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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Vaccine. Author manuscript; available in PMC 2016 Aug 26.
Published in final edited form as:
Vaccine. 2015 Aug 26; 33(36): 4422–4429.
Published online 2015 Jul 8. doi: 10.1016/j.vaccine.2015.06.101
PMCID: PMC4547886
NIHMSID: NIHMS707491
PMID: 26163925

The weight of obesity on the human immune response to vaccination

Scott D. Painter,a Inna G. Ovsyannikova,a and Gregory A. Polanda,*
Author information Copyright and License information Disclaimer

Abstract

Despite the high success of protection against several infectious diseases through effective vaccines, some sub-populations have been observed to respond poorly to vaccines, putting them at increased risk for vaccine-preventable diseases. In particular, the limited data concerning the effect of obesity on vaccine immunogenicity and efficacy suggests that obesity is a factor that increases the likelihood of a poor vaccine-induced immune response. Obesity occurs through the deposition of excess lipids into adipose tissue through the production of adipocytes, and is defined as a body-mass index (BMI) ≥ 30 kg/m2. The immune system is adversely affected by obesity, and these “immune consequences” raise concern for the lack of vaccine-induced immunity in the obese patient requiring discussion of how this sub-population might be better protected.

MeSH Keywords: Vaccination, Immunization, Obesity, Immunity, Communicable Diseases

1. Introduction

Vaccination has played a crucial role in decreasing global infectious diseases. After almost 220 years since the creation of the first vaccine by Edward Jenner, vaccination is still considered the most feasible and effective means of protection from multiple infectious diseases [1]. However, some individuals experience vaccine-preventable illnesses and complications even after vaccination. Despite highly effective vaccine surveillance and increased vaccine use in the population, hospitalizations and deaths from vaccine-preventable illnesses continue to occur, suggesting that current immunizations do not protect all vaccinated individuals.

The efficacy of a vaccine-induced immune response relies on the initiation and amplification of the immune response. Upon an immune system challenge, innate immune pathways provide a general response to infection (or vaccination) by recruiting effector cells that release cytokines to initiate an antigen-specific adaptive immune response. Simultaneously, proper adaptive immune responses require seroconversion, the process of responding to antigens in serum with antigen-specific antibodies. Vaccines contain components (antigens) of the pathogen that activate the host’s adaptive immune system to provide a rapid antigen-specific response during a subsequent infection. However, research has identified certain sub-populations that have a propensity for a diminished immune response to vaccinations. Failure to induce a protective immune response by vaccination places these groups at a higher risk for infection and vaccine-preventable complications that occur from natural exposure.

One important factor correlating with decreased vaccine-induced immune response is obesity, a condition caused by the uptake of lipids into adipocytes and the accumulation of excess adipose tissue within body fat stores and organs, such as the liver [2]. Obesity is a product of biological and environmental influences that leads to an increase of excess adipose tissue, which correlates with an increase in debilitating conditions associated with increased morbidity and mortality [2]. The pro-inflammatory hormone leptin, which has many immunologic functions, has been shown to correlate with body fat mass since it is produced and secreted from adipocytes [3]. Obesity may interfere with an obese individual’s ability to mount an effective immune response to vaccination or an infection due to increased body fat and the increased production of leptin [4]. Further, there is some evidence for the involvement of leptin and leptin-related gene polymorphisms in the serum leptin concentrations [3]. The body-mass index (BMI), also referred to as the Quetelet index, is an important proxy measurement for rapid identification of patients at a heightened risk for weight-related health complications [5], such as poor vaccine-induced immune response [6]. The BMI is used by the National Institutes of Health to classify an individual as underweight (BMI ≤ 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), obese (30.0–34.9 kg/m2), or severely obese (≥35 kg/m2) [7]. Currently, it is estimated that over a third of the U.S. population is obese, and since this trend is predicted to continue, the percentage of obese individuals in the U.S. will most likely increase [8–10]. Data also suggest that the global prevalence of overweight and obesity has significantly increased (28.8% to 36.9% in men, 29.8% to 38.0% in women) over the past three decades, and no country has had a significant decrease in obesity during this same time period [11]. These data indicate that vaccines may not provide this growing subpopulation the protection they require.

The correlation between obesity and poor vaccine-induced immune response was first observed in 1985 when obese hospital employees received the hepatitis B vaccine [12]. Twenty-five years later, clinical and laboratory data published on pandemic influenza A/pH1N1 indicated that the obese population was at an increased risk for influenza-like illnesses and complications [13]. Additionally, two studies observed a significant decline in tetanus [14] and rabies [15] vaccine-induced antibody protection in the obese, furthering the concern that underlying factors related to obesity limit vaccine response, leaving many individuals vulnerable to disease-related complications. The vaccine-induced immune response discrepancy between lean and obese individuals suggests that medical and other issues related to or caused by obesity could play a significant role in suboptimal vaccine-induced seroconversion in obese persons.

While poor vaccine-induced immune responses have been observed in the obese for hepatitis B, influenza A/pH1N1, tetanus and rabies vaccines, there is a lack of depth in the data to describe the burden obesity has on vaccine-induced immunity for other vaccines. If obese persons respond poorly to current vaccines, further efforts are required to ensure this population is protected. A review that collects and examines data for vaccine-induced immune response in obese populations is needed. The effect of obesity on immune responses has been previously described [16–18]; however, this review seeks to examine the data connecting obesity to poor vaccine-related adaptive immune responses. We searched the PubMed database to identify publications that provided data of the effect of obesity on vaccine-induced immune responses. Upon further review of the search results, we included human studies that provided data on prophylactic vaccines that generate virus-specific antibody titers to protect against a subsequent immune challenge in an overweight or obese cohort. We review previously published data (Table 1) on diminished hepatitis B, influenza A/pH1N1, tetanus and rabies vaccine-induced immune responses in obese persons, and we suggest more data are required to understand the mechanisms behind the immunologic aspects of obesity (e.g., the chronic inflammatory state) that could hinder effective vaccination outcomes.

Table 1

Publications with data for vaccine-induced immune responses in the obese

AuthorsYearAge of study subjectsTimepoint of antibody measurementCriteria of obese populationFindings related to lowered vaccine-induced responses
HBV
1Weber, et al.1985Adult hospital employees11 monthsBMI ≥ 32.88BMI correlates to poor seroconversion
2Weber, et a.1986Adult hospital employees17 monthsBMI ≥ 36.4The site of injection (deltoid v. buttock) is not a factor for seroprotection
3Roome, et al.1993Public safety personnel1–6 monthsBMI ≥ 35Severe obesity is a factor of inadequate Ab response
4Wood, et al.1993Adult hospital employees6 monthsBMI ≥ 29Increasing BMI is a factor for inadequate Ab response (Recombivax HB™)
5Simo, et al.1996Preadolescents1 monthBMI > 90th %BMI is the only factor with a significant correlation to decreased seroprotection (Engerix B™)
6Goldwater, et al.1997Healthy adults3 monthsN/AObesity did not hinder anti-HBs responses after a fifth booster dose of vaccination (Recombivax HB™)
7Averhoff, et al.1998Health care workers1 monthBMI > 95th %Obesity is an increased risk for non-protective vaccine-induced seroprotection
8Ingardia, et al.1999Pregnant women1, 6 monthsBMI ≥ 34Obese pregnant women are at increased risk for non-protective vaccine-induced anti-HBs levels
9ul-Haq, et al.2003Adolescents and adults1, 2 and 5 monthsBMI ≥ 29BMI is a significant factor for poor vaccine-induced antibody production (Heberbiovac HB™)
10Kulkarni, et al.2006Healthy adults1 monthBMI > 25Obesity was not a significant factor for poor seroprotection (GeneVac-B™)
11Chow, et al.2006End-stage renal disease patients1–3 monthsBMI 25.2 ± 3.2Increased BMI inversely correlated with antibody response (Engerix B™)
12Estevez, et al.2007Healthy adults30 daysBMI > 30Seroprotection decreased as BMI increased (Heberbiovac HB™)
13Middleman, et al.2010Adolescents64 days1in needle lengthAdolescents have improved seroconversion with longer (1.5in) needle
14Ozdemir, et al.2012Neonatal infants1 month5/8in. needle lengthMacrosomic neonates have improved seroconversion with longer (1in) needle
15Young, et al.2013Adult women33–66 daysMedian BMI 32.66Non-responders had significantly higher BMI than responders (Engerix B™)
HAV
1Reuman, et al.1997Healthy adults2, 4, 24, 28 weeks; 1 yearMean BMI 27.8 ± 7.8Decreased weight and lower BMI increased odds of seroconversion
2Van der Wielen, et al.2006Older adults23–40 daysNot reportedBMI had most significant influence on HAV response
3Lim, et al.2014Young adults11 monthsBMI ≥ 25Obesity did not significantly affect HAV seroconversion
IAV
1Talbot, et al.2012Older adults21–28 daysBMI ≥ 30Obesity had increase in seroconversion for A/Brisbane/10/2007 (H3N2) but not for other 2008–2009 S- TIV components
2Sheridan, et al.2012Adults1, 12 monthsMean BMI 35.4 ± 5.4BMI negatively correlated to fold increase 12 months post-immunization
3Sperling, et al.2012Pregnant and postpartum women4–8 weeksBMI ≥ 30Obese women had slightly lower odds of seroconversion
4Segerstrom, et al.2012Older and elderly adults2–4 weeksMean BMI 32Low BMI and low distress associated with higher antibody responses
5Yang, et al.2013Adults21, 42 and 182 daysNot reportedBMI not a factor through 182 days post-immunization; however,
6Paich, et al.2013Adults28–35 daysBMI ≥ 25CD4+, CD8+ T cells from overweight and obese have lower activity, function
7Callahan, et al.2014Children, adolescents, adults21 daysNot reportedNo difference in seroconversion between child or adolescent BMI groups
Tetanus
1Eliakim, et al.2006Children and adolescentsVarying time pointsBMI > 85th %Obese subjects had lower anti-tetanus antibodies and elevated IL-6 levels
Rabies
1Banga, et al.2014Veterinary students2 yearsBMI ≥ 25BMI was associated with inadequate anti-rabies titers

This table summarizes some of the publications with major findings on vaccine-induced immune responses in the obese. Timepoint of antibody measurement is considered to be when blood samples were taken after the last vaccine dose of the vaccination schedule.

HBV - hepatitis B virus; HAV- hepatitis A virus; IAV- influenza A virus.

2. Hepatitis B virus (HBV)

2.1 HBV infection and obesity

Each year, there are four million new cases of HBV infection, and one million people die from chronic HBV-related complications annually. Chronic HBV infection can lead to other serious liver conditions, such as steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). HCC is the fifth most common cancer worldwide, and an estimated 620,000 people die from HBV-related causes [19]. Obesity has been correlated with non-alcoholic fatty liver disease (NAFLD), a condition of steatosis that is caused by excess lipid storage in the liver. Steatosis causes inflammation and triggers cytotoxic mechanisms that could lead to fibrosis [20]. Symptoms rarely develop in obese patients with NAFLD, but NAFLD can eventually lead to non-alcoholic steatohepatitis (NASH), which causes fibrosis and damages hepatic enzyme activity [20, 21]. Viral replication of HBV occurs in the liver, also causing inflammation that could lead to fibrosis and cirrhosis. Since chronic HBV can lead to cirrhosis, obesity paired with HBV infection significantly increases the risk for chronic liver disease and HCC [22, 23]. Obese individuals most likely have a pre-existing burden on liver function, and HBV-related liver disease could further increase serious complications from hepatitis infection in obese individuals with NAFLD [24, 25]. This places the obese patient at a higher risk for both vaccine non-response and serious chronic HBV-related diseases, leaving obese individuals vulnerable to excess morbidity and mortality caused by HBV.

2.2 HBV vaccine-induced immune outcomes in the obese

Since the hepatitis B surface antigen (HBsAg) is crucial for infection, proper protection from HBV is identified by the induction of antibodies that detect HBsAg in circulation. Individuals with HBsAg-specific antibody (anti-HBs) titers ≥ 10 milli-international units per milliliter (mIU/mL), detected by enzyme-linked immunosorbent assay (ELISA), are considered protected against subsequent HBV infections [26, 27]. Four years after the licensure of the first HBV vaccine, Weber et al. performed a study that reported a significant decline (p=0.002) in protective levels (< 10 mIU/mL) of anti-HBs 11 months post-vaccination in obese hepatitis B-vaccinated healthcare workers [12]. 55.7% of the subjects tested negative for protective anti-HBs titers, and a higher weight-height index (≥ 32.88 kg/m2) was identified as one of the greatest risk factors for HBV vaccine non-response. Only 29.5% of individuals with a gender-specific BMI greater than or equal to the 75th percentile developed protective anti-HBs titers, compared to 63.3% of individuals below the 75th percentile that achieved protective seroconversion [12]. Since all patients received the three-dose regimen from a 2.5-cm needle injection, Weber et al. speculated that the location of injection, the buttock, could play a role in the poor vaccine-induced seroconversion of the obese, and a shorter needle caused the low seroconversion by accidental injection into fat pad rather than muscle[12]. Therefore, Weber et al. conducted a follow-up study that used a longer (3.75-cm) needle for the third dose and compared deltoid and buttock HBV vaccination [28]. In the follow-up study, the authors confirmed that an inverse correlation existed between BMI > 30 kg/m2 and significantly decreased (p< 0.001) positive anti-HBs titer seroconversion 17 months post-vaccination. Similar to their previous study [12], only 36% of severely obese individuals with a BMI greater than the 75th percentile had detectable anti-HBs titers compared to 66% of those with a BMI < 75th percentile [28]. However, multivariable analyses indicated that age (p=0.025) and BMI (p<0.001), but not injection site (deltoid and buttock location, p=0.43), were significant independent predictors of poor HBV vaccine-induced anti-HBs titers [28]. Several studies indicate that HBV vaccination in the buttocks of overweight infants, adolescents and obese adults is correlated with a poor vaccine-induced immune response [29–31], and studies support deltoid injection or the use of a longer needle to decrease the risk of HBV vaccine non-response [32, 33]. However, Weber et al. suggest that other systemic factors related to obesity, other than just site of injection, could influence poor anti-HBs responses [28].

By 1990, the original plasma-derived HBV vaccine was discontinued and replaced by two recombinant vaccines: Recombivax HB™ and Engerix-B™. In 1991, the Occupational Safety and Health Administration issued the blood-borne pathogens standard that required employers to provide hepatitis B vaccination for employees [34]. Due to this mandate, many previously unvaccinated adults received the HBV vaccination. Concern for low vaccine-induced anti-HBs titers grew after a study observed a high percentage of healthcare workers with non-protective (< 10 mIU/mL) post HBV-vaccination anti-HBs titers [35]. 11.0–11.5% of individuals with a BMI 25–35 kg/m2 had an inadequate response. However, protective anti-HBs titers dropped significantly as an individual’s BMI exceeded 35 kg/m2 (p<0.05). Data showed that 61.5% of severely obese subjects (BMI ≥ 35 kg/m2) had an inadequate response (≤ 10 mIU/mL), and 45% of severely obese individuals had no detectable anti-HBs titers (≤ 2 mIU/mL). This contrasts with a rate of only 4.3% of non-responders in healthy weight individuals (BMI < 25 kg/m2) [35]. Another study compared the two HBV vaccines, observing obesity as an independent risk factor (p< 0.01) for non-protective anti-HBs titers in Recombivax HB™-vaccinated health care workers in Minnesota [36]. Although the Engerix-B™-vaccinated cohort (n=169) lacked the same statistical power as the Recombivax HB™ cohort (n=426) [36], it was confirmed through later studies [37, 38] that obesity was related to a significant decline (p< 0.01, p= 0.015, respectively) in Engerix-B™ vaccine-induced anti-HBs titers. Since then, several studies have included analyses that continue to identify obesity as a risk factor for diminished or non-protective anti-HBs titers over time [39–42].

2.3 Hepatitis A virus (HAV) vaccine and obesity

In addition to HBV vaccination, obesity has been shown to correlate with poor HAV vaccine-induced immune responses. One study [43] measured hepatitis A antibody titers (anti-HAV) seven months after older individuals (mean 55.2 years of age, standard deviation 9.6) were vaccinated with the combined HAV/HBV vaccine Twinrix™. Elevated BMI was identified as the most significant factor correlated with a significant decline (p< 0.05) in anti-HAV titers and the third most significant factor for poor vaccine-induced anti-HBs titers. Another study [44] observed a slower antibody response to HAV vaccination in overweight individuals, despite an increase in antibody response after a second booster dose. When anti-HAV titers were measured four weeks post-vaccination, both weight (p=0.019) and BMI (p=0.016) were significant predictors of non-protective (anti-HAV titers < 10 mIU/mL) seroresponse, with the odds of being a responder increasing as weight and BMI decreased. However, another study showed no difference in anti-HAV titers between healthy and obese individuals, suggesting obesity may not significantly affect seroconversion after hepatitis A vaccine in some populations [45]. To our knowledge, these are the only data suggesting a poor HAV vaccine-induced immune response in obese individuals.

3. Influenza A virus (IAV)

3.1 IAV infection and obesity

Two surface antigens of influenza viruses are responsible for infection: hemagglutinin (HA) and neuraminidase (NA). Upon entering the respiratory tract, the influenza A virus HA surface protein binds to sialic acid-containing receptors on lung epithelial cells to initiate viral replication in the host cell. The NA surface protein cleaves the sialic acid-HA bond to release the viral capsule from the infected cell surface [46]. Thus, while the NA receptor is crucial for continued infection of epithelial cells, the goal of influenza vaccination is to neutralize the HA surface protein and prevent further infection. Individuals with IAV HA-specific antibody titers ≥ 1:40, detected by hemagglutination inhibition assay (HAI), are considered protected for subsequent IAV infection [47], though this cut-off is controversial.

Obesity was not investigated as an independent risk factor for increased IAV-related morbidity and mortality before the novel 2009 influenza A/H1N1 (pH1N1) pandemic. Prior to 2009, obese individuals were considered high risk for IAV-like illnesses due to underlying and pre-existing conditions, such as chronic cardiovascular or metabolic disease [48]. During the first three months of the initial influenza A/pH1N1 outbreak in April 2009, severe obesity emerged as a common comorbid condition in critically ill patients. For example, between the time when the first case was identified in April 2009 to mid-June 2009 in California, 45% of individuals experiencing influenza A/pH1N1 infection-related illnesses were obese [49]. 26% of the obese were severely obese, and it was suggested that obesity could be linked to an increased risk of IAV infection-related complications [49]. In July 2009, the CDC reported that over 94,500 cases of influenza A/pH1N1 infections occurred worldwide, with 170 of the 429 fatalities occurring in the United States [13]. As influenza A/pH1N1 continued to spread throughout the world, higher trends of influenza-related hospitalizations and fatalities in the obese continued to indicate that obesity, especially severe obesity, increased the risk for serious influenza-like illnesses [6, 50–52]. Obesity was reported to be one of the most frequent underlying metabolic conditions for IAV-related fatalities in individuals over 20 years of age [53]. Severely obese individuals (BMI ≥ 40 kg/m2) infected with influenza A/pH1N1 were twice as likely to be admitted to the ICU from influenza-like illnesses (ILIs) than infected individuals who were not obese [54]. Post-pandemic analyses of clinical cases indicated that, in all ages, obesity was associated with an extended time of IAV-related hospitalization, prolonged mechanical ventilation, and time spent in intensive care [55, 56]. Other studies concluded that IAV-related deaths in adults 20 years of age and older without chronic medical conditions were more likely to be obese or severely obese, suggesting that severe obesity was an independent risk factor for 2009 influenza A/pH1N1-related mortality in adults [57, 58]. However, another study did not observe a correlation between obesity and IAV-related morbidity and mortality, suggesting that influenza-related complications may not be elevated in all obese or severely obese individuals [59]. Nonetheless, data from the 2009 pandemic influenza A/pH1N1 strongly suggest that obese individuals are vulnerable to serious IAV illnesses that could potentially be prevented by vaccination.

3.2 IAV vaccine-induced immune outcomes in the obese

Limited literature exists that explores the relationship between obesity and IAV vaccine-induced immune responses in humans. However, some murine studies have observed important pathways of influenza infection in diet-induced obese mice that would be difficult to study in humans. Several mouse studies indicate that diet-induced obesity leads to poor pathogen-induced immune response against influenza infection [60]. In these studies, diet-induced obesity is correlated with hindered innate immune responses, such as dysregulated inflammatory responses and reduced natural killer cell functioning [61], and poor initiation of the adaptive immune response, such as impaired antigen presentation by dendritic cells and reduced CD8+ T cell function [62, 63]. Other murine studies suggest that diet-induced obesity hinders these immunological pathways that are crucial to amplifying IAV vaccine-induced immune responses [64, 65].

In human studies, data suggest that obese individuals mount a sufficient (HAI antibody titers ≥ 1:40 serum dilution) antibody response to various IAV vaccinations after immunization, including the 2009 pandemic [66, 67], 2008–2009 seasonal [68], and 2009–2010 seasonal [69] vaccines. In one study [69], obese individuals (BMI 35.7 ± 4.5) had a marginally significant (p=0.04) increase in antibody titers one month after vaccination for influenza B/Brisbane/60/2008 when compared to healthy-weight (BMI 22.2 ± 1.7) individuals. However, the same study indicated that increasing BMI could be inversely correlated with antibody response at 12 months post-IAV vaccination. One year after 2009–2010 seasonal TIV vaccination, obese individuals had significantly lower (p=0.01) HAI titers for each of the three TIV strains when compared to healthy-weight individuals [69]. Other studies demonstrated that obesity could lead to diminished influenza vaccine-induced immune response in addition to pregnancy, age and psychological distress [70, 71]. However, the lower IAV-vaccine induced antibody responses in obese persons were either statistically insignificant (p=0.16) [70] or correlated with additional factors (high distress) [71].

3.3 Obesity impairs T cell activation, differentiation in IAV-vaccinated individuals

The high morbidity and mortality related to 2009 pandemic influenza A/H1N1 infection among obese persons generated studies that examined immune pathways that may be perturbed by obesity. While there are limited studies of vaccine-induced immunity, several studies examined the burden of obesity on immune response to influenza infection, which may lead to an impaired vaccine-induced memory response. In addition to producing antigen-specific antibodies, influenza vaccination stimulates T cell production [72]. CD4+ T cells primarily amplify cytokine production and secretion, and CD8+ T cells primarily target infected cells through cytotoxicity. Activation of T cell-mediated immunity through vaccination could provide cross-protective IAV antibodies from subsequent infections of a similar strain [63, 73].

Originally, mouse models suggested that T cell responses to IAV infection may be impaired in obesity [62, 63]. Recently, two human studies have supported this hypothesis and observed inhibited T cell activation and expression in IAV-vaccinated obese individuals [69, 74]. In one study [69], peripheral blood mononuclear cells (PBMCs) were obtained from obese subjects 12 months after immunization with the 2010–2011 seasonal IAV vaccine. PBMCs from obese (BMI 35.7 ± 4.5) subjects had a significantly lower (p=0.015) increase in the percentage of CD8+ T cell surface marker CD69, a T cell activation marker, than PBMCs from healthy-weight (BMI 22.2 ± 1.7) individuals, despite the two weight groups having similar numbers of CD8+ T cells at the 12-month timepoint. Also, CD8+ T cells from obese individuals expressed lower levels of IFNγ (p=0.006) and granzyme B (GrB) (p=0.026), two cytokines essential for proper CD8+ T cell activity [69]. Another study [74] obtained PBMCs from healthy-weight (BMI 22.3 ± 1.6), overweight (BMI 27.2 ± 1.5) and obese (BMI 37.8 ± 7.9) adults 28–35 days after vaccination with 2010–2011 seasonal TIV to compare the number of CD4+ T cell activation markers (CD69, CD28, CD40L, IL12R, IFNγ, GrB). When compared to healthy-weight individuals, both overweight and obese individuals had significantly (p<0.05) diminished levels of each activation marker. Additionally, the authors observed higher levels of IL-5, a cytokine responsible for CD4+ T cell differentiation to helper T cell 2 subsets (Th2) instead of helper T cell 1 subsets (Th1) [74]. An imbalance of helper T cell subsets has been shown to dampen the potency of immune response and increase the severity of IAV-related complications, especially since Th1 subsets have been demonstrated to play a prominent role in the clearance of IAV from the host [75, 76]. Maintaining a balance of Th1:Th2 is crucial for IAV defense, and the lack of Th1 subsets may lead to increased morbidity from IAV infection in obesity [75, 77]. Since obese individuals have been shown to be deficient in markers of CD8+ and CD4+ T cell activation and function after influenza vaccination, overweight and obese individuals may also have an impaired ability to generate proper T cell responses to IAV infection.

4. Tetanus infection and vaccine-induced antibody response in obese children

Tetanus immune protection is evaluated by tetanus-specific IgG antibodies, similar to the mechanisms of seroconversion that have been discussed in relation to the hepatitis B and influenza A vaccines. Tetanus antibody titers ≥ 0.1 IU/ml constitute a serologic correlate of protection, which is assessed by ELISA, and titers > 5 IU/ml indicate long-term protection [78, 79]. One study demonstrated that children (8–17 years of age) with a BMI above the 85th percentile (BMI 29.1 ± 1.6) had significantly reduced (p<0.05) tetanus-specific IgG levels (2.6 ± 0.6 IU/ml) when compared to healthy-weight (BMI 18.4 ± 0.7) children (4.2 ± 0.5 IU/ml) [14]. The same study observed that overweight children exhibited significantly higher (p<0.05) levels of interleukin 6 (IL-6) than healthy-weight children. IL-6 is a pro-inflammatory cytokine that becomes activated during infection, but excess or chronically elevated IL-6 levels can lead to a muted vaccine-specific antibody response against infection [80, 81]. Therefore, the elevated IL-6 levels in obese children suggest that altered cytokine production observed in overweight individuals may play a role in diminished tetanus-specific antibody levels [14].

5. Rabies infection and vaccine-induced antibody response in obese adults

Antibody titers < 0.5 IU/ml are considered inadequate for rabies-specific immunity from pre-exposure rabies vaccination, and individuals exhibiting inadequate titers after the initial rabies vaccination are advised to receive a second booster dose of vaccine [82]. A recent study of veterinary students [15] identified that overweight individuals (BMI ≥ 25 kg/m2) had an increased likelihood for inadequate rabies-specific antibody titers two years post-vaccination (p=0.043). This was the first observance of lower rabies-specific antibody response in overweight individuals. To our knowledge, this was the first study to correlate a poor rabies-specific vaccine-induced immune response in obese humans. These data supported an animal study that indicated larger breeds of dogs had an increased risk for inadequate vaccine-induced rabies-specific antibody levels [83].

6. Conclusion

Obesity is a serious global problem, and the suboptimal vaccine-induced immune responses observed in the obese population cannot be ignored. While we continue to seek strategies that reduce diet-induced obesity, the obese population remains at higher risk for vaccine-preventable illnesses. The lack of data regarding obesity’s influence on vaccine-induced immunity is alarming, and there a need to further understand the burden that obesity places on vaccine immunogenicity and efficacy. More importantly, there is a need for data that include infants and young children, who are the fundamental target of vaccinations.

The vaccines discussed in this review target separate and distinct diseases, but data on each pathogen provide clues to potentially improve vaccine strategies for the obese in regard to other pathogens. Findings of obesity’s role on HBV vaccination outcomes could relate to other blood or sexually transmitted diseases, such as the pursuit of a human immunodeficiency virus 1 (HIV-1) vaccine [41]. The 2009 influenza A/pH1N1 pandemic exposed an increased vulnerability to serious influenza complications, and data suggest that obesity alters the repertoire of T cell responses. The data collected on IAV outcomes are potential areas of interest in protecting the obese from other respiratory pathogens [84]. If the obese do not develop long-term immunity to these vaccines, many individuals, especially those in occupations with an increased risk for these diseases, may not be protected.

Data suggest that obesity burdens the cellular immune response in addition to environmental or genetic factors. The answer may lie within the adipose tissue. Initially, adipocytes were considered to be used exclusively for lipid storage. However, adipose tissue consists of adipocytes and macrophages that can produce signaling molecules, such as TNFα, IL-6, leptin and resistin, that induce a chronic state of inflammation, which could exacerbate the metabolic and immune complications of obesity [85, 86]. Adipose tissue is recognized as an endocrine organ [87], and inflammatory cytokines and hormones could play a role in poor vaccine-induced immune responses in the obese [88]. The chronic inflammatory state has been shown to interfere with a proper vaccine-induced immune response through several mechanisms, including altered production of cytokines and T cells, diminished natural killer cell activity, and poor response to antigens, which leads to a dysregulated immune system (Table 2) [17, 18]. However, these findings include several mouse studies, and the exact pathways and mechanisms whereby chronic inflammation hinders vaccine-induced immune responses in obese humans have yet to be discovered. One such mechanism inadequately studied is a physical one. We and others have demonstrated that as weight and BMI increase, longer needle lengths are needed to ensure intramuscular deposition of vaccines [29–31, 33]. It is likely that vaccines deposited into fat pads are less immunogenic, and may lead to greater local side effects than those deposited deeper into muscle tissue [32, 89]. Moreover, studies examining genetic markers that may elucidate or predict vaccine-induced immune responses in obese individuals are in progress [3]. Further research on such physical factors, in addition to genetic, endocrine, and immunological factors, is needed.

Table 2

Comparison of diet-induced obesity and healthy weight immune outcomes

Outcomes in the obese that could affect vaccine outcomesSource
Pre-exposure (innate response)↑ cytokines from adipocytes (TNF-α, IL-6)Karlsson, et al. *
Impaired dendritic cell functionMacia, et al.*;Smith, et al.*
Vaccination or viral exposure (cellular response)↑ IAV-specific antibodiesTalbot, et al.; Sheridan, et al.
↓ serum cytokines (TNF-α, IL-6)Karlsson, et al.*
↑ lung cytokines (TNF-α, IL-6)Kim, et al.*
↓ Type 1 IFNs (IFN-α, IFN-β)Karlsson, et al.*; Smith, et al.*
↓ Natural killer cytotoxicitySmith, et al.*
Long-term immune response↓ anti-HBs(a) Weber, et al.; (b) Weber, et al.; Roome, et al.; Averhoff, et al.; Simo, et al.; ul-Haq, et al.; Chow, et al.
↓ anti-rabiesBanga, et al.
↓ tetanus-specific antibodiesEliakim, et al.
↓ IAV-specific antibodiesKim, et al.*; Sheridan, et al.
↓ CD8+ T cell activity(a) Karlsson, et al.*; Sheridan, et al.*; Paich, et al.; (b) Karlsson, et al.*
↓ CD4+ T cell activityPaich, et al.
*Indicates a murine study with significant implications for human vaccine-induced immune responses
(a)Weber DJ, Rutala WA, Samsa GP, Santimaw JE, Lemon SM. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. Jama 1985 Dec 13;254(22):3187–9.
(b)Weber DJ, Rutala WA, Samsa GP, Bradshaw SE, Lemon SM. Impaired immunogenicity of hepatitis B vaccine in obese persons. The New England Journal of Medicine 1986 May 22;314(21):1393.
(a)Karlsson EA, Sheridan PA, Beck MA. Diet-induced obesity impairs the T cell memory response to influenza virus infection. J Immunol 2010;184(6):3127–33.
(b)Karlsson EA, Sheridan PA, Beck MA. Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells. Journal of Nutrition 2010;140(9):1691–7.

In conclusion, data suggest that obesity is correlated with poor vaccine-induced immune responses in humans, and further research is required to understand immune mechanisms that are altered in obese individuals. Doing so could provide foundational data used to improve vaccine-induced protection in the obese, a subpopulation with an elevated risk for serious vaccine-preventable illnesses and suboptimal vaccine-induced protective responses.

Acknowledgments

We thank the Mayo Clinic Vaccine Research Group and Caroline L. Vitse for her editorial assistance. This work was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under award number U01AI089859. This publication was supported by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Competing Interests

Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland offers consultative advice on vaccine development to Merck & Co. Inc., CSL Biotherapies, Avianax, Sanofi Pasteur, Dynavax, Novartis Vaccines and Therapeutics, PAXVAX Inc., Emergent Biosolutions, Vaxess, and Adjuvance. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies.

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