Influences of obesity on the immunogenicity of Hepatitis B vaccine

ABSTRACT

Objective: Hepatitis B vaccine is regarded as the most effective method for the prevention of hepatitis B virus (HBV) infection. However, several factors such as age, body mass index and immunocompetent state have been reported to be associated with reduced immunization responses. The present commentary was aimed to discuss the influences of obesity on the immunogenicity of hepatitis B vaccines. Data sources: Available peer-reviewed literatures, practice guidelines, and statistics published on hepatitis B vaccine in obesity between 1973 and 2015. Conclusions: Obesity was significantly associated with non-response to hepatitis B vaccine immunization. The risk of nonresponsiveness of hepatitis B vaccine among obese people increased with BMI. Moreover, the obesity might lead to an increased risk of HBV vaccine-escape mutations. The mechanism responsible for decreased immunization responses in obesity included leptin-induced systemic and B cell intrinsic inflammation, impaired T cell responses and lymphocyte division and proliferation. Therefore, more studies should be performed to analyze the influences of obesity on the immunogenicity of hepatitis B vaccines to improve the immunoprotecive effect of hepatitis B vaccines in future.

Introduction

Hepatitis B virus (HBV) infection is a major global public health issues, especially in East Asia and Africa. Worldwide, it is estimated that 30% of the world's population has been infected with HBV. Among of them, more than 350 million are chronic carriers of the virus and about 780,000 die per year because of the HBV infection or its related liver diseases, including hepatic decompensation, cirrhosis, and hepatocellular carcinoma.¹

The first vaccine used for prevention of HBV infection was approved in 1981, which contained purified hepatitis B surface antigen (HBsAg) obtained from the plasma of chronic HBV infection patients. Duo to potential safety issues with regard to the presence of adventitious infectious agents in blood of chronic HBV carriers, the second generation of recombinant hepatitis B vaccine has been developed and first licensed in 1986, which consisted of HBsAg generated from culturing genetically engineered yeast or mammalian cells carrying the gene of HBsAg.² To date, more than 200 countries have implemented a universal hepatitis B immunization program for infants or neonates, and/or adolescents according to the World Health Organization (WHO) recommendation. Consequent to this global prevention strategy, a dramatic reduction of HBV infection among vaccinated children and adolescents has been documented.^3,4 However, several factors such as age, body mass index, drinking, smoking and immunocompetent state have been reported to be associated with decreased immunization responses.^5,6

Obesity is a metabolic disorder characterized by the accumulation of excessive body fat and low-grade chronic inflammation. It is not only considered as a risk factor of metabolic diseases but also contributes to increased susceptibility to bacterial, viral and fungal infections.^7,8 Additionally, more and more evidences have suggested that obese individuals had lower rate of antibody responses to vaccines, as compared with those non-obese subjects.^9,10 In the present commentary, we discussed the potential influences of obesity on the immunogenicity of hepatitis B vaccines.

Relevant peer-reviewed medical literature was obtained using the electric search engines of Pubmed. EMbase, Web of Science and Cochrane Library. keywords included obesity, body mass index, BMI, hepatitis B vaccine and other related words to the present topic. Additional practice guidelines and publically available statistics provided by the Chinese Center for Disease Control and Prevention were also reviewed.

Discussion

Antibody responses to virus infections or immunizations are classified as thymus-dependent responses or thymus-independent responses, according to whether B cells receive help from T cells. Typically, the protective ability of current vaccines is dependent on the neutralizing antibodies induced by B cells.¹¹ However, T cells, such as natural killer T cells and neutrophils, are also crucial for the induction of humoral memory in primary responses and become of secondary importance in secondary responses to the immunization.¹²

Although numerous clinical studies have supported the idea that antibody responses to vaccines or virus infections are perturbed in obesity, few studies have been performed to investigate the mechanisms of the effects of obesity on the vaccinations. Miyake et al. reported that dendritic cells (DCs) from the mice fed with a high-fat diet exhibited impaired functions, leading to decreased anti–hepatitis B surface and core antigen-specific immune responses.¹³ Additionally, the results from a South Korea study indicated that the functions of memory T cell response may be impaired in obesity subjects because the titers of neutralizing antibodies in obese mice were more quickly decreased than those in the normal mice.¹⁴

Another mechanism responsible for impaired immunization responses in obese individuals may be leptin-induced systemic and B cell intrinsic inflammation.¹⁵ Leptin is produced by fat cells and can modulate both innate and adaptive immune responses. Incubation of B cells from lean individuals with leptin increased phospho-signal tranducer and activation of transcription factor (STAT)-3, crucial for TNF-a production, and decreased phospho-AMP-activated protein kinase, the energy-sensing enzyme which could influence the immune responses to the virus infections or vaccines.¹⁶

Telomeres are the tips of linear chromosomes and the lengths of telomeres progressively shorten with each cell division. Because the cellular proliferation is a key component of an effective adaptive immune response, the role of telomeres in lymphocyte and vaccine responses has been discussed recently. Najarro et al. reported that B cells from the persons with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Moreover, M1-specific CD8+ T cells that underwent more expansions had significantly longer telomeres than cells with fewer divisions.¹⁷ Additionally, the previous studies also suggested that shorter telomeres were significantly associated with overweight/obesity because of the chronic low-grade inflammatory and oxidative stress.^18,19

In 1985, Weber et al. first reported that the predictors of poor immunogenic response to hepatitis B vaccine included higher weight-height index, older age, and vaccine batch.²⁰ After that, a large number of studies showed that antibody responses to hepatitis B vaccine were significantly reduced in obese individuals compared with those non-obese people.^21-24 Moreover, the study conducted by Dinelli et al. reported that the obese women who did not response to 6 doses of recombinant hepatitis B vaccine, was seroconverted after weight reduction.²⁵

To further understand the impaired responses of HBV vaccination, we recently performed a meta-analysis to characterize the relationship between obesity and immune response to hepatitis B vaccine.²⁶ Based on the collection the original papers about hepatitis B vaccine in obesity published between 1973 and 2015, our results further showed that obesity was significantly associated with non-response to hepatitis B immunization (adjusted OR: 2.46, 95% CI: 1.50–4.03). In addition, when we extracted the data with uniformed BMI cut-off value (BMI < 25 kg/m², BMI: 25–30 kg/m² and BMI > 30 kg/m²), the results showed that individuals with more than 25 kg/m² of BMI were less prone to respond to hepatitis B vaccines compared with those people with less than 25 kg/m² of BMI (OR: 1.78, 95% CI: 1.13–2.81 for BMI 25–30 kg/m²; and OR: 2.26, 95% CI: 1.31–3.88 for BMI > 30 kg/m²). Furthermore, our analysis showed that the risk of nonresponsiveness of hepatitis B vaccine among obese people increased with BMI values (p for the trend test: 0.003). It should be noted here that our conclusions were reliable because the removal of any of the included studies only yielded minimal changes on the present results.

To date, seldom studies were performed to investigate the effects of obesity on antibody persistence after hepatitis B vaccines immunization. Moreover, the results from previous studies on other vaccines were contradictory. For example, the results from a Korea study reported that after the second administration of influenza vaccine, the obesity mice have similar antibody responses to influenza vaccines as compared with non-obesity animals. However, the mice with high fat diet consistently showed significantly decreased neutralizing antibody titers as compared with the regular fat diet mice at 17 wk after the second administration of vaccine.¹⁴ However, Callahan et al. reported that no significant difference in the immune response to pandemic H1N1 vaccine among children and adolescents of various BMIs who had received 2 doses of after either the first or the second vaccine dose.²⁷ Similar to Callahan et al. study, our recent unpublished analysis observed that there was no significant difference of anti-HBsAg antibody persistence between the vaccinated individuals with/without obesity during 5 y follow-up. However, these primary results are needed to be further validated in different population in future.

HBsAg is the major envelope protein and includes the regions involved in the attachment of the virus to the hepatocyte, and also the main epitopes recognized by neutralizing antibodies. In particular, the immunodominant determinant bearing the anti-HBs neutralization domain, termed “a” determinant, has been mapped to amino acids 124–147 of the S-protein.²⁸ Mutations at this region may lead to conformational change of this epitope and caused the evasion of vaccine induced immunity. In the majority of cases, the HBV vaccine escape variants carry nucleotide mutations causing amino acid substitution in the “a” determinant of the HBsAg, such as T116N, M133L, P142S and G145R.²⁹ In the past decade, more and more studies demonstrated that the obesity and obesity-related diseases, such as type 2 diabetes mellitus, metabolic syndromes and vitamin D deficiency could significantly increase the risk of HBV infections because of the immune system dysregulation.^30,31 However, the effect of obesity or obesity-related diseases on HBV vaccine-escape mutation remains unclear. In our recent studies, we first reported that the amino acid substitution rates in the “a” determinant were significantly higher in the patients with type 2 diabetes mellitus, as compared with non-diabetic individuals.³² Additionally, our another studies observed that vitamin D deficiency was significantly associated with the mutation frequency of M133 in HBV infected patients, indicating that the obesity might lead to an increased risk of HBV vaccine-escape mutations.³³

Conclusions

Although the short-term responses of hepatitis B vaccine in obesity could be enhanced by the improvement immunization methods, such as prolonged needle and better immune adjuvant, the impaired longitudinal vaccine response in obesity remains a problem of hepatitis B immunization program. Therefore, investigation of the mechanisms underlying the relationship between obesity and immune response to hepatitis B vaccines is of importance in future.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.