Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) demonstrates distinct autoimmune and autoinflammatory disease associations according to the adjuvant subtype: Insights from an analysis of 500 cases

Abstract

Background

We investigated the pattern of reported immune diseases in the international ASIA syndrome registry.

Methods

Data from 500 subjects exposed to adjuvants from the ASIA syndrome international registry were analysed.

Results

The patient mean age was 43 ± 17 years and 89% were female. Within the reported immune diseases, 69% were well-defined immune diseases (autoimmune, autoinflammation, and mixed pattern diseases). Among the well-defined immune diseases following the exposure to adjuvants, polygenic autoimmune diseases were significantly higher than autoinflammatory disorders (92.7% vs 5.8%, respectively, p < 0.001). Polygenic autoimmune diseases such as connective tissue diseases were significantly linked to the exposure to HBV vaccine (OR 3.15 [95%CI 1.08–9.23], p = 0.036). Polygenic autoinflammatory diseases were significantly associated with the exposure to influenza vaccination (OR 10.98 [95%CI 3.81–31.67], p < 0.0001).

Conclusions

Immune conditions following vaccination are rare, and among these, polygenic autoimmune diseases represent the vast majority of the well-defined immune diseases reported under the umbrella ASIA syndrome. However, vaccines benefit outweighs their autoimmune side effects.

Introduction

The term autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was first coined in 2011 with the aim of codifying a growing number of disorders characterised by innate and adaptive immune system dysregulation after adjuvant exposure [1]. The term adjuvant denotes several substances that drive innate immune system pattern recognition receptor (PRR) activation and are commonly used in vaccines to boost immune reactivity towards antigens [2,3]. Many substances beyond vaccine adjuvants such as liquid paraffin, silicone gel, acrylamides, hyaluronic acid, and methacrylate compounds have adjuvant properties [[4], [5], [6]]. Aluminium is the most commonly incorporated adjuvant into vaccines and, after many years of widespread use, contrasting data on its toxicity and immune adverse events have been reported [7,8]. Nevertheless, over the last decade, a number of case reports and series reported that vaccines containing aluminium adjuvant might occasionally be associated with serious immunological adverse events including autoimmune diseases [[9], [10], [11]].

Autoimmune diseases are fundamentally linked to aberrant B and T cell dysnfunction against self-antigensthat result from a complex interplay between genetic background and environmental triggers such as infection, dysbiosis, drugs or adjuvants [[12], [13], [14]]. However, the resulting self-directed inflammation with loss of tolerance, and the induction of immune reactions against self-antigens is relatively rare [15]. Of note, the vast majority of people who are exposed to different adjuvant subtypes do not develop autoimmune phenomena.

It is now widely accepted that at the population level, many diseases viewed as autoimmune actually have a predominantly innate immune mediated or autoinflammatory based pathology such as inflammatory bowel disease or polymyalgia rheumatica (PMR) [15]. It is further recognised that diseases previously viewed as autoimmune including psoriasis and allied seronegative arthropathies are intermediate innate-adaptive overlap disorders [32]. Therefore, an immune disease can be classified as autoimmune or autoinflammatory condition and according to the genetic involvement, each be can be stratified into monogenic or polygenic disease.

In order to better understand the link between the different adjuvant subtypes and the spectrum of inflammation against self, an international registry of ASIA syndrome was created in 2011 [16]. A preliminary analysis of 300 patients in 2016 showed that most of the ASIA syndrome patients were female and had a mean age of 38 years. Furthermore, the most commonly reported disease was undifferentiated connective tissue disease (UCTD), found in 26% of the cases [16].

Thus, the aim of the previous study was to increase the awareness of existing conditions that may emerge following the exposure to an adjuvant although a cause-effect relationship is debatable due to the paucity of the described clinical cases, a lack of precise temporal-causal link, and the multitude of exposures to suspected adjuvants. In the current study, we performed an updated analysis of the registry by adding all the cases accumulated between April 2016 and January 2019, giving a total of 500 cases of ASIA syndrome. We also explored the relationship between different immune-mediated disease subtypes (autoimmune versus autoinflammation or intermediate diseases) following the exposure to the various adjuvants.