The term «original antigenic sin» (OAS) was coined by T. Francis Jr at the Michigan
University in the late 1950s to describe patterns of antibody response to influenza
vaccination [1]. The basic concept has been recently summarized by the slang «first
flu is forever», which depicts how is important the first imprinting of a dominant
viral or bacterial antigen throughout life [2]. In the 70s, T. W. Hoskins of the Christ's
Hospital in the West Sussex, working with his collaborators on influenza vaccination,
noticed that the development of A/England/42/72 hemagglutinin antibody was less frequent
after revaccination of young male students, in whom the A/Hong Kong/68 hemagglutinin
antibody had been already induced by previous vaccination [3]. This strange phenomenon
went down in history as the «Hoskins paradox», a classical example of OAS. In practice,
it refers to the propensity of the human immune system to exploit the immunological
memory B and T cells, selected on the basis of a previous contact with a specific
epitope, when a new, slightly different, version of the original antigen is encountered,
in order to gain time in the attempt to fight the infection. However, in this way,
the immune system gets entrapped inside the first response against the antigenic determinant,
becoming unable to mount potentially more effective responses during subsequent infections
from the mutated pathogen (Fig. 1
). OAS has been reported not only in relation to influenza virus, but also to dengue
virus and human immunodeficiency virus (HIV) [4], [5]. On March 11th, the World Health
Organization has declared the ongoing ‘coronavirus-disease-2019’ (COVID-19) an emerging
pandemic due to the widespread severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2),
the etiological agent of the disease, first identified in Wuhan [6]. The positive-sense
single-stranded RNA of SARS-CoV-2 is almost identical to bat and pangolin coronaviruses;
therefore, an animal origin from spillover event is alleged [7]. A recent study on
95 full-length genomic sequences of SARS-CoV-2 strains has highlighted that there
may be selective mutations inside the virus [8]; a further study concerning with 86
complete or near-complete genomes of SARS-CoV-2 has provided evidences of genetic
diversity and rapid evolution of the virus [9]. The metatranscriptome sequencing of
the bronchoalveolar lavage fluid coming from 8 SARS-CoV-2 patients has confirmed that
the virus evolves in vivo after infection, a feature which may determine its virulence,
infectivity and transmissibility [10]. If we exclude conspiracy theories, SARS-CoV-2
can be hypothetically considered as the natural result of an antigenic shift from
SARS-CoV, the etiological agent of the ‘severe acute respiratory syndrome’ (SARS),
since they share about 80% of the whole genome and almost all the encoded proteins
[11]. During SARS outbreak, it was observed that the onset of ‘acute respiratory distress
syndrome’, the most dramatic complication of the disease, overlapped with antiviral
immunoglobulin G seroconversion in 80% of patients [12]. Besides, it was found that
patients who developed more quickly the anti-spike neutralizing antibody showed a
higher risk of dying from the disease [13]. In addition to the formation and tissue
deposition of pro-inflammatory immunocomplexes, these alarming data have been explained
by means of complement-dependent enhancement and antibody-dependent enhancement (ADE),
immunological escape mechanisms also exploited by other viruses, such as dengue virus,
Ebola virus and HIV [14], [15], [16], [17], [18]. Briefly, an ineffective immune response
against the mutated virus due to OAS can produce a large amount of sub-neutralizing
cross-reactive antibodies, which raise inflammation and may paradoxically facilitate
the virus entry into host cells, e.g. macrophages, complement mediated or via fragment
crystallizable (Fc) receptors. The intracellular presence of the pathogen triggers
a pyroptosis process with subsequent release of danger-associated molecular patterns
(DAMPs) aimed to invoke in loco further inflammatory cells, which in turn secrete
a massive number of cytokines; both ADE and pyroptosis could well explain the «cytokine
storm», which has been described in the fatal cases of COVID-19 [19]. J.A. Tetro of
the Guelph University has advanced the question if SARS-CoV-2 may receive ADE from
other coronaviruses [20]; in this regard, 4 human coronaviruses (HCoV-HKU1, HCoV-NL63,
HCoV-OC43, HCoV-229E) are spread all over the world, and they continually circulate
among humans causing respiratory infections in adults and children, usually mild as
common cold, while the Middle-East-respiratory-syndrome-related-coronavirus (MERS-CoV),
responsible for the homonymous, often serious, respiratory illness, has been reported
in over 25 countries to date [21]. Faced with this scenario and to the potential adaptive
mutation of SARS-CoV-2, the development of an effective subunit vaccine appears quite
complicated; therefore, the most viable solution is to focus on an alternative vaccination
source able to stimulate the innate immunity rather than the acquired one. The former
immunity is more active in children, where the immune system is still immature and
prone to receive new antigenic stimuli, while the latter in adults: is maybe here
the reason why the child population rarely experiences fatal complications during
the ongoing COVID-19 pandemic?...the arduous sentence to near future research lines.
Fig. 1
In an ideal immune system (on the left) to SARS-CoV-2 and its antigenic variants corresponds
always a specific adaptive immunity, as shown by the color matching (red-red, blue-blue,
green-green) between a symbolic antibody and the spike proteins, which surround the
outer surface of the virion conferring to it the characteristic corona aspect on electron
microscopy; in an OAS model (on the right), the specific adaptive immune response
(red antibody) is only mounted against the original virus (red colored) and it is
also used to fight the mutated versions (blue colored and green colored) of the virus,
resulting in a maladaptive response less specific and less effective [the 3D illustration
of SARS-CoV-2 with the spike proteins in red has been created by Alissa Eckert, MS,
and Dan Higgins, MAM, at the Centers for Disease Control and Prevention (CDC) of Atlanta,
Georgia, USA, placed in the public domain and thus free of any copyright restrictions].
Conflict of interest statement:
no conflict of interest.