Travis Salway Hottes

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. METHODS AND FINDINGS STUDIES INCLUDED (1) test-negative case-control design based on Canadas 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.

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.

Immuno-epidemiologic Correlates of Pandemic H1N1 Surveillance Observations: Higher Antibody and Lower Cell-Mediated Immune Responses with Advanced Age

BACKGROUND Pandemic H1N1 (pH1N1) surveillance data showed lower attack rates but higher risk of severe outcomes with advanced age. We explored immuno-epidemiologic correlates of surveillance findings including humoral and cell-mediated immunity (CMI). METHODS In an age-based design, ∼100 banked/residual sera per 10-year age stratum were assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays for preexisting antibody to pH1N1 and recent seasonal H1N1 and H3N2 strains. In a separate birth cohort design defined by childhood influenza A/subtype priming (1919-1929: H1N1; 1945-1949: H1N1; 1958-1960: H2N2; 1969-1970: H3N2; 1978-1989: H3N2/H1N1), whole blood was collected from up to 50 volunteers per birth cohort. The ratio of Th1(IFN-γ):Th2(IL-10) cytokine responses was evaluated in vitro. RESULTS Antibody to seasonal viruses was highest in school-age children. Cross-reactive HI/MN antibody to pH1N1 was low among participants <70 years of age (yoa; 6%/4% ≥ 40), but seroprevalence increased at 70-79 yoa (27%/6%), increased even more at 80-89 yoa (65%/47%), and was highest at ≥90 yoa (88%/76%). CMI to pH1N1 was evident in all 5 birth cohorts but was lower compared with seasonal strains. There was little differentiation by subtype priming, but the Th1:Th2 ratio for all viruses dropped significantly in the 2 oldest cohorts. CONCLUSIONS Preexisting antibody may have protected the very old from pH1N1 infection, while diminished CMI may have contributed to greater severity once infected. In the young, cross-reactive pH1N1 antibody was mostly absent, while more intact CMI may have protected against severe outcomes.

Seasonal Influenza Vaccine and Increased Risk of Pandemic A/H1N1-Related Illness: First Detection of the Association in British Columbia, Canada

Abstract Background. In April 2009, an elementary school outbreak of pandemic H1N1 (pH1N1) influenza was reported in a community in northern British Columbia, Canada-an area that includes both non-Aboriginal and Aboriginal residents living on or off a reserve. During the outbreak investigation, we explored the relationship between prior receipt of trivalent inactivated influenza vaccine (TIV) and pH1N1-related illness. Methods. A telephone survey was conducted from 15 May through 5 June 2009 among households of children attending any school in the affected community. Members of participating households where influenza-like illness (ILI) was described were then invited to submit blood samples for confirmation of pH1N1 infection by hemagglutination inhibition and microneutralization assays. Circulation of pH1N1 was concentrated among households of the elementary school and elsewhere on-reserve to which analyses of TIV effect were thus restricted. Odds ratios (ORs) for the TIV effect on ILI were computed through logistic regression, with adjustment for age, comorbidity, household density, and Aboriginal status. The influence of within-household clustering was assessed through generalized-linear-mixed models. Results. Of 408 participants, 92 (23%) met ILI criteria: 29 (32%) of 92 persons with ILI, compared with 61 (19%) 316 persons without ILI, had received the 2008–2009 formulation of TIV. Fully adjusted ORs for 2008- 2009 TIV effect on ILI were 2.45 (95% confidence interval, 1.34–4.48) by logistic regression and 2.68 [95% confidence interval, 1.37–5.25) by generalized-linear-mixed model. Conclusions. An outbreak investigation in British Columbia during the late spring of 2009 provided the first indication of an unexpected association between receipt of TIV and pH1N1 illness. This led to 5 additional studies through the summer 2009 in Canada, each of which corroborated these initial findings.

Estimates of Influenza Vaccine Effectiveness for 2007–2008 From Canada's Sentinel Surveillance System: Cross-Protection Against Major and Minor Variants

OBJECTIVES To estimate influenza vaccine effectiveness (VE) for the 2007-2008 season and assess the sentinel surveillance system in Canada for monitoring virus evolution and impact on VE. METHODS Nasal/nasopharyngeal swabs and epidemiologic details were collected from patients presenting to a sentinel physician within 7 days of influenza-like illness onset. Cases tested positive for influenza A/B virus by real-time polymerase chain reaction; controls tested negative. Hemagglutination inhibition (HI) and gene sequencing explored virus relatedness to vaccine. VE was calculated as 1 minus the odds ratio for influenza in vaccinated versus nonvaccinated participants, with adjustment for confounders. RESULTS Of 1425 participants, 21% were vaccinated. Influenza virus was detected in 689 (48%), of which isolates from 663 were typed/subtyped: 189 (29%) were A/H1, 210 (32%) were A/H3, and 264 (40%) were B. Of A/H1N1 isolates, 6% showed minor HI antigenic mismatch to vaccine, with greater variation based on genetic identity. All A/H3N2 isolates showed moderate antigenic mismatch, and 98% of influenza B virus isolates showed major lineage-level mismatch to vaccine. Adjusted VE for A/H1N1, A/H3N2, and B components was 69% (95% confidence interval [CI], 44%-83%), 57% (95% CI, 32%-73%), and 55% (95% CI, 32%-70%), respectively, with an overall VE of 60% (95% CI, 45%-71%). CONCLUSIONS Detailed antigenic and genotypic analysis of influenza viruses was consistent with epidemiologic estimates of VE showing cross-protection. A routine sentinel surveillance system that combines detailed virus and VE monitoring annually, as modeled in Canada, may guide improved vaccine selection and protection.

Internet-Based HIV and Sexually Transmitted Infection Testing in British Columbia, Canada: Opinions and Expectations of Prospective Clients

Background The feasibility and acceptability of Internet-based sexually transmitted infection (STI) testing have been demonstrated; however, few programs have included testing for human immunodeficiency virus (HIV). In British Columbia, Canada, a new initiative will offer online access to chlamydia, gonorrhea, syphilis, and HIV testing, integrated with existing clinic-based services. We presented the model to gay men and other men who have sex with men (MSM) and existing clinic clients through a series of focus groups. Objective To identify perceived benefits, concerns, and expectations of a new model for Internet-based STI and HIV testing among potential end users. Methods Participants were recruited through email invitations, online classifieds, and flyers in STI clinics. A structured interview guide was used. Focus groups were audio recorded, and an observer took detailed field notes. Analysts then listened to audio recordings to validate field notes. Data were coded and analyzed using a scissor-and-sort technique. Results In total, 39 people participated in six focus groups. Most were MSM, and all were active Internet users and experienced with STI/HIV testing. Perceived benefits of Internet-based STI testing included anonymity, convenience, and client-centered control. Salient concerns were reluctance to provide personal information online, distrust of security of data provided online, and the need for comprehensive pretest information and support for those receiving positive results, particularly for HIV. Suggestions emerged for mitigation of these concerns: provide up-front and detailed information about the model, ask only the minimal information required for testing, give positive results only by phone or in person, and ensure that those testing positive are referred for counseling and support. End users expected Internet testing to offer continuous online service delivery, from booking appointments, to transmitting information to the laboratory, to getting prescriptions. Most participants said they would use the service or recommend it to others. Those who indicated they would be unlikely to use it generally either lived near an STI clinic or routinely saw a family doctor with whom they were comfortable testing. Participants expected that the service would provide the greatest benefit to individuals who do not already have access to sensitive sexual health services, are reluctant to test due to stigma, or want to take immediate action (eg, because of a recent potential STI/HIV exposure). Conclusions Internet-based STI/HIV testing has the potential to reduce barriers to testing, as a complement to existing clinic-based services. Trust in the new online service, however, is a prerequisite to client uptake and may be engendered by transparency of information about the model, and by accounting for concerns related to confidentiality, data usage, and provision of positive (especially HIV) results. Ongoing evaluation of this new model will be essential to its success and to the confidence of its users.

Prevalence of seroprotection against the pandemic (H1N1) virus after the 2009 pandemic

Background: Before pandemic (H1N1) 2009, less than 10% of serum samples collected from all age groups in the Lower Mainland of British Columbia, Canada, showed seroprotection against the pandemic (H1N1) 2009 virus, except those from very elderly people. We reassessed this profile of seroprotection by age in the same region six months after the fall 2009 pandemic and vaccination campaign. Methods: We evaluated 100 anonymized serum samples per 10-year age group based on convenience sampling. We measured levels of antibody against the pandemic virus by hemagglutination inhibition and microneutralization assays. We assessed geometric mean titres and the proportion of people with seroprotective antibody levels (hemagglutination inhibition titre ≥ 40). We performed sensitivity analyses to evaluate titre thresholds of 80, 20 and 10. Results: Serum samples from 1127 people aged 9 months to 101 years were obtained. The overall age-standardized proportion of people with seroprotective antibody levels was 46%. A U-shaped age distribution was identified regardless of assay or titre threshold applied. Among those less than 20 years old and those 80 years and older, the prevalence of seroprotection was comparably high at about 70%. Seroprotection was 44% among those aged 20–49 and 30% among those 50–79 years. It was lowest among people aged 70–79 years (21%) and highest among those 90 years and older (88%). Interpretation: We measured much higher levels of seroprotection after the 2009 pandemic compared than before the pandemic, with a U-shaped age distribution now evident. These findings, particularly the low levels of seroprotection among people aged 50–79 years, should be confirmed in other settings and closer to the influenza season.

Randomized Controlled Trial of Dose Response to Influenza Vaccine in Children Aged 6 to 23 Months

OBJECTIVES: We assessed whether 2 full versus 2 half-doses of trivalent inactivated influenza vaccine (TIV) could improve immunogenicity without increasing reactogenicity in infants (aged 6–11 months) and toddlers (aged 12–23 months). METHODS: Previously unimmunized infants and toddlers were separately randomly assigned to receive 2 full (0.5-mL) or 2 half (0.25-mL) doses of 2008–2009 split TIV. Sera were collected at enrollment and at 27 to 45 days after the second injection. Parents recorded adverse events after each injection. The primary immunogenicity outcome was superiority (1-sided, α = 0.025) of the full versus the half-dose based on a >10% increase in rates of seroprotection (hemagglutination inhibition titer of ≥40). The primary reactogenicity outcome was fever of ≥38°C within 3 days of either injection. RESULTS: In per-protocol analyses, 252 participants (full dose: n = 124; half-dose: n = 128) were included. In toddlers, postimmunization seroprotection rates exceeded 85% for all 3 vaccine components without significant difference by dose. In infants, the full dose induced higher responses for all 3 vaccine components, meeting the 10% test of superiority for the H3N2 (75.4% vs 47.6%; Δ = 27.8% [95% confidence interval (CI): 11.2–44.5]; P = .02) and B/Yamagata (70.2% vs 41.3%; Δ = 28.9% [95% CI: 11.9–45.9]; P = .02) components but not H1N1 (71.9% vs 54.0%; Δ = 18.0% [95% CI: 1.0–34.9]; P = .2). Rates of fever were not increased among full- versus half-dose recipients in either age group (5.6% vs 12.7% combined). CONCLUSIONS: Administration of 2 full TIV doses may improve immunogenicity without increasing reactogenicity in infants. Current TIV dosing recommendations for young children warrant additional evaluation.

Influenza B/Victoria Antigen Induces Strong Recall of B/Yamagata But Lower B/Victoria Response in Children Primed With Two Doses of B/Yamagata

Objectives: Trivalent inactivated influenza vaccine (TIV) contains 1 of 2 influenza B/lineages (B/Yamagata or B/Victoria) annually. We assessed prime-boost responses in young children following a change in the B/lineage included in TIV. Methods: Participants were primed during a clinical trial as infants or toddlers with two 0.25 or two 0.5 mL doses of 2008–2009 TIV containing B/Florida/4/06(Yamagata) antigen. In subsequent years, sequential subsets received annual age-appropriate doses of 2009–2010 and 2010–2011 TIV containing the changed influenza B/lineage antigen (B/Brisbane/60/08(Victoria)). Serologic response was assessed pre- and postimmunization by hemagglutination inhibition (HI; with/without ether treatment of influenza B antigen) and microneutralization. The primary immunogenicity outcome was the seroprotection rate (SPR) measured by HI without ether treatment (SPR:HI titers ≥40). Results: Fifty-six children were included in 2009–2010 and 36 in 2010–2011 analyses. Before the 2009–2010 TIV dose, antibody to all 2008–2009 TIV components had fallen to low levels: SPR <10% for B/Florida/4/06(Yamagata) and B/Brisbane/60/08(Victoria) antigens. A single 2009–2010 TIV dose boosted antibody to the shared 2008–2009/2009–2010 influenza A antigens and to the priming 2008–2009 B/Florida/4/06(Yamagata) antigen with SPRs >85%. In contrast, antibody to the B/Brisbane/60/08(Victoria) antigen included in the 2009–2010 TIV remained low: SPR <25%. Antibody to the B/Brisbane/60/08(Victoria) antigen was not improved from a further dose in the 2010–2011 TIV: SPR 31% versus SPR 69% to B/Yamagata. A similar pattern of B/Yamagata dominance was observed when HI testing was conducted with antigen prepared by ether treatment. Conclusions: Repeated annual TIV doses containing B/Victoria-lineage antigen strongly recalled antibodies to the B/Yamagata antigen of first exposure, but elicited lower B/Victoria responses.

Cephalosporin and azithromycin susceptibility in Neisseria gonorrhoeae isolates by site of infection, British Columbia, 2006 to 2011.

Background Widespread resistance of Neisseria gonorrhoeae to penicillin, tetracycline, and fluoroquinolones has challenged effective treatment and control; recent international case reports of cefixime, ceftriaxone, and azithromycin resistance suggest that the remaining treatment options are now additionally threatened. To explore trends in antimicrobial susceptibility of N. gonorrhoeae, we reviewed provincial laboratory data from British Columbia, 2006 to 2011. Methods Susceptibility testing was performed for all N. gonorrhoeae isolates detected in-house or forwarded to the reference laboratory. Resistance or intermediate resistance (nonsusceptibility) was defined by standard breakpoints for penicillin, tetracycline, ciprofloxacin, and spectinomycin. Elevated minimum inhibitory concentrations (MICs) at serial dilutions of 0.064 &mgr;g/mL or greater were explored for cefixime/ceftriaxone and 0.5 &mgr;g/mL or greater for azithromycin. Nonsusceptibility/elevated MIC was compared by year, site of infection, sex, and age. Results A total of 1837 isolates representing 22% of all reported gonorrhea cases were analyzed. Nonsusceptibility to penicillin was established at baseline. Nonsusceptibility to tetracycline and ciprofloxacin increased over the study period, reaching 96% and 36%, respectively, in 2011. Sixteen isolates (1%) had a cefixime MIC of 0.25 &mgr;g/mL (none ≥0.5), none had a ceftriaxone MIC of 0.25 &mgr;g/mL or greater, and 15 (1%) had an azithromycin MIC of 2.0 &mgr;g/mL or greater. Elevated MIC of these agents showed an increasing trend over time. Nonsusceptibility and elevated MIC were consistently highest at the rectal and pharyngeal sites and higher in isolates from males, including when stratified to the pharyngeal site. Interpretation Increases in elevated MIC of cefixime/ceftriaxone/azithromycin were superimposed on a background of established resistance to penicillin, tetracycline, and ciprofloxacin and may signal impending gonococcal resistance to first-line treatments. Ongoing surveillance will inform timely shifts in treatment recommendations.