Correlations Between Vaccinia-Specific Immune Responses Within a Cohort of Armed Forces Members

Abstract

Widespread vaccination with vaccinia virus (VACV) resulted in the eradication of smallpox; however, the licensed VACV-containing vaccines are associated with adverse events (AEs), making them unsuitable for certain high-risk populations. A better understanding of the host immune response following smallpox vaccination could result in vaccines with similar immunogenicity profiles to pre-eradication vaccines with a lower incidence of AEs. To study the immune response to VACV, we recruited 1,076 armed forces members who had been vaccinated with one dose of Dryvax Ò . We measured multiple VACV-specific immune responses: neutralizing antibody titer, the level of 12 secreted cytokines in peripheral blood mononuclear cell (PBMC) cultures (IL-1b, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, TNF-a, IFN-c, IFN-a, , and the number of IFNc-and CD8 + IFN-c-secreting cells. We analyzed these data to determine correlations between immune response measures. We detected a strong proinflammatory response in concert with a Th-1-like cytokine response pattern at a median time point of 15.3 mo following primary vaccination. We also detected correlations between neutralizing antibody titer and secreted IL-2, as well as secreted IFN-c ( p = 0.009 and p = 0.0007, respectively). We also detected strong correlations between the proinflammatory cytokines IL-1b, TNF-a, IL-6, and IL-12p40 ( p < 0.0001). These results further advance our knowledge of vaccinia-specific cellular immune responses. Notably, vaccine-induced proinflammatory responses were not correlated with neutralizing antibody titers, suggesting that further attenuation to reduce inflammatory immune responses may result in decreased AEs without sacrificing VACV immunogenicity and population seropositivity.

Genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients

“…PBMCs from vaccine recipients exhibited a predominantly Th1 type response to viral stimulation characterized by robust secretion of IL-2, IL-12p40, TNFα, and IFNγ as well as high levels of proinflammatory cytokines IFNα, IL-1β, and IL-6 (Umlauf et al 2011). In contrast, we saw low levels IL-10 and negligible amounts of IL-4, IL-12p70, IL-18, and IFNβ.…”

Race and sex-based differences in cytokine immune responses to smallpox vaccine in healthy individuals

“…The methods described below are similar or identical to those published for our previous studies [17,20,21]. The recruitment of the study subjects and the demographic and vaccination data have been previously reported [17,20,21].…”

“…The recruitment of the study subjects and the demographic and vaccination data have been previously reported [17,20,21]. Briefly, all subjects (n=1,071) were recruited as participants in a smallpox immunization program at the Naval Health Research Center (NHRC) in San Diego, CA, and civilian healthcare worker smallpox immunization program at the Mayo Clinic in Rochester, MN.…”

“…Twelve vaccinia-specific Th1, Th2 and innate/inflammatory cytokines were quantified using commercial ELISA kits (BD Pharmingen) in peripheral blood mononuclear cell (PBMC) cultures after in vitro stimulation with inactivated vaccinia virus (NYCBOH strain) at optimal (for each cytokine) multiplicity of infection/MOI and incubation periods, as previously reported [21]. The frequencies of IFNγ-positive cells (in spot-forming units/SFUs) were measured in PBMC cultures using commercial total IFNγ and CD8 + IFNγ ELISPOT kits (R&D Systems, Minneapolis, MN) following the manufacturer’s specifications, with good measurement reproducibility (intraclass correlation coefficients/ICCs comparing multiple observations per subject of 0.94 and 0.85 for stimulated and unstimulated values, respectively) [21,22].…”

“…The frequencies of IFNγ-positive cells (in spot-forming units/SFUs) were measured in PBMC cultures using commercial total IFNγ and CD8 + IFNγ ELISPOT kits (R&D Systems, Minneapolis, MN) following the manufacturer’s specifications, with good measurement reproducibility (intraclass correlation coefficients/ICCs comparing multiple observations per subject of 0.94 and 0.85 for stimulated and unstimulated values, respectively) [21,22]. …”