Influenza Vaccine Effectiveness in Preventing Influenza A(H3N2)-Related Hospitalizations in Adults Targeted for Vaccination by Type of Vaccine: A Hospital-Based Test-Negative Study, 2011–2012 A(H3N2) Predominant Influenza Season, Valencia, Spain

<div><p>Background</p><p>Most evidence of the effectiveness of influenza vaccines comes from studies conducted in primary care, but less is known about their effectiveness in preventing serious complications. Here, we examined the influenza vaccine effectiveness (IVE) against hospitalization with PCR-confirmed influenza in the predominant A(H3N2) 2011–2012 influenza season.</p><p>Methods</p><p>A hospital-based, test-negative study was conducted in nine hospitals in Valencia, Spain. All emergency admissions with a predefined subset of symptoms were eligible. We enrolled consenting adults age 18 and over, targeted for influenza vaccination because of comorbidity, with symptoms of influenza-like-illness within seven days of admission. We estimated IVE as (1-adjusted vaccination odds ratio)*100 after accounting for major confounders, calendar time and recruitment hospital.</p><p>Results</p><p>The subjects included 544 positive for influenza A(H3N2) and 1,370 negative for influenza admissions. Age was an IVE modifying factor. Regardless of vaccine administration, IVE was 72% (38 to 88%) in subjects aged under 65 and 21% (−5% to 40%) in subjects aged 65 and over. By type of vaccine, the IVE of classical intramuscular split-influenza vaccine, used in subjects 18 to 64, was 68% (12% to 88%). The IVE for intradermal and virosomal influenza vaccines, used in subjects aged 65 and over, was 39% (11% to 58%) and 16% (−39% to 49%), respectively.</p><p>Conclusions</p><p>The split-influenza vaccine was effective in preventing influenza-associated hospitalizations in adults aged under 65. The intradermal vaccine was moderately effective in those aged 65 and over.</p></div

Sensitivity analysis of adjusted influenza vaccine effectiveness.

<p>Adjusted influenza vaccine effectiveness (IVE) assessed for all ages, <65 and> = 65, and by: a) vaccination ascertainment method: Vaccine Information System (VIS), as reported by the patient (recall) and both combined; b) days to swab: seven or less, four or less. Reference category for all analyses includes all patients irrespective of time elapsed to swab and vaccination according to VIS or recall. OR: adjusted odds ratio. OR adjusted as reported in footnotes in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0112294#pone-0112294-t006" target="_blank">Table 6</a>.</p

Flow diagram of study subjects.

<p>Flow diagram of study subjects.</p

Main complaint at admission, influenza-like-illness symptoms within seven days to admission and clinical outcomes in influenza positive compared to influenza negative admissions

<p>CI Confidence Interval. LR Likelihood ratio. SD (standard deviation).</p><p>SIRS: Systemic inflammatory response syndrome.</p><p>Metabolic failure: hyperglycemic or hypoglycemic commas, acute renal failure, and disorders of fluid, electrolyte and acid-base balance.</p><p>Main complaint at admission, influenza-like-illness symptoms within seven days to admission and clinical outcomes in influenza positive compared to influenza negative admissions</p

Influenza vaccines recorded as administered by type of vaccine, age group, and PCR result.

<p>PCR real-time reverse transcription-polymerase chain reaction.</p>a.<p>Recorded vaccinations in the Vaccine Information System only (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0112294#pone-0112294-t004" target="_blank">Table 4</a> for the percentage of patients included in the Vaccine Information System). The percentages reported over all participants included in the Vaccine Information System and with any vaccination ever recorded in the Vaccine Information System.</p>b.<p>Encompassing epidemiological weeks 52 to 12, with influenza related admissions identified in> = 65 years subjects. This was the age group targeted to receive this type of vaccine.</p>c.<p>Encompassing epidemiological weeks 4 to 10, with influenza related admissions identified in <65 years old subjects. This was the age group targeted to receive this type of vaccine.</p><p>Influenza vaccines recorded as administered by type of vaccine, age group, and PCR result.</p

Influenza vaccine effectiveness in preventing admissions related to H3N2 influenza.

<p>Positives admissions with influenza confirmed influenza by real time reverse transcription polymerase chain reaction (rtRT-PCR). Negatives admissions with a negative rtRT-PCR result for influenza. IVE influenza vaccine effectiveness. CI Confidence Interval.</p><p>a Strong evidence (<i>P</i><0.002) of between hospital and between epidemiological week variability. Hospital and epidemiological week included as random effect parameters in the multilevel analysis to estimate influenza vaccine effectiveness adjusted by age (deciles), sex, number of outpatient consultations in the last three months, and previous administration of plain 23 polysaccharide pneumococcal vaccine.</p><p>b Moderate evidence of between hospital variability (<i>P</i> = 0.045) and of between epidemiological week variability (<i>P</i> = 0.015). Hospital and epidemiological week included as a random effect parameter in the multilevel analysis to estimate influenza vaccine effectiveness in this group, adjusted as in (a).</p><p>c Weak evidence of between hospital variability (<i>P</i>>0.05). Strong evidence (<i>P</i> = <0.001) of between epidemiological week variability. Epidemiological week included as a random effect parameter in the multilevel analysis to estimate split conventional influenza vaccine effectiveness in this age group, adjusted as in (a) with hospital included in the model as an indicator variable.</p><p>d Weak evidence of between hospital variability (<i>P</i> = 0.497). Strong evidence (<i>P</i> = <0.001) of between epidemiological week variability. Epidemiological week included as a random effect parameter in the multilevel analysis to estimate influenza vaccine effectiveness in this group, adjusted as in (a) with hospital included in the model as an indicator variable.</p><p>e Moderate evidence (<i>P</i> = 0.042) of between hospital variability and strong evidence (<i>P</i> = <0.001) of between epidemiological week variability. Hospital and epidemiological included as random effect parameters in a multilevel analysis to estimate influenza vaccine effectiveness adjusted as in (a).</p><p>Influenza vaccine effectiveness in preventing admissions related to H3N2 influenza.</p

Characteristics of study subjects according to PCR result.

<p>PCR real-time reverse transcription-polymerase chain reaction. CI Confidence Interval. LR Likelihood ratio.</p><p>Characteristics of study subjects according to PCR result.</p

Admissions by epidemiological week and laboratory result.

<p>Admissions by epidemiological week and laboratory result.</p

Vaccination according to PCR result.

<p>PCR real-time reverse transcription-polymerase chain reaction. CI Confidence Interval. LR Likelihood ratio.</p>a<p>Any vaccination ever recorded in the Vaccine Information System.</p>b.<p>A patient was considered immunized with the 2011–2012 influenza seasonal vaccine if the vaccine was recorded in the Vaccine Information System as administered more than 14 days before the date of the ILI onset or if the patients reported vaccination more than two weeks before symptoms onset.</p>c<p>Data from 1,086 (288 positive and 798 negative) patients vaccinated 15 or more days before onset of symptoms according to the information in the Vaccine Information System out of 1,169 classified as immunized because of information retrieved from the Vaccine Information System or by patient's recall of vaccination two weeks before symptoms onset.</p><p>Vaccination according to PCR result.</p