( 95 % CI , 27.0%–71.7 % ) compared with TIV . Efficacy trended higher in those ≥24 months of age compared with those aged 6 to 23 months . In placebo-controlled trials , among children who acquired influenza despite vaccination , AOM was diagnosed in 10.3 % of LAIV recipients and 16.8 % of placebo recipients , representing a 38.2 % ( 95 % CI , 11.0%–58.2 % ) relative reduction in the development of AOM . In TIV-controlled studies , among subjects with breakthrough influenza illness , the proportions of LAIV and TIV recipients who developed AOM were similar . Conclusions : Children receiving LAIV  had a high level of protection against influenza-associated AOM when compared with placebo or TIV . This was most evident in children older than 2 years , for whom LAIV is indicated . LAIV recipients who contracted breakthrough influenza illness despite vaccination developed AOM at a significantly lower rate than did unvaccinated children who developed influenza A r and omized , blinded , pilot study of influenza vaccine administered to children attending day care centers was conducted during the 1996 - 1997 winter . Vaccine efficacy in preventing serologically proven influenza virus infection was 0.45 ( 95 % confidence limit [ CL ] : -0.02 , 0.69 ) for influenza B and 0.31 ( 95 % CL : -0.95 , 0.73 ) for influenza A(H3N2 ) . For both influenza A(H3N2 ) and B , children without preexisting hemagglutination inhibition ( HI ) antibody to these antigens had lower antibody responses to vaccine , were less likely to develop a serological response , and were more likely to develop serological evidence of influenza infection . Although there were no reductions in respiratory or febrile respiratory illnesses among all vaccinated children , there was a trend for reductions in such illnesses among vaccinated children with preexisting HI antibodies to influenza A(H3N2 ) and B. Therefore , immunologic priming in young children may be important for vaccine response and for protection against infection . Larger studies are needed in other influenza seasons to assess vaccine efficacy and clinical effectiveness CONTEXT Although the cost-effectiveness and cost-benefit of influenza vaccination are well established for persons aged 65 years or older , the benefits for healthy adults younger than 65 years are less clear . OBJECTIVE To evaluate the effectiveness and cost-benefit of influenza vaccine in preventing influenza-like illness ( ILI ) and reducing societal costs of ILI  among healthy working adults . DESIGN Double-blind , r and omized , placebo-controlled trial conducted during 2 influenza seasons . SETTING AND PARTICIPANTS Healthy adults aged 18 to 64 years and employed full-time by a US manufacturing company ( for 1997 - 1998 season , n = 1184 ; for 1998 - 1999 season , n = 1191 ) . INTERVENTIONS For each season , participants were r and omly assigned to receive either trivalent inactivated influenza vaccine ( n = 595 in 1997 - 1998 and n = 587 in 1998 - 1999 ) or sterile saline injection ( placebo ; n = 589 in 1997 - 1998 and n = 604 in 1998 - 1999 ) . Participants in 1997 - 1998 were rer and omized if they participated in 1998 - 1999 . MAIN OUTCOME MEASURES Influenza-like illnesses and associated physician visits and work absenteeism reported in biweekly question naires by all participants , and serologically confirmed influenza illness among 23 % of participants in each year ( n = 275 in 1997 - 1998 ; n = 278 in 1998 - 1999 ) ; societal cost of ILI per vaccinated vs unvaccinated person . RESULTS For 1997 - 1998 and 1998 - 1999 , respectively , 95 % ( 1130/1184 ) and 99 % ( 1178/1191 ) of participants had complete follow-up , and 23 % in each year had serologic testing . In 1997 - 1998 , when the vaccine virus differed from the predominant circulating viruses , vaccine efficacy against serologically confirmed influenza illness was 50 % ( P = .33 ) . In this season , vaccination did not reduce ILI , physician visits , or lost workdays ; the net societal cost was $ 65.59 per person compared with no vaccination . In 1998 - 1999 , the vaccine and predominant circulating viruses were well matched . Vaccine efficacy was 86 % ( P = .001 ) , and vaccination reduced ILI , physician visits , and lost workdays by 34 % , 42 % , and 32 % , respectively . However , vaccination result ed in a net societal cost of $ 11.17 per person compared with no vaccination . CONCLUSION Influenza vaccination of healthy working adults younger than 65 years can reduce the rates of ILI , lost workdays , and physician visits during years when the vaccine and circulating viruses are similar , but vaccination may not provide overall economic benefits in most years . JAMA . 2000;284:1655 - 1663 A reassortant cold-adapted ( ca ) influenza B experimental live attenuated intranasal vaccine was evaluated for safety and immunogenicity in children by means of a blind , placebo controlled study . The vaccine contained the haemagglutinin and neuraminidase genes , and the gene for its non-structural proteins from wild-type ( wt ) B/Ann Arbor/1/86 virus , the contemporary strain at the time of the study . Other genes were derived from ca B/Leningrad/14/55 virus . No increase in illness rates was seen in the children from ages 3 - 15 years given vaccine at maximum potency ( a one in two dilution of infectious allantoic fluid , having a titre of 10(7.0 ) EID50 ) compared to children given placebo . About 60 % of seronegative children , ages 3 - 7 years , exhibited a detectible antibody response following one dose of intranasal vaccine , with the seroresponse rate rising to greater than 70 % after two doses of vaccine . Immunogenicity was lowest in seropositive children age 8 - 15 years , reaching a maximum of 36 % after two doses . Results indicated that the vaccine was highly attenuated , and probably of adequate immunogenicity for kindergarten age children . The lower immunogenicity in older children suggests the vaccine might be overly attenuated for use in school-age children who are more likely to have a history of prior natural infection with influenza B virus . Further clinical and epidemiological studies of protection are needed to fully assess this This study was carried out to compare reactogenicity , immunogenicity , and efficacy of live attenuated and inactivated influenza vaccines prepared from influenza A/Philippines/2/82-like virus strains . Schoolchildren of a boarding school of Moscow were r and omly divided into three groups : ( 1 ) vaccinated with a live attenuated vaccine , ( 2 ) vaccinated with inactivated influenza vaccine , and ( 3 ) given placebo . Both vaccines were well tolerated by the children , with practically no severe general or local reactions . The inactivated vaccine was found to be superior to the live one in its capacity to stimulate humoral immunity studied by HI , EIA , and microneutralization tests . In 69.7 % of the children given the inactivated vaccine , seroconversion to the vaccine strain was detected by two or three methods of antibody titration used . Only 35.4 % seroconversions were demonstrated in children immunized with the live influenza vaccine . Enzyme immunoassay was found to be a more sensitive but less specific method for antibody titration as compared with HI test whereas microneutralization proved to be more specific but less sensitive for titration of antibodies to influenza A ( H3N2 ) viruses Abstract A trial of inactivated influenza vaccine containing the A/Hong Kong/68 strain was made in 800 boys in a boarding-school starting in 1970 . The boys had serum sample s withdrawn for antibody estimations and were allocated at r and om to vaccine and control groups . During an outbreak of influenza A due to the A/Engl and /42/72 strain , all boys with clinical influenza reported to the medical officer and the diagnosis was confirmed by laboratory examination . The vaccine was shown to confer substantial protection against the new virus strain . The presence of haemagglutinating ( H.I. ) antibody to either strain 6 weeks before the outbreak was associated with protection against influenza . In boys with H.I. antibody to A/Hong Kong/68 virus the attack-rate was 6 % , compared with 25 % in boys with no H.I. antibody to either virus strain . No influenza occurred in boys known to have H.I. antibody to the A/Engl and /42/72 strain . Three-quarters of the boys in whom A/Hong Kong/68 H.I. antibody had been naturally acquired developed A/Engl and / 42/72 H.I. antibody after vaccination . In contrast , the development of A/Engl and /42/72 H.I. antibody was less frequent after revaccination of boys in whom the A/Hong Kong/68 H.I. antibody had been induced by vaccination . A vaccine prepared from the A/Hong Kong/68 strain conferred substantial protection despite the recent antigenic shift of the influenza virus Albert Leibovitz , * Raymond L. Coultrip , Edwin D. Kilbourne , Llewellyn J. Legters , Creed D. Smith , James Chin , and Jerome L. Schulman From the Sixth U.S. Army Medical Laboratory , Fort Baker , California ; Preventive Medicine Division , Office of the Surgeon , Fort Ord , California ; Department of Microbiology , Mount Sinai School of Medicine , City University of New York , New York ; and the Infectious Disease Element , California State Department of Public Health , Berkeley , This study evaluated the safety , immunogenicity , and protective efficacy of vaccines containing purified recombinant uncleaved hemagglutinin ( rHA0 ) from influenza A/Beijing/32/92 ( H3N2 ) virus . In a r and omized , double-blinded trial , 127 adult volunteers were immunized with 15 micrograms of rHA0 , 15 micrograms of rHA0 plus alum , 90 micrograms of rHA0 , licensed subvirion vaccine , or saline placebo . The rHA0 vaccines caused fewer local adverse reactions than did the commercial subvirion preparation . Neutralizing hemagglutinin-specific antibody responses to 15 micrograms of rHA0 were comparable to those elicited by licensed vaccine , not enhanced by the addition of alum , and significantly increased by raising the rHA0 dose from 15 to 90 micrograms . Compared with placebo recipients , rHA0-vaccinated subjects had significantly lower rates of influenza A ( H3N2 ) virus infection and illness during the epidemic winter season . These results suggest that influenza vaccines containing purified rHA0 may offer an advantage over licensed preparations containing egg-grown antigens by inducing equivalent protective immune responses while being potentially less reactogenic Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s ) than in those receiving it for the first time . This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available , inactivated whole-virus vaccine . Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods . However , it reduced influenza virus shedding by an average of 38.8 % and conferred protection against influenza virus infection during each epidemic . Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization , and between years , but no consistent pattern of differences was noted in relation to number of successive years of vaccination . These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate , but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed In 1985 , we enrolled 189 school-age children by family in a double-blind study to determine protection against influenza by a single dose of cold-recombinant bivalent A vaccine or commercial trivalent inactivated vaccine compared with placebo .  All children in school or day care , 3 to 18 years of age , in an enrolled family received the same preparation . Following vaccination , 60 % and 21 % of cold-recombinant bivalent A vaccine recipients and 73 % and 83 % of trivalent inactivated vaccine recipients demonstrated fourfold or greater response in hemagglutination-inhibition antibody titer to A/H1N1 and A/H3N2 , respectively . Sixty-seven percent of all trivalent inactivated vaccine recipients demonstrated a fourfold or greater serologic response to H1N1 , H3N2 , and influenza B following a single dose of vaccine . During the 1985 - 1986 influenza B/Ann Arbor epidemic , heterotypic protection afforded by the influenza B/USSR component of trivalent inactivated vaccine was 62 % compared with placebo . A single dose of trivalent inactivated vaccine protected school-age children , 6 to 19 years of age , from influenza B infection ; the rate of protection was 64 % against infection and 73 % against febrile illness The purpose of this field trial on influenza vaccine , which was done with a population of university students , was to compare the aerosol route with the subcutaneous route of vaccine administration and the Hong Kong influenza vaccine with the older A2 influenza vaccine ( " bivalent " vaccine ) .  Side-effects of the vaccines were significantly higher in the groups that received the vaccine subcutaneously . There were no more side-effects in those who received vaccine by aerosol . There was a significant reduction in the rate of illness in all groups vaccinated except for the group given bivalent vaccine subcutaneously . Recipents of Hong Kong vaccine had significantly greater protection than did recipients of the bivalent vaccine . Recipients of aerosol vaccine had significantly better protection than did those who received vaccine by the subcutaneous route . The data suggest that protection was closely related to the ability of the vaccine to stimulate nasalsecretion antibody to the A2 Hong Kong influenza virus Summary Currently three different inactivated influenza vaccine types are available : whole virus ( WV ) , split ( SPL ) and subunit ( SU ) vaccines .  Physicians and patients at risk for influenza complications may wonder whether there are important differences between the vaccine types with respect to antibody induction ( serology ) and adverse effects ( reactogenicity ) . A literature review ( 1975 to 1995 ) was performed to evaluate the serology and reactogenicity of SU vaccines in comparison with either split or whole virus vaccines .  22 publications with r and omised allocation were identified describing a total of 5416 serological observations , 2858 observations of local reactions , and 2990 observations of systemic reactions . Subjects included those from all age groups from children to the elderly .  Absolute protection and reaction rate differences ( RD ) were calculated for the comparisons SU vs SPL or SU vs WV vaccine . These were subjected to a method of meta- analysis , result ing in pooled rate differences and their 95 % confidence intervals . With the exception of the comparison SU vs WV vaccine in subjects born after 1957 and unexposed to the reappearing H1N1 subtype after 1977 , no evidence was found to suggest relevant differences in seroresponse among the three currently available inactivated influenza vaccine types . Although insufficient data were available in the meta- analysis for vaccines in children for whom specific recommendations concerning these vaccines exist , adverse events after administration of any of the three vaccine types were generally mild and transitory ; however , SU vaccines were associated with a lower frequency of local and systemic reactions We report the safety and antigenicity of influenza A vaccines  in seronegative children one to seven years of age . A natural H1N1 challenge that occurred shortly after completion of the vaccination program permitted an evaluation of efficacy . Twenty-eight subjects were inoculated with live cold-adapted ( ca ) influenza A/Washington/897/80 ( H3N2 ) , 29 with ca influenza A/California/10/78 ( H1N1 ) , 24 with inactivated whole-virus influenza A/Bangkok/79 ( H3N2 ) , and 30 with a placebo . The ca vaccines were well tolerated , whereas the inactivated vaccine caused adverse reactions in about one-third of the children . Fifty-seven percent of the ca H1N1 recipients showed serological responses , contrasted with 84 % and 100 % of subjects receiving the ca or inactivated H3N2 vaccines , respectively . None of the 16 children with induced H1N1 antibody developed clinical ly apparent influenza-like illness , compared with eleven of the 51 initially seronegative children who did not receive the ca H1N1 vaccine and with four of the 12 who failed to respond . Results of the efficacy field trial suggest protection against infection and symptomatic illness in children inoculated with ca H1N1 , despite its failure to stimulate high levels of hemagglutinin-inhibiting antibody The performance of two doses of cold-adapted live attenuated vaccine versus one dose of whole-virus inactivated vaccine was compared in 8 - 15-year-old schoolchildren in two schools in Moscow , Russia , during the winter of 1987/88 . Both vaccines gave rise to low frequencies of associated febrile or systemic reactions , but the inactivated vaccine , delivered by jet injector , did cause small local reactions in about half of the children . Immunogenicity was higher for both vaccines in antibody-free children , and higher levels of serum antibody were detected following use of inactivated vaccine . During the winter , influenza A ( H3N2 ) and influenza B viruses circulated in Moscow . A clear outbreak of ( H3N2 ) virus occurred in both schools , and infections with type B virus also occurred in one school . The influenza A/Philippines/2/82 ( H3N2 ) component of both vaccines exhibited protective efficacy of about 40 % ( p < 0.05 ) against serologically proven infection caused by the antigenically drifted A/Sichuan/2/87 (H3N2)-like epidemic viruses in one school . In another school where illnesses associated with antibody rise were documented , efficacy was seen for both vaccines in reduction of illnesses , and of illnesses with serological evidence of infection , but statistical significance was not achieved Schoolchildren of 30 to 34 schools of Novgorod were vaccinated over a three-year period with Russian live cold-adapted attenuated vaccine for children and whole-virus inactivated vaccines and placebo for comparative field study of the vaccines properties and efficacy . In control trials both bi- and trivalent live attenuated vaccines were well tolerated and areactogenic . A whole-virus inactivated trivalent vaccine induced mild and moderate fever and local reactions in 2 - 4 % of the vaccinees . Special observations are necessary to establish the possibility of use and to determine a dose of this inactivated vaccine for immunization of children , especially those of 7 - 10 years of age . All the vaccines induced HI antibody production in 50 - 80 % and antineuraminidase in 50 - 70 % of seronegative children . The pattern of the results was similar to that in revaccinated children with preexisting antibody at a level of 1:20 , but much lower in children with the initial titre above 1:20 . After the 3rd year of vaccination the immune response of the vaccinees was similar , most of the results depending on the initial antibody titre and also on the change of vaccine strains . This raises a question of the expediency of annual influenza revaccination of the same person after 2 years of successful immunization and of the necessity of vaccine strains replacement after 2 - 3 years of use Background . Influenza is a common and potentially serious infection in children . Although there is interest in broadening the use of influenza vaccine in healthy children , there are few large , r and omized , controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population . Methods . From 1985 through 1990 a r and omized , controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at V and erbilt University , and the cumulative results from this trial in patients of all ages have been previously published . We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation . We determined vaccine safety , immunogenicity and efficacy , based on culture-positive illness and seroconversion , in this subset of patients . Results . During the 5 years of the study , 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo . The vaccines were well-tolerated , and there were no serious reactions . Inactivated trivalent influenza vaccines were 91.4 and 77.3 % efficacious in preventing symptomatic , culture-positive influenza A H1N1 and H3N2 illness , respectively . The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5 % , respectively , for H1N1 and H3N2 serotypes . Conclusions . Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old Forty-three school children from 8 to 11 years old were vaccinated intranasally with two doses of a paediatric attenuated influenza vaccine developed by reassortment between cold-adapted A/Leningrad/134/57(H2N2 ) and an A/Brazil/11/78(H1N1)-like strain . Two vaccine doses were administered 1 month apart in a r and omized , blind , placebo-controlled study . Although the first vaccine dose had a low infectivity titre , overall 65 % of children who received two doses of vaccine showed serological evidence of infection by HI tests . Serum IgA antibody responses against the vaccine strain were detected in nearly 50 % of the vaccines and serum IgG antibody responses were detected in approximately equal to 40 % by an enzyme immunoassay A trial of influenza A vaccines in general practice is described . Five hundred and seven subjects were vaccinated with either inactivated monovalent A/Hong Kong vaccine , A/Engl and vaccine or influenza B vaccine as control . Local reactions were noted in 24 % and general reactions in 12 % of patients . Antibody titres in serum were measured by haemagglutination inhibition ( HI ) and complement fixation ( CF ) tests in 465 subjects . The influenza vaccines produced substantial increases in both homologous and heterologous antibodies as measured by the HI test and a comparatively poor response as measured by the CF test . Although clinical influenza was confirmed in only a few cases , there was serological evidence of significant sub clinical infection in the control group Live cold-adapted recombinant bivalent vaccine of influenza type A was studied in a controlled field trial in 1982 - 1983 among nearly 30,000 children 3 - 15 years old . The bivalent vaccine consisted of recombinants 47/25/1 ( H1N1 ) and 47/7/2 ( H3N2 ) of wild-type viruses A/Brazil/11/78 ( H1N1 ) and A/Bangkok/1/79 ( H3N2 ) with cold-adapted donor A/Leningrad/134/47/57 ( H2N2 ) . The recombinants which received mutant nonglycoprotein genes from cold-adapted donor did not suppress each other after simultaneous inoculation of children and stimulated antibody response to both strains . The bivalent vaccine was completely attenuated for children . It caused less than 1 % transient febrile reactions during five days after the first vaccination , including double seronegative individuals with low antibody titres to both vaccinal strains . The cold-adapted bivalent vaccine tested proved to be safe for children according to the analysis of morbidity studies among vaccines and a control group performed during the five days and the following six months after the first immunization . There is a similar distribution of non-influenza illnesses and a statistically significant decrease in influenza-like diseases among vaccines compared to the control group . In the four months after the immunization programme was completed , epidemics of influenza A H1N1 and H3N2 occurred . The incidence of influenza-like diseases was approximately 50 % less in the vaccinated than in the control groups . This is the first evidence of safety and protective efficacy of recombinant live influenza vaccine for children 3 - 15 years of age Children ( n = 192 ) aged 3 - 19 years from 98 families completed this double-blind , placebo-controlled study comparing the efficacy of a bivalent attenuated ( CR ) vaccine with trivalent inactivated ( TI ) vaccine . Both vaccines contained A/Chile/83 (H1N1)-like antigens . After vaccination the geometric mean titer to A/Taiwan/86 ( H1N1 ) was 1:36 in the CR group , 1:92 in the TI group , and 1:5 in the placebo group . During the influenza A/Taiwan/86 ( H1N1 ) epidemic , 21.4 % of CR recipients , 16.7 % of TI recipients , and 43.9 % of placebo recipients were infected with influenza A/Taiwan . TI vaccine provided better heterotypic protection than did CR vaccine for children aged 10 - 18 years ( infection rate , 0 vs. 24 % , respectively ; P less than .025 ) ; in contrast , in the younger children ( 3 - 9 years ) , CR vaccine tended to be more protective ( 19 % vs. 26 % for TI ) In the trial of the trivalent subunit influenza vaccine Grippovac CE-AK observations on children aged 3 - 6 years were made . The preparation showed insignificant reactogenicity and moderate antigenic potency . The trial established that at the period of the epidemic rise of influenza B morbidity the vaccine showed , according to the data of the clinical diagnosis of influenza , insignificant effectiveness , its index of effectiveness ( IE ) being 1.08 ; according to the data of the serological diagnosis of influenza , only the A ( H1N1 ) component of the vaccine was found to have IE equal to 1.58 BACKGROUND The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992 - 1993 to 74 in 1993 - 1994 , arousing concern about a possible increase in vaccine-associated risk . METHODS Patients given a diagnosis of the Guillain-Barré syndrome in the 1992 - 1993 and 1993 - 1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states . Vaccination histories were obtained by telephone interviews during 1995 - 1996 and were confirmed by the vaccine providers . Disease with an onset within six weeks after vaccination was defined as vaccine-associated .  Vaccine coverage in the population was measured through a r and om-digit-dialing telephone survey . RESULTS We interviewed 180 of 273 adults with the Guillain-Barré syndrome ; 15 declined to participate , and the remaining 78 could not be contacted . The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients . The relative risk of the Guillain-Barré syndrome associated with vaccination , adjusted for age , sex , and vaccine season , was 1.7 ( 95 percent confidence interval , 1.0 to 2.8 ; P=0.04 ) . The adjusted relative risks were 2.0 for the 1992 - 1993 season ( 95 percent confidence interval , 1.0 to 4.3 ) and 1.5 for the 1993 - 1994 season ( 95 percent confidence interval , 0.8 to 2.9 ) . In 9 of the 19 vaccine-associated cases , the onset was in the second week after vaccination , all between day 9 and day 12 . CONCLUSIONS There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992 - 1993 to 1993 - 1994 . For the two seasons combined , the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza OBJECTIVE To determine if the use of influenza vaccine in children in day care decreases the incidence of otitis media during the influenza season . DESIGN Prospect i ve cohort study . SETTING Eight day-care centers in North Carolina . PARTICIPANTS One hundred eighty-six children aged 6 to 30 months . INTERVENTION Half the participants received trivalent subvirion influenza virus vaccine . MEASUREMENTS Acute otitis media ( AOM ) and serous otitis media ( SOM ) were assessed biweekly from mid-November 1993 to mid-March 1994 by visual and tympanometric examinations performed by " blinded " observers . The winter season was divided into three periods-before , during , and after influenza season-- and the number of children with AOM or SOM during each period was determined . Unadjusted and adjusted odds ratios ( ORs ) were computed , while controlling for race and sex using logistic regression methods . RESULTS Influenza vaccine was protective against AOM ( OR = 0.69 , 95 % CI , 0.49 - 0.98 ) during the influenza season . Although there may have been some protection against SOM ( OR = 0.75 , 95 % CI , 0.54 - 1.02 ) statistical significance was not achieved . Myringotomy tubes were also significantly protective against AOM and SOM during all three time periods , with ORs between 0.34 and 0.52 , but the greatest protection was seen during the influenza period . CONCLUSIONS Influenza vaccination of 6- to 30-month-old children in day care was associated with a decreased incidence of otitis media during the influenza season . Myringotomy tubes protected against AOM and SOM during all 16 weeks monitored A double-blind , r and omized controlled trial over 5 years compared the safety , immunogenicity , and efficacy of cold-adapted and inactivated influenza A vaccines in 5210 normal subjects . Both vaccines were well tolerated . Inactivated vaccine significantly increased hemagglutination inhibition antibody titers . Significant titer rises were also noted after cold-adapted vaccine but of lesser magnitude than with inactivated vaccine . The efficacy of inactivated vaccine in preventing culture-positive influenza was 76 % ( 95 % confidence interval [ CI ] , 58%-87 % ) for H1N1 disease and 74 % ( 95 % CI , 52%-86 % ) for H3N2 ; for cold-adapted vaccine , 85 % ( 95 % CI , 70%-92 % ) and 58 % ( 95 % CI , 29%-75 % ) , respectively . The efficacy of inactivated  vaccine in preventing a four-fold rise in antibody titer over the influenza season was 69 % ( 95 % CI , 61%-76 % ) for H1N1 and 73 % ( 95 % CI , 65%-79 % ) for H3N2 ; for cold-adapted vaccine , 54 % ( 95 % CI , 44%-62 % ) and 32 % ( 95 % CI , 17%-44 % ) , respectively . Cold-adapted and inactivated influenza vaccines are safe and effective for preventing influenza A disease During the autumn-winter epidemic of influenza-like diseases in December , 1983 - -first quarter , 1984 , in Moscow commissioned coded observations on the effectiveness of  prophylactic vaccination against influenza of 3 - 7-year-old children with a preparation " Grippovak SE-AZh "  were carried out in day-care centers . In the previous large-scale trials , 1981 - 1984 , the " Grippovak " had been evaluated positively as a completely harmless , serologically and immunologically active preparation reducing 3 - 3.5-fold the number of laboratory-verified cases of viral type A and B influenza in the vaccinees . In 1986 , however , the " Journal of Microbiology , Epidemiology , Immunology " ( JMEI , 2 : 49 - 54 ) published a paper whose authors , on behalf of the Commission which had checked the preparation in the day-care centers ( Z.A. Bashliaeva , A.A. Sumarokov , et al. ) , came to a conclusion that " Grippovak " was ineffective in children . Other members of the above Commission disagreeing with this conclusion made a repeat analysis of the decoded material s of the observations in the day-care centers using computer methods and demonstrated that because of significant prevalence of non-influenza ARD cases and recurrent ( up to 44 % ) ARD cases in children in the 4 months of observation , it was impossible to judge the effectiveness of the vaccine by comparison of the total incidence of influenza and ARD from the clinical data alone in the vaccinees and controls . ( ABSTRACT TRUNCATED AT 250 WORDS The study of the based on the A/Leningrad/134/17/57/(H2N2 ) attenuated adult live influenza vaccine ( LIV ) investigated features for immunization of the children , aged 3 - 6 years . During autumn , 1999 , out of 256 children , aged 3 - 6 years , residents of the Leningrad region , who attended the kindergarten , 184 children were immunized with 1 or 2 doses of the live influenza vaccine  , and 72 ones were given placebo .  There were no any moderate or strong temperature reactions revealed after the inoculation . The LIV was shown to be genetically stable . After a single dose of the vaccine seroconversion to influenza type A virus and to influenza type B virus was observed respectively in 58 % and in 39 % of seronegative 3 - 6 year old vaccinees . The twofold LIV administration failed to give any advantages in stimulation of the immune response . During 6 months after immunization the morbidity rate in vaccinees did not exceed the morbidity rate in unvaccinated children . Thus LIV for adults proved safe and immunogenic and can be recommended for single dose immunization both of adults and children A limited controlled comparative study for the evaluation of the epidemiological efficacy of live recombinant and inactivated virion vaccines from A/Philippines/2/82-like strains of influenza A ( H3N2 ) virus was carried out in schoolchildren of 8 to 15 years of age . During the influenza epidemic of 1987 - 1988 caused by influenza A/Sichuan/2/87 (H3N2)-like strains and by influenza B virus in 8.2 - 17 % of cases , a statistically significant efficacy index for live influenza vaccine was 1.8 for the laboratory confirmed A ( H3N2 ) cases . In the group vaccinated with the inactivated vaccine the number of serologically diagnosed A ( H3N2 ) cases was 1.6 times lower than in the group receiving placebo , this difference being statistically significant . Thus , under the conditions of significant difference in the antigenic structure of the vaccine and epidemic A ( H3N2 ) strains , both vaccines produced some diminished but statistically significant preventive effect in vaccinated children although its level was below the optimal . Revaccination of some children with a live influenza vaccine from a new A/Sichuan/2/87-like variant of A ( H3N2 ) virus in the autumn of 1988 with reisolation of the vaccine strain also revealed the presence of some , though weak , resistance to this strain in the children vaccinated with both vaccines A field study was undertaken in Tampa , Fla. , to assess the efficacy of subcutaneous and aerosol methods of administering vaccine , and to compare the protection afforded by bivalent ( A2 and B ) influenza virus vaccine and by A2/Hong Kong/68 virus vaccine . Further objectives of the study included a comparison of the effectiveness of single-dose and 2-dose immunization . Approximately 2100 volunteers received , in a double-blind manner , both an injection and an aerosol administration on 2 occasions 3 weeks apart . The results showed that aerosol administration gave a lower over-all protection rate , although the booster dose seemed to have a marked effect . The protection afforded by A2/Hong Kong/68 virus vaccine was considerably greater than that afforded by the bivalent vaccine , particularly when administration was subcutaneous . Results are also given on the occurrence of side-effects and on the correlation between cigarette smoking and the occurrence of influenza-like illness OBJECTIVE To determine if a vaccine against influenza significantly decreases episodes of acute upper respiratory infection ( AURI ) and work absenteeism caused by AURI , in healthy adult employees of a banking entity in the city of Medellín , Colombia . METHODS This was a double-blind r and omized placebo-controlled study with 493 volunteers . The volunteers were r and omly assigned to two groups , an experimental group and a control group , with 247 and 246 employees , respectively . The experimental group participants received a dose of 0.5 mL of an influenza vaccine containing surface antigens of the strains recommended by the World Health Organization for the 1996 - 1997 period , with subtypes A/Wuhan/359/95 ( H3N2 ) , A/Texas/36/91 ( H1N1 ) , and B/Beijing/184/93 . An illness was considered an episode of AURI when a participant reported having a sore throat , fever , and a cough lasting more than 24 hours . Evaluations were made every 2 weeks over a 6-month period ; the severity of the episodes was assessed in terms of lost workdays due to AURI ( defined according to the ninth revision of the International Classification of Diseases , or ICD-9 ) , through monthly evaluations of incapacitating work absences certified by the Colombian Social Security system , over the period of a year . RESULTS Side effects associated with the vaccine were erythema ( relative risk ( RR ) = 8.0 ; P = 0.02 ) and local edema ( RR = 4.5 ; P = 0.03 ) . The proportion of the annual cumulative incidence of episodes of AURI was 78.5 % for the vaccinated persons and 91.5 % for those in the placebo group , with a reduction of 14 % , with values between 7 % and 20 % ( RR = 0.86 ; 95 % confidence interval ( CI ) = 0.80 - 0.93 ) . The annual cumulative incidence of incapacitating AURI was 15.8 % in those vaccinated , with a reduction of 31 % in comparison to the placebo group ( 22.8 % ) , with values between 0 % and 52 % ( RR = 0.69 ; 95 % CI = 0.48 - 1.0 ) . These levels of protection , both against more mildly symptomatic forms of AURI and those causing lost workdays , increased significantly ( between 62 % and 89 % ) in the months of May and October , when outbreaks caused by the influenza virus were confirmed in Colombia . CONCLUSIONS The results demonstrated that the influenza vaccination strategy decreased the AURI episodes as well as the number of work absences due to AURI in the healthy adult employees of a banking entity in the city of Medellín , Colombia . The impact that influenza has on this population group is small , and the effect of this vaccination measure is greater then the influenza virus is in circulation In a blinded , placebo-controlled study , the reactogenicity , immunogenicity , and clinical efficacy of single doses of US inactivated split-virus and Russian live attenuated , cold-adapted influenza vaccines were compared in 555 schoolchildren in Vologda , Russia . Serial serum sample s were collected and school absenteeism was assessed . Systemic reactions were rare , but local reactions ( primarily erythema at the injection site ) were observed in 27 % of the inactivated vaccine group , and coryza ( 12 % ) and sore throat ( 8 % ) were observed in the attenuated vaccine group . At 4 weeks after vaccination a > or = 4-fold rise in titer of hemagglutination inhibition antibody to A ( H1N1 ) , A ( H3N2 ) , and B was noted , respectively , among 78 % , 88 % , and 53 % of children who received inactivated vaccine and among 55 % , 79 % , and 30 % of children who received attenuated vaccine . The vaccine efficacy for preventing school absenteeism due to respiratory illness during the period of peak influenza activity was 56 % for inactivated vaccine and 47 % for attenuated vaccine Immunization with an influenza subunit vaccine given in one dose about 1 month to 2 months before onset of an epidemic of influenza afforded from 80 % to 90 % protection in a double-blind clinical trial which was supported by isolation of virus and serological studies . In the vaccinated group , 20 % failed to develop antibodies to the vaccine . Either serology tests or attempted isolation of virus alone would have failed to detect some of the cases ABSTRACT The highly sensitive gamma interferon ( IFN-γ ) enzyme-linked immunosorbent spot ( ELISPOT ) assay permits the investigation of the role of cell-mediated immunity ( CMI ) in the protection of young children against influenza . Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to < 36 months , an intranasal dose of 107 fluorescent focus units ( FFU ) of a live attenuated influenza virus vaccine ( CAIV-T ) elicited substantial CMI responses . A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination . The role of CMI in actual protection against community-acquired , culture-confirmed clinical influenza by CAIV-T was investigated in a large r and omized , double-blind , placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to < 36 months in the Philippines and Thail and . The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza , establishing a possible target level of CMI for future influenza vaccine development . The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza , especially those used for children BACKGROUND The efficacy of influenza vaccines may vary from year to year , depending on a variety of factors , and may differ for inactivated and live attenuated vaccines . METHODS We carried out a r and omized , double-blind , placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007 - 2008 influenza season and estimated the absolute and relative efficacies of the two vaccines . RESULTS A total of 1952 subjects were enrolled and received study vaccines in the fall of 2007 . Influenza activity occurred from January through April 2008 , with the circulation of influenza types A ( H3N2 ) ( about 90 % ) and B ( about 9 % ) . Absolute efficacy against both types of influenza , as measured by isolating the virus in culture , identifying it on real-time polymerase-chain-reaction assay , or both , was 68 % ( 95 % confidence interval [ CI ] , 46 to 81 ) for the inactivated vaccine and 36 % ( 95 % CI , 0 to 59 ) for the live attenuated vaccine . In terms of relative efficacy , there was a 50 % ( 95 % CI , 20 to 69 ) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine . The absolute efficacy against the influenza A virus was 72 % ( 95 % CI , 49 to 84 ) for the inactivated vaccine and 29 % ( 95 % CI , -14 to 55 ) for the live attenuated vaccine , with a relative efficacy of 60 % ( 95 % CI , 33 to 77 ) for the inactivated vaccine . CONCLUSIONS In the 2007 - 2008 season , the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A ( predominately H3N2 ) in healthy adults . The live attenuated vaccine also prevented influenza illnesses but was less efficacious . ( Clinical Trials.gov number , NCT00538512 . A cluster-r and omised controlled trial of antiviral treatment to control influenza outbreaks in aged-care facilities ( ACFs ) provided an opportunity to assess VE in the frail , institutionalised elderly . Data were pooled from five influenza outbreaks in 2007 . Rapid testing methods for influenza were used to confirm outbreaks and /or identify further cases .  Vaccination coverage among ACF residents ranged from 59 % to 100 % , whereas it was consistently low in staff ( 11 - 33 % ) . The attack rates for laboratory-confirmed influenza in residents ranged from 9 % to 24 % , with the predominate strain determined to be influenza A. Sequencing of the hemagglutinin gene from a sub- sample demonstrated an incomplete match with the 2007 southern hemisphere influenza vaccine . Influenza VE was estimated to be 61 % ( 95%CI 6 % , 84 % ) against laboratory-confirmed influenza , 51 % ( 95%CI -16 % , 79 % ) against influenza-like illness , 82 % ( 95%CI 27 % , 96 % ) against pneumonia-related and influenza-related hospitalisations and 71 % ( 95%CI -28 % , 95 % ) against death from all causes . This supports the continued policy of targeted vaccination of the institutionalised , frail elderly . There is also reassurance that influenza vaccine can be effective against disease and severe outcomes , despite an incomplete vaccine match . This benefit is additional to protection from antivirals Background Seasonal influenza imposes a substantial personal morbidity and societal cost burden . Vaccination is the major strategy for influenza prevention ; however , because antigenically drifted influenza A and B viruses circulate annually , influenza vaccines must be up date d to provide protection against the predicted prevalent strains for the next influenza season . The aim of this study was to assess the efficacy , safety , reactogenicity , and immunogenicity of a trivalent inactivated split virion influenza vaccine ( TIV ) in healthy adults over two influenza seasons in the US . Methods The primary endpoint of this double-blind , r and omized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched , culture-confirmed influenza ( VMCCI ) across the 2005 - 2006 and 2006 - 2007 influenza seasons . Secondary endpoints included the prevention of laboratory-confirmed ( defined by culture and /or serology ) influenza , as well as safety , reactogenicity , immunogenicity , and consistency between three consecutive vaccine lots . Participants were assessed actively during both influenza seasons , and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness . Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season 's surveillance period . Results Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2 % ( 97.5 % confidence interval [ CI ] lower bound of 48.2 % ) , the point estimate for the primary endpoint , efficacy of TIV against VMCCI across both influenza seasons , was 46.3 % with a 97.5 % CI lower bound of 9.8 % . This did not satisfy the pre-specified success criterion of a one-sided 97.5 % CI lower bound of > 35 % for vaccine efficacy . The VMCCI attack rates were very low overall at 0.6 % and 1.2 % in the TIV and placebo groups , respectively . Apart from a mismatch for influenza B virus lineage in 2005 - 2006 , there was a good match between TIV and the circulating strains . TIV was highly immunogenic , and immune responses were consistent between three different TIV lots . The most common reactogenicity events and spontaneous adverse events were associated with the injection site , and were mild in severity . Conclusions Despite a good immune response , and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2 % , the pre-specified target ( lower one-sided 97.5 % confidence bound for efficacy > 35 % ) for the primary efficacy endpoint , the prevention of VMCCI , was not met . However , the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005 - 2006 and 2006 - 2007 , which corresponded to relatively mild influenza seasons in the US . Overall , the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk . Trial registration
Fifteen meta-analyses have been published between 1995 and 2011 to evaluate the efficacy/effectiveness and harms of diverse influenza vaccines -- seasonal , H5N1 and 2009 (H1N1)--in  various age-classes ( healthy children , adults or elderly ) .
These meta-analyses have often adopted different analyses and study selection criteria .
Because it is difficult to have a clear picture of vaccine benefits and harms examining single systematic review s , we compiled the main findings and evaluated which could be the most reasonable explanations for some differences in findings ( or their interpretation ) across previously published meta-analyses .