LitCovid-sentences  

PMC:7105881 / 21329-57072 JSONTXT 14 Projects

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Id Subject Object Predicate Lexical cue
T130 0-46 Sentence denotes Subunit Vaccines Against Sars-CoV and Mers-CoV
T131 47-143 Sentence denotes Subunit vaccines are vaccines developed based on the synthetic peptides or recombinant proteins.
T132 144-487 Sentence denotes Unlike inactivated or live-attenuated virus and some viral vectored vaccines, this vaccine type mainly contains specific viral antigenic fragments, but without including any components of infectious viruses, eliminating the concerns of incomplete inactivation, virulence recovery, or pre-existing immunity (Du et al., 2008; Deng et al., 2012).
T133 488-655 Sentence denotes Similar to DNA or VLP-based vaccines, subunit vaccines are generally safe without causing potential harmful immune responses, making them promising vaccine candidates.
T134 656-822 Sentence denotes Moreover, subunit vaccines may target specific, well-defined neutralizing epitopes with improved immunogenicity and/or efficacy (Du et al., 2008; Zhang et al., 2014).
T135 823-960 Sentence denotes A number of subunit vaccines against SARS-CoV and MERS-CoV have been developed, and these are described in detail in the next paragraphs.
T136 961-1062 Sentence denotes The targets used for the development of SARS-CoV and MERS-CoV subunit vaccines are also be discussed.
T137 1064-1139 Sentence denotes Potential Targets for Development of SARS-CoV and MERS-CoV Subunit Vaccines
T138 1140-1238 Sentence denotes The S protein of SARS-CoV and MERS-CoV plays a vital role in receptor binding and membrane fusion.
T139 1239-1536 Sentence denotes Thus, the S protein, but not other structural proteins, is the major antigen to induce protective neutralizing antibodies to block viruses from binding their respective receptor and thus inhibit viral infection (Bisht et al., 2004; Buchholz et al., 2004; Bukreyev et al., 2004; Yang et al., 2004).
T140 1537-1657 Sentence denotes As a result, the S protein is also a major target for the development of subunit vaccines against SARS-CoV and MERS-CoV.
T141 1658-1930 Sentence denotes Both full-length S protein and its antigenic fragments, including S1 subunit, NTD, RBD, and S2 subunit, can serve as important targets for the development of subunit vaccines (Guo et al., 2005; Mou et al., 2013; Wang et al., 2015; Jiaming et al., 2017; Zhou et al., 2018).
T142 1931-2353 Sentence denotes Although subunit vaccines based on the full-length S protein may elicit potent immune responses and/or protection, studies have found that antibodies induced by some of these vaccines mediate enhancement of viral infection in vitro, as in the case of SARS-CoV (Kam et al., 2007; Jaume et al., 2012), raising safety concerns for the development of full-length S protein-based subunit vaccines against SARS-CoV and MERS-CoV.
T143 2354-2482 Sentence denotes In contrast, RBD-based subunit vaccines comprise the major critical neutralizing domain (Du and Jiang, 2015; Zhou et al., 2019).
T144 2483-2609 Sentence denotes Therefore, these vaccines may generate potent neutralizing antibodies with strong protective immunity against viral infection.
T145 2610-2820 Sentence denotes S1 subunit, for example, is much shorter than the full-length S protein, but it is no less able to induce strong immune responses and/or protection against viral infection (Li et al., 2013; Adney et al., 2019).
T146 2821-2910 Sentence denotes Thus, this fragment can be used as an alternative target for subunit vaccine development.
T147 2911-3250 Sentence denotes Despite their ability to induce immune responses and/or neutralizing antibodies, NTD and S2 as the targets of subunit vaccines are less immunogenic, eliciting significantly lower antibody titers, cellular immune responses, and/or protection than the other regions, such as full-length, S1, and RBD (Guo et al., 2005; Jiaming et al., 2017).
T148 3251-3466 Sentence denotes Therefore, in terms of safety and efficacy, the RBD and/or S1 of S protein could be applied as critical targets for the development of subunit vaccine candidates against SARS-CoV, MERS-CoV, SARSr-CoV, and MERSr-CoV.
T149 3467-3733 Sentence denotes Because of its conserved amino acid sequences and high homology among different virus strains (Elshabrawy et al., 2012; Zhou et al., 2018), the S2 subunit has potential to be used as a target for the development of universal vaccines against divergent virus strains.
T150 3734-3877 Sentence denotes In addition to the S protein, the N protein of SARS-CoV and MERS-CoV may serve as an additional target for the development of subunit vaccines.
T151 3878-4132 Sentence denotes Unlike S protein, the N protein has no ability to elicit neutralizing antibodies to block virus-receptor interaction and neutralize viral infection, but it may induce specific antibody and cellular immune responses (Liu et al., 2006; Zheng et al., 2009).
T152 4133-4372 Sentence denotes Several immunodominant B-cell and T-cell epitopes have been identified in the N protein of SARS-CoV and MERS-CoV, some of which are conserved in mice, non-human primates, and humans (Liu et al., 2006; Chan et al., 2011; Veit et al., 2018).
T153 4373-4483 Sentence denotes Other proteins, such as M protein, can be used as potential targets of SARS-CoV and MERS-CoV subunit vaccines.
T154 4484-4714 Sentence denotes Notably, SARS-CoV M protein-derived peptides have immunogenicity to induce high-titer antibody responses in the immunized animals (He et al., 2005b), suggesting the potential for utilizing this protein to develop subunit vaccines.
T155 4716-4749 Sentence denotes Subunit Vaccines Against SARS-CoV
T156 4750-4965 Sentence denotes Numerous subunit vaccines against SARS-CoV have been developed since the outbreak of SARS, the majority of which use the S protein and/or its antigenic fragments, in particular, RBD, as the vaccine target (Table 1).
T157 4966-5010 Sentence denotes TABLE 1 Subunit Vaccines against SARS-CoVa.
T158 5011-5148 Sentence denotes Name Antigenicity and functionality Adjuvant Route Animal models Antibody response Cellular immune response Protection References
T159 5149-5217 Sentence denotes Subunit vaccines based on SARS-CoV full-length or trimeric S protein
T160 5218-5310 Sentence denotes FL-S and EC-S proteins Bind to SARS-CoV S1, NTD, RBD, and S2-specific mAbs MPL + TDM S.C.
T161 5312-5366 Sentence denotes BALB/c mice Elicit SARS-CoV S-specific Abs (IgG, > 1:
T162 5367-5484 Sentence denotes 2 × 105), neutralizing (> 1:2.4 × 104) pseudotyped SARS-CoV (Tor2, GD03, and SZ3 strains) N/A N/A He et al., 2006a
T163 5485-5557 Sentence denotes S andS-foldon proteins N/A TiterMax Gold; Alum Hydro+MPL S.C. or I.M.
T164 5559-5853 Sentence denotes BALB/c mice Elicit SARS-CoV S-specific Abs (IgG, > 1:104) in mice, neutralizing (∼2.4 × 102 for S; ∼1:7 × 102 for S-foldon) live SARS-CoV (Urbani strain) N/A Protect vaccinated mice from challenge of SARS-CoV (Urbani strain, 105 TCID50) with undetectable viral load in lungs Li et al., 2013
T165 5854-5901 Sentence denotes triSpike protein N/A Alum hydro I.P. or S.C.
T166 5903-6284 Sentence denotes BALB/c mice; Hamsters Elicits SARS-CoV S-specific mucosal and serum Abs (IgA and IgG) in mice and hamsters, blocking S-ACE2 receptor binding and neutralizing live SARS-CoV (HKU-39849 strain); induces ADE N/A Protects vaccinated hamsters from challenge of SARS-CoV (Urbani strain, 103 TCID50) with undetectable or reduced viral load in lungs Kam et al., 2007; Jaume et al., 2012
T167 6285-6331 Sentence denotes Subunit vaccines based on SARS-CoV RBD protein
T168 6332-6375 Sentence denotes RBD-Fc protein N/A Freund’s I.D. or I.M.
T169 6377-6525 Sentence denotes BALB/c mice; Rabbits Elicits SARS-CoV S/RBD-specific Abs (IgG) in mice and rabbits, neutralizing pseudotyped (rabbits: ≥ 7.3 × 104) and live (mice:
T170 6526-6773 Sentence denotes 1:4 × 103; rabbits: > 1:1.5 × 104) SARS-CoV (BJ01 strain) N/A Protects majority (4/5) of vaccinated mice from challenge of SARS-CoV (BJ01 strain, 106 TCID50), with one mouse showing mild alveolar damage in lungs He et al., 2004; Du et al., 2007
T171 6774-6926 Sentence denotes RBD193-CHO; RBD219-CHO proteins Binds to SARS-CoV RBD-specific mAbs (neutralizing 24H8, 31H12, 35B5, 33G4, 19B2; non-neutralizing 17H9) Freund’s S.C.
T172 6928-7495 Sentence denotes BALB/c mice Elicit SARS-CoV RBD-specific Abs, neutralizing pseudotyped (< 1:104 for RBD193-CHO; 1:5.8 × 104 for RBD219-CHO) and live (< 1:103 for RBD193-CHO; 1:103 for RBD219-CHO) SARS-CoV (GZ50 strain) Induce SARS-CoV RBD-specific cellular immune responses (IFN-γ, IL-2, IL-4, IL-10) in mice Protect all (for RBD219-CHO) or majority (3/5, for RBD219-CHO) of vaccinated mice from challenge of SARS-CoV (GZ50 strain, 100 TCID50 for RBD193-CHO; 5 × 105 TCID50 for RBD219-CHO) with undetectable viral RNA or no, to reduced, viral load in lungs Du et al., 2009c, 2010
T173 7496-7628 Sentence denotes RBD-293T protein Binds to SARS-CoV RBD-specific mAbs (neutralizing 24H8, 31H12, 35B5, 33G4, 19B2; non-neutralizing 17H9) SAS S.C.
T174 7630-7926 Sentence denotes BALB/c mice Elicits SARS-CoV RBD-specific Abs (IgG), neutralizing pseudotyped (1:6.9 × 105) and live (1:1.6 × 103) SARS-CoV (GZ50 strain) N/A Protects all vaccinated mice from challenge of SARS-CoV (GZ50 strain, 100 TCID50) with undetectable viral RNA and viral load in lungs Du et al., 2009b
T175 7927-7972 Sentence denotes S318-510 protein N/A Alum; Alum + CpG S.C.
T176 7974-8052 Sentence denotes 129S6/SvEv mice Elicits SARS-CoV-specific Abs (IgG, IgG1, and IgG2a) in mice.
T177 8053-8207 Sentence denotes Reduces neutralization after removing glycosylation Induces SARS-CoV S-specific cellular immune responses (IFN-γ) in mice N/A Zakhartchouk et al., 2007
T178 8208-8270 Sentence denotes Subunit vaccines based on non-RBD SARS-CoV S protein fragments
T179 8271-8348 Sentence denotes S1 and S1-foldon proteins N/A TiterMax Gold; Alum Hydro + MPL S.C. or I.M.
T180 8350-8641 Sentence denotes BALB/c mice Elicit SARS-CoV S-specific Abs (IgG, > 1:104) in mice, neutralizing (1:1.7 × 102 for S1; 1:90 for S1-foldon) live SARS-CoV (Urbani strain) N/A Protect vaccinated mice from challenge of SARS-CoV (Urbani strain, 105 TCID50) with undetectable viral load in lungs Li et al., 2013
T181 8642-8673 Sentence denotes S2 protein N/A Freund’s S.C.
T182 8675-8881 Sentence denotes BALB/c mice Elicits SARS-CoV S2-specific Abs (IgG, 1:1.6 × 103) in mice with no neutralizing activity Induces SARS-CoV S2-specific cellular immune responses (IFN-γ and IL-4) in mice N/A Guo et al., 2005
T183 8882-8957 Sentence denotes Subunit vaccines based on SARS-CoV non-S structural proteins (i.e. N and M)
T184 8958-8989 Sentence denotes rN protein N/A Freund’s I.P.
T185 8991-9192 Sentence denotes BALB/c mice Elicits SARS-CoV N-specific Abs (IgG (1:1.8 × 103), IgG1, and IgG2a) in mice Induces cellular immune responses with up-regulated IFN-γ and IL-10 cytokines in mice N/A Zheng et al., 2009
T186 9193-9241 Sentence denotes rN protein N/A Montanide + CpG; Freund’s S.C.
T187 9243-9396 Sentence denotes BALB/c mice Elicits SARS-CoV N-specific Abs (IgG) in mice Induces SARS-CoV N-specific cellular immune responses (IFN- γ) in mice N/A Liu et al., 2006
T188 9397-9503 Sentence denotes M1-31 and M132-161 peptides Bind to sera from SARS patients or immunized mice and rabbits Freund’s I.D.
T189 9505-9606 Sentence denotes BALB/c mice; NZW rabbits Induce SARS-CoV M-specific Abs (IgG) in rabbits N/A N/A He et al., 2005b
T190 9607-10239 Sentence denotes aAbs, antibodies; ADE, antibody-dependent enhancement; Alum hydro, aluminum hydroxide; CHO, Chinese hamster ovary; CpG, cysteine-phosphate-guanine; I.D., intradermal; I.M., intramuscular; IFN-γ, interferon gamma; IL-2, interleukin 2; IL-4, interleukin 4; IL-10, Interleukin 10; I.P., intraperitoneal; mAbs, monoclonal antibodies; Montanide, Montanide ISA-51; MPL + TDM, monophosphoryl lipid A and trehalose dicorynomycolate; N/A, not reported; NTD, N-terminal domain; NZW rabbits, New Zealand White rabbits; RBD, receptor-binding domain; SAS, Sigma adjuvant system; S.C., subcutaneous; TCID50, median tissue culture infectious dose.
T191 10241-10297 Sentence denotes SARS-CoV Subunit Vaccines Based on Full-Length S Protein
T192 10298-10502 Sentence denotes Subunit vaccines based on SARS-CoV S protein, including full-length or trimeric S protein, are immunogenic with protection against SARS-CoV infection (He et al., 2006a; Kam et al., 2007; Li et al., 2013).
T193 10503-10879 Sentence denotes Either insect cell-expressed full-length (FL-S) or extracellular domain (EC-S) SARS-CoV S protein developed high-titer S-specific antibodies with neutralizing activity against pseudotyped SARS-CoV expressing S protein of representative SARS-CoV human and palm civet strains (Tor2, GD03, and SZ3) isolated during the 2002 and 2003 or 2003 and 2004 outbreaks (He et al., 2006a).
T194 10880-11174 Sentence denotes In addition, full-length S-ectodomain proteins fused with or without a foldon trimeric motif (S or S-foldon) could elicit specific antibody responses and neutralizing antibodies, protecting immunized mice against SARS-CoV challenge with undetectable virus titers in the lungs (Li et al., 2013).
T195 11175-11392 Sentence denotes Moreover, a subunit vaccine (triSpike) based on a full-length S protein trimer induced specific serum and mucosal antibody responses and efficient neutralizing antibodies against SARS-CoV infection (Kam et al., 2007).
T196 11393-11823 Sentence denotes Nevertheless, this vaccine also resulted in Fcγ receptor II (FcγRII)-dependent and ACE2-independent ADE, particularly in human monocytic or lymphoblastic cell lines infected with pseudotyped SARS-CoV expressing viral S protein, or in Raji B cells (B-cell lymphoma line) infected with live SARS-CoV (Kam et al., 2007; Jaume et al., 2012), raising significant concerns over the use of full-length S protein as a SARS vaccine target.
T197 11825-11863 Sentence denotes SARS-CoV Subunit Vaccines Based on RBD
T198 11864-12111 Sentence denotes SARS-CoV RBD contains multiple conformation-dependent epitopes capable of eliciting high-titer neutralizing antibodies; thus, it is a major target for the development of SARS vaccines (He et al., 2004, 2005a; Jiang et al., 2012; Zhu et al., 2013).
T199 12112-12186 Sentence denotes Subunit vaccines based on the SARS-CoV RBD have been extensively explored.
T200 12187-12508 Sentence denotes Studies have found that a fusion protein containing RBD and the fragment crystallizable (Fc) region of human IgG1 (RBD-Fc) elicited highly potent neutralizing antibodies against SARS-CoV in the immunized rabbits and mice, which strongly blocked the binding between S1 protein and SARS-CoV receptor ACE2 (He et al., 2004).
T201 12509-12758 Sentence denotes This RBD protein induced long-term, high-level SARS-CoV S-specific antibodies and neutralizing antibodies that could be maintained for 12 months after immunization, protecting most of the vaccinated mice against SARS-CoV infection (Du et al., 2007).
T202 12759-13175 Sentence denotes In addition, recombinant RBDs (residues 318–510 or 318–536) stably or transiently expressed in Chinese hamster ovary (CHO) cells bound strongly to RBD-specific monoclonal antibodies (mAbs), elicited high-titer anti-SARS-CoV neutralizing antibodies, and protected most, or all, of the SARS-CoV-challenged mice, with undetectable viral RNA and undetectable or significantly reduced viral load (Du et al., 2009c, 2010).
T203 13176-13328 Sentence denotes Significantly, a 293T cell-expressed RBD protein maintains excellent conformation and good antigenicity to bind SARS-CoV RBD-specific neutralizing mAbs.
T204 13329-13466 Sentence denotes It elicited highly potent neutralizing antibodies that completely protected immunized mice against SARS-CoV challenge (Du et al., 2009b).
T205 13467-13764 Sentence denotes Particularly, RBDs from the S proteins of Tor2, GD03, and SZ3, representative strains of SARS-CoV isolated from human 2002–2003, 2003–2004, and palm civet strains, can induce high-titer cross-neutralizing antibodies against pseudotyped SARS-CoV expressing respective S proteins (He et al., 2006c).
T206 13765-13964 Sentence denotes Different from the full-length S protein-based SARS subunit vaccines, no obvious pathogenic effects have been identified in the RBD-based SARS subunit vaccines (Kam et al., 2007; Jaume et al., 2012).
T207 13966-14028 Sentence denotes SARS-CoV Subunit Vaccines Based on Non-RBD S Protein Fragments
T208 14029-14229 Sentence denotes SARS subunit vaccines based on S protein fragments (S1 and S2), other than the RBD, have shown immunogenicity and/or protective efficacy against SARS-CoV infection (Guo et al., 2005; Li et al., 2013).
T209 14230-14437 Sentence denotes For example, recombinant S1 proteins fused with or without foldon elicited specific antibodies with neutralizing activity that protected immunized mice against high-dose SARS-CoV challenge (Li et al., 2013).
T210 14438-14986 Sentence denotes Although some studies have demonstrated that recombinant SARS-CoV S2 (residues 681–980) protein elicits specific non-neutralizing antibody response in mice (Guo et al., 2005), others have indicated that mAbs targeting highly conserved heptad repeat 1 (HR1) and HR2 domains of SARS-CoV S protein have broad neutralizing activity against pseudotyped SARS-CoV expressing S protein of divergent strains (Elshabrawy et al., 2012), indicating the potential of utilizing the S2 region as a broad-spectrum anti-SARS-CoV vaccine target (Zheng et al., 2009).
T211 14988-15048 Sentence denotes SARS-CoV Subunit Vaccines Based on Non-S Structural Proteins
T212 15049-15195 Sentence denotes Subunit vaccines based on the N and M proteins of SARS-CoV have shown immunogenicity in vaccinated animals (Liu et al., 2006; Zheng et al., 2009).
T213 15196-15640 Sentence denotes Studies have revealed that a plant-expressed SARS-CoV N protein conjugated with Freund’s adjuvant elicited specific IgG antibodies, including IgG1 and IgG2a subtypes, and cellular immune responses in mice, whereas another E. coli-expressed N protein conjugated with Montanide ISA-51 and cysteine-phosphate-guanine (CpG) adjuvants induced specific IgG antibodies toward a Th1 (IgG2a)-type response in mice (Liu et al., 2006; Zheng et al., 2009).
T214 15641-15834 Sentence denotes Although N-specific antibodies have been detected in convalescent-phase SARS patient and immunized rabbit sera, they have no neutralizing activity against SARS-CoV infection (Qiu et al., 2005).
T215 15835-16081 Sentence denotes In addition, immunodominant M protein peptides (M1-31 and M132-161) identified using convalescent-phase sera of SARS patients and immunized mouse and rabbit sera have immunogenicity to elicit specific IgG antibodies in rabbits (He et al., 2005b).
T216 16082-16259 Sentence denotes In spite of their immunogenicity, it appears that these N- and M-based SARS subunit vaccines have not been investigated for their protective efficacy against SARS-CoV infection.
T217 16260-16378 Sentence denotes Thus, it is unclear whether these non-S structural protein-based SARS subunit vaccines can prevent SARS-CoV infection.
T218 16380-16433 Sentence denotes Potential Factors Affecting SARS-CoV Subunit Vaccines
T219 16434-16588 Sentence denotes A number of factors may affect the expression of proteins to be used as SARS subunit vaccines; apart from their immunogenicity and/or protective efficacy.
T220 16589-16754 Sentence denotes Understanding of these factors is important to generate subunit vaccines with good quality, high immunogenicity, and excellent protection against SARS-CoV infection.
T221 16755-16861 Sentence denotes The expression of recombinant protein-based SARS subunit vaccines may be changed by the following factors.
T222 16862-17161 Sentence denotes First, addition of an intron splicing enhancer to the truncated SARS-CoV S protein fragments results in better enhancement of protein expression in mammalian cells than the exon splicing enhancers, and different cells may result in different fold increase of protein expression (Chang et al., 2006).
T223 17162-17382 Sentence denotes Second, inclusion of a post-transcriptional gene silencing suppressor p19 protein from tomato bushy stunt virus to a SARS-CoV N protein may significantly increase its transient expression in tobacco (Zheng et al., 2009).
T224 17383-17678 Sentence denotes The following factors may affect the immunogenicity and protective efficacy of protein-based SARS subunit vaccines, including same proteins expressed in different expression systems, and same proteins with various lengths, amino acid mutations, or deletions (He et al., 2006b; Du et al., 2009b).
T225 17679-17891 Sentence denotes For example, RBD proteins containing different lengths (193-mer: RBD193-CHO or 219-mer: RBD219-CHO) elicited different immune responses and protective efficacy against SARS-CoV challenge (Du et al., 2009c, 2010).
T226 17892-18260 Sentence denotes A recombinant SARS-CoV RBD (RBD-293T) protein expressed in mammalian cell system was able to induce stronger neutralizing antibody response than those expressed in insect cells (RBD-Sf9) and E. coli (RBD-Ec) (Du et al., 2009b), suggesting that RBD purified from mammalian cells has preference for further development due to its ability to maintain native conformation.
T227 18261-18546 Sentence denotes Notably, a single mutation (R441A) in the RBD of SARS-CoV disrupted its major neutralizing epitopes and affinity to bind viral receptor ACE2, thus abolishing the vaccine’s immunogenicity, and hence, its ability to induce neutralizing antibodies in immunized animals (He et al., 2006b).
T228 18547-18750 Sentence denotes Additionally, deletion of a particular amino acid by changing a glycosylation site in the SARS-CoV RBD (RBD219-N1) also resulted in the alteration of subunit vaccine’s immunogenicity (Chen et al., 2014).
T229 18751-18920 Sentence denotes Other factors that potentially affect the immunogenicity of SARS subunit vaccines include immunization routes and adjuvants (Zakhartchouk et al., 2007; Li et al., 2013).
T230 18921-19121 Sentence denotes Significantly high-titer antibodies were induced by monomeric or trimeric SARS-CoV S and S1 proteins through the intramuscular (I.M.) route compared to the subcutaneous (S.C.) route (Li et al., 2013).
T231 19122-19341 Sentence denotes Moreover, a SARS-CoV RBD subunit vaccine conjugated with Alum plus CpG adjuvants elicited a higher level of IgG2a antibody and interferon gamma (IFN-γ) secretion than the RBD with Alum alone (Zakhartchouk et al., 2007).
T232 19343-19376 Sentence denotes Subunit Vaccines Against MERS-CoV
T233 19377-19557 Sentence denotes Subunit vaccines against MERS-CoV have been developed extensively, almost all of which are based on the S protein, including full-length S timer, NTD, S1, and S2, particularly RBD.
T234 19558-19721 Sentence denotes These subunit vaccines, including their antigenicity, functionality, immunogenicity, and protective efficacy in different animal models, are summarized in Table 2.
T235 19722-19766 Sentence denotes TABLE 2 Subunit Vaccines against MERS-CoVa.
T236 19767-19913 Sentence denotes Name Functionality and antigenicity Adjuvant Route Animal models Antibody response Cellular immune response Protective efficacy References
T237 19914-19970 Sentence denotes Subunit vaccines based on MERS-CoV full-length S protein
T238 19971-20114 Sentence denotes MERS S-2P protein Binds to DPP4 receptor and MERS-CoV S-NTD, RBD, and S2-specific neutralizing mAbs (G2, D12, and G4, respectively) SAS I.M.
T239 20116-20231 Sentence denotes BALB/c mice Elicits neutralizing Abs in mice, neutralizing 7 pseudotyped MERS-CoV N/A N/A Pallesen et al., 2017
T240 20232-20278 Sentence denotes Subunit vaccines based on MERS-CoV RBD protein
T241 20279-20384 Sentence denotes rRBD (S367-606) protein N/A Alum Hydro + CpG or poly(I:C); IFA + CpG (mouse); Alum (NHPs) I.M. or S.C.
T242 20386-20890 Sentence denotes BALB/c mice; NHPs Elicits MERS-CoV RBD-specific Abs in mice (IgG, IgG1, IgG2a, and IgG2b) and NHPs (IgG), neutralizing pseudotyped (mouse: < 1:5 × 102) and live (NHPs: < 1:5 × 102) MERS-CoV (EMC2012 strain) Induces MERS-CoV RBD-specific cellular immune responses (IFN-γ, TNF-α, IL-2, IL-4, IL-6, and IL-10) in mice and/or monkeys Partially protects vaccinated NHPs from challenge of MERS-CoV (EMC2012 strain, 6.5 × 107 TCID50) with alleviated pneumonia and decreased viral load Lan et al., 2014, 2015
T243 20891-20976 Sentence denotes RBD (S377-662)-Fc protein Binds to DPP4 receptor Poly(I:C); Montanide I.N. or S.C.
T244 20978-21267 Sentence denotes BALB/c mice Elicits MERS-CoV S1- and RBD-specific Abs (IgA, IgG (> 1:104), IgG1, IgG2a, and IgG3) in mice, neutralizing (≥ 1:2.4 × 102) live MERS-CoV (EMC2012 strain) Induces MERS-CoV S1-specific cellular immune responses (IFN-γ and IL-2) in mice N/A Du et al., 2013c; Ma et al., 2014b
T245 21268-21434 Sentence denotes RBD (S377-588)-Fc protein Binds to DPP4 receptor and MERS-CoV RBD specific neutralizing mAbs (Mersmab1, m336, m337, and m338) Montanide; MF59; AddaVax I.M. or S.C.
T246 21436-22101 Sentence denotes BALB/c mice; hDPP4-Tg mice; Rabbits Elicits MERS-CoV S1 and RBD-specific Abs in mice (IgG (> 1:105), IgG1, and IgG2a) and rabbits (IgG), neutralizing 17 pseudotyped (≥ 1:104) and 2 live (≥ 1:103) MERS-CoV (EMC2012 and London1-2012 strains) Induces MERS-CoV S1-specific cellular immune responses (IFN-γ and IL-2) in mice Protects vaccinated Ad5/hDPP4-transduced BALB/c mice and majority (4/6) of vaccinated hDPP4-Tg mice from MERS-CoV (EMC2012 strain, 105 PFU for BALB/c; 103–4 TCID50 for Tg) challenge, without immunological toxicity or eosinophilic immune enhancement Du et al., 2013a; Ma et al., 2014b; Tang et al., 2015; Zhang et al., 2016; Nyon et al., 2018
T247 22102-22243 Sentence denotes RBD-Fd protein Binds to DPP4 receptor and MERS-CoV RBD-specific neutralizing mAbs (Mersmab1, m336, m337, and m338) MF59; Alum I.M. or S.C.
T248 22245-22570 Sentence denotes BALB/c mice; hDPP4-Tg mice Elicits MERS-CoV S1-specific Abs (IgG (> 1:105), IgG1, and IgG2a) in mice, neutralizing at least 9 pseudotyped (> 1:104) and live (> 1:103) MERS-CoV (EMC2012 strain) N/A Protects majority (5/6) of vaccinated hDPP4-Tg mice from challenge of MERS-CoV (EMC2012 strain, 104 TCID50) Tai et al., 2016
T249 22571-22719 Sentence denotes RBD (T579N) protein Binds to receptor DPP4 and MERS-CoV RBD-specific neutralizing mAbs (hMS-1, m336, m337, and m338) Montanide; Alum I.M. or S.C.
T250 22721-22952 Sentence denotes BALB/c mice; hDPP4-Tg mice Elicits neutralizing Abs (> 1:3 × 103) in mice against live MERS-CoV (EMC2012 strain) N/A Protects all vaccinated hDPP4-Tg mice from challenge of MERS-CoV (EMC2012 strain, 104 TCID50) Du et al., 2016a
T251 22953-23015 Sentence denotes Subunit vaccines based on non-RBD MERS-CoV S protein fragments
T252 23016-23053 Sentence denotes S1 protein N/A Ribi; Alum pho I.M.
T253 23055-23355 Sentence denotes BALB/c mice; NHPs Elicits MERS-CoV S1-specific Abs in mice (IgG and IgG1) and NHPs (IgG), neutralizing 8 pseudotyped and live MERS-CoV (JordanN3 strain) N/A Protects vaccinated NHPs from challenge of MERS-CoV (JordanN3 strain, 5 × 106 PFU) with reduced abnormalities on chest CT Wang et al., 2015
T254 23356-23390 Sentence denotes S1 protein N/A Advax + SAS I.M.
T255 23392-23779 Sentence denotes Dromedary camels; Alpacas Elicits neutralizing Abs in dromedary camels (≥ 1:80) and alpacas (≥ 1:6.4 × 102) against live MERS-CoV (EMC2012 strain) N/A Protects vaccinated dromedary camels and alpacas from challenge of MERS-CoV (EMC2012 strain, 107 TCID50) with reduced and delayed viral shedding in the upper airways (in camels) or complete protection (in alpacas) Adney et al., 2019
T256 23780-23819 Sentence denotes rNTD protein N/A Alum pho + CpG I.M.
T257 23821-24268 Sentence denotes BALB/c mice; Ad5-hDPP4 mice Elicits MERS-CoV S-NTD-specific Abs (IgG, ≥ 1:104) in mice, neutralizing pseudotyped and live (1:40) MERS-CoV (EMC2012 strain) Induces MERS-CoV S-NTD-specific cellular immune responses (IFN-γ, IL-2, IL-6, IL-10, and IL-17A) in mice Protects vaccinated Ad5-hDPP4-transduced mice from challenge of MERS-CoV (EMC2012 strain, 105 PFU) with reduced lung abnormalities and respiratory tract pathology Jiaming et al., 2017
T258 24269-24460 Sentence denotes SP3 peptide (aa736-761) N/A Freund’s N/A BALB/c mice; NZW rabbits Elicits MERS-CoV S-specific Abs (IgG, 1:104) in rabbits, neutralizing pseudotyped MERS-CoV N/A N/A Yang et al., 2014a
T259 24461-25138 Sentence denotes aaa, amino acid; Abs, antibodies; Ad5, adenovirus serotype 5; Ad5-hDPP4 mice, Ad5-hDPP4-transuced mice; Alum hydro, aluminum hydroxide; Alum pho, Aluminum phosphate; hDPP4, human dipeptidyl peptidase 4; hDPP4-Tg mice, transgenic mice expressing MERS-CoV receptor human DPP4; IFA, incomplete Freund’s adjuvant; I.M., intramuscular; I.N., intranasal; mAbs, monoclonal antibodies; Montanide, Montanide ISA51; N/A, not reported; NHPs, non-human primates; NZW, rabbits, New Zealand White rabbits; PFU, plaque-forming unit; rRBD, recombinant RBD; SAS, Sigma Adjuvant System; S.C., subcutaneous; TCID50, median tissue culture infectious dose; TNF-α, tumor necrosis factor (TNF)-alpha.
T260 25140-25196 Sentence denotes MERS-CoV Subunit Vaccines Based on Full-Length S Protein
T261 25197-25450 Sentence denotes Subunit vaccines based on the full-length S protein cover both RBD and non-RBD neutralizing epitopes, some of which may be located in the conserved S2 subunit; thus this type of subunit vaccines are expected to induce high-titer neutralizing antibodies.
T262 25451-25762 Sentence denotes Although several MERS-CoV full-length S protein-based vaccines have been reported in other vaccine types, including viral vectors and DNAs (Wang et al., 2015; Wang C. et al., 2017; Haagmans et al., 2016; Zhou et al., 2018), only a few subunit vaccines have been developed that rely on the full-length S protein.
T263 25763-25977 Sentence denotes For example, a recombinant MERS-CoV S protein trimer (MERS S-2P) in prefusion conformation binds to the DPP4 receptor, as well as to the MERS-CoV NTD, RBD, and S2-specific neutralizing mAbs (Pallesen et al., 2017).
T264 25978-26182 Sentence denotes Whereas this protein induces neutralizing antibodies in mice against divergent pseudotyped MERS-CoV in vitro, its in vivo protective activity against MERS-CoV infection is unknown (Pallesen et al., 2017).
T265 26183-26415 Sentence denotes Therefore, more studies are needed to elucidate the potential for the development of MERS-CoV full-length S-based subunit vaccines, including understanding their protective efficacy and identifying possible harmful immune responses.
T266 26417-26455 Sentence denotes MERS-CoV Subunit Vaccines Based on RBD
T267 26456-26672 Sentence denotes Numerous MERS-CoV RBD-based subunit vaccines have been developed and extensively evaluated in available animal models since the emergence of MERS-CoV (Table 2) (Du et al., 2013c; Tai et al., 2017; Zhou et al., 2018).
T268 26673-26916 Sentence denotes In general, these subunit vaccines have strong immunogenicity and are capable of inducing high neutralizing antibodies and/or protection against MERS-CoV infection (Ma et al., 2014b; Zhang et al., 2016; Tai et al., 2017; Wang Y. et al., 2017).
T269 26917-27044 Sentence denotes Most subunit vaccines based on the MERS-CoV RBD have been described in detail in a previous review article (Zhou et al., 2019).
T270 27045-27228 Sentence denotes In this section, we will briefly introduce these RBD-targeting MERS vaccines, and compare their functionality, antigenicity, immunogenicity, and protection against MERS-CoV infection.
T271 27229-27438 Sentence denotes Co-crystallographic analyses of MERS-CoV RBD and/or RBD/DPP4 complexes have confirmed that the RBD is attributed to residues 367–588 (Chen et al., 2013) or 367–606 (Lu et al., 2013) in the MERS-CoV S1 subunit.
T272 27439-27663 Sentence denotes Indeed, a recombinant MERS-CoV RBD (rRBD) fragment (residues 367–606) elicits RBD-specific antibody and cellular immune responses and neutralizing antibodies in mice and/or non-human primates (NHPs) (Lan et al., 2014, 2015).
T273 27664-27835 Sentence denotes However, it only partially protects NHPs from MERS-CoV infection by alleviating pneumonia and clinical manifestations, as well as decreasing viral load (Lan et al., 2015).
T274 27836-28144 Sentence denotes In addition, an RBD protein fragment containing MERS-CoV S residues 377–622 fused with the Fc tag of human IgG can induce MERS-CoV S1- and/or RBD-specific humoral and cellular immune responses in the immunized mice with neutralizing activity against MERS-CoV infection (Du et al., 2013c; Jiang et al., 2013).
T275 28145-28493 Sentence denotes However, after comparing several versions of MERS-CoV RBD fragments with different lengths, it was found that a truncated RBD (residues 377–588) had the highest DPP4-binding affinity and induced the highest-titer IgG antibodies and neutralizing antibodies against MERS-CoV, identifying its role as a critical neutralizing domain (Ma et al., 2014b).
T276 28494-28918 Sentence denotes Subsequently, several MERS-CoV subunit vaccines have been designed based on the identified critical neutralizing domain of RBD fragment, including those expressed in a stable CHO cell line (S377-588-Fc), fusing with a trimeric motif foldon (RBD-Fd), or containing single or multiple mutations in the RBD of representative human and camel strains from the 2012–2015 MERS outbreaks (Tai et al., 2016, 2017; Nyon et al., 2018).
T277 28919-29254 Sentence denotes These RBD proteins maintain good conformation, functionality, antigenicity, and immunogenicity, with ability to bind the DPP4 receptor and RBD-specific neutralizing mAbs and to elicit robust neutralizing antibodies cross-neutralizing multiple strains of MERS pseudoviruses and live MERS-CoV (Tai et al., 2016, 2017; Nyon et al., 2018).
T278 29255-29925 Sentence denotes It is noted that the wild-type MERS-CoV RBD proteins consisting of the identified critical neutralizing domain confer partial protection of hDPP4-transgenic (hDPP4-Tg) mice from MERS-CoV infection without causing immunological toxicity or eosinophilic immune enhancement (Tai et al., 2016; Wang Y. et al., 2017; Nyon et al., 2018); nevertheless, a structurally designed mutant version of such RBD protein with a non-neutralizing epitope masked (T579N) preserves intact conformation and significantly improves overall neutralizing activity and protective efficacy, resulting in the full protection of hDPP4-Tg mice against high-dose MERS-CoV challenge (Du et al., 2016a).
T279 29926-30135 Sentence denotes The above studies indicate that protein lengths to be chosen as MERS-CoV subunit vaccines and/or structure-based vaccine design can impact on the immunogenicity and/or protection of RBD-based subunit vaccines.
T280 30137-30199 Sentence denotes MERS-CoV Subunit Vaccines Based on Non-RBD S Protein Fragments
T281 30200-30307 Sentence denotes MERS vaccines targeting non-RBD regions of S protein have been developed and investigated in mice and NHPs.
T282 30308-30604 Sentence denotes It has been shown that a MERS-CoV S1 protein formulated with Ribi (for mice) or aluminum phosphate (for NHPs) adjuvant elicited robust neutralizing antibodies in mice and NHPs against divergent strains of pseudotyped and live MERS-CoV, protecting NHPs from MERS-CoV infection (Wang et al., 2015).
T283 30605-31064 Sentence denotes In addition, MERS-CoV S1 protein adjuvanted with Advax and Sigma Adjuvant System induced low-titer neutralizing antibodies in dromedary camels with reduced and delayed viral shedding after MERS-CoV challenge, but high-titer neutralizing antibodies in alpacas with complete protection of viral shedding from viral infection, indicating that protection of MERS-CoV infection is positively correlated with serum neutralizing antibody titers (Adney et al., 2019).
T284 31065-31285 Sentence denotes Moreover, immunization with a recombinant MERS-CoV NTD protein (rNTD) can induce neutralizing antibodies and cell-mediated responses, protecting Ad-hDPP4-transduced mice against MERS-CoV challenge (Jiaming et al., 2017).
T285 31286-31513 Sentence denotes Notably, specific antibodies with neutralizing activity have been elicited by a S2 peptide sequence (residues 736–761) of MERS-CoV in rabbits (Yang et al., 2014a), but the protective efficacy of this peptide vaccine is unknown.
T286 31514-31656 Sentence denotes The above reports demonstrate the potential for the development of MERS subunit vaccines based on the non-RBD fragments of MERS-CoV S protein.
T287 31658-31718 Sentence denotes MERS-CoV Subunit Vaccines Based on Non-S Structural Proteins
T288 31719-31921 Sentence denotes Unlike SARS subunit vaccines which have been designed based on viral N and M proteins, it appears that very few subunit vaccines have been developed based on the non-S structural protein(s) of MERS-CoV.
T289 31922-32187 Sentence denotes One study reports the induction of specific antibodies by MERS-CoV N peptides (Yang et al., 2014a), and another report shows that N protein is used for development of vaccines based on viral vector Vaccinia virus, modified Vaccinia Ankara (MVA) (Veit et al., 2018).
T290 32188-32443 Sentence denotes This may be potentially a consequence of the weak immunogenicity and/or protective efficacy of non-S structural proteins, further confirming the role of MERS-CoV S protein as the key target for the development of MERS vaccines, including subunit vaccines.
T291 32445-32498 Sentence denotes Potential Factors Affecting MERS-CoV Subunit Vaccines
T292 32499-32779 Sentence denotes Similar to SARS-CoV subunit vaccines, the immunogenicity and/or protection of MERS-CoV subunit vaccines may also be affected by a number of factors, such as antigen sequences, fragment lengths, adjuvants, vaccination pathways, antigen doses, immunization doses and intervals used.
T293 32780-33208 Sentence denotes As described above, MERS-CoV subunit vaccines containing different antigens or fragment lengths, particularly those based on the RBD, have apparently variable immunogenicity and/or protective efficacy, and a critical neutralizing domain that contains an RBD fragment corresponding to residues 377–588 of S protein elicits the highest neutralizing antibodies among several fragments tested (Ma et al., 2014b; Zhang et al., 2015).
T294 33209-33456 Sentence denotes Adjuvants play an essential role in enhancing host immune responses to MERS-CoV subunit vaccines, including those based on the RBD, and different adjuvants can promote host immune responses to variant levels (Lan et al., 2014; Zhang et al., 2016).
T295 33457-33680 Sentence denotes For example, while a MERS-CoV RBD subunit vaccine (S377-588 protein fused with Fc) alone induced detectable neutralizing antibody and T-cell responses in immunized mice, inclusion of an adjuvant enhanced its immunogenicity.
T296 33681-33998 Sentence denotes Particularly, among the adjuvants (Freund’s, aluminum, Monophosphoryl lipid A, Montanide ISA51 and MF59) conjugated with this RBD protein, MF59 could best potentiate the protein to induce the highest-titer anti-S antibodies and neutralizing antibodies, protecting mice against MERS-CoV infection (Zhang et al., 2016).
T297 33999-34274 Sentence denotes Moreover, a recombinant RBD (rRBD) protein plus alum and CpG adjuvants elicited the highest neutralizing antibodies against pseudotyped MERS-CoV infection, whereas the strongest T-cell responses were induced by this protein plus Freund’s and CpG adjuvants (Lan et al., 2014).
T298 34275-34451 Sentence denotes Vaccination pathways are important in inducing efficient immune responses, and different immunization routes may elicit different immune responses to the same protein antigens.
T299 34452-34768 Sentence denotes For example, immunization of mice with a MERS-CoV subunit vaccine (RBD-Fc) via the intranasal route induced higher levels of cellular immune responses and stronger local mucosal neutralizing antibody responses against MERS-CoV infection than those induced by the same vaccine via the S.C. pathway (Ma et al., 2014a).
T300 34769-35096 Sentence denotes In addition, while Freund’s and CpG-adjuvanted rRBD protein elicited higher-level systematic and local IFN-γ-producing T cells via the S.C. route, this protein adjuvanted with Alum and CpG induced higher-level tumor necrosis factor-alpha (TNF-α) and interleukin 4 (IL-4)-secreting T cells via the I.M. route (Lan et al., 2014).
T301 35097-35220 Sentence denotes Antigen dosage, immunization doses, and intervals may significantly affect the immunogenicity of MERS-CoV subunit vaccines.
T302 35221-35495 Sentence denotes Notably, a MERS-CoV RBD (S377-588-Fc) subunit vaccine immunized at 1 μg elicited strong humoral and cellular immune responses and neutralizing antibodies in mice although the one immunized at 5 and 20 μg elicited a higher level of S1-specific antibodies (Tang et al., 2015).
T303 35496-35743 Sentence denotes In addition, among the regimens at one dose and two doses at 1-, 2-, and 3-week intervals, 2 doses of this protein boosted at 4 weeks resulted in the highest antibodies and neutralizing antibodies against MERS-CoV infection (Wang Y. et al., 2017).