Observations placeholder

Increased Risk of Noninfluenza Respiratory Virus Infections Associated With Receipt of Inactivated Influenza Vaccine
Benjamin J. Cowling, Vicky J. Fang, Hiroshi Nishiura, Kwok-Hung Chan, Sophia Ng, Dennis K. M. Ip, Susan S. Chiu, Gabriel M. Leung, J. S. Malik Peiris
Clinical Infectious Diseases, Volume 54, Issue 12, 15 June 2012, Pages 1778–1783, https://doi.org/10.1093/cid/cis307
Published:
15 March 2012

We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses.

Influenza vaccination is effective in preventing influenza virus infection and associated morbidity among school-aged children [1, 2]. The potential for temporary nonspecific immunity between respiratory viruses after an infection and consequent interference at the population level between epidemics of these viruses has been hypothesized, with limited empirical evidence to date, mainly from ecological studies [3–15]. We investigated the incidence of acute upper respiratory tract infections (URTIs) associated with virologically confirmed respiratory virus infections in a randomized controlled trial of influenza vaccination.

...........................................

DISCUSSION
In the prepandemic period of our study, we did not observe a statistically significant reduction in confirmed seasonal influenza virus infections in the TIV recipients (Table 3), although serological evidence (Supplementary Appendix) and point estimates of vaccine efficacy based on confirmed infections were consistent with protection of TIV recipients against the seasonal influenza viruses that circulated from January through March 2009 [16]. We identified a statistically significant increased risk of noninfluenza respiratory virus infection among TIV recipients (Table 3), including significant increases in the risk of rhinovirus and coxsackie/echovirus infection, which were most frequently detected in March 2009, immediately after the peak in seasonal influenza activity in February 2009 (Figure 1).

The increased risk of noninfluenza respiratory virus infection among TIV recipients could be an artefactual finding; for example, measurement bias could have resulted if participants were more likely to report their first ARI episode but less likely to report subsequent episodes, whereas there was no real difference in rhinovirus or other noninfluenza respiratory virus infections after the winter influenza season. The increased risk could also indicate a real effect. Receipt of TIV could increase influenza immunity at the expense of reduced immunity to noninfluenza respiratory viruses, by some unknown biological mechanism. Alternatively, our results could be explained by temporary nonspecific immunity after influenza virus infection, through the cell-mediated response or, more likely, the innate immune response to infection [21–23]. Participants who received TIV would have been protected against influenza in February 2009 but then would not have had heightened nonspecific immunity in the following weeks. They would then face a higher risk of certain other virus infections in March 2009, compared with placebo recipients (Figure 1). The duration of any temporary nonspecific immunity remains uncertain [13] but could be of the order of 2–4 weeks based on these observations. It is less likely that the interference observed here could be explained by reduced community exposures during convalescence (ie, behavioral rather than immunologic factors) [14].

The phenomenon of virus interference has been well known in virology for >60 years [24–27]. Ecological studies have reported phenomena potentially explained by viral interference [3–11]. Nonspecific immunity against noninfluenza respiratory viruses was reported in children for 1–2 weeks after receipt of live attenuated influenza vaccine [28]. Interference in respiratory and gastrointestinal infections has been reported after receipt of live oral poliovirus vaccine [29–32].

Our results are limited by the small sample size and the small number of confirmed infections. Despite this limitation, we were able to observe a statistically significant increased risk of confirmed noninfluenza respiratory virus infection among TIV recipients (Table 3). A negative association between serologic evidence of influenza infection and confirmed noninfluenza virus infection in winter 2009 was not statistically significant (odds ratio, 0.27; 95% CI, .01–2.05) (Supplementary Appendix). One must be cautious in interpreting serology in children who have received TIV [2, 33]. Finally, acute URTI incidence was based on self-report with regular telephone reminders, and we may have failed to identify some illnesses despite rigorous prospective follow-up.

Temporary nonspecific immunity leading to interference between epidemics of respiratory viruses could have important implications. First, as observed in our trial, TIV appeared to have poor efficacy against acute URTIs (Table 2), apparently because the protection against influenza virus infection conferred by TIV was offset by an increased risk of other respiratory virus infection (Table 3). Second, interference between respiratory viruses could suggest new approaches to mitigating epidemics [32]. Mass administration of live polio vaccine in children has been used to control enterovirus 71 epidemics [10, 31]. Finally, viral interference could bias estimates of influenza vaccine effectiveness in test-negative case-control studies (Supplementary Appendix) [2, 34–43]. One test-negative study reported an association between receipt of TIV and the risk of influenza-like illness associated with a noninfluenza virus [38].

Additional work is required to more fully characterize temporary nonspecific immunity overall and in specific groups, such as children. Animal studies [44–50] and volunteer adult human challenge studies [51] could provide useful evidence. Additional community-based observational cohort studies and community-based experimental studies, such as our vaccine trial, may be particularly suitable for investigating temporary nonspecific immunity, because most acute URTIs do not require medical attention