title: Sieve analysis: methods for assessing from vaccine trial data how vaccine efficacy varies with genotypic and phenotypic pathogen variation.
abstract: A key component in the evaluation of efficacy of a vaccine to protect against disease caused by an antigenically diverse infectious pathogen in a preventative vaccine trial is assessing how vaccine-induced protection depends on genotypic and phenotypic variations of the exposing pathogen. This assessment is made by comparing pathogen isolates between infected vaccinated subjects and infected unvaccinated subjects. A survey of efficacy trial reports reveals a lack of systematic, quantitative investigation in this question. Analysis tools for testing if vaccine protection against disease is superior against some pathogen strains, and for estimating the magnitude of this differential vaccine protection, are described. The broad applicability of the methods is illustrated through analysis of isolates taken from persons infected while participating in vaccine trails for cholera, HIV-1, hepatitis B, rotavirus, and pneumococcus. These analyses reveal intriguing trends for Genentech's monovalent rgp120 HIV-1 vaccine, for two whole-killed-cell oral cholera vaccines, and for other vaccines.
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, 655 Huntington Ave., Boston, MA 02115, USA. Pgilbert@hsph.harvard.edu
authors.forename: P
authors.initials: P
authors.lastname: Gilbert
authors.forename: S
authors.initials: S
authors.lastname: Self
authors.forename: M
authors.initials: M
authors.lastname: Rao
authors.forename: A
authors.initials: A
authors.lastname: Naficy
authors.forename: J
authors.initials: J
authors.lastname: Clemens
mesh_terms: D002771:Cholera / Q000517:prevention & control / Q000821:virology; D002986:Clinical Trials as Topic; D004269:DNA, Bacterial / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D003627:Data Interpretation, Statistical; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006509:Hepatitis B / Q000517:prevention & control / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D007239:Infections / Q000382:microbiology*; D015233:Models, Statistical; D016017:Odds Ratio; D010641:Phenotype; D011008:Pneumococcal Infections / Q000382:microbiology / Q000517:prevention & control; D015203:Reproducibility of Results; D012401:Rotavirus / Q000235:genetics; D012400:Rotavirus Infections / Q000517:prevention & control / Q000821:virology; D012680:Sensitivity and Specificity; D013296:Streptococcus pneumoniae / Q000235:genetics; D014612:Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000592:standards*; D014734:Vibrio cholerae / Q000235:genetics
chemical_list: D004269:DNA, Bacterial; D004279:DNA, Viral; D014612:Vaccines