Effects of exposure to per- and polyfluoroalkyl substances on vaccine antibodies: A systematic review and meta-analysis based on epidemiological studies

Highlights

• Associations between five PFAS and tetanus and diphtheria antibodies were assessed.

• PFOA and PFOS exposure were negatively correlated to children tetanus antibody.

• PFHxS was negatively correlated to children tetanus antibody with heterogeneity.

• Effects of PFAS on the other four vaccines are uncertain due to limited studies.

Abstract

Vaccines are essential for children to defend against infection. Per- and polyfluoroalkyl substances (PFAS) are emerging contaminants with the characteristics of persistence and bioaccumulation. PFAS exposure can affect the function of the nervous, endocrine, and immune system of animals and humans. We aimed to conduct a systematic review and meta-analysis of the epidemiological studies investigating potential relationships between PFAS exposure and vaccine antibody levels, and assessed whether PFAS would affect vaccine response in healthy children. A literature search was conducted in PubMed, Web of Science, and Scopus databases up to February 2022. We chose studies that measured serum vaccines antibodies and PFAS concentrations of the participants. Essential information, including mean difference of percentage change, regression coefficient, odds ratio, Spearman correlation coefficient, and 95% confidence intervals, were extracted from the selected studies to conduct descriptive analysis and meta-analysis where appropriate. The qualities of these studies were evaluated as well. Finally, nine epidemiological studies about children met our inclusion criteria. A high degree of heterogeneity is observed in terms of breastfeeding time, confounder control, and detection method. Exposure to perfluorooctanoic acid and perfluorohexane sulfonic acid is negatively associated with tetanus antibody level in children without heterogeneity by Cochran's Q test (p = 0.26; p = 0.55), and exposure to perfluorohexane sulfonate is negatively associated with tetanus antibody level but with heterogeneity (p = 0.04). This comprehensive review suggests that PFAS can have adverse health effects on children by hindering the production of vaccine antibodies. There are some consistent and negative associations between children exposure to certain PFAS and tetanus antibody level. The association of the other four vaccines (measles, rubella, mumps, and influenza) with PFAS remains uncertain, because very few studies are available. Further studies are needed to validate the possible associations.

Introduction

Per- and polyfluoroalkyl substances (PFAS), a class of persistent organic pollutants, have been extensively used in water/stain repellents, firefighting foams, and food-contact paper coatings since the 1940s (Sun et al., 2016). In 2000, the 3 M company, the first fluorochemical producer, voluntarily took action for phase-out of C8-based products, followed by the actual phase-out in 2003 (Renner, 2006). Following the goal of the voluntary 2010/15 perfluorooctanoic acid (PFOA) Stewardship Program, more companies participated in the stewardship program from the United States Environmental Protectin Agency on reduced emission of PFOA, PFOA precursors (Janousek et al., 2019). The legacy PFAS started to shift from more developed countries to less developed countries in Asia (Wang et al., 2014). However, due to their high stability derived from the covalent C–F bond, PFAS are ubiquitously present in the environment and could be detected in the Arctic and wildlife in remote regions (O'Rourke et al., 2022), which is becoming a serious global environmental problem. Meanwhile, PFAS can accumulate in the human body through multiple exposure routes, such as skin adsorption and digestive and respiratory systems, and for fetus and babies, placental transfer and breastfeeding can be two important exposure routes (Pasecnaja et al., 2022). So far, more and more information on adverse health effects of PFAS on humans and animals has been known, e.g., reproductive and developmental toxicology and thyroid dysfunction (Sunderland et al., 2019).

Apart from the toxicities mentioned above, assessment of the association between PFAS exposure and immunomodulation has become an interesting topic in the past decade. A systematic review of animal and epidemiological studies demonstrated that PFAS are potentially hazardous to the immune system (DeWitt et al., 2012). Toxicological studies have found that PFAS are suspected of immunotoxicity or immune suppression. For example, perfluorooctane sulfonate (PFOS) exposure could modulate the immune system in mice by changing the structure and function of the liver (Dong et al., 2009). This study revealed that the developing immune system is sensitive to the effects of PFOS exposure, which will lead to functional deficits in innate and humoral immunity. Animal studies also indicated that PFOS and PFOA could have immunosuppression in mice indirectly through preventing the increases of Immunoglobulin M (IgM) and Immunoglobulin G (IgG) levels in serum by humoral immunity (Keil et al., 2008; Yang et al., 2002).

Several studies have explored the associations between antibody concentrations of influenza and hepatitis vaccines in adults with PFAS, but no significant correlation was yielded (Looker et al., 2014; Shih et al., 2021; Zeng et al., 2020), or only PFAS at relatively high concentrations were inversely associated with influenza vaccine antibodies (Stein et al., 2016a). In general, xenobiotic exposures are more likely to affect the immune system in children, as they are in a critical and sensitive period of development (Feng et al., 2014). An epidemiological study of children demonstrated that PFOA and PFOS exposure was associated with reduced humoral immune response to routine childhood immunizations (Grandjean et al., 2012). As one of the essential measures to protect the immune system, vaccines can stimulate the human body to produce antibodies, thus protecting them from infection, especially for children. All people, especially young children, are advised to vaccinate in order to improve their immunity to various diseases (Wen et al., 2020). According to the health guidance of different countries, children at a certain age often receive the same dose of antigen by taking officially recommended vaccines. Childhood vaccination responses, usually reflected by antibody titer, can be applied as feasible and clinically relevant outcomes for vaccination effect evaluation (Mogensen et al., 2015).

Given the potential immunotoxicity of PFAS, increased attention has been paid to investigating the relationship between PFAS exposure and vaccine antibodies production. Although some of the existing studies have proven that exposure to PFAS would affect the generation of vaccine antibodies in children, their conclusions are not consistent. Two of them reported a positive association between perfluorononanoic acid (PFNA) exposure and diphtheria antibody concentration for children (Grandjean et al., 2017b; Shih et al., 2021), while some other studies reported a negative association between PFNA and diphtheria antibody concentration (Grandjean et al., 2012; Mogensen et al., 2015; Timmermann et al., 2021).

Considering the inconsistency in literature and lack of sufficient evidence with regards to the impact of PFAS exposure on vaccination antibody response, this work is aimed to (1) examine peer-reviewed literature focused on the relationship between PFAS exposure and vaccine antibody levels based on epidemiology; (2) identify the difficulties and challenges in relevant research of PFAS exposure and vaccine antibody so as to suggest potential perspectives for future research.