title: Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE smallpox vaccine.
abstract: BACKGROUND
  Previous research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox.
  
  
  METHODS
  We conducted a participant-level meta-analysis (N=275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1×10(8)TCID₅₀/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log₂ ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data.
  
  
  RESULTS
  In each study the mean peak log₂ ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log₂-titer in men compared with women (absolute difference [men-women]: 0.32, 95% CI: 0.02-0.60). Fixed effects models controlling for study showed a similar result (log₂ ELISA titer, men-women: 0.34, 95% CI: 0.04-0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3-55%). Peak log₂ PRNT titers were also higher (although not significantly) in men (men-women: 0.14, 95% CI: -0.30 to 0.58).
  
  
  CONCLUSIONS
  Our results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.
authors: The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, United States. Electronic address: jesse.troy@duke.edu.
authors: Jesse D
authors: JD
authors: Troy
authors: The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, United States. Electronic address: hhill@emmes.com.
authors: Heather R
authors: HR
authors: Hill
authors: The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, United States. Electronic address: mewell@emmes.com.
authors: Marian G
authors: MG
authors: Ewell
authors: Saint Louis University School of Medicine, Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Bld., Saint Louis, MO 63104, United States. Electronic address: freyse@slu.edu.
authors: Sharon E
authors: SE
authors: Frey
mesh_terms: D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007109:Immunity; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012737:Sex Factors; D012899:Smallpox / Q000517:prevention & control*; D012900:Smallpox Vaccine / Q000276:immunology*; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; D012900:Smallpox Vaccine
keywords: Imvamune; MVA vaccine; Meta-analysis; Smallpox; Vaccines; Vaccinia virus