A Perfect Storm: Impact of Genomic Variation and Serial Vaccination on Low Influenza Vaccine Effectiveness During the 2014-2015 Season.

BACKGROUND: The 2014-2015 influenza season was distinguished by an epidemic of antigenically-drifted A(H3N2) viruses and vaccine components identical to 2013-2014. We report 2014-2015 vaccine effectiveness (VE) from Canada and explore contributing agent-host factors. METHODS: VE against laboratory-confirmed influenza was derived using a test-negative design among outpatients with influenza-like illness. Sequencing identified amino acid mutations at key antigenic sites of the viral hemagglutinin protein. RESULTS: Overall, 815/1930 (42%) patients tested influenza-positive: 590 (72%) influenza A and 226 (28%) influenza B. Most influenza A viruses with known subtype were A(H3N2) (570/577; 99%); 409/460 (89%) sequenced viruses belonged to genetic clade 3C.2a and 39/460 (8%) to clade 3C.3b. Dominant clade 3C.2a viruses bore the pivotal mutations F159Y (a cluster-transition position) and K160T (a predicted gain of glycosylation) compared to the mismatched clade 3C.1 vaccine. VE against A(H3N2) was -17% (95% confidence interval [CI], -50% to 9%) overall with clade-specific VE of -13% (95% CI, -51% to 15%) for clade 3C.2a but 52% (95% CI, -17% to 80%) for clade 3C.3b. VE against A(H3N2) was 53% (95% CI, 10% to 75%) for patients vaccinated in 2014-2015 only, significantly lower at -32% (95% CI, -75% to 0%) if also vaccinated in 2013-2014 and -54% (95% CI, -108% to -14%) if vaccinated each year since 2012-2013. VE against clade-mismatched B(Yamagata) viruses was 42% (95% CI, 10% to 62%) with less-pronounced reduction from prior vaccination compared to A(H3N2). CONCLUSIONS: Variation in the viral genome and negative effects of serial vaccination likely contributed to poor influenza vaccine performance in 2014-2015.

Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses.

BACKGROUND: Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012-13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. METHODS/FINDINGS: Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33-63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17-59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16-80%) against A(H1N1)pdm09, 67% (95%CI: 30-85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29-91%) against B/Victoria (non-vaccine-lineage) viruses. CONCLUSIONS: These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

Influenza A/subtype and B/lineage effectiveness estimates for the 2011-2012 trivalent vaccine: cross-season and cross-lineage protection with unchanged vaccine.

BACKGROUND: We estimate vaccine effectiveness (VE) against both influenza A/subtypes and B/lineages in Canada for the 2011-2012 trivalent inactivated influenza vaccine (TIV) with components entirely unchanged from the 2010-2011 TIV and in the context of phenotypic and genotypic characterization of circulating viruses. METHODS: In a test-negative case-control study VE was estimated as [1-(adjusted)OddsRatio] × 100 for RT-PCR-confirmed influenza in vaccinated vs nonvaccinated participants. Viruses were characterized by hemagglutination inhibition (HI) and sequencing of antigenic sites of the hemagglutinin (HA) gene. RESULTS: There were 1507 participants. VE against A(H1N1)pdm09 was 80% (95% confidence interval [CI], 52%-92%): circulating viruses were HI-characterized as vaccine-matched and bore just 2 aminoacid (AA) differences from vaccine. VE against A/H3N2 was 51% (95% CI, 10%-73%): circulating viruses were HI-characterized as vaccine-related but bore ≥11AA differences from vaccine. VE against influenza B was 51% (95% CI, 26%-67%) in total: 71% (95% CI, 40%-86%) for lineage-matched B/Victoria and 27% (95% CI, -21% to 56%) for lineage-mismatched B/Yamagata. For both influenza A and B types, VE was similar among recipients of either 2010-2011 or 2011-2012 TIV alone, higher when vaccinated both seasons. CONCLUSIONS: Phenotypic and genotypic characterization of circulating and vaccine viruses enhances understanding of TIV performance, shown in 2011-2012 to be substantial against well-conserved A(H1N1)pdm09 and lineage-matched influenza B, suboptimal against genetic-variants of A/H3N2, and further reduced against lineage-mismatched influenza B. With unchanged vaccine components, protection may extend beyond a single season.

Effectiveness of AS03 adjuvanted pandemic H1N1 vaccine: case-control evaluation based on sentinel surveillance system in Canada, autumn 2009.

OBJECTIVE: To assess the effectiveness of the pandemic influenza A/H1N1 vaccine used in Canada during autumn 2009. DESIGN: Test negative incident case-control study based on sentinel physician surveillance system. SETTING: Community based clinics contributing to sentinel networks in British Columbia, Alberta, Ontario, and Quebec, Canada. PARTICIPANTS: 552 patients who presented to a sentinel site within seven days of onset of influenza-like illness during the primary analysis period between 8 November and 5 December 2009; participants were mostly (>80%) children and adults under 50 years old. INTERVENTIONS: Monovalent AS03 adjuvanted pandemic influenza A/H1N1 vaccine as the predominant formulation (>95%) distributed in Canada. MAIN OUTCOME MEASURES: Vaccine effectiveness calculated as 1-(odds ratio for influenza in vaccinated (received pandemic H1N1 vaccine at least two weeks before onset of influenza-like illness) versus unvaccinated participants), with adjustment for age, comorbidity, province, timeliness of specimen collection, and week of illness onset. Sensitivity analyses explored the influence of varying analysis periods between 1 November and 31 December, receipt of trivalent seasonal influenza vaccine, and restriction to participants without comorbidity. RESULTS: During the primary analysis period, pandemic H1N1 was detected by reverse transcription polymerase chain reaction in 209/552 (38%) participants; rates were highest in children and young adults (40%) and lowest in people aged 65 or over (9%). Among the 209 cases, 35 (17%) reported comorbidity compared with 80/343 (23%) controls. Two (1%) cases had received pandemic H1N1 vaccine at least two weeks before the onset of illness, compared with 58/343 (17%) controls, all single dose. Adjusted vaccine effectiveness overall was 93% (95% confidence interval 69% to 98%). High estimates of vaccine protection-generally at least 90%-were maintained across most sensitivity analyses. CONCLUSIONS: Although limited by a small number of vaccine failures, this study suggests that the monovalent AS03 adjuvanted vaccine used in Canada during autumn 2009 was highly effective in preventing medically attended, laboratory confirmed pandemic H1N1 illness, with reference in particular to a single dose in children and young adults.

Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during Spring-Summer 2009: four observational studies from Canada.

BACKGROUND: In late spring 2009, concern was raised in Canada that prior vaccination with the 2008-09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association. STUDIES INCLUDED: (1) test-negative case-control design based on Canada's sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008-09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33-0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases. CONCLUSIONS: Prior receipt of 2008-09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.

Component-specific effectiveness of trivalent influenza vaccine as monitored through a sentinel surveillance network in Canada, 2006-2007.

BACKGROUND: Trivalent inactivated influenza vaccine (TIV) is reformulated annually to contain representative strains of 2 influenza A subtypes (H1N1 and H3N2) and 1 B lineage (Yamagata or Victoria). We describe a sentinel surveillance approach to link influenza variant detection with component-specific vaccine effectiveness (VE) estimation. METHODS: The 2006-2007 TIV included A/NewCaledonia/20/1999(H1N1)-like, A/Wisconsin/67/2005(H3N2)-like, and B/Malaysia/2506/2004(Victoria)-like components. Included participants were individuals >or=9 years of age who presented within 1 week after influenza like illness onset to a sentinel physician between November 2006 and April 2007. Influenza was identified by real-time reverse-transcriptase polymerase chain reaction and/or culture. Isolates were characterized by hemagglutination inhibition assay (HI) and HA1 gene sequence. VE was estimated as 1-[odds ratio for influenza in vaccinated versus nonvaccinated persons]. RESULTS: A total of 841 participants contributed: 69 (8%) were >or=65 years of age; 166 (20%) received the 2006-2007 TIV. Influenza was detected in 337 subjects (40%), distributed as follows: A/H3N2, 242 (72%); A/H1N1, 55 (16%); and B, 36 (11%). All but 1 of the A/H1N1 isolates were well matched, half of A/H3N2 isolates were strain mismatched, and all B isolates were lineage-level mismatched to vaccine. Age-adjusted estimated VE for A/H1N1, A/H3N2, and B components was 92% (95% CI, 40%-91%), 41% (95% CI, 6%-63%), and 19% (95% CI, -112% to 69%), respectively, with an overall VE estimate of 47% (95% CI, 18%-65%). Restriction of the analysis to include only working-age adults resulted in lower VE estimates with wide confidence intervals but similar component-specific trends. CONCLUSIONS: Sentinel surveillance provides a broad platform to link new variant detection and the composite of circulating viruses to annual monitoring of component-specific VE.