Kevin Fonseca

Effect of Influenza Vaccination of Children on Infection Rates in Hutterite Communities: A Randomized Trial

CONTEXT Children and adolescents appear to play an important role in the transmission of influenza. Selectively vaccinating youngsters against influenza may interrupt virus transmission and protect those not immunized. OBJECTIVE To assess whether vaccinating children and adolescents with inactivated influenza vaccine could prevent influenza in other community members. DESIGN, SETTING, AND PARTICIPANTS A cluster randomized trial involving 947 Canadian children and adolescents aged 36 months to 15 years who received study vaccine and 2326 community members who did not receive the study vaccine in 49 Hutterite colonies in Alberta, Saskatchewan, and Manitoba. Follow-up began December 28, 2008, and ended June 23, 2009. INTERVENTION Children were randomly assigned according to community and in a blinded manner to receive standard dosing of either inactivated trivalent influenza vaccine or hepatitis A vaccine, which was used as a control. MAIN OUTCOME MEASURES Confirmed influenza A and B infection using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay and by measuring serum hemagglutination inhibition titers. RESULTS The mean rate of study vaccine coverage among eligible participants was 83% (range, 53%-100%) for the influenza vaccine colonies and 79% (range, 50%-100%) for the hepatitis A vaccine colonies. Among nonrecipients, 39 of 1271 (3.1%) in the influenza vaccine colonies and 80 of 1055 (7.6%) in the hepatitis A vaccine colonies had influenza illness confirmed by RT-PCR, for a protective effectiveness of 61% (95% confidence interval [CI], 8%-83%; P = .03). Among all study participants (those who were and those who were not vaccinated), 80 of 1773 (4.5%) in the influenza vaccine colonies and 159 of 1500 (10.6%) in the hepatitis A vaccine colonies had influenza illness confirmed by RT-PCR for an overall protective effectiveness of 59% (95% CI, 5%-82%; P = .04). No serious vaccine adverse events were observed. CONCLUSION Immunizing children and adolescents with inactivated influenza vaccine significantly protected unimmunized residents of rural communities against influenza. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00877396.

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.

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.

First Case of Zika Virus Infection in a Returning Canadian Traveler

A woman who recently traveled to Thailand came to a local emergency department with a fever and papular rash. She was tested for measles, malaria, and dengue. Positive finding for IgM antibody against dengue and a failure to seroconvert for IgG against dengue for multiple blood samples suggested an alternate flavivirus etiology. Amplification of a conserved region of the non-structural protein 5 gene of the genus Flavivirus yielded a polymerase chain reaction product with a matching sequence of 99% identity with Zika virus. A urine sample and a nasopharygeal swab specimen obtained for the measles investigation were also positive for this virus by reverse transcription polymerase chain reaction. Subsequently, the urine sample yielded a Zika virus isolate in cell culture. This case report describes a number of novel clinical and laboratory findings, the first documentation of this virus in Canada, and the second documentation from this region in Thailand.

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.

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.

A Sentinel Platform to Evaluate Influenza Vaccine Effectiveness and New Variant Circulation, Canada 2010–2011 Season

BACKGROUND During the 2010-2011 winter, a large number of outbreaks due to influenza A/H3N2 at long-term care facilities, including higher-than-expected attack rates among vaccinated staff, were reported in some regions of Canada. Interim analysis from the community-based sentinel surveillance system showed circulating H3N2 variants and suboptimal vaccine effectiveness (VE), assessed here for the entire seasons data set. METHODS Nasal/nasopharyngeal swabs and epidemiologic details were collected from patients presenting to sentinel sites within 7 days of onset of influenza-like illness. Cases tested positive for influenza by real-time reverse-transcription polymerase chain reaction; controls tested negative. Odds ratios for medically attended, laboratory-confirmed influenza in vaccinated vs nonvaccinated participants were used to derive adjusted VE. Viruses were characterized by hemagglutination inhibition (HI), and the hemagglutinin genes of a subset were sequenced to explore vaccine relatedness. RESULTS Final 2010-2011 VE analysis included 1718 participants (half aged 20-49 years), 93 with A(H1N1)pdm09, 408 with A/H3N2, and 199 with influenza B. Among adults aged 20-49 years, adjusted VE was 65% (95% confidence interval [CI], 8%-87%) for A(H1N1)pdm09 and 66% (95% CI, 10%-87%) for influenza B. Vaccine effectiveness was substantially lower for A/H3N2, at 39% (95% CI, 0%-63%). Phylogenetic analysis identified 2 circulating H3N2 variant clades, A/HongKong/2121/2010 (87%) and A/Victoria/208/2009 (11%), bearing multiple amino acid substitutions at antigenic sites (12 and 8, respectively) compared with the H3N2 vaccine component used in Canada (A/Victoria/210/2009[NYMC X-187]). However, HI characterized all H3N2 isolates as well matched to the vaccine. CONCLUSIONS Public health observations of increased facility H3N2 outbreaks were consistent with the sentinel networks detection of genetic variants and suboptimal VE but not with conventional HI characterization. We highlight the utility of a multicomponent sentinel surveillance platform that incorporates genotypic, phenotypic, and epidemiologic indicators into the assessment of influenza virus, new variant circulation, vaccine relatedness, and VE.

Effects of School Closure on Incidence of Pandemic Influenza in Alberta, Canada

BACKGROUND Control of pandemic influenza by social-distancing measures, such as school closures, is a controversial aspect of pandemic planning. However, investigations of the extent to which these measures actually affect the progression of a pandemic have been limited. OBJECTIVE To examine correlations between the incidence of pandemic H1N1 (pH1N1) influenza in Alberta, Canada, in 2009 and school closures or weather changes, and to estimate the effects of school closures and weather changes on pH1N1 transmission. DESIGN Mathematical transmission models were fit to data that compared the pattern of confirmed pH1N1 cases with the school calendar and weather patterns. SETTING Alberta, Canada, from 19 April 2009 to 2 January 2010. DATA SOURCES 2009 virologic test results, 2006 census data, 2009 daily temperature and humidity data, and 2009 school calendars. MEASUREMENTS Age-specific daily counts of positive results for pH1N1 from the complete database of 35 510 specimens submitted to the Alberta Provincial Laboratory for Public Health for virologic testing from 19 April 2009 to 2 January 2010. RESULTS The ending and restarting of school terms had a major effect in attenuating the first wave and starting the second wave of pandemic influenza cases. Mathematical models suggested that school closure reduced transmission among school-age children by more than 50% and that this was a key factor in interrupting transmission. The models also indicated that seasonal changes in weather had a significant effect on the temporal pattern of the epidemic. LIMITATIONS Data probably represent a small sample of all viral infections. The mathematical models make simplifying assumptions in order to make simulations and analysis feasible. CONCLUSION Analysis of data from unrestricted virologic testing during an influenza pandemic provides compelling evidence that closing schools can have dramatic effects on transmission of pandemic influenza. School closure seems to be an effective strategy for slowing the spread of pandemic influenza in countries with social contact networks similar to those in Canada. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Public Health Agency of Canada.

Comparison of the Luminex xTAG™ Respiratory Viral Panel with xTAG® Respiratory Viral Panel Fast for diagnosis of respiratory virus infections

ABSTRACT Nucleic acid tests are sensitive and specific and provide a rapid diagnosis, making them invaluable for patient and outbreak management. Multiplex PCR assays have additional advantages in providing an economical and comprehensive panel for many common respiratory viruses. Previous reports have shown the utility of the xTAG respiratory viral panel (RVP) assay manufactured by Luminex Molecular Diagnostics for this purpose. A newer generation of this kit, released in Canada in early 2010, is designed to simplify the procedure and reduce the turnaround time by about 24 h. The assay methodology and targets included in this version of the kit are different; consequently, the objective of this study was to compare the detection of a panel of respiratory viral targets using the older Luminex xTAG RVP (RVP Classic) assay with that using the newer xTAG RVP Fast assay. This study included 334 respiratory specimens that had been characterized for a variety of respiratory viral targets; all samples were tested by both versions of the RVP assay in parallel. Overall, the RVP Classic assay was more sensitive than the RVP Fast assay (88.6% and 77.5% sensitivities, respectively) for all the viral targets combined. Targets not detected by the RVP Fast assay included primarily influenza B virus, parainfluenza virus type 2, and human coronavirus 229E. A small number of samples positive for influenza A virus, respiratory syncytial virus B, human metapneumovirus, and parainfluenza virus type 1 were not detected by the RVP Classic assay and in general had low viral loads.

Interim estimates of 2014/15 vaccine effectiveness against influenza A(H3N2) from Canada's Sentinel Physician Surveillance Network, January 2015.

The 2014/15 influenza season to date in Canada has been characterised by predominant influenza A(H3N2) activity. Canadas Sentinel Physician Surveillance Network (SPSN) assessed interim vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza A(H3N2) infection in January 2015 using a test-negative case-control design. Of 861 participants, 410 (48%) were test-positive cases (35% vaccinated) and 451 (52%) were test-negative controls (33% vaccinated). Among test-positive cases, the majority (391; 95%) were diagnosed with influenza A, and of those with available subtype information, almost all influenza A viruses (379/381; 99%) were A(H3N2). Among 226 (60%) A(H3N2) viruses that were sequenced, 205 (91%) clustered with phylogenetic clade 3C.2a, considered genetically and antigenically distinct from the 2014/15 A/Texas/50/2012(H3N2)-like clade 3C.1 vaccine reference strain, and typically bearing 10 to 11 amino acid differences from the vaccine at key antigenic sites of the haemagglutinin protein. Consistent with substantial vaccine mismatch, little or no vaccine protection was observed overall, with adjusted VE against medically attended influenza A(H3N2) infection of ?8% (95% CI: ?50 to 23%). Given these findings, other adjunct protective measures should be considered to minimise morbidity and mortality, particularly among high-risk individuals. Virus and/or host factors influencing this reduced vaccine protection warrant further in-depth investigation. .