NON-PROTECTED. The impact of perfluorinated toxicants and the gut microbiome on vaccine responses in children

Vaccination programs are one of the greatest successes of medicine but may now be threatened by the effects of environmental toxicants on the immune system. A study from the Faroe Islands showed that exposure to the environmental toxicants perfluoralkyl and polyfluoroalkyl substances (PFAS), substances found in Gortex, Teflon, water repellent paper and more, were related to children's vaccine antibody response. Children exposed to the highest levels of toxicants had a greater risk that the vaccines would not provide full protection. Other factors in modern life, such as Caesarean section and antibiotics, are also of concern as they change the composition of the gut microbiota and reduce diversity. An early encounter with certain bacteria is considered crucial for a well-functioning immune system. The main aim of this project is to investigate whether PFAS, even at lower levels, is of importance for the vaccine response, as well as investigating the role of the gut microbiota for vaccine responses. An exciting first result was the publication of the first paper investigating the influence of environmental toxicants, including PFAS, in breast milk on the developing infant gut microbiome. PFOS was associated with less microbiome diversity. Importantly, breast milk toxicants were associated with microbiome functionality, explaining up to 34% of variance in short-chain fatty acids. High PFOA was associated with the absence of a strain of Lactobacillus, an important genus in early life, and 61% more proprionic acid, which is implicated in a variety of diseases with components of immune dysfunction. Our findings could point to a mechanism of action for PFAS on the immune system (Iszatt et al. 2019). We measured 11 individual PFAS in 800 children’s samples, providing new information on PFAS exposure in Norwegian children 7-14 years old. Eight PFAS were found in more than 50 % of the samples, with levels in boys generally higher than in girls. Almost a third of the children had blood levels of the sum of PFAS (including PFOA, PFNA, PFHxS and PFOS) higher than the level that the European Food Safety Authority (EFSA) considers safe (Paulsen et al. 2023). In pooled studies from several European countries, the Norwegian teenagers (12-14 years), had higher PFAS concentrations than teenagers from South or Eastern Europe, and higher consumption of fish and eggs related to around 20 % higher concentrations (Richterova et al. 2023). Mixture risk assessment also indicted that PFAS exposure may result in immunological health risks for Norwegian teenagers (Bil et al. 2023). We also found that PFAS was related to factors that can influence the immune response, with lower body mass index (Schillemans et al. 2023), and higher testosterone in girls and lower FSH levels in boys (Rodriguez-Carrillo et al. 2023), suggesting the potential for interactions. Finally, we have established a state-of-the art analytical platform (Multiplex) for the measurement of vaccine response antibodies at the Norwegian Institute of Public health, which provides a more accurate measure of how the immune system responds to the vaccines than traditional instruments (ELISA). We analysed 1000 child samples for DTP and MMR antibodies, IgE allergic response in 800 child samples, and 10 PFAS in maternal samples from the second trimester of pregnancy. These data are being combined in the final phase of the project to determine whether low levels of PFAS influence immune response.

Vaccinations programs is a success story of modern medicine but may be threatened by an insufficient response to vaccines due to immune depriving factors. Of concern is a recent Faroese study reporting vaccine responses below clinically protective levels observed in children with high exposure to the ubiquitous perfluoroalkyl and polyfluoroalkyl substances (PFASs). Another concern is the effect of modern lifestyle, such as mode of delivery and antibiotics, which alters microbial composition and diversity in the gut, an input which is crucial for the development of the immune system and which also may affect vaccine responses. Finally, in a pilot study from our group, PFASs affected gut microbiota diversity and composition. Infants may thus be affected by a double hit: an altered gut microbiome, exposure to the ubiquitous PFAS, as well as a possible interaction between the two. The primary aim of this research proposal is to i) confirm or refute the Faroese study by investigating the association between PFASs and antibody responses to vaccines. ii) investigate the potential mechanistic roles of gut microbiota and thyroid hormones, iii) investigate the role of an aberrant early life gut microbiome towards the mentioned immune outcomes in its own right. We will utilize several unique birth cohort, amongst others cohorts with data on PFASs, as well as gut microbiome composition and short chain fatty acids in early life in children now 12 years. The vast amount of existing data, and the novel mobilisation of existing health resources will enable a highly cost effective project. The project brings together the requisite multidisciplinary expertise in collaboration with international experts at the very forefront of the research area. We expect that our findings will be of importance for policy makers and could lead to innovative knowledge on the gut microbiome, possibly providing insight in how it can be rebalanced to ensure optimal vaccine responses.