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 µg/mL or greater were explored for cefixime/ceftriaxone and 0.5 µg/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 µg/mL (none ≥0.5), none had a ceftriaxone MIC of 0.25 µg/mL or greater, and 15 (1%) had an azithromycin MIC of 2.0 µg/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.

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.

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/H1N1­related illness: first detection of the association in British Columbia, Canada.

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-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.

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.

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.

A syndemic approach to assess the effect of substance use and social disparities on the evolution of HIV/HCV infections in British Columbia.

BACKGROUND: Co-occurrence of social conditions and infections may affect HIV/HCV disease risk and progression. We examined the changes in relationship of these social conditions and infections on HIV and hepatitis C virus (HCV) infections over time in British Columbia during 1990-2013. METHODS: The BC Hepatitis Testers Cohort (BC-HTC) includes ~1.5 million individuals tested for HIV or HCV, or reported as a case of HCV, HIV, HBV, or tuberculosis linked to administrative healthcare databases. We classified HCV and HIV infection status into five combinations: HIV-/HCV-, HIV+monoinfected, HIV-/HCV+seroconverters, HIV-/HCV+prevalent, and HIV+/HCV+. RESULTS: Of 1.37 million eligible individuals, 4.1% were HIV-/HCV+prevalent, 0.5% HIV+monoinfected, 0.3% HIV+/HCV+ co-infected and 0.5% HIV-/HCV+seroconverters. Overall, HIV+monoinfected individuals lived in urban areas (92%), had low injection drug use (IDU) (4%), problematic alcohol use (4%) and were materially more privileged than other groups. HIV+/HCV+ co-infected and HIV-/HCV+seroconverters were materially most deprived (37%, 32%), had higher IDU (28%, 49%), problematic alcohol use (14%, 17%) and major mental illnesses (12%, 21%). IDU, opioid substitution therapy, and material deprivation increased in HIV-/HCV+seroconverters over time. In multivariable multinomial regression models, over time, the odds of IDU declined among HIV-/HCV+prevalent and HIV+monoinfected individuals but not in HIV-/HCV+seroconverters. Declines in odds of problematic alcohol use were observed in HIV-/HCV+seroconverters and coinfected individuals over time. CONCLUSIONS: These results highlight need for designing prevention, care and support services for HIV and HCV infected populations based on the evolving syndemics of infections and social conditions which vary across groups.

Contribution of influenza viruses to medically attended acute respiratory illnesses in children in high-income countries: a meta-analysis.

AIM: The burden of disease in children attributable to influenza viruses is difficult to quantify given the similarity of symptoms caused by infection due to influenza and other viruses. This uncertainty impacts clinical decision-making and estimates of burden. We aimed to systematically review the literature to determine the proportion of healthy children presenting for health care with an acute respiratory illness (ARI) who have laboratory-confirmed seasonal influenza (PROSPERO ID#CRD42014013896). METHOD: We searched Ovid MEDLINE, EMBASE, Scopus, and references of included articles. We included studies that used polymerase chain reaction methods to test for influenza in healthy children aged ≤5 years who presented for health care in high-income countries with an influenza-like or ARI. A standardized form was used to collect data on positivity and other relevant study elements. RESULTS: Seventeen studies covering 12 different influenza seasons were included. The proportion of influenza positivity ranged from 11% to 56%. Subgroup analyses were performed by influenza season, continent, healthcare setting, age group, and vaccination status. Higher influenza positivity was reported among children aged 3-5 years compared with children aged ≤2 years, and for unvaccinated children. CONCLUSION: The minority of healthy patients aged ≤5 years with medically attended influenza-like or acute respiratory symptoms have laboratory-confirmed influenza virus infection, although this varied by influenza season. Prevention efforts should be targeted accordingly. STATEMENT: Most influenza-like illnesses are not laboratory-confirmed and have similar clinical presentations. Consequently, the true contribution of influenza to acute respiratory infections in children remains uncertain. Our systematic review estimates that this proportion ranges from 11% to 56%. This finding can help both clinicians and public health professionals target prevention.

Time since last negative HIV test among men who have sex with men and people who use injection drugs in British Columbia, 2006-2011.

OBJECTIVES: Canadian surveys of men who have sex with men (MSM) and people using injection drugs (IDU) demonstrate that most have tested for HIV at least once, but that half or fewer have done so in the previous year. To better inform targeted HIV testing guidelines for these populations, we derived estimates of inter-test interval (ITI) for persons newly diagnosed with HIV in British Columbia (BC) between 2006 and 2011, and assessed variables associated with longer ITI among MSM and IDU. METHODS: Provincial HIV case report and testing data were linked by deterministic and probabilistic matching (based on unique personal health number, name, and date of birth). ITI was defined as time from last recorded negative to first positive HIV result; those with ITI ≤30 days were excluded. RESULTS: Of 2,004 eligible individuals, 1,116 (55.7%) had a recorded negative HIV test result in the previous ten years. Overall median ITI was 20 months with a skewed distribution (inter-quartile range 8-46); median ITI was 15 months for MSM and 21 months for IDU with 41.2% and 33.1% testing in the past year, respectively. Longer ITI was associated with older age for both groups, and among MSM with residence outside Vancouver and not known to have an HIV-positive partner. CONCLUSIONS: These findings highlight potential missed opportunities for earlier detection of HIV and prevention of secondary transmission among newly diagnosed MSM and IDU, and provide evidence to inform recommendations for HIV test frequency and testing strategies for these populations in BC.

Transmission dynamics and risk factors for pandemic H1N1-related illness: outbreak investigation in a rural community of British Columbia, Canada.

OBJECTIVE: To characterize the first-wave epidemiologic features of influenza-like illness (ILI) associated with the novel pandemic A/H1N1 [A(H1N1)pdm09] virus. METHODS: We used generalized linear mixed models (GLMM) to assess risk factors and non-parametric and/or parametric distributions to estimate attack rates, secondary attack rates (SAR), duration of illness, and serial interval during a laboratory-confirmed community outbreak of A(H1N1)pdm09 clustered around on-reserve residents and households of an elementary school in rural British Columbia, Canada, in late April/early May 2009. ILI details were collected as part of outbreak investigation by community telephone survey in early June 2009. RESULTS: Overall, 92/408 (23%) of participants developed ILI and 36/408 (9%) experienced medically attended ILI (MAILI). The overall SAR in households was 22%: highest among participants 1-4 years of age (yoa) (50%) followed by < 1 yoa (38%), 5-8 yoa (20%), 10-19 yoa (13%), 20-49 yoa (20%), and 50-64 yoa (0%). The median serial interval was estimated at 3·5 days (95% CI: 2·1-5·1). In multivariable GLMM analysis, having a chronic condition (OR: 2·58; 95% CI: 1·1-6·04), younger age [1-8 yoa: OR: 4·63; 95% CI: 2·25-9·52; 9-19 yoa: OR: 1·95; 95% CI: 0·97-3·9 (referent: ≥ 20 yoa)] and receipt of 2008-2009 influenza vaccine (OR: 2·68; 95% CI: 1·37-5·25) were associated with increased risk of ILI. Median duration of illness was 9 days, longer among those with chronic conditions (21 days). Median time to seeking care after developing illness was 4·5 days. On-reserve participants had higher chronic conditions, household density, ILI, MAILI, and SAR. CONCLUSIONS: During a community outbreak of A(H1N1)pdm09-related illness, we identified substantial clinical ILI attack rates exceeding 20% with secondary household attack rates as high as 50% in young children. The serial interval was short suggesting a narrow period to prevent transmission.

Influenza Β/Victoria antigen induces strong recall of Β/Yamagata but lower Β/Victoria response in children primed with two doses of Β/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.

Influenza vaccine effectiveness in the elderly based on administrative databases: change in immunization habit as a marker for bias.

BACKGROUND: Administrative databases provide efficient methods to estimate influenza vaccine effectiveness (IVE) against severe outcomes in the elderly but are prone to intractable bias. This study returns to one of the linked population databases by which IVE against hospitalization and death in the elderly was first assessed. We explore IVE across six more recent influenza seasons, including periods before, during, and after peak activity to identify potential markers for bias. METHODS AND FINDINGS: Acute respiratory hospitalization and all-cause mortality were compared between immunized/non-immunized community-dwelling seniors ≥65 years through administrative databases in Manitoba, Canada between 2000-01 and 2005-06. IVE was compared during pre-season/influenza/post-season periods through logistic regression with multivariable adjustment (age/sex/income/residence/prior influenza or pneumococcal immunization/medical visits/comorbidity), stratification based on prior influenza immunization history, and propensity scores. Analysis during pre-season periods assessed baseline differences between immunized and unimmunized groups. The study population included ∼140,000 seniors, of whom 50-60% were immunized annually. Adjustment for key covariates and use of propensity scores consistently increased IVE. Estimates were paradoxically higher pre-season and for all-cause mortality vs. acute respiratory hospitalization. Stratified analysis showed that those twice consecutively and currently immunized were always at significantly lower hospitalization/mortality risk with odds ratios (OR) of 0.60 [95%CI0.48-0.75] and 0.58 [0.53-0.64] pre-season and 0.77 [0.69-0.86] and 0.71 [0.66-0.77] during influenza circulation, relative to the consistently unimmunized. Conversely, those forgoing immunization when twice previously immunized were always at significantly higher hospitalization/mortality risk with OR of 1.41 [1.14-1.73] and 2.45 [2.21-2.72] pre-season and 1.21 [1.03-1.43] and 1.78 [1.61-1.96] during influenza circulation. CONCLUSIONS: The most pronounced IVE estimates were paradoxically observed pre-season, indicating bias tending to over-estimate vaccine protection. Change in immunization habit from that of the prior two years may be a marker for this bias in administrative data sets; however, no analytic technique explored could adjust for its influence. Improved methods to achieve valid interpretation of protection in the elderly are needed.

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.

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.