Heterogeneous Sex Differences in the Immunogenicity, Effectiveness of Influenza Vaccine

Woman receiving flu shot
Woman receiving flu shot
Evidence of higher quality is needed to better understand sex differences in response to influenza vaccine.

Although women tend to experience more adverse events following seasonal influenza immunization than men, no clear conclusions can be drawn based on sex differences, according to a study published in Vaccine

To investigate sex differences in the immunogenicity after receipt of the seasonal influenza vaccine, researchers conducted a systematic review of studies that evaluated exposure to the vaccine and any other intervention (vaccine, placebo, or no intervention). Additionally, researchers reviewed each study to investigate immune response, efficacy, effectiveness, and/or safety. Standard procedures for systematic reviews were performed, including the review of literature in 5 electronic databases (PubMed, EMBASE, CINAHL, Web of Science, and ClinicalTrials.gov), establishment of keywords and their derivatives, as well as a standardized screening and selection process. 

Studies included in the systematic review were published between January 1, 1990, and June 1, 2018. The study researchers excluded “studies on the H5N1 and pandemic 2009 H1N1 vaccines as well as those conducted during 2009 to 2010.” The primary end point of the systematic review was immune response in participants.

Study researchers retrieved 5745 unique articles on the seasonal influenza vaccine; 46 were eligible for the systematic review. Eighteen of the studies evaluated immunogenicity (1 measured immunogenicity and efficacy, and 3 evaluated immune response and safety), 22 investigated safety, and 6 were conducted to estimate effectiveness. Four of the included studies reported on sex-stratified outcomes.

In adults, healthy young adults, and older adults, several of the studies showed significantly higher immune responses from women compared with men; however a greater immune response from men was observed in 2 studies. Regarding safety, the study researchers observed that women more commonly experienced local adverse reactions, headaches, and fatigue following vaccination. One study in the systematic review reported on efficacy; the study showed a significantly higher average influenza efficacy in healthy young men than women (P =.0123). The studies that illustrated effectiveness were of lower quality and did not allow pooled estimates. 

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As a result of low quality data and heterogeneity, the study results could not be pooled into a meta-analysis. Several additional limitations included the use of a small total number of studies, neglecting to investigate cellular responses to the seasonal influenza vaccine, and a high risk for bias observed in many of the studies reviewed.

The study researchers concluded that although the “influenza vaccination seems to be associated with more [adverse events following immunization] in [women] compared to [men], the available evidence on sex differences in the immunogenicity and effectiveness of seasonal influenza vaccine in adults is heterogeneous.” They further noted that more research on phase III randomized controlled trials that allowed for “an individual patient data meta-analysis…would help better assess and understand sex difference in response to influenza vaccines.”


Tadount F, Doyon-Plourde P, Rafferty E, MacDonald S, Sadarangani M, Quach C. Is there a difference in the immune response, efficacy, effectiveness and safety of seasonal influenza vaccine in males and females? – A systematic review [published online November 9, 2019]. Vaccine. doi: 10.1016/j.vaccine.2019.10.091