Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE ® smallpox vaccine

Abstract

Introduction 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 (1×108 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-.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: −0.30–0.58). Conclusion 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.

Polyfunctional T Cell and Neutralizing Antibody Responses to ACAM2000<sup>TM</sup> Smallpox Vaccine Immunization in Primary-Vaccinated Individuals

“…Gender was significantly associated with vari-ations in Nt antibody development after smallpox vaccination, with female shaving a significantly higher Nt antibody titer than males [22]. On the other hand, Troy et al, reported higher PRNT titers in men after vaccination [23]. In our study, Nt antibody titer between males and females were similar.…”

Impaired innate, humoral, and cellular immunity despite a take in smallpox vaccine recipients

“…Most of the other immune outcomes also exhibited a reduced response, but the reduction did not meet statistical significance (e.g., IL-2 secretion reduced by 50%: p=0.055). As noted earlier, we and others have described sex-based differences in humoral immunity to smallpox vaccination [30,36,37]. Sex differences have also been noted for numerous other vaccines as well [38, 39] and is an important factor that deserves to be studied in greater detail and taken into account when developing vaccination schedules and dosage recommendations, evaluating adverse event rates, and when planning clinical trials of new vaccines.…”

Vaccination evokes gender-dependent protection against tularemia infection in C57BL/6Tac mice

“…In addition, when using the 23-valent pneumococcal polysaccharide vaccine (PPV23), vaccine efficacy was higher in females versus males [21]. In contrast to the above studies, men demonstrated superior Ab responses to diphtheria, measles, and smallpox vaccines when compared to women [19,22]. Men were also better protected against diphtheria and tetanus than their female counterparts [23,24].…”