Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus
Open accessAbstract
Designer Vaccine: Respiratory syncytial virus (RSV) is one of the last remaining childhood diseases without an approved vaccine. Using a structure-based approach, McLellan et al. (p. 592 ) designed over 150 fusion glycoprotein variants, assessed their antibody reactivity, determined crystal structures of stabilized variants, and measured their ability to elicit protective responses. This approach yielded an immunogen that elicits higher protective responses than the postfusion form of the fusion glycoprotein, which is one of the current leading RSV vaccine candidates entering clinical trials. Importantly, highly protective responses were elicited in both mice and macaques.
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Written from the paper’s full text.
TL;DR
Structure-based design stabilized the prefusion-specific antigenic site Ø of RSV fusion (F) glycoprotein, yielding variants that retained the site under physical extremes. The optimized DS-Cav1 immunogen elicited RSV-neutralizing titers many times the protective threshold in mice and macaques.
Key findings
- Stabilized RSV F variants DS, Cav1, TriC, and especially DS-Cav1 retained antigenic site Ø under extremes of pH, osmolality, temperature, and freeze-thaw; DS-Cav1 was optimal for trimer yield and physical stability.
- Six crystal structures showed the engineered variants were substantially in the D25-bound prefusion conformation; DS-Cav1-TriC diffracted to 2.8 Å, and a tetragonal Cav1 crystal to 2.4 Å.
- In CB6F1/J mice, DS, Cav1, and TriC elicited geometric mean neutralizing EC50s of 1826–2422, versus 504 for postfusion F and ~20-fold above the protective threshold; DS-Cav1 elicited 3937 EC50, ~8-fold higher than postfusion F and ~40-fold above threshold.
- In rhesus macaques at week 6, DS-Cav1 elicited 2578 EC50 versus 1222 for DS and 287 for postfusion F; by week 8, DS-Cav1 titers were ~60-fold higher than postfusion against RSV subtype A and >80-fold higher against subtype B.
Methods
- Structure-based design and mutagenesis: over 100 RSV F variants were expressed in a 96-well format and screened by ELISA for D25 and motavizumab binding; selected trimers were purified and characterized by negative-stain EM, size-exclusion chromatography, and crystallography.
- Immunogenicity: CB6F1/J mice received 10 μg RSV F plus 50 μg poly I:C at weeks 0 and 3, with week 5 sera tested for neutralization of RSV infection of HEp-2 cells; site Ø-occluded forms were also tested at 20 μg. Rhesus macaques received 50 μg RSV F plus 500 μg poly I:C at weeks 0 and 4, with sera collected at weeks 2, 4, 6, 8, 10, and 14.
- Analysis included neutralization EC50 titers, correlations between physical/antigenic properties and immunogenicity, Octet biosensor binding responses, and calculated shared/unique surface areas from crystal structures.
Limitations
- Stated: whether the “neutralization-sensitive site” strategy succeeds in other contexts depends on virus-specific factors such as circulating viral diversity and the required level of neutralizing activity for protection.
- Evident from the text: the DS structure failed to fix antigenic site Ø in its D25-bound conformation, with disorder or altered conformation in membrane-distal regions; V207L in Cav1 was unable to stabilize the α4-helix in the D25-bound conformation.
- Evident from the text: immunogenicity was assessed only in mice and rhesus macaques, with no human efficacy or challenge data reported; Cav1 and TriC also showed low-level trimer-to-aggregate conversion on size-exclusion chromatography.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 27 cited sources checked · 0 supported · 0 flagged
- Findingown data
Potential inter-chain double cysteine modifications did not express at levels sufficient for ELISA detection.
“We also tested potential inter-chain double cysteine modifications, but none expressed at levels sufficient for ELISA detection (table S1) (25).”
Quote in the paperNot a substantial claim - Findingown data
The DS variant formed stable RSV F trimers.
“A S155C-S290C double mutant (DS) formed stable RSV F trimers, expressed at 1.4 mg/L, retained antigenic site Ø, and was homogeneous as judged by negative stain-electron microscopy (Table 1, fig. S3) (23, 24).”
Quote in the paperSubstantial claim - Findingown data
Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature.
“Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature.”
- Also stated in: § Combinatorial Optimization of Site Ø Stability · plain
“Combinations of the three variants improved retention of D25 reactivity to physical extremes, a characteristic helpful to manufacturing.”
Quote in the paperSubstantial claim - Also stated in: § Combinatorial Optimization of Site Ø Stability · plain
- Findingown data
The DS variant was homogeneous as judged by negative stain electron microscopy.
“A S155C-S290C double mutant (DS) formed stable RSV F trimers, expressed at 1.4 mg/L, retained antigenic site Ø, and was homogeneous as judged by negative stain-electron microscopy (Table 1, fig. S3) (23, 24).”
Quote in the paperSubstantial claim - Findingown data
The DS variant retained antigenic site Ø.
“A S155C-S290C double mutant (DS) formed stable RSV F trimers, expressed at 1.4 mg/L, retained antigenic site Ø, and was homogeneous as judged by negative stain-electron microscopy (Table 1, fig. S3) (23, 24).”
Quote in the paperSubstantial claim
- Findingown data
Other intra-chain cysteine modifications, such as those between regions of RSV F that do not rearrange between pre- and postfusion states, did not stabilize antigenic site Ø.
“Other intra-chain cysteine modifications, such as those between regions of RSV F that do not rearrange between pre- and postfusion states (e.g. S403C and T420C), did not stabilize antigenic site Ø (Table 1).”
Quote in the paperNot a substantial claim - Findingown data
Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability.
“Six RSV F-crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability.”
Quote in the paperSubstantial claim - Findingown data
Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
“Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.”
Quote in the paperSubstantial claim- Rests on an assumption: Neutralizing antibody titers in mice and macaques are predictive of protection against RSV disease in humans.
- Findingown data
The critical F488W substitution in the TriC alteration of residues 486-489 packed directly against the F488W substitutions of neighboring protomers of the RSV F trimer.
“The critical F488W substitution in the TriC alteration of residues 486-489 packed directly against the F488W substitutions of neighboring protomers of the RSV F trimer.”
Quote in the paperSubstantial claim - Findingown data
The structure of the DS variant revealed that cysteine-substituted residues at 155 and 290 formed a disulfide bond that prevented triggering to the postfusion state.
“Although the structure of the DS variant (Fig. 2, left column) revealed the cysteine-substituted residues at 155 and 290 formed a disulfide bond that prevented triggering to the postfusion state, much of the membrane-distal portion of the RSV F trimer, including antigenic site Ø, was either disordered (residues 63-72 and 169-216) or in a different conformation.”
Quote in the paperSubstantial claim - Findingown data
The Cav1 structure was more ordered at its membrane-distal apex than the DS structure.
“In comparison to DS, the Cav1 structure (Fig. 2, second and third columns) was more ordered at its membrane-distal apex, with α3-helix, β3/β4 hairpin, and α4-helix clearly defined.”
Quote in the paperSubstantial claim - Findingown data
DS, Cav1, and TriC each elicited high titers of neutralizing activity in mice (geometric mean EC50s of 1826-2422).
“DS, Cav1, and TriC each elicited high titers of neutralizing activity (geometric mean 50% effective concentrations (EC50s) of 1826-2422).”
Quote in the paperSubstantial claim - Findingcitation
Comparison of the DS-Cav1 structures from the two cubic crystal forms to those of Cav1 revealed only minor differences.
“Comparison of the DS-Cav1 structures from the two cubic crystal forms (Fig. 2, second and third columns from right) to those of Cav1 revealed only minor differences (31).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Cα-root mean square deviations of 0.86 Å for 447 residues between Cav1 and DS-Cav1 grown in ammonium sulfate condition; Cα-root mean square deviations of 0.47 Å for 447 residues of DS-Cav1 in cubic lattices
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
Residues 137-202 in the Cav1 structure had a Cα-root mean square deviation of 0.6 Å when compared to the D25-bound F structure.
“Residues 137-202, which contain the S190F substitution, had a Cα-root mean square deviation of 0.6 Å when compared to the D25-bound F structure.”
Quote in the paperSubstantial claim - Findingown data
In the DS structure, much of the membrane-distal portion of the RSV F trimer, including antigenic site Ø, was either disordered or in a different conformation.
“Although the structure of the DS variant (Fig. 2, left column) revealed the cysteine-substituted residues at 155 and 290 formed a disulfide bond that prevented triggering to the postfusion state, much of the membrane-distal portion of the RSV F trimer, including antigenic site Ø, was either disordered (residues 63-72 and 169-216) or in a different conformation.”
Quote in the paperSubstantial claim - Findingown data
Overall the crystal structures revealed the engineered RSV F variants to be substantially in the D25-bound conformation.
“Overall these structures revealed the engineered RSV F variants to be substantially in the D25-bound conformation (28).”
Quote in the paperSubstantial claim- Rests on an assumption: The crystal structures of engineered RSV F variants represent the conformations relevant to their behavior as immunogens in solution.
- Findingown data
There was a strong correlation between retention of D25 binding for at least 7 days at 4°C in 96-well supernatants and yield of purified trimers after large scale expression and purification.
“Overall, we observed strong correlation between retention of D25 binding for at least 7 days at 4°C in 96-well supernatants and yield of purified trimers after large scale expression and purification (Fig. S5).”
Quote in the paperSubstantial claim - Findingcitation
In the Cav1 structure, the C terminus ends with Ala107, and not Arg109, as expected after cleavage of the furin site.
“Interestingly, the C terminus ends with Ala107, and not Arg109, as expected after cleavage of the furin site (Arg106-Ala107-Arg108-Arg109) (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Observing Ala107 rather than Arg109 at the C terminus of F2 is not totally unexpected: Garten and Klenk (47) found that an arginine at the cleavage site of influenza hemagglutinin was trimmed by a cellular carboxypeptidase activity
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
The DS-Cav1 combination appeared optimal in terms of trimer yield and physical stability to extremes of temperature, pH, osmolality, and freeze-thaw.
“Overall, the DS-Cav1 combination appeared optimal in terms of trimer yield and physical stability to extremes of temperature, pH, osmolality, and freeze-thaw (Table 1), and was homogeneous as judged by negative stain electron microscopy (fig. S2).”
Quote in the paperSubstantial claim - Findingown data
In the Cav1 structure, the C-terminus of F2 tunnels into the trimeric cavity alongside the fusion peptide.
“A striking feature of the Cav1 structure in the tetragonal crystal lattice is the C-terminus of F2, which is disordered in the D25-bound F structure, but in Cav1, tunnels into the trimeric cavity alongside the fusion peptide.”
Quote in the paperNot a substantial claim - Findingown data
Site Ø has low atomic mobility when bound by D25.
“Interestingly, however, site Ø has low atomic mobility when bound by D25, revealing the ability of D25 to stabilize both overall and local RSV F conformations.”
Quote in the paperNot a substantial claim - Findingown data
The atomic mobility (B-factor) was highest in the apex region for all of the site Ø-stabilized variants, perhaps indicative of intrinsic site Ø flexibility.
“Notably, the atomic mobility (B-factor) was highest in this apex region for all of the site Ø-stabilized variants, perhaps indicative of intrinsic site Ø flexibility.”
Quote in the paperNot a substantial claim - Findingown data
Strong correlation was observed between binding responses and calculated surface areas.
“Strong correlation was observed between binding responses and calculated surface areas (Fig. 4D).”
Quote in the paperSubstantial claim- Rests on an assumption: The crystal structures of engineered RSV F variants represent the conformations relevant to their behavior as immunogens in solution.
- Premisecitation
The major target of RSV-neutralizing antibodies elicited by natural infection resides primarily on the prefusion conformation of RSV F.
“Recently, however, the major target of RSV-neutralizing antibodies elicited by natural infection was found to reside primarily on the prefusion conformation of RSV F (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Magro M Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention Proc. Natl. Acad. Sci. U.S.A 2012 109 3089 3094 22323598 PMC3286924 source
Not checked in the free run.
- Premisecitation
Structure-based design of epitopes recognized by template neutralizing antibodies can engineer antigenicity.
“We and others have engineered antigenicity (13-17) through structure-based design of the epitopes recognized by template neutralizing antibodies.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [13] Burton DR Antibodies, viruses and vaccines Nat. Rev. Immunol 2002 2 706 713 12209139 source
Not checked in the free run.
- cites [14] Zhou T Structural definition of a conserved neutralization epitope on HIV-1 gp120 Nature 2007 445 732 737 17301785 PMC2584968 source
Not checked in the free run.
- cites [15] Ofek G Elicitation of structure-specific antibodies by epitope scaffolds Proc. Natl. Acad. Sci. U.S.A 2010 107 17880 17887 20876137 PMC2964213 source
Not checked in the free run.
- cites [16] Jardine J Rational HIV immunogen design to target specific germline B cell receptors Science 2013 340 711 716 23539181 PMC3689846 source
Not checked in the free run.
- cites [17] McGuire AT Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies J. Exp. Med 2013 210 655 663 23530120 PMC3620356 source
Not checked in the free run.
- Interpretationown data
The higher degree of structural order in Cav1 was likely due to the S190F mutation that filled a cavity observed in the D25-bound F structure and increased van der Waals contacts.
“The higher degree of structural order was likely due to the S190F mutation that filled a cavity observed in the D25-bound F structure, and increased van der Waals contacts with residues Ile57, Lys176, Val192, Glu256, Ser259 and Leu260.”
Quote in the paperNot a substantial claim - Interpretationreasoning
This fusion peptide interaction likely inhibits the extraction of the fusion peptide from the prefusion trimer cavity, providing a structural rationale for the ability of the F488W substitution to stabilize the prefusion state of RSV F.
“This fusion peptide interaction, which is not observed in any of the Phe488-containing structures, likely inhibits the extraction of the fusion peptide from the prefusion trimer cavity, providing a structural rationale for the ability of the F488W substitution to stabilize the prefusion state of RSV F (Table 1).”
Quote in the paperSubstantial claim - Interpretationown data
Enhancing structural mimicry of antigenic site Ø in its D25-bound conformation appears to be a promising strategy for improving protective antibody responses.
“Specifically, enhancing structural mimicry of antigenic site Ø in its D25-bound conformation appears to be a promising strategy for improving protective antibody responses (Fig. 4B).”
Quote in the paperSubstantial claim - Interpretationcitation
Correlations indicate that increasing site Ø stability to physical extremes should increase protective titers elicited upon immunization.
“Such correlations indicate that increasing site Ø stability to physical extremes should increase protective titers elicited upon immunization (Fig. 4A) (35).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] By contrast, affinity of RSV F variants for D25 antibody did not show correlation with elicitation of protective titers. Yield of RSV F trimers also did not correlate with protective titers
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
These findings suggested that the very high titers elicited by immunization with RSV F variants stabilized in the prefusion state, especially DS-Cav1, were a result of antibodies targeting antigenic site Ø.
“These findings suggested that the very high titers elicited by immunization with RSV F variants stabilized in the prefusion state, especially DS-Cav1, were a result of antibodies targeting antigenic site Ø.”
Quote in the paperSubstantial claim - Premisecitation
Atomic-level control of antigenicity increasingly appears to be within the reach of structure-based design.
“Importantly, atomic-level control of antigenicity increasingly appears to be within the reach of structure-based design (16, 39, 40).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [16] Jardine J Rational HIV immunogen design to target specific germline B cell receptors Science 2013 340 711 716 23539181 PMC3689846 source
Not checked in the free run.
- cites [39] Dormitzer PR Grandi G Rappuoli R Structural vaccinology starts to deliver Nat. Rev. Microbiol 2012 10 807 813 23154260 source
Not checked in the free run.
- cites [40] Azoitei ML Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold Science 2011 334 373 376 22021856 source
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- Interpretationcitation
The steep slope of this correlation likely reflects the substantially higher neutralization potency observed for prefusion-specific antibodies that target antigenic site Ø.
“Notably, the steep slope of this correlation likely reflects the substantially higher neutralization potency observed for prefusion-specific antibodies that target antigenic site Ø (7, 38).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] McLellan JS Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody Science 2013 340 1113 1117 23618766 PMC4459498 source
Not checked in the free run.
- cites [38] It should be possible to deconvolute the elicited response, by using structurally defined probes, as shown with D25 and motavizumab-bound RSV F in fig. S12
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- May combine two claims. 23
- Classified as probably not a substantial claim. 1
May combine two claims.
Findingown dataThe S190F-V207L pair (Cav1) formed stable RSV F trimers, expressed at 2.2 mg/l, and retained antigenic site Ø.
“A S190F-V207L pair (Cav1) (Fig. 1), formed stable RSV F trimers, expressed at 2.2 mg/l, and retained antigenic site Ø (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataK87F-V90L, S190F-V296F and V207L-V220L variants showed enhanced retention of D25 recognition but expressed at less than 0.1 mg/l.
“Meanwhile, K87F-V90L, S190F-V296F and V207L-V220L variants showed enhanced retention of D25 recognition, but expressed at less than 0.1 mg/l (Table 1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe DS, Cav1, DS-Cav1 and DS-Cav1-TriC variants crystallized in similar 1.5 M tartrate pH 9.5 conditions and diffracted X-rays to resolutions of 3.2 Å, 3.1 Å, 3.1 Å and 2.8 Å, respectively.
“The DS, Cav1, DS-Cav1 and DS-Cav1-TriC variants all crystallized in similar 1.5 M tartrate pH 9.5 conditions, and these cubic crystals diffracted X-rays to resolutions of 3.2 Å, 3.1 Å, 3.1 Å and 2.8 Å, respectively (table S2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe D486H-E487Q-F488W-D489H variant (TriC) formed stable RSV F trimers, expressed at 0.8 mg/l, and retained antigenic site Ø.
“The D486H-E487Q-F488W-D489H variant (TriC) formed stable RSV F trimers, expressed at 0.8 mg/l, and retained antigenic site Ø (Fig. 1 and Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt week 6, DS and DS-Cav1 elicited geometric mean titers of 1222 and 2578 EC50 in macaques, respectively, roughly 5- and 10-fold higher than postfusion F (287 EC50).
“At week 6, DS and DS-Cav1 elicited geometric mean titers of 1222 and 2578 EC50, respectively, roughly 5- and 10-fold higher than postfusion F (287 EC50) (Fig. 4B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBy week 8, geometric mean titers of DS-Cav1 were roughly 60-fold higher than those elicited by postfusion F against the homologous RSV subtype A and more than 80-fold higher against RSV subtype B.
“By week 8, geometric mean titers of DS-Cav1 were roughly 60-fold higher than those elicited by postfusion F against the homologous RSV subtype A (fig. S10) and more than 80-fold higher against RSV subtype B (table S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe indole side chain of Trp488 pointed towards the trimer apex and formed ring-stacking interactions with the side chain of Phe140 of the fusion peptide.
“The indole side chain of Trp488 pointed towards the trimer apex and also formed ring-stacking interactions with the side chain of Phe140 of the fusion peptide (Fig. 2C, far right panel).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataV178N did not stabilize antigenic site Ø, nor did V185E or I506K.
“The substitution V178N, which is predicted to introduce an N-linked glycan compatible with the prefusion but not the postfusion conformation of F, did not appear to stabilize antigenic site Ø, nor did V185E or I506K, which were predicted to place a glutamic acid or a lysine into the interior of the postfusion six-helix bundle (Table 1).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationThis level was ~4-fold higher than that elicited by postfusion F (504 EC50), and ~20-fold higher than the protective threshold.
“This level was ~4-fold higher than that elicited by postfusion F (504 EC50), and ~20-fold higher than the protective threshold (33).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] When palivizumab (Synagis®) is dosed at a concentration of 15 mg/kg, serum levels at trough are ~40 μg/ml, which provides protection in infants from severe disease and protection in cotton rats from RSV infection. In our neutralization assay, ~40 ug/ml of palivizumab yields an EC50 of 100
Not checked in the free run.
- Rests on an assumption: The protective threshold derived from palivizumab serum levels is applicable to vaccine-induced neutralizing activity in humans.
May combine two claims.
Findingown dataFifteen constructs were compatible with D25 binding, six retained D25 recognition for at least 7 days at 4°C, and three could be purified as homogeneous trimers that retained antigenic site Ø.
“Fifteen constructs were compatible with D25 binding, six of which retained D25 recognition for at least 7 days at 4°C, and three of these could be purified as homogeneous trimers that retained antigenic site Ø (Table 1 and fig. S7).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDS-Cav1 elicited neutralizing activity of 3937 EC50 in mice, roughly 8-fold higher than postfusion F and 40-fold higher than the protective threshold.
“By comparison, DS-Cav1 elicited neutralizing activity of 3937 EC50, roughly 8-fold higher than postfusion F and 40-fold higher than the protective threshold (33) (Fig. 3A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] When palivizumab (Synagis®) is dosed at a concentration of 15 mg/kg, serum levels at trough are ~40 μg/ml, which provides protection in infants from severe disease and protection in cotton rats from RSV infection. In our neutralization assay, ~40 ug/ml of palivizumab yields an EC50 of 100
Not checked in the free run.
- Rests on an assumption: The protective threshold derived from palivizumab serum levels is applicable to vaccine-induced neutralizing activity in humans.
May combine two claims.
Findingown dataOf six combinations tested, only two (F488W and D486H-E487Q-F488W-D489H) expressed levels of purified RSV F trimer at greater than 0.1 mg/l and retained D25 recognition.
“Of the six combinations tested, only two (F488W and D486H-E487Q-F488W-D489H) expressed levels of purified RSV F trimer at greater than 0.1 mg/l and retained D25 recognition.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe DS variant retained many features of the prefusion state of RSV F, including the fusion peptide in the interior of the trimeric cavity, but failed to fix antigenic site Ø in its D25-bound conformation.
“Overall, the DS variant retained many of the features of the prefusion state of RSV F, including the fusion peptide in the interior of the trimeric cavity; however, it failed to fix antigenic site Ø in its D25-bound conformation (fig. S8).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMice immunized with 20 μg RSV F bound by antigenic site Ø-directed antibodies developed week 5 geometric mean neutralizing titers of 911 and 1274 EC50 for AM22 and D25 complexes, respectively, roughly double that of postfusion at 10 μg/ml and comparable to those elicited by postfusion at 20 μg/ml.
“CB6F1/J mice immunized with 20 μg RSV F bound by antigenic site Ø-directed antibodies (comprising ~10 μg of RSV F and ~10 μg of the antigen-binding fragment of antibody) developed week 5 geometric mean neutralizing titers of 911 and 1274 EC50 for AM22 and D25 complexes, respectively, roughly double that of postfusion at 10 μg/ml and comparable to those elicited by postfusion at 20 μg/ml (Fig. 3A).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationElicited EC50 titers did not correlate with antigenic responses measured against either prefusion or postfusion forms of RSV F, but did correlate with the level of prefusion-specific responses, either measured as a difference or as a ratio (p=0.005) between prefusion-specific and postfusion-specific RSV F-directed responses.
“Overall, elicited EC50 titers did not correlate with antigenic responses measured against either prefusion or postfusion forms of RSV F, but did correlate with the level of prefusion-specific responses, either measured as a difference or as a ratio (p=0.005) between prefusion-specific and postfusion-specific RSV F-directed responses (Fig. 4E) (37).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] For the “prefusion” form of RSV F, we used the DS-Cav1 stabilized variant of RSV F
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationAntigenic site Ø is a metastable site specific to the prefusion state of RSV F and is targeted by extremely potent RSV-neutralizing antibodies.
“focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies.”
- Also stated in: § Abstract · plain
“Antibodies such as 5C4 (7), AM22, and D25 (11, 12) are substantially more potent than palivizumab and target antigenic site Ø, a metastable site located at the membrane-distal apex of the prefusion RSV F trimer (7).”
- Also stated in: § Engineering of RSV F Antigens · plain
“Antigenic site Ø was chosen as the target site because of its recognition by RSV-neutralizing antibodies that are 10-100-fold more potent than palivizumab (7, 11, 12).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] McLellan JS Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody Science 2013 340 1113 1117 23618766 PMC4459498 source
Not checked in the free run.
- cites [11] Spits H Beaumont T RSV-specific binding molecules and means for producing them 2010 Patent Application 12/600,950
Not checked in the free run.
- cites [12] Beaumont T Bakker AQ Yasuda E RSV specific binding molecule 2012 Patent Application 12/898,325
Not checked in the free run.
- Also stated in: § Abstract · plain
May combine two claims.
PremisecitationAntibodies 5C4, AM22, and D25 are substantially more potent than palivizumab and target antigenic site Ø.
“Antibodies such as 5C4 (7), AM22, and D25 (11, 12) are substantially more potent than palivizumab and target antigenic site Ø, a metastable site located at the membrane-distal apex of the prefusion RSV F trimer (7).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] McLellan JS Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody Science 2013 340 1113 1117 23618766 PMC4459498 source
Not checked in the free run.
- cites [11] Spits H Beaumont T RSV-specific binding molecules and means for producing them 2010 Patent Application 12/600,950
Not checked in the free run.
- cites [12] Beaumont T Bakker AQ Yasuda E RSV specific binding molecule 2012 Patent Application 12/898,325
Not checked in the free run.
May combine two claims.
PremisecitationAntibodies against the RSV F glycoprotein can prevent severe disease in humans, as demonstrated by passive prophylaxis with palivizumab.
“Although RSV infection does not induce fully protective immunity, antibodies against the RSV fusion (F) glycoprotein can prevent severe disease in humans as demonstrated by passive prophylaxis with the F-directed antibody, palivizumab (Synagis®) (2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Johnson S Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus J. Infect. Dis 1997 176 1215 1224 9359721
Not checked in the free run.
May combine two claims.
PremisecitationMotavizumab-epitope scaffolds could elicit immune responses that recognized F, but substantial neutralizing activity was not induced.
“Although motavizumab-epitope scaffolds could elicit immune responses that recognized F, substantial neutralizing activity was not induced (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] McLellan JS Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus J. Mol. Biol 2011 409 853 866 21549714 PMC3107930
Not checked in the free run.
May combine two claims.
PremisecitationThe β-carbons of serine residues 155 and 290 are 4.4 Å apart in the D25-bound RSV F structure and 124.2 Å apart in the postfusion structure.
“The β-carbons of serine residues 155 and 290 are 4.4 Å apart in the D25-bound RSV F structure (7) and 124.2 Å apart in the postfusion structure (5) (Fig. 1 and fig. S2).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] McLellan JS Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody Science 2013 340 1113 1117 23618766 PMC4459498 source
Not checked in the free run.
- cites [5] McLellan JS Yang Y Graham BS Kwong PD Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes J. Virol 2011 85 7788 7796 21613394 PMC3147929
Not checked in the free run.
May combine two claims.
Interpretationown dataThe V207L mutation in Cav1 was shifted by 5.5 Å compared to the D25-bound F structure, suggesting that it is unable to stabilize the α4-helix in the D25-bound conformation.
“The other cavity-filling mutation in Cav1, V207L, was shifted by 5.5 Å compared to the D25-bound F structure, with the C-terminal portion of the α4-helix kinking near Pro205 and adopting distinct conformations in the two crystallization conditions (Fig. 2, second and third panels from left), suggesting that the V207L mutation is unable to stabilize the α4-helix in the D25-bound conformation.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThese results demonstrate a conservation of the relative immunogenicity for the different forms of RSV F immunogen between mice and primates, with DS-Cav1 eliciting RSV-protective titers many times the protective threshold in a primate immune system against both major RSV subtypes.
“Overall, these results demonstrate a conservation of the relative immunogenicity for the different forms of RSV F immunogen between mice and primates, with DS-Cav1 eliciting RSV-protective titers many times the protective threshold in a primate immune system against both major RSV subtypes.”
Quote in the paperSubstantial claim- Rests on an assumption: Neutralizing antibody titers in mice and macaques are predictive of protection against RSV disease in humans.
May combine two claims.
Interpretationown dataThe results suggest that increased structural mimicry would likely not have much effect on immunogenicity, but that additional physical stabilization of antigenic site Ø might improve the protective titers by up to 4-fold.
“The results (Fig. 4A,B) suggest that increased structural mimicry would likely not have much effect on immunogenicity, but that additional physical stabilization of antigenic site Ø might improve the protective titers by up to 4-fold.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningFor pathogens such as HIV-1, influenza, or RSV, where neutralizing antibodies act almost exclusively through one or two envelope glycoproteins, a site- or supersite-specific strategy might have advantages.
“However, for pathogens such as HIV-1, influenza, or RSV, where neutralizing antibodies act almost exclusively through one or two envelope glycoproteins, a site- or supersite-specific strategy might have advantages.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Neutralizing antibody titers in mice and macaques are predictive of protection against RSV disease in humans.
“Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.”
“Overall, these results demonstrate a conservation of the relative immunogenicity for the different forms of RSV F immunogen between mice and primates, with DS-Cav1 eliciting RSV-protective titers many times the protective threshold in a primate immune system against both major RSV subtypes.”
The paper relies on this without support.
The protective threshold derived from palivizumab serum levels is applicable to vaccine-induced neutralizing activity in humans.
“This level was ~4-fold higher than that elicited by postfusion F (504 EC50), and ~20-fold higher than the protective threshold (33).”
“By comparison, DS-Cav1 elicited neutralizing activity of 3937 EC50, roughly 8-fold higher than postfusion F and 40-fold higher than the protective threshold (33) (Fig. 3A).”
The paper relies on this without support.
The crystal structures of engineered RSV F variants represent the conformations relevant to their behavior as immunogens in solution.
“Overall these structures revealed the engineered RSV F variants to be substantially in the D25-bound conformation (28).”
“Strong correlation was observed between binding responses and calculated surface areas (Fig. 4D).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Our data support the idea that the spike does not need to be prefusion stabilized to induce a potent and protective response, unlike respiratory syncytial virus.
“Our data support the idea that the spike does not need to be prefusion stabilized to induce a potent and protective response, unlike respiratory syncytial virus 8 .”
From Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial (2022) · cites this paper as [8]
The Immunogenicity section reports that prefusion-stabilized RSV F elicited neutralizing titers about 4–8 times higher than postfusion F, supporting the contrast the citing sentence draws. But postfusion F also elicited titers above the stated protective threshold, so the paper does not establish that prefusion stabilization is necessary for an RSV-protective response. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNewfound structural insights into F protein conformation have revealed that vaccinating against the prefusion conformation elicits superior neutralizing antibody response.
“Although some candidates have failed clinical trials owing to insufficient neutralizing antibody titres174, newfound structural insights into F protein conformation have revealed that vaccinating against the prefusion conformation elicits superior neutralizing antibody response175–178.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [177]
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mRNA vaccines for infectious diseases: principles, delivery and clinical translation
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Self-citationSARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness
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Self-citationDistinct conformational states of SARS-CoV-2 spike protein
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Self-citationPre-fusion structure of a human coronavirus spike protein
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Self-citationA highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism
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Self-citationA proof of concept for structure-based vaccine design targeting RSV in humans
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Self-citationA thermostable, closed SARS-CoV-2 spike protein trimer
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Self-citationStructure-Based Vaccine Antigen Design
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Self-citationDe novo protein design enables the precise induction of RSV-neutralizing antibodies
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Vaccines against human respiratory syncytial virus in clinical trials, where are we now?
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- Authors
- McLellan, J. S., Chen, M., Joyce, M. G., Sastry, M., Stewart-Jones, G. B. E., Yang, Y., Zhang, B., Chen, L., Srivatsan, S., Zheng, A., Zhou, T., Graepel, K. W., Kumar, A., Moin, S., Boyington, J. C., Chuang, G.-Y., Soto, C., Baxa, U., Bakker, A. Q., Spits, H., Beaumont, T., Zheng, Z., Xia, N., Ko, S.-Y., Todd, J.-P., Rao, S., Graham, B. S., & Kwong, P. D.
- Affiliations
- National Institutes of Health (US)
- Frederick National Laboratory for Cancer Research (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- Xiamen University (CN)
- Corresponding author
- Chen, Man
- Joyce, M. Gordon
- Sastry, Mallika
- Stewart-Jones, Guillaume B. E.
- Yang, Yongping
- Zhang, Baoshan
- Graham, Barney S.
- Kwong, Peter D.
- ORCID
- McLellan, Jason S.
- Joyce, M. Gordon
- Stewart-Jones, Guillaume B. E.
- Yang, Yongping
- Zhang, Baoshan
- Srivatsan, Sanjay
- Zheng, Anqi
- Zhou, Tongqing
- Graepel, Kevin W.
- Moin, Syed
- Boyington, Jeffrey C.
- Chuang, Gwo-Yu
- Soto, Cinque
- Baxa, Ulrich
- Bakker, Arjen Q.
- Spits, Hergen
- Beaumont, Tim
- Zheng, Zizheng
- Xia, Ningshao
- Ko, Sung-Youl
- Todd, John-Paul
- Graham, Barney S.
- Kwong, Peter D.
- Venue
- Science
- Published
- 2013-11
- Volume
- 342
- Issue
- 6158
- Pages
- 592-598
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4461862
- OpenAlex
- W2126114330
- Semantic Scholar
- d90a11553824b7d801817ede252606ed96583a22
- Cited by
- 1,126
- References
- 43
- Citations by year
- 2026: 122 · 2025: 113 · 2024: 116 · 2023: 97 · 2022: 100 · 2021: 106 · 2020: 102 · 2019: 73 · 2018: 50 · 2017: 66 · 2016: 60 · 2015: 72 · 2014: 46 · 2013: 3
- FWCI
- 44.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (ZIAAI005061, ZIAAI005024)
- Topics
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Keywords
- respiratory syncytial virus, RSV F glycoprotein, fusion protein, structure-based vaccine design, antigenic determinants, cysteine engineering, neutralizing antibodies, RSV vaccine, mouse immunization
- MeSH terms
- Animals, Antigens, Viral, Cysteine, Glycoproteins, Humans, Macaca, Vaccination, Viral Fusion Proteins, Protein Engineering, Protein Structure, Tertiary, Respiratory Syncytial Virus Infections, Crystallography, X-Ray, Respiratory Syncytial Virus Vaccines, Mice, Protein Multimerization, Protein Stability, Antibodies, Neutralizing
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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