Modeling Control Strategies of Respiratory Pathogens

Contact network epidemiology can provide quantitative input even before pathogen is fully characterized

Seroconversion to Seasonal Influenza Viruses after A(H1N1)pdm09 Virus Infection, Quebec, Canada

We looked for cross-reactive antibodies in 122 persons with paired serum samples collected during the 2009 pandemic of influenza virus A(H1N1)pdm09. Eight (12%) of 67 persons with A(H1N1)pdm09 infection confirmed by reverse transcription PCR and/or serology also seroconverted to the seasonal A/Brisbane/59/2007 (H1N1) virus, compared with 1 (2%) of 55 A(H1N1)pdm09-negative persons (p<0.05)

Human Illness from Avian Influenza H7N3, British Columbia

Avian influenza that infects poultry in close proximity to humans is a concern because of its pandemic potential. In 2004, an outbreak of highly pathogenic avian influenza H7N3 occurred in poultry in British Columbia, Canada. Surveillance identified two persons with confirmed avian influenza infection. Symptoms included conjunctivitis and mild influenzalike illness

Influenza Vaccination of Healthcare Workers: Critical Analysis of the Evidence for Patient Benefit Underpinning Policies of Enforcement

Background: Four cluster randomized controlled trials (cRCTs) conducted in long-term care facilities (LTCFs) have reported reductions in patient risk through increased healthcare worker (HCW) influenza vaccination. This evidence has led to expansive policies of enforcement that include all staff of acute care hospitals and other healthcare settings beyond LTCFs. We critique and quantify the cRCT evidence for indirect patient benefit underpinning policies of mandatory HCW influenza vaccination. Methods: Plausibility of the four cRCT findings attributing indirect patient benefits to HCW influenza vaccination was assessed by comparing percentage reductions in patient risk reported by the cRCTs to predicted values. Plausibly predicted values were derived according to the basic mathematical principle of dilution, taking into account HCW influenza vaccine coverage and the specificity of patient outcomes for influenza. Accordingly, predicted values were calculated as a function of relevant compound probabilities including vaccine efficacy (ranging 40–60% in HCWs and favourably assuming the same indirect protection conferred through them to patients) × change in proportionate HCW influenza vaccine coverage (as reported by each cRCT) × percentage of a given patient outcome (e.g. influenza-like illness (ILI) or all-cause mortality) plausibly due to influenza virus. The number needed to vaccinate (NNV) for HCWs to indirectly prevent patient death was recalibrated based on real patient data of hospital-acquired influenza, with adjustment for potential under-detection (5.2-fold), and using favourable assumptions of HCW-attributable risk (ranging 60–80%). Results: In attributing patient benefit to increased HCW influenza vaccine coverage, each cRCT was found to violate the basic mathematical principle of dilution by reporting greater percentage reductions with less influenza-specific patient outcomes (i.e., all-cause mortality > ILI > laboratory-confirmed influenza) and/or patient mortality reductions exceeding even favourably-derived predicted values by at least 6- to 15-fold. If extrapolated to all LTCF and hospital staff in the United States, the prior cRCT-claimed NNV of 8 would implausibly mean >200,000 and >675,000 patient deaths, respectively, could be prevented annually by HCW influenza vaccination, inconceivably exceeding total US population mortality estimates due to seasonal influenza each year, or during the 1918 pandemic, respectively. More realistic recalibration based on actual patient data instead shows that at least 6000 to 32,000 hospital workers would need to be vaccinated before a single patient death could potentially be averted. Conclusions: The four cRCTs underpinning policies of enforced HCW influenza vaccination attribute implausibly large reductions in patient risk to HCW vaccination, casting serious doubts on their validity. The impression that unvaccinated HCWs place their patients at great influenza peril is exaggerated. Instead, the HCW-attributable risk and vaccine-preventable fraction both remain unknown and the NNV to achieve patient benefit still requires better understanding. Although current scientific data are inadequate to support the ethical implementation of enforced HCW influenza vaccination, they do not refute approaches to support voluntary vaccination or other more broadly protective practices, such as staying home or masking when acutely illFunding support in the form of wages for Dr. Gaston De Serres was provided foremost by the Quebec Public Health Institute (Institut national de sante´ publique du Que´bec), Que´bec, Canada and in part by the Ontario Nurses’ Associatio

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

Randomized Controlled Ferret Study to Assess the Direct Impact of 2008–09 Trivalent Inactivated Influenza Vaccine on A(H1N1)pdm09 Disease Risk

During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008–09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008–09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian-manufactured, commercially-available, non-adjuvanted, split 2008–09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naïve animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p&gt;0.05). At Ch+14, both groups had recovered. Findings in influenza-naïve, systematically-infected ferrets may not replicate the human experience. While they cannot be considered conclusive to explain human observations, these ferret findings are consistent with direct, adverse effect of prior 2008–09 TIV receipt on A(H1N1)pdm09 illness. As such, they warrant further in-depth investigation and search for possible mechanistic explanations

School Absenteeism As an Adjunct Surveillance Indicator: Experience during the Second Wave of the 2009 H1N1 Pandemic in Quebec, Canada

A school absenteeism surveillance system was implemented in the province of Quebec, Canada during the second wave of the 2009 H1N1 pandemic. This paper compares this surveillance approach with other available indicators.All (3432) elementary and high schools from Quebec were included. Each school was required to report through a web-based system any day where the proportion of students absent for influenza-like illness (ILI) exceeded 10% of current school enrolment.Between October 18 and December 12 2009, 35.6% of all schools met the 10% absenteeism threshold. This proportion was greater in elementary compared to high schools (40% vs 19%) and in smaller compared to larger schools (44% vs 22%). The maximum absenteeism rate was reached the first day of reporting or within the next two days in 55% and 31% of schools respectively. The first reports and subsequent peak in school absenteeism provincially preceded the peak in paediatric hospitalization by two and one weeks, respectively. Trends in school surveillance otherwise mirrored other indicators.During a pandemic, school outbreak surveillance based on a 10% threshold appears insufficient to trigger timely intervention within a given affected school. However, school surveillance appears well-correlated and slightly anticipatory compared to other population indicators. As such, school absenteeism warrants further evaluation as an adjunct surveillance indicator whose overall utility will depend upon specified objectives, and other existing capacity for monitoring and response

Randomized controlled ferret study to assess the direct impact of 2008-09 trivalent inactivated influenza vaccine on A(H1N1)pdm09 disease risk

During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008-09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008-09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian-manufactured, commercially-available, non-adjuvanted, split 2008-09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naïve animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+ 5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p.0.05). At Ch+14, both groups had recovered. Findings in influenza-naïve, systematically-infected ferrets may not replicate the human experience. While they cannot be considered conclusive to explain human observations, these ferret findings are consistent with direct, adverse effect of prior 2008-09 TIV receipt on A(H1N1)pdm09 illness. As such, they warrant further in-depth investigation and search for possible mechanistic explanations

Cross-Lineage Influenza B and Heterologous Influenza A Antibody Responses in Vaccinated Mice: Immunologic Interactions and B/Yamagata Dominance

The annually reformulated trivalent inactivated influenza vaccine (TIV) includes both influenza A/subtypes (H3N2 and H1N1) but only one of two influenza B/lineages (Yamagata or Victoria). In a recent series of clinical trials to evaluate prime-boost response across influenza B/lineages, influenza-naïve infants and toddlers originally primed with two doses of 2008–09 B/Yamagata-containing TIV were assessed after two doses of B/Victoria-containing TIV administered in the subsequent 2009–10 and 2010–11 seasons. In these children, the Victoria-containing vaccines strongly recalled antibody to the initiating B/Yamagata antigen but induced only low B/Victoria antibody responses. To further evaluate this unexpected pattern of cross-lineage vaccine responses, we conducted additional immunogenicity assessment in mice. In the current study, mice were primed with two doses of 2008–09 Yamagata-containing TIV and subsequently boosted with two doses of 2010–11 Victoria-containing TIV (Group-Yam/Vic). With the same vaccines, we also assessed the reverse order of two-dose Victoria followed by two-dose Yamagata immunization (Group-Vic/Yam). The Group-Yam/Vic mice showed strong homologous responses to Yamagata antigen. However, as previously reported in children, subsequent doses of Victoria antigen substantially boosted Yamagata but induced only low antibody response to the immunizing Victoria component. The reverse order of Group-Vic/Yam mice also showed low homologous responses to Victoria but subsequent heterologous immunization with even a single dose of Yamagata antigen induced substantial boost response to both lineages. For influenza A/H3N2, homologous responses were comparably robust for the differing TIV variants and even a single follow-up dose of the heterologous strain, regardless of vaccine sequence, substantially boosted antibody to both strains. For H1N1, two doses of 2008–09 seasonal antigen significantly blunted response to two doses of the 2010–11 pandemic H1N1 antigen. Immunologic interactions between influenza viruses considered antigenically distant and in particular the cross-lineage influenza B and dominant Yamagata boost responses we have observed in both human and animal studies warrant further evaluation