۱- Introduction

۲- Materials and methods

۳- Results

۴- Discussion

References

Abstract

Almost a third of Irish children are now overweight and the country ranks 58th out of 200 countries for its proportion of overweight youths. With the rising obesity epidemic, and the impaired immune responses of this population, it is vital to understand the effects that obesity has on the immune system and to design future therapeutics, adjuvants and vaccines with overweight and obese populations in mind. Many current vaccines use adjuvants that have been found to be less effective at stimulating the immune response in children compared with adults and there is now substantial effort to design paediatric-focused adjuvants. Additionally, vaccine responses have been shown to be less effective in obese populations indicating that this is a particularly vulnerable population. We have recently identified cytosolic nucleic acids (CNAs), as novel candidate adjuvants for childhood vaccines. Here we investigated whether immune responses to these candidate adjuvants were adversely affected in infants born to overweight or obese mothers, and in overweight and obese children. Type I Interferon (IFN) and proinflammatory cytokines such as Tumor Necrosis Factor α (TNFα) are vital for driving innate and adaptive immune responses. We found that childhood obesity conferred no significant adverse effect on CNA-induced Type I IFN responses when compared with lean children. Similarly, Type I IFN responses were intact in the cord blood of babies delivered from overweight and obese mothers, when compared with lean mothers. There was also no significant impact of obesity on CNA-induced TNFα responses in children or from cord blood of infants born to overweight/obese mothers. In all cases, there was a tendency towards decreased production of innate cytokine Type I Interferon and TNFα, however there was no significant negative correlation. Interestingly, high maternal BMI showed weak and moderate positive correlation with IL-12p70 and IFNγ, respectively, in response to CNA stimulation. This study demonstrates that future adjuvants can be tailored for these populations through the use of activators of CNA sensors.

Introduction

Obesity has become a global epidemic over a period of only two decades. It now represents an urgent medical and a major societal challenge for which the solution certainly requires a multidisciplinary approach. Obese individuals are at higher risk of a wide range of infections including postoperative infections and other nosocomial infections, and also of developing serious complications resulting from common infections [1]. Obese individuals have been shown to be at increased risk of infection from certain vaccine-preventable diseases, such as tetanus, hepatitis B and influenza, due to poorer responses to vaccines in these individuals [2–۴]. Although there is limited data concerning the effect of obesity on vaccine efficacy in neonates born to obese mothers, limited data from overweight and obese children suggest that responses to vaccinations are impaired in these groups [2,5]. Data from obese adults would also suggest that obesity increases the chances of a poor vaccine-induced immune response [3,4,6,7]. One study investigating the effect of increased body mass index (BMI) on vaccination responses showed that overweight children had reduced tetanus titers following vaccination when compared to lean children [2]. Another study in adults receiving Hepatitis B vaccination showed that obese adults have limited protection against the disease compared to lean adults [3]. Influenza vaccine responses are also affected by obesity, with increased risk of influenza among vaccinated adults who are obese [4]. Interestingly, initial antibody production is intact in obese individuals, however at later sampling, 12 months post vaccination, these antibody titers decreased below healthy weight individuals [7]. CD4+ and CD8+ T cell responses ex vivo were also decreased in obesity [7,8]. Obesity in adults is defined as a BMI ≥ ۳۰ kg/m [6], while for children it is more appropriate to use a BMI z-score. BMI zscores are measures of relative weight adjusted for child age and sex [5].