The observed intra-seasonal decreases of measured influenza vaccine effectiveness was only partially accounted for by leaky vaccine bias, according to data published in Clinical Infectious Diseases. Therefore, further strategies are needed to deal with declines in intra-seasonal vaccine effectiveness.

To determine if vaccine effectiveness is stable and if vaccines provide partial protection in all recipients rather than complete protection in a subset of vaccinees, termed a leaky vaccine effect, investigators simulated the 4 influenza seasons between 2011 and 2015, and estimated the potential contribution of leaky vaccine effect to the observed declines in measured influenza vaccine effectiveness.

Investigators estimated daily numbers of vaccinations for and infections with A/H1N1, A/H3N2 and B viruses from the simulated data. The vaccine effect was assumed to be leaky and measured influenza vaccine effectiveness calculated as 1 minus the Mantel-Haenszel relative risk of vaccine on incident cases. The mean measured influenza vaccine effectiveness change per 30 days from vaccination was then determined. As measured influenza vaccine effectiveness was highly dependent on infection rate simulations using low and high infection rates, determined as 15% and 31% total seasonal infection rates including symptomatic and asymptomatic cases, respectively, were performed.

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Among parameters affecting declines in measured influenza vaccine effectiveness, total (symptomatic and asymptomatic) infection rate had the greatest effect.  With the assumption of a 25% rate of symptomatic cases, researchers established a pooled 31% rate of totally infections across all seasons and age groups. On the basis of these season/age-group categories, the change in vaccine effectiveness per 30 days since vaccination varied from -8.6% to -0.3% for A/H1N1 viruses, -12.6% to -0.5% for A/H3N2 viruses, and -7.2% to -0.4% for B viruses.

Researchers also evaluated the effects of total infection rates between 15% and 31%: for the leaky mechanism with no reinfections for A/H1N1 viruses, the measure vaccine effectiveness change was -4.6% for the higher rate compared with -1.7% for the lower rate. In a third determination, the investigators evaluated the percentage of measured influenza vaccine effectiveness that may be accounted for by leaky or variable vaccine mechanisms compared with changes observed in a previous study. In terms of the leaky mechanism without reinfections and a total infection rate of 31%, simulated measure vaccine effectiveness change was 48% of the observed change for A/H1N1, 53 for A/H3, and 42% for B viruses.

This study’s primary limitation was the uncertainty in input values, especially the percentage of asymptomatic cases and therefore total infection rate. But investigators also noted a limitation in the estimated numbers of symptomatic cases and vaccinations. Investigators reported that varied input values along a range of possibilities results in, “widely varying estimates of the potential contribution of the leaky vaccine effect.” However, the aim of the work was not to test statistical significance, but rather to determine how the magnitude of observed vaccine effectiveness compares with expectations if the vaccine were leaky.

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Several assumptions for the simulations that might not reflect reality were also noted, including the assumption that all individuals were susceptible at the onset of flu season and that the vaccine works by reducing infections. In fact, many persons will have pre-existing immunity and vaccinations can work by reducing illness severity. Investigators also did not consider mixed vaccine effects or possible antigenic drift during the season.

The results of the simulations suggested that a leaky vaccine mechanism is only likely to account for some of the observed declines in measured influenza vaccine effectiveness. The investigators recommended production of vaccines with higher vaccine effectiveness or more durable protection, as well as changes in timing of vaccine administration as possible strategies to improve late-season protection.


Tokars JI, Patel MM, Foppa IM, Reed C, Fry AM, Ferdinands JM. Waning of measured influenza vaccine effectiveness over time: the potential contribution of leaky vaccine effect [published online March 28 2020]. Clin Infect Dis. doi:10.1093/cid/ciaa340