title: Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates.
abstract: BACKGROUND
  Vaccine protection investigation includes three processes: vaccination, pathogen challenge, and vaccine protection efficacy assessment. Many variables can affect the results of vaccine protection. Brucella, a genus of facultative intracellular bacteria, is the etiologic agent of brucellosis in humans and multiple animal species. Extensive research has been conducted in developing effective live attenuated Brucella vaccines. We hypothesized that some variables play a more important role than others in determining vaccine protective efficacy. Using Brucella vaccines and vaccine candidates as study models, this hypothesis was tested by meta-analysis of Brucella vaccine studies reported in the literature.
  
  
  RESULTS
  Nineteen variables related to vaccine-induced protection of mice against infection with virulent brucellae were selected based on modeling investigation of the vaccine protection processes. The variable "vaccine protection efficacy" was set as a dependent variable while the other eighteen were set as independent variables. Discrete or continuous values were collected from papers for each variable of each data set. In total, 401 experimental groups were manually annotated from 74 peer-reviewed publications containing mouse protection data for live attenuated Brucella vaccines or vaccine candidates. Our ANOVA analysis indicated that nine variables contributed significantly (P-value < 0.05) to Brucella vaccine protection efficacy: vaccine strain, vaccination host (mouse) strain, vaccination dose, vaccination route, challenge pathogen strain, challenge route, challenge-killing interval, colony forming units (CFUs) in mouse spleen, and CFU reduction compared to control group. The other 10 variables (e.g., mouse age, vaccination-challenge interval, and challenge dose) were not found to be statistically significant (P-value > 0.05). The protection level of RB51 was sacrificed when the values of several variables (e.g., vaccination route, vaccine viability, and challenge pathogen strain) change. It is suggestive that it is difficult to protect against aerosol challenge. Somewhat counter-intuitively, our results indicate that intraperitoneal and subcutaneous vaccinations are much more effective to protect against aerosol Brucella challenge than intranasal vaccination.
  
  
  CONCLUSIONS
  Literature meta-analysis identified variables that significantly contribute to Brucella vaccine protection efficacy. The results obtained provide critical information for rational vaccine study design. Literature meta-analysis is generic and can be applied to analyze variables critical for vaccine protection against other infectious diseases.
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Todd
authors.forename: Omar
authors.initials: O
authors.lastname: Tibi
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.forename: Samantha
authors.initials: S
authors.lastname: Sayers
authors.forename: Denise N
authors.initials: DN
authors.lastname: Bronner
authors.forename: Zuoshuang
authors.initials: Z
authors.lastname: Xiang
authors.forename: Yongqun
authors.initials: Y
authors.lastname: He
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002002:Brucella / Q000276:immunology / Q000502:physiology*; D002004:Brucella Vaccine / Q000008:administration & dosage* / Q000276:immunology; D002006:Brucellosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D019295:Computational Biology / Q000379:methods; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D002004:Brucella Vaccine; D014613:Vaccines, Attenuated