Introduction
The pandemic caused by severe acute respiratory syndrome coronavirus-2
(SARS-CoV-2) has persisted since December 2019,1,2despite the widespread use of rapidly developed
vaccines.3,4 Coronaviruses are classified into four
genera (alpha-, beta-, gamma- and delta-coronaviruses) in theCoronaviridae family. Alpha and beta coronaviruses infect
mammals, whereas gamma and delta coronaviruses primarily infect birds,
though some can infect mammals.5 Certain coronaviruses
are causative agents of important epidemics or pandemics in animals and
humans, whereas others cause infection in their hosts in the absence of
any apparent clinical manifestation.6 The oldest
coronavirus pandemic reported in animals was caused by the avian
coronavirus infectious bronchitis virus (AvCoV or
IBV).7 This IBV pandemic has persisted in chicken
flocks since 1931 despite mass or flock-based vaccination of the
chickens globally with mostly live attenuated IBV strains by aerosol
application.8
Vaccine implementers are exposed conjunctivally as well as through their
respiratory tract almost on a daily basis during the application of live
attenuated strains of IBV vaccines in hatcheries and poultry houses.
This intensive vaccine virus exposure continues throughout their working
lives. Poultry workers are in close contact only via vaccinated poultry
with the IBV vaccine, but not with vaccine viruses directly. Therefore,
their exposure to IBV vaccines seems to be significantly lower than that
of vaccine implementers.
Like all coronaviruses, SARS-CoV-2 and IBV have a spherical pleomorphic
electron-microscopic appearance, with an average size of 80 to 120 nm,
similar genome organizations, and structural and non-structural
proteins. IBV has seven genotypes and a number of recombinants based on
the differences in nucleotide sequence of the S1 gene, which encodes the
major immunological determinants.9,10 Thus, amino acid
alterations (<5%) in the S1 protein in field viruses may
influence the vaccine effectiveness and
cross-protection.11,12 Hence, neutralizing antibodies
against the S1 protein of each genotype by vaccination may not protect
against infection with novel genotypes and recombinants. Clinical IBV
cases persist unless vaccine strains homologous to the field IBV strains
are used. On the surface of the envelope, S (spike), M (membrane), and E
(envelope) proteins are found, while inside the envelope, the major
protein present around the RNA of the virus is the nucleocapsid (N)
protein.5 Concerning the spike sequence, a highly
conserved region between SARS-CoV-2 and IBV can be found between the
amino acids 807 and 830 (Figure S8).
During the course of an infection, the first contact of a coronavirus
with its host is established by binding of the S protein to its specific
receptor(s), which are located on the mucous surfaces of the respiratory
tract.13,14 The S proteins of coronaviruses are formed
by two subunits, S1 and S2. S1 contains a receptor binding domain (RBD)
responsible for virus binding to its receptor and thus, determining the
host and cell specificity of the virus.15 S1 is the
most frequent mutation-developing site of coronaviruses, while the S2
region is relatively constant and rarely develops
mutations.16,17 Besides the morphological and genomic
similarities between coronaviruses infecting different animals and
humans, there are large differences in the nucleotide and amino acid
sequences of both structural and non-structural genes and proteins.
However, there are also regions showing similarities. Despite their
genetic and protein sequence differences, the topology and
stereo-morphic structures of the antibody binding epitopes found in the
S1 and N proteins of SARS-CoV-2 and IBV18 may result
in cross-reactivity of antibodies developed during an infection or
vaccination in one species against the other. Coronavirus-specific IgG
and IgA antibodies in serum and mucosal surfaces can function as
neutralizing antibodies.19,20 On the other hand,
antibodies to other structural parts of the coronaviruses such as S2 and
N can play an important role in antibody-dependent cell-mediated
immunity, T cell immunity and in vivo viral neutralization
although they do not directly affect RBD binding and thus epithelial
cell infectivity.21-23 Cross-reactive antibodies
generated in response to exposure to coronaviruses other than SARS-CoV-2
may therefore provide a certain level of protection against SARS-CoV-2
infection and/or severe disease.24 Conversely,
non-neutralizing cross-reactive antibodies recognizing SARS-CoV-2 may
also have detrimental effects if they facilitate antibody-dependent
enhancement of viral entry into host cells.25
Although IBV and SARS-CoV-2 are in different genera of theCoronaviridae family, exposure to IBV may result in the
development of cross-reactive antibodies to SARS-CoV-2. We hypothesized
that poultry farm personnel, who are exposed to aerosolized IBV vaccines
as a result of their occupation, will develop antibody responses to IBV,
which may display cross-reactivity to SARS-CoV-2. Therefore, we measured
serum IgG in three different cohorts: 1) poultry farm personnel, who had
been previously frequently exposed to one of the IBV vaccine strains, 2)
pre-pandemic controls, and 3) COVID-19 patients. IgG specific for the
SARS-CoV-2 antigens S1, RBD, S2, and N antigen, including selected
peptides from these antigens, were measured. In addition, we determined
SARS-CoV-2 neutralization and IgG reactivity to the IBV S1 genotypes
Massachusetts 41 (M41), Dutch 274 (D274), IS/1494/06 (Israel variant2),
and 4/91.