Childhood obesity is one of the most serious worldwide health concerns in the twenty-first century and its prevalence has increased at an alarming rate. The prevalence of obesity in Thailand is one of the highest in Asia [1
]. In 2011, the National Thai Food Consumption Survey examined the prevalence of overweight and obesity in a nationally representative sample of Thai children and adults [2
]. Among children and adolescents aged three to eighteen years, the prevalence of overweight and obesity were 9.1% and 6.5%, respectively. Using the World Health Organization (WHO) standard for Asian populations, the combined prevalence of overweight and obesity in Thai adults aged nineteen years and over was 23.9%.
Overweight and obese children are likely to stay obese into adulthood. In addition, they are more likely to develop noncommunicable diseases such as non-alcoholic fatty liver disease, diabetes, and cardiovascular disease at a younger age. Alarmingly, obesity is characterized by a low-level systemic inflammation that might lead to a reduction in immune system responsiveness to vaccines [3
]. In research involving hepatitis B virus (HBV) vaccine, several studies showed that obesity was a risk factor for vaccine non-responsiveness [7
]. In contrast, results in studies involving killed hepatitis A virus (HAV) vaccine were inconclusive. Reuman et al. [10
] and Van der Wielen et al. [11
] argued that a higher vaccine response was associated with lower body mass index (BMI) and lower weight. Yet, Lim et al. [12
] demonstrated that obesity did not significantly affect immunogenicity. Currently, there is no data focused on live HAV vaccines.
WHO recommends that any vaccination against HAV be integrated into the national immunization schedule for children aged ≥1 year [13
]. Both inactivated and live attenuated HAV vaccines are highly immunogenic, generating long-lasting protection against HAV in children and adults. Presently, there is a trend to use the live HAV vaccine variant because it involves a single dose. In 2014, the Indian Academy of Pediatrics (IAP) updated their recommendations for live attenuated HAV vaccine in favor of the single dose variant as opposed to the previous two-dose schedule [15
Because of the limited amount of immunogenicity data for live attenuated HAV vaccine in obese populations, the primary objective of our study was to evaluate the effects of overweight and obesity on the immune response to live attenuated HAV vaccine in children and young adults. Secondary objectives included identifying potential factors associated with postvaccination anti-HAV titers and assessing the reactogenicity of live attenuated HAV vaccine in non-obese and obese vaccine recipients.
The continuing decline in hepatitis A infection prevalence induced by a rise in socioeconomic status, improvements in sanitary conditions, and the availability of a hepatitis A vaccine has been observed in many parts of the world including Thailand [25
]. Results from a 2014 survey in Thailand reported an age-standardized hepatitis A seroprevalence rate of 48.6%, revealing a much lower value among younger age groups than corresponding studies from 1971–1972 (86.4%), 1976 (59.7%), and 1996 (64.5%) [26
]. The present study corroborates this decreasing trend, finding a prevalence of hepatitis A infection in subjects aged seven to twenty-five years of only 7.2%, as determined by the number of subjects with an initial seropositive blood sample. This significant change in hepatitis A epidemiology has resulted in a rising number of symptomatic cases on account of the increase in average age at infection. Consequently, immunization against HAV is a useful tool to prevent symptomatic infections and outbreaks.
Zhang et al. [27
] reported that a single dose of either inactivated HAV (Healive®
) or live attenuated HAV (H2
strain) resulted in seroprotection for 70% of their subjects, with the inactivated vaccine having a higher immunogenic potential 24 months postvaccination. In our study, the seroprotection rate was 100% at eight to nine weeks postvaccination, which is in agreement with the two previous studies using live attenuated hepatitis A vaccine that reported seroprotection rates of 95.8% [28
] and 99% [22
] at six and eight weeks after vaccination, respectively. As of 2019, two live attenuated HAV vaccines are available but their use is presently limited to China, with scattered use in other countries such as India [29
] and Thailand.
Individuals with fatty liver disease, a common complication of obesity, may develop chronic liver disease and ultimately cirrhosis. Such individuals carry a higher risk for developing severe liver impairment and fulminant hepatic failure, should a HAV infection occur. Therefore, vaccination against HAV is generally recommended in patients with chronic liver diseases. Obesity is considered a low-grade chronic inflammatory condition [30
], placing obese individuals in a pro-inflammatory state that may interfere with immunogenicity to vaccine formulations. A review of influenza virus by Honce and Schultz-Cherry [33
] notes how a baseline inflammatory state can negatively influence the induction of an adequate response to virus, resulting in longer infections, delayed viral clearance, and increased viral shedding. In addition, prior research has shown that obesity reduces the antibody response to a number of vaccines, including those for HBV, inactivated HAV, influenza, tetanus, and rabies [6
]. Yet, there are studies showing that obesity is not a significant factor for poor seroprotection following immunization [12
]. Our study also finds that obesity is not a risk factor for non-responsiveness to live attenuated hepatitis A vaccine. Obese participants did have a higher antibody response to live HAV vaccination than non-obese subjects but there was no statistical difference. Though our study lack data on complete blood count with differential along with inflammatory markers, such as high-sensitivity C-reactive protein and pro-inflammatory cytokines, the correlation between these markers and vaccine response should be further explored.
To date, there is limited data regarding the impact of obesity on the immune system response to live attenuated vaccines. Bollaerts et al. [36
] examined the risk factors influencing vaccine effectiveness for the live attenuated zoster vaccine among 111,376 elderly subjects in England and found that zoster vaccine effectiveness was not altered by BMI. Through the use of diet-induced obese (DIO) mice, Estrada, Vazquez-Pagan, and Schultz-Cherry [37
] reported that live attenuated influenza virus was successful in protecting obese hosts from severe disease through the action of elevated effector memory CD4 and CD8 T cells in mouse lung tissue. Although research on immune responses to live attenuated HAV vaccine in obese subjects is sparse, a relationship between obesity and inactivated HAV vaccine-induced immune responses has been reported by three groups, all showing variable results. Reuman et al. [10
] showed that weight (p
= 0.019) and BMI (p
= 0.016) were significant negative predictors of seroresponse (anti-HAV titers ≥ 10 mIU/mL) when anti-HAV titers were measured in 100 participants in the United States (half of whom were younger than 40 years) four weeks after vaccination with alum-adjuvanted formalin-inactivated hepatitis A vaccine. Later, Van der Wielen et al. [11
] measured anti-HAV levels seven months after vaccination, with the combined HAV/HBV vaccine (Twin-rix®
), in 596 adult subjects from Europe (Germany, Belgium, and Czech Republic). The most consequential factor correlated with a significant decline in anti-HAV titers was an elevated BMI. Yet Lim et al. [12
] found no difference in anti-HAV titers, measured eleven months after the primary dose of inactivated HAV vaccine, between healthy and obese individuals, indicating that obesity did not significantly affect seroconversion following hepatitis A vaccination in their subjects [451 medical school students, of which 98.7% were aged 17–22]. Similarly, Sheridan et al. [38
] showed that obese participants had a vigorous initial antibody response to inactivated trivalent influenza vaccine. Nevertheless, when examining the level of antibody maintenance twelve months after immunization, higher BMI values were positively correlated with a four-fold or greater drop in influenza antibody titer. Along with this significant decline in influenza antibody levels, CD8+ T-cell responses were found to be defective in obese participants when compared to normal weight participants. Studies monitoring antibody maintenance levels for longer time durations following live attenuated hepatitis A vaccination may uncover other differences between non-obese and obese populations [39
Although seroconversion rates in adults were similar between male and female populations [40
], females consistently mounted higher anti-HAV antibody responses than males [1
]. The present study also showed that females develop significantly higher immunogenicity than males. Although female gender was a borderline significant univariate predictor (p
= 0.044), it became a significant factor associated with higher antibody response based on multivariate analysis (p
= 0.013). A possible explanation lies in the observation that major sex steroid hormones promote opposing effects on the cells of the adaptive and innate immune systems, e.g., estradiol may play an enhancing role while testosterone may play a suppressing role [43
]. As a result, immune responses to some vaccines will differ between male and female subjects [44
]. For the influenza and hepatitis B vaccines, females exhibit a stronger humoral response. However, this is not the case for the pneumococcal polysaccharide vaccine, where males display a stronger response. We are unaware of any study that differentiates between the male and female responses to live attenuated HAV vaccination.
Currently, there are limited data regarding how waist circumference, truncal obesity, or metabolic syndrome may be linked to vaccine efficacy. Our study revealed that truncal obesity subjects mounted a significantly higher anti-HAV response than the balance of the study population. Truncal obesity involves an increase in lipid storage within adipocytes, as evidenced by a buildup of adipose tissue in the abdominal region. Because adipose tissue has an inherent endocrine function as well as a lipid storage function, it can exhibit varying pathologies according to its classification as either visceral or peripheral/truncal adipose tissue. Whereas visceral adipose tissue is associated with conditions such as dyslipidemia, cardiovascular disease, and type-2 diabetes, peripheral adipose tissue protects against dysfunction by collecting excess lipid that would otherwise accumulate in other tissues [45
]. As adipocytes engage in endocrine signaling, they release a variety of adipokines including leptin, which is capable of regulating innate and adaptive immune responses. In vitro and in vivo studies have revealed that leptin is a crucial factor for T-cell proliferation and differentiation [46
]. Moreover, adipocytes express functional pattern recognition receptors and can subsequently respond to viral antigens, strengthening the link between adipose tissues and the immune system signaling network [47
]. Because females have a greater amount of adipose tissue than males (20–30% and 10–20% of total body weight in females and males, respectively) [48
], the properties of adipocytes and their greater presence in females may explain the elevated immunogenicity to HAV vaccine among females and truncal obesity subjects in the present study. Stoddart et al. [49
] studied in 2205 participants aged 5–40 years (454 were 5–19 years of age) and reported that acanthosis nigricans was independently associated with hyperinsulinemia. A study in 74 obese children revealed that individuals with acanthosis nigricans had significantly greater fasting insulin level and homeostatic model assessment insulin resistance (HOMA-IR) score [50
]. These data support the role of acanthosis nigricans as a potential early indicator of high risk for diabetes. Our study demonstrated the comparable immunogenicity between obese subjects with and without acanthosis nigricans.
Prior investigations indicate that live attenuated HAV vaccine is safe and well tolerated [13
], with no reports of any serious AEs related to the vaccine. The most commonly observed AEs were fever and pain, along with redness and swelling at the injection site, all of which resolve themselves within a few hours or days [10
]. In the present study, there was no difference between the non-obese and obese participants in terms of observed AEs during the safety follow-up duration of 8–9 weeks, all of which were mild.
Age and gender matching of controls were not performed for this study. To expand our findings of excellent immunogenicity for a single HAV vaccine dose, both a long-term follow-up study to determine the persistence of vaccine protective efficacy and a short-term study to evaluate the potential protective efficacy during imminent viral outbreaks or travel preparations are necessary.