Elsevier

Vaccine

Volume 39, Issue 28, 23 June 2021, Pages 3678-3695
Vaccine

Review
Does influenza vaccination attenuate the severity of breakthrough infections? A narrative review and recommendations for further research

https://doi.org/10.1016/j.vaccine.2021.05.011Get rights and content

Abstract

The effect of influenza vaccination on influenza severity remains uncertain. We reviewed the literature for evidence to inform the question of whether influenza illness is less severe among individuals who received influenza vaccination compared with individuals with influenza illness who were unvaccinated prior to their illnesses. We conducted a narrative review to identify published findings comparing severity of influenza outcomes by vaccination status among community-dwelling adults and children ≥ 6 months of age with laboratory-confirmed influenza illness. When at least four effect estimates of the same type (e.g., odds ratio) were available for a specific outcome and age category (children versus adults), data were pooled with meta-analysis to generate a summary effect estimate. We identified 38 published articles reporting ≥ 1 association between influenza vaccination status and one of 21 indicators of severity of influenza illness among individuals with laboratory-confirmed influenza. Study methodologies and effect estimates were highly heterogenous, with only five severity indicators meeting criteria for calculating a combined effect. Among eight studies, influenza vaccination was associated with 26% reduction in odds of ICU admission among adults with influenza-associated hospitalization (OR = 0.74, 95% CI 0.58, 0.93). Among five studies of adults with influenza-associated hospitalization, vaccinated patients had 31% reduced risk of death compared with unvaccinated patients (OR = 0.69, 95% CI 0.52, 0.92). Among four studies of children with influenza virus infection, vaccination was associated with an estimated 45% reduction in the odds of manifesting fever (OR = 0.55, 95% CI 0.42, 0.71). Vaccination was not significantly associated with receiving a clinical diagnosis of pneumonia among adults hospitalized with influenza (OR = 0.92, 95% CI 0.82, 1.04) or with risk of hospitalization following outpatient influenza illness among adults (OR = 0.60, 95% CI 0.28, 1.28). Overall, our findings support the hypothesis that influenza vaccination may attenuate the course of disease among individuals with breakthrough influenza virus infection.

Introduction

The possibility that influenza vaccines can attenuate the severity of influenza disease among those who become infected despite vaccination has been an intermittent topic of research and debate for decades [1]. Multiple animal and human virus challenge studies have demonstrated that influenza vaccines can reduce the signs and duration of influenza disease among those infected despite vaccination [e.g., [2], [3], [4], [5], [6], [7], but extrapolation from these studies is limited due to small sample sizes, use of challenge viruses that do not elicit severe disease, and lack of comparability between naïve animal models and the complex influenza exposure histories typical of people. Although attenuation of disease severity among vaccinees has been widely reported anecdotally, it has not been systematically or routinely evaluated. A major challenge lies in the heterogeneous and imprecise measurement of what constitutes severe influenza illness, with many indicators of disease severity based on types and levels of medical care rather than physiologic markers of disease severity. To our knowledge, there has been no review of published findings that report the frequency of influenza disease outcomes (e.g., hospital admission, ICU admission) among those who were vaccinated compared with those who were unvaccinated prior to their illnesses, leaving under-examined this potential protective benefit of vaccination.

We reviewed the literature for evidence to inform the question of whether influenza illness is less severe among individuals who received influenza vaccination compared with individuals with influenza illness who were unvaccinated prior to their illnesses. The primary objectives of the review are to (1) identify published articles that compare the occurrence of severe outcomes among influenza vaccinated versus unvaccinated individuals who have laboratory-confirmed influenza illness; (2) describe the features of these studies; (3) describe and summarize the findings of these studies and, if possible, calculate pooled estimate(s) for outcomes from studies with similar methodologies; (4) recommend methodological improvements that can be made to improve the ability to assess these proposed benefits of influenza vaccination.

Section snippets

Methods

We conducted a literature review to identify published findings comparing severity of influenza outcomes by vaccination status among individuals with laboratory-confirmed influenza virus infection. We began with a systematic review of the literature using key terms intended to identify reports of interest. We supplemented the systematic review with manual reviews of the literature based on consultation with colleagues and subject matter experts and with review of citations within the identified

Results

We identified 38 published articles reporting ≥ 1 association between influenza vaccination status and an indicator of the severity of influenza illness among individuals with laboratory-confirmed influenza [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46]. The systematic literature review, summarized in Supplemental Fig.

Discussion

In our narrative review of 38 publications that examined the association between influenza vaccination and the severity of laboratory-confirmed influenza disease, we identified multiple findings consistent with the argument that vaccination attenuates disease severity. Among five indicators of influenza disease severity that met criteria for calculating a combined effect, we found significantly reduced risk of three outcomes among vaccinated compared with unvaccinated individuals: Among eight

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Ferdinands reports non-financial support from Institute for Influenza Epidemiology (funded in part by Sanofi Pasteur), outside the submitted work. All other authors report no conflicts.].

Acknowledgments

The authors thank Palak Patel and Julie Mayo Lamberte for contributing to the review of articles. We also thank Manish Patel for feedback on an earlier draft of this manuscript.

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    1

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