Are Higher Neuraminidase Antibody Concentrations Associated With Decreased Disease Severity in Individuals With Influenza?

Influenza virus. Computer illustration showing the surface glycoprotein spikes hemagglutinin (violet) and neuraminidase (green).
Immunity against neuraminidase is important to consider in development of therapeutics and influenza vaccines with improved efficacy and protection.

Higher mean neuraminidase antibody concentrations were predictive of decreased disease severity and better outcomes among individuals with influenza virus infection, according to results of an influenza challenge study published in The Journal of Infectious Diseases. The investigators also found that women with influenza were more likely to be symptomatic and have a greater number of symptoms compared with men.

 A team of investigators synthesized data from 4 previous influenza challenge studies performed by their group: H1N1 pdMIST, HAI pdMIST, FLU-V, and CR6261. Their goal was “to characterize differences between [men] and [women] and explore the underlying factors contributing to these differences.” The analysis included only participants who had received a challenge virus dose of 107TCID50. Data on participants’ clinical outcomes and baseline characteristics were collected and differences between the men and women were compared. Baseline characteristics included reproductive hormone concentrations; titers for hemagglutination-inhibition (HAI) antibodies; and titers for neuraminidase-inhibition (NAI) antibodies, which are known to be protective against influenza by decreasing symptoms and disease severity. The investigators employed linear and logistic regression models to identify variables that were significantly predictive for the outcomes of interest.

Of the 4 studies included in the analysis, there were 164 healthy participants, 91 of whom were men. The mean age for all participants was approximately 29 years. At baseline, participants’ testosterone concentrations were higher among men (P <.001) and estradiol concentrations were higher among women (P <.001). Preliminary analysis showed that mean HAI and NAI titers were similar between men and women.

Of note, mean NAI titers were higher in men at both week 4 (P =.046) and week 8 of the study (P =.039) compared with women. Post hoc analysis showed that mean HAI titers were similar between men and women.

Men were 16% less likely to have influenza symptoms than women (mean, 0.96 vs 0.80; P =.003) and women were more likely to have a greater number of symptoms (median, 3 vs 4; P =.011) than men. The likelihood of viral shedding was similar between men and women.

Linear and logistic regression models showed that participants’ age, sex, and preliminary measurements of NAI titers — but not HAI titers or reproductive hormones—, were predictive of all shedding and symptom outcomes of interest, with statistical significance in regard to presence of symptoms (P =.042), occurrence of shedding (P <.001), duration of symptoms (P =.001), duration of shedding (P <.001), number of symptoms (P <.001), and mild to moderate influenza severity (P <.001).

Study limitations included that 2 of the studies specifically recruited only participants with low HAI titers; confounding due to differences in inclusion/exclusion criteria and unequal proportions of men vs women in each cohort; and the use of a single reproductive hormone measurement rather than serial measurements.

The investigators concluded that their findings “further [support] recent efforts drawing attention to the importance of immunity against [neuraminidase] to develop novel therapeutics and vaccines with improved efficacy and breadth of protection.”


Giurgea LT, Cervantes-Medina A, Walters K-A, et al. Sex differences in influenza: The challenge study experience. J Infect Dis. Published online Aug 23, 2021. doi:10.1093/infdis/jiab422