Antigenicity and Immunogenicity of SARS-CoV
Yuxian He and Shibo Jiang*
Viral Immunology Laboratory,Lindsley F. Kimball Research Institute,New York Blood Center,New
York,NY 10021 USA
- *Corresponding Author:
- E-mail: [email protected]
A new coronavirus, severe acute respiratory syndrome (SARS)-associated coronavirus (SARSCoV), has been identified as the causal agent of SARS. Phylogenetic analyses indicate that it is distinct from the three known antigenic groups of coronaviruses. Similar to other coronaviruses, SARS-CoV contains four structural proteins, including spike (S), nucleocapsid (N), membrane (M) and envelope (E) proteins. All these proteins may induce humoral and cellular immune responses during viral infection. Characterization on the antigenicity and immunogenicity of SARS-CoV is important for developing effective diagnostics, therapeutics and vaccines.
The global outbreak of severe acute respiratory
syndrome [SARS] was caused by a new
coronavirus [SARS-CoV] within the family
Coronaviridae [1-4]. With aggressive quarantine
measures,the epidemic of SARS has been
successfully controlled. However,SARS-CoV may
re-emerge from an animal reservoir,or from a
laboratory source due to accidental release. Also,there is serious concern over the possibility of
SARS-CoV being utilized as a bioterrorism agent.
Therefore,post-genomic characterization of SARSCoV
is important for exploring the mysteries of
SARS and for developing effective diagnostics,therapeutics and vaccines. Similar to other
coronaviruses [CoVs],SARS-CoV features a large
positive-stranded RNA genome encoding a large
polyprotein required for virus replication,four
structural proteins [spike,S; envelop,E; membrane,M; and nucleocapsid,N] and eight additional
polypeptides of unknown function [3,4]. All these
proteins may serve as antigens to trigger immune
responses in the infected humans and immunized
animals. Here we will mainly discuss the antigenicity
and immunogenicity of SARS-CoV S,N and M
proteins as well as their cross-reactivity with other
1. SARS-CoV S Protein
The S protein of SARS-CoV is a type I
transmembrane glycoprotein responsible for
receptor binding and membrane fusion. Recent
studies indicate that the S protein is highly
immunogenic to induce antibody responses in
SARS patients and is a potent inducer of
neutralizing antibodies against SARS-CoV in the
immunized animals [5-7]. Therefore,it has been
used as a major antigen for developing diagnostics
and as a major immunogen for developing SARS
vaccines. Several genetically engineered vaccines
encoding the SARS-CoV S protein have been
evaluated in pre-clinical studies. A DNA vaccine and
a recombinant modified vaccinia virus Ankara [MVA]
expressing full-length S protein of SARS-CoV has
been shown to induce protective neutralizing
antibody responses [8,9].
The S protein of SARS-CoV can be divided into
S1 and S2 domains by sequence alignment with
other CoV S proteins [4,10]. A 193-amino acid
fragment [residues 318-510] in the S1 domain has
been characterized as the minimal receptor-binding
domain [RBD] of SARS-CoV to mediate the S
protein binding to the cell receptor angiotensinconverting
enzyme 2 [ACE2] [11-17]. We have
recently found that the RBD of SARS S protein
contains multiple conformational epitopes capable of
inducing highly potent neutralizing antibody
responses [18-21]. The protective neutralizing
antibodies induced by MVA that expresses SARSCoV
S protein primarily target the RBD .
Therefore,the RBD of S protein may serve as a
major neutralization determinant of SARS-CoV.
Using Pepscan analysis,we have shown that the
full-length S protein contains several linear
immunodominant domains that do not induce
neutralizing antibodies . It was reported that
vaccination of ferrets with vaccinia virus-based
SARS vaccine expressing the full-length S protein
enhanced liver damage caused by SARS-CoV
infection [22,23]. Yang et al  found that
polyclonal and monoclonal antibodies specific for
the S protein of SARS-CoV is effective to neutralize
homologous virus [Urbani strain]. However,these
antibodies could not neutralize,but rather enhanced
infections by the early human SARS-CoV isolate
[GD03T0013] and palm civet SARS-CoV-like viruses . The S2 domain of SARS-CoV S protein
containing a putative fusion peptide and two heptad
repeat [HR1 and HR2] regions is responsible for
fusion between viral and target cell membranes
. Recent data suggest that the S2 also contains
epitopes for neutralizing antibodies [26-28] and
several immunodominant T-cell epitopes [29-31].
2. SARS-CoV N Protein
The N proteins of CoVs play important roles in viral
pathogenesis,replication and RNA package [32,33]. They are also immunodominant antigens in the
CoV family [34-38]. Antigenic studies have
demonstrated that the N proteins are capable of
inducing protective immune responses against CoV
infection [39-41]. These features make them
suitable candidates for developing diagnostic
agents and subunit vaccines. Recent studies have
shown that the antibodies to SARS-CoV N protein
are highly detectable in the sera of SARS patients
[42-44],suggesting its potential application for
SARS diagnosis. The SARS-CoV N protein has also
been considered as a vaccine candidate. A number
of reports indicate that DNA vaccines encoding N
protein can induce potent humoral and cellular
immune responses against SARS-CoV [45-47].
However,it is unclear whether the antibody
responses induced by these vaccines are effective
in neutralizing infectivity of SARS-CoV. We and
others have found that SARS-CoV N protein
contains several immunodominant epitopes with a
major antigenic site located at the C-terminal region
[48,49],suggesting that truncated proteins
containing the immunodominant epitopes may serve
as antigens for developing SARS diagnostics and
3. SARS-CoV M Protein
The M protein of CoV is the most abundant
glycoprotein in the virus particles and is the key
player for viral particle formation. The structure of M
protein is characterized as having three domains: a
short N-terminal ectodomain,a triple-spanning
transmembrane domain,and a large interior Cterminal
domain. Previous studies demonstrated
that the M proteins of CoVs were able to induce
antibody responses in the host infected by CoV or
immunized by attenuated recombinant virus that
express the M protein [41,51-54]. Computer-aided
analyses reveal that the M protein of SARS-CoV
has a similar structure with M proteins of other
CoVs. The antigenicity of M protein has been shown
by its reactivity with the serum samples from SARS
patients . Furthermore,Pang et al 
demonstrated that a recombinant M protein
expressed in Pichia Pastoris was able to induce
protective humoral responses against SARS-CoV,suggesting its potential application for designing
SARS vaccine. We have recently identified two
major immunodominant epitopes on the M protein located in the extreme N-terminal region [residues
1-31] and the interior C-terminal region [residues
132-161],respectively,by Pepscan analyses
against convalescent sera from SARS patients and
antisera from virus-immunized mice and rabbits.
Synthetic peptides M1-31 derived from the Nterminal
epitope and M132-161 derived from the Cterminal
epitope were able to induce high titers of
antibody responses in the immunized rabbits;
highlighting the antigenic and immunogenic
properties of SARS-CoV M protein [He et al.
4. Antigenic Cross-reactions between
SARS-CoV and Other CoVs
SARS-CoV may originate from animals and have a
broad host range besides humans [57,58]. How this
pathogen crosses the species barrier to humans is
still a mystery. There exist three known antigenic
groups of CoVs: i.e.,Group I,including
transmissible gastroenteritis virus [TGEV],porcine
epidemic diarrhea virus [PEDV],porcine respiratory
CoV [PRCV],feline infectious peritonitis virus
[FIPV],canine CoV [CCoV],and human CoV
[HCoV-229E],etc.; Group 2,including bovine
coronavirus [BCoV],murine hepatitis virus [MHV],and human CoV [HCoV-OC43]; and Group III,consisting of avian CoVs - infectious bronchitis virus
[IBV] that causes respiratory disease in chickens
and turkey CoV [TCoV] that causes enteritis in
young turkeys. Phylogenetically,the SARS-CoV is
most closely related to group II CoVs .
Sequence analyses by Stavrinides et al  suggest
an evolutionary origin of SARS-CoV through
recombination events between mammalian [group I]
and avian [group III] CoVs. Infection with SARSCoV-
related viruses has been detected in a number
of wildlife species - the Himalayan masked palm
civet [Paguma larvata],the Chinese ferret badger
[Melogale moschata],and the raccoon dog
[Nyctereutes procyonoides] [57,58]. The macaques,ferrets and domestic cats are experimentally
susceptible to SARS-CoV [61,62]. Antigenic
relationships within group I CoVs have been
extensively studied. Four group I CoVs,including
TGEV,PRCV,CCoV and FIPV,share antigenic
determinants to cross-react with each other in virus
neutralization and immunofluorescence tests and
with MAbs to the S,N or M proteins of these CoVs.
A number of studies have shown the interspecies
transmission of several group I CoVs [TGEV,FIPV,and CCoV],supporting their close genetic and
Since the emergence of SARS,the serological
tests have been widely used since the
seroconversion to SARS-CoV is a definitive criterion
for laboratory determination of SARS-CoV infection
in humans or animals [63,64]. However,we still lack
sensitive and specific laboratory diagnostic tests for
differential diagnosis of infection by SARS-CoV and other CoVs in humans and animals. The major
problem with current serologic tests is antigenic
cross-reactions between SARS-CoV and other
CoVs. The antigenic cross-reactivity between
SARS-CoV and group I CoVs has been
documented by recent observations [2,65].
Ksiazek et al showed that polyclonal antibodies to
TGEV,FIPV and human CoV 229E cross-reacted
with SARS-CoV-infected cells ; Sun and Meng
showed that the N protein of SARS-CoV crossreacted
with the polyclonal antibodies against group
I CoVs including TGEV,canine CoV,and FIPV,but
not with the antibodies to group II and III CoVs .
Che et al have recently demonstrated that SARSCoV
shares antigenic reactivity with other two
human CoVs [229E and OC43] that cause ~30%
common colds . Yuen and colleagues found that
false-positive results in a recombinant SARS-CoV N
protein-based ELISA were due to HCoV OC43 and
229E infections . It was also reported that the
recombinant N protein-based ELISA showed
approximately 1% positivity among healthy blood
donors [6,68]. Therefore,further characterization of
antigenic relationships between SARS-CoV and
other CoVs is very important for developing specific
and sensitive serologic tests and for investigating
the animal reservoirs of SARS-CoV.
In conclusion,identification of the immuno-dominant
antigenic sites and neutralizing epitopes involved in
the immune responses against SARS-CoV is highly
important for developing SARS diagnostics,therapeutics and vaccines. We believe that the
immunodominant epitopes specific for SARS-CoV
can be used as ideal antigens for designing SARS
diagnostic kits. We are in process to develop
immunoassays using a peptide pool and a set of
mosaic fusion proteins bearing the selected
immunodominant epitopes on the SARS-CoV
proteins without cross-reactivity with antibodies
against other CoVs as antigens for specific
serologic detection. We also believe that a safe and
effective vaccine will be developed using antigens
containing the neutralizing epitopes but no
sequences to induce antibodies mediating
enhancement of SARS-CoV infection. We propose
to use the receptor-binding domain of S protein as a
major target for developing SARS vaccines and
immunotherapeutics since it contains multiple
conformational neutralizing epitopes and is a major
neutralization determinant of SARS-CoV.
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