During the 2009 H1N1 influenza pandemic, obesity was recognized as an independent risk factor for increased influenza morbidity and mortality.7, 8, 9
Influenza vaccination is the single most effective method for reducing morbidity and mortality from influenza. Despite recognition that obesity is immunosuppressive,4
this is the first study to examine antibody and CD8+
T-cell responses to influenza vaccination in healthy weight, overweight and obese individuals.
Because obesity reduces antibody responses to hepatitis B vaccine in adults and to tetanus vaccine in children,4, 12, 13, 14
elevated antibody response to influenza vaccination in our obese study participants was unexpected. Our data show that obese individuals mount a vigorous initial antibody response to TIV. However, a vaccine is protective only if the antibody titer is maintained throughout the period when influenza virus is circulating in the population. To examine the level of antibody maintenance after vaccination, we measured antibody levels 12 months after vaccination. Increases in BMI were positively correlated to decreases in antibody titer. More than 50% of the obese participants had a
4-fold decrease in HAI titers to A/Brisbane/10 and B/Brisbane/60, and 47% had a
4-fold decrease in HAI titer to A/Brisbane/59 at 12 months compared with 1 month post vaccination. By comparison, <25% of healthy weight participants had a >4-fold decrease in HAI titer to A/Brisbane/59 and B/Brisbane/60. The objectives of our ongoing study include more precise definition of the kinetics of this differential decline in antibody titer as well as follow-up of participants to determine whether BMI influences the actual rates of laboratory-confirmed influenza in vaccinated individuals. In addition to stimulating production of influenza antigen-specific antibodies, influenza vaccination also functions to generate a CD8+
T-cell response. The importance of a robust CD8+
T-cell memory response has been appreciated, and there is great interest in developing influenza vaccines that can promote a heightened T-cell memory response. Our own work in a murine diet-induced obesity model demonstrated an impaired CD8+
T-cell memory response leading to increased morbidity and mortality from an influenza challenge.16
In addition, it has also been suggested that there is an obesity-associated decrease in naive T cells and T-cell diversity,21
which could contribute to the impaired CD8+
T-cell response seen in our study.
T cells do not protect against infection, but instead act to limit progression of disease, allow for more rapid viral clearance and lessen the severity of disease.22
Whereas the targets for antibodies are the proteins on the surface of the influenza virus, the targets for CD8+
T cells are located on the internal, highly conserved proteins of the virus, which allow for extensive cross reactivity against multiple strains of influenza virus. The influenza virus surface proteins have a tendency to change frequently; as such, an antibody-based vaccine may be protective for 1 year, but not the next.23
Because memory CD8+
T cells are specific to internal influenza proteins that vary little from year to year, it is likely more effective and efficient to develop influenza vaccines which expand memory CD8+
T-cell populations, in addition to invoking a robust antibody response.24
T-cell cytotoxic activity correlates better with influenza protection than antibody titer in an elderly population.25
We found that percentage of influenza-activated CD8+
T cells were decreased in the obese participants, and two markers of functional CD8+
activity, IFNγ and granzyme B, were also significantly decreased in the obese participants. CD8+
T cells kill virus-infected cells by release of perforin and granzyme B26
and inhibit viral replication by the release of IFNγ.27
The fact that influenza-stimulated CD8+
T cells from obese individuals were deficient in the expression of both of these proteins strongly suggests that protection from an influenza infection may be not be optimal in the obese population.
We report here, for the first time, that influenza vaccine antibody levels decline significantly and CD8+ T-cell responses are defective in obese compared with healthy weight individuals. These findings suggest a mechanism for the increased risk of severe disease from pH1N1 infection in the obese population. If antibody titers and influenza vaccination-induced memory CD8+ T-cell populations are not maintained over time by the obese individuals, they may be at risk for suboptimal vaccine response. Additional studies are needed to determine the risk of influenza infection in a vaccinated obese population.