Assessment of Virus Interference in a Test-negative Study of Influenza Vaccine Effectiveness

Abstract

Background The observational test-negative study design is used to estimate vaccine effectiveness against influenza virus infection. An important assumption of the test-negative design is that vaccination does not affect the risk of infection with another virus. If such virus interference occurred, detection of other respiratory viruses would be more common among influenza vaccine recipients and vaccine effectiveness estimates could differ. We evaluated the potential for virus interference using data from the Influenza Incidence Surveillance Project. Methods From 2010 to 2013, outpatients presenting to clinics in 13 US jurisdictions with acute respiratory infections were tested for influenza and other respiratory viruses. We investigated whether virus interference might affect vaccine effectiveness estimates by first evaluating the sensitivity of estimates using alternative control groups that include or exclude patients with other respiratory virus detections by age group and early/middle/late stage of influenza seasons. Second, we evaluated the association between influenza vaccination receipt and other respiratory virus detection among influenza test negative patients. Results Influenza was detected in 3,743/10,650 patients (35%), and overall vaccine effectiveness was 47% (95% CI: 42%, 52%). Estimates using each control group were consistent overall or when stratified by age groups, and there were no differences among early, middle, or late phase during influenza season. We found no associations between detection of other respiratory viruses and receipt of influenza vaccination. Conclusions In this 3-year test-negative design study in an outpatient setting in the United States, we found no evidence of virus interference or impact on influenza vaccine effectiveness estimation.

Influenza vaccination and respiratory virus interference among Department of Defense personnel during the 2017–2018 influenza season

“…Virus interference associated with influenza vaccination has been previously investigated [7][8][9][10][11][12]. However, this study was the first virus interference study conducted among highly vaccinated DoD personnel.…”

“…While influenza vaccination offers protection against influenza, natural influenza infection may reduce the risk of non-influenza respiratory viruses by providing temporary, non-specific immunity against these viruses [7,8]. On the other hand, recently published studies have described the phenomenon of vaccine-associated virus interference; that is, vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection [7][8][9][10]. There has been limited evidence that the influenza vaccine may actually be associated with the virus interference process [8,11].…”

Estimating Influenza Vaccine Effectiveness With the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis

“…The studies covered the 2003/2004 to 2013/2014 influenza seasons and 7 countries, including Australia (4 studies ( 24 , 27 , 28 , 31 )), the United States (3 studies ( 26 , 32 , 34 )), Japan (1 study ( 33 )), China (Hong Kong; 1 study ( 25 )), Portugal (1 study ( 29 )), New Zealand (1 study ( 30 )), and the Netherlands (1 study ( 35 )) (Table 1 ). Five studies reported estimates for a single year ( 27 , 29 – 31 , 33 ), while others reported estimates across multiple years ( 24 – 26 , 28 , 32 , 34 , 35 ). Among 7 studies reporting pooled estimates across more than 1 year/season, 3 studies also provided season-specific estimates ( 28 , 34 , 35 ).…”

“…Five studies reported estimates for a single year ( 27 , 29 – 31 , 33 ), while others reported estimates across multiple years ( 24 – 26 , 28 , 32 , 34 , 35 ). Among 7 studies reporting pooled estimates across more than 1 year/season, 3 studies also provided season-specific estimates ( 28 , 34 , 35 ).…”

“…Patients of all ages were investigated in 7 studies ( 26 , 28 – 31 , 34 , 35 ), children in 4 studies ( 24 , 25 , 27 , 32 ), and children, adults, and elderly persons in 2 studies ( 30 , 34 ). Eight studies were carried out exclusively in outpatient settings ( 24 , 27 – 29 , 31 , 33 – 35 ), including 1 in an ED ( 24 ); 2 were carried out in inpatient settings ( 25 , 26 ); 1 used both inpatients and outpatients, with estimates broken down by setting ( 30 ); and 1 recruited outpatients (including ED patients), urgent-care patients, and acute-care patients ( 32 ).…”