Serial Vaccination and the Antigenic Distance Hypothesis: Effects on Influenza Vaccine Effectiveness During A(H3N2) Epidemics in Canada, 2010-2011 to 2014-2015

Background. The antigenic distance hypothesis (ADH) predicts that negative interference from prior season's influenza vaccine (v1) on the current season's vaccine (v2) protection may occur when the antigenic distance is small between v1 and v2 (v1 approximate to v2) but large between v1 and the current epidemic (e) strain (v1 not equal e). Methods. Vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza A(H3N2) illness was estimated by test-negative design during 3 A(H3N2) epidemics (2010-2011, 2012-2013, 2014-2015) in Canada. Vaccine effectiveness was derived with covariate adjustment across v2 and/or v1 categories relative to no vaccine receipt among outpatients aged >= 9 years. Prior vaccination effects were interpreted within the ADH framework. Results. Prior vaccination effects varied significantly by season, consistent with the ADH. There was no interference by v1 in 20102011 when v1 not equal v2 and v1 not equal e, with comparable VE for v2 alone or v2 + v1: 34% (95% confidence interval [CI] = -51% to 71%) versus 34% (95% CI = -5% to 58%). Negative interference by v1 was suggested in 2012-2013 with nonsignificant reduction in VE when v1 approximate to v2 and v1 not equal e: 49% (95% CI = -47% to 83%) versus 28% (95% CI = -12% to 54%). Negative effects of prior vaccination were pronounced and statistically significant in 2014-2015 when v1 v2 and v1 not equal e: 65% (95% CI = 25% to 83%) versus -33% (95% CI = -78% to 1%). Conclusions. Effects of repeat influenza vaccination were consistent with the ADH and may have contributed to findings of low VE across recent A(H3N2) epidemics since 2010 in Canada.