Review articleOriginal antigenic sin: A comprehensive review
Introduction
The concept of “original antigenic sin” was first proposed by Thomas Francis Jr., in his treatise “On the Doctrine of Original Antigenic Sin” and has been advocated to explain a number of immunological phenomena. In the 1940s the concept of “original antigenic sin” was used to explain the way by which the immune system contributed to the requirement for yearly influenza vaccines. As early as 1958, there was evidence that the clinical pandemics of influenza in the early 20th century depended on interaction between immunological patterns of the human host and viral characteristics [1]. “Original antigenic sin” is not limited to humans [2], [3], [4], this was demonstrated in a study in rabbits primed with beef myoglobulin, and thence boosted with myoglobulin from other species including sheep, chicken, pig and sperm whale, that mounted an increased antibody response to the original beef myoglobulin [5].
With many viruses, the clinical presentation of an infection can be quite different depending on the original virus or first serotype to which the individual was exposed. For example, human Bocavirus 1 (HBoV1) infects the respiratory tract, causes lower respiratory infections including pneumonia with high prevalence in children [6]. However, the serotype HBoV2, affects the gastrointestinal tract causing gastroenteritis. At first sight, the topic of evolving serotypes should not be a problem, as the immune system, in theory, should be able to combat each subsequent serotype effectively. However, as we delve deeper, a strange phenomenon emerges. After prior exposure to a virus, the immune system has an ineffective to no response to a subsequent exposure of a different serotype of the virus [6]. This observation can be explained with the concept of “original antigenic sin”.
Although simple, the concept has extreme implications. It can be explained in the following way. A body contacts a hypothetical first virus, since the body has no prior exposure to this virus; it must establish a primary response, a slow and intricate process of identifying an antigen of a virus and develop the classic immune response through innate and adaptive components with the aim to activate both cellular and humoral defenses to combat the virus. Subsequent exposure to the virus elicits a secondary amplified response, in which the body responds much quicker against the signal of a familiar antigen. Normally, classical understanding of the mammalian immune system would suggest that exposure to a closely related form of the virus, should trigger a secondary response. If the virus is significantly different, the body should recognize this as a completely new infection and undergoes a primary response (Fig. 1).
But according to “original antigenic sin”, reality is somewhere in between, and it is indeed this hole that can trigger immune evasion by the pathogen. In “original antigenic sin”, if an individual is exposed to a serotype very similar to the pioneer virus, the immune system can mistakenly identify the secondary virus antigens as antigens from the first virus encountered, and progress to a classical memory response producing virus1-specific antibodies, which may be ineffective towards the second virus. Another way of looking at this is that the immune system is unable to differentiate between the two serotypes (Fig. 1) [7], and makes a misdirection error [8]. Actual clinical events that illustrate the effects of “original antigenic sin” include the influenza epidemics, as it was observed that people born prior to 1956 had a worse outcome than young people exposed to influenza virus for the first time. This effect was modeled in rats in a study by Angelova and Schvartzman in 1982 [9]. “Original antigenic sin” can affect a varied array of microbials, including RNA viruses, bacteria and parasites [10]. In this manuscript we will describe the mechanism of “original antigenic sin” and its relevance in different human pathogens and clinical outcomes.
Section snippets
Mechanism
The cellular mechanism of “original antigenic sin” has been discussed in a triad of papers by Deutsch et al. in the 1970s [11], [12], [13]. The pathophysiologic mechanism of “original antigenic sin” includes two immunological components, the innate and adaptive immune systems, which influence the way by which the body mounts a secondary response on re-exposure to an antigen. Normally, on first exposure to a pathogenic antigen, the initial response involves the innate immune system, which
Human Bocavirus (HBoV)
The lapse in the capability of the immune system to mount a proper response to a pathogen through the mechanism of “original antigenic sin” can obviously lead to dire consequences within clinical practice. An example of this occurred with HBoV, a recently identified human-pathogenic parvovirus. HBoV has several similar serotypes that affect the human body in vastly different ways. HBoV1 infection is relatively common among children. It causes lower respiratory tract infections including
Mitigating the effects of “original antigenic sin”
From the standpoint of vaccine strategies, the development of newer vaccines against the same organisms with an increased number of serotypes is one method of counteracting “original antigenic sin” [60]. In the development of vaccines against viruses with common antigenic determinants, all virus that could reasonably be encountered must be inoculated concurrently and prior to any infection in order to stem off the effects of “original antigenic sin”. This is what is being attempted with the
Discussion and perspectives
The concept of “original antigenic sin” can be employed to explain the failure of the immune system to generate an immune response against microbials that are closely related to a strain to which the host had been either infected with or vaccinated against. While this phenomenon has been recognized since the 1960s, recognition or appreciation of the clinical implications have been rather muted [65]. The concept of vaccination is based on generated efficient production of memory B and T-cells
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