scholarly journals Original antigenic sin responses to Betacoronavirus spike proteins are observed in a mouse model, but are not apparent in children following SARS-CoV-2 infection

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256482
Author(s):  
Stacey A. Lapp ◽  
Venkata Viswanadh Edara ◽  
Austin Lu ◽  
Lilin Lai ◽  
Laila Hussaini ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Healthy Children ◽  
Healthy Controls ◽  
Igg Antibodies ◽  
Human Coronavirus ◽  
Clinical Responses ◽  
Original Antigenic Sin ◽  
Inflammatory Syndrome

Background The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Results Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Conclusions Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.

scholarly journals Original antigenic sin responses to heterologous Betacoronavirus spike proteins are observed in mice following intramuscular administration, but are not apparent in children following SARS-CoV-2 infection

2021 ◽  
Author(s):  
Stacey A. Lapp ◽  
Venkata Viswanadh Edara ◽  
Austin Lu ◽  
Lilin Lai ◽  
Laila Hussaini ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Intramuscular Administration ◽  
Healthy Children ◽  
Healthy Controls ◽  
Igg Antibodies ◽  
Clinical Responses ◽  
Original Antigenic Sin ◽  
Inflammatory Syndrome

Background: The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives: We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods: Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n=14 per group) were analyzed for these same antibodies. Results: Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P=0.012), these titers correlated positively with both SARS-CoV-2 binding (r=0.7577, P<0.001) and neutralizing (r=0.6201, P=0.001) antibodies. Conclusions: Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.

scholarly journals Neutralization Assessments Reveal High Cardiothoracic Ratio and Old Age as Independent Predictors of Low Neutralizing Antibody Titers in Hemodialysis Patients Receiving a Single Dose of COVID-19 Vaccine

2022 ◽  
Vol 12 (1) ◽  
pp. 68
Author(s):  
Chun-Yu Chen ◽  
Kuan-Ting Liu ◽  
Shin-Ru Shih ◽  
Jung-Jr Ye ◽  
Yih-Ting Chen ◽  
...  
Keyword(s):  
Single Dose ◽  
Old Age ◽  
Neutralizing Antibodies ◽  
Additive Model ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Neutralization Titer ◽  
Cardiothoracic Ratio

Background: Data are lacking regarding predictors of quantification of neutralizing antibodies (nAbs) based on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 50% neutralization titer (NT50) after a single dose of COVID-19 vaccine in hemodialysis (HD) patients. Methods: This prospective single-center study enrolled 200 HD patients and 82 healthy subjects to estimate antibodies against the SARS-CoV-2 viral spike protein 1 and receptor-binding domain after a first dose of a COVID-19 vaccine (ChAdOx1 or mRNA-1273), measured by enzyme-linked immunosorbent assay and applied spline-based generalized additive model regression analysis to predict NT50 converted to international units. Results: After the first dose of ChAdOx1, multiple linear regression showed that age (p = 0.011) and cardiothoracic ratio (p = 0.002) were negatively associated with NT50. Older age (OR = 0.958, p = 0.052) and higher cardiothoracic ratio (OR < 0.001, p = 0.037) could predict negative humoral response (NT50 < 35.13 IU/mL). NT50 was lower in HD patients compared with healthy controls receiving ChAdOx1 (10.68 vs. 43.01 IU/m, p < 0.001) or mRNA-1273 (36.39 vs. 262.2 IU/mL, p < 0.001). ChAdOx1 elicited lower GMTs than mRNA-1273 in the HD cohort (10.68 vs. 36.39 IU/mL, p < 0.001) and in healthy controls (43.01 vs. 262.22 IU/mL, p < 0.001). Conclusion: High cardiothoracic ratio and old age could independently predict a decline in nAb titers in an HD cohort vaccinated with a single dose of ChAdOx1.

scholarly journals Long-term persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific and neutralizing antibodies in recovered COVID-19 patients

2021 ◽  
Author(s):  
Jira Chansaenroj ◽  
Ritthideach Yorsaeng ◽  
Nasamon Wanlapakorn ◽  
Chintana Chirathaworn ◽  
Natthinee Sudhinaraset ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Symptom Onset ◽  
Neutralizing Antibodies ◽  
Serum Antibody ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Spike Protein ◽  
Immunological Study ◽  
Igg Antibody ◽  
Vaccine Schedule

Abstract Understanding antibody responses after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can guide the coronavirus disease 2019 (COVID-19) vaccine schedule. This study aimed to assess the dynamics of SARS-CoV-2 antibodies, including anti-spike protein 1 (S1) immunoglobulin (Ig)G, anti-receptor-binding domain (RBD) total Ig, anti-S1 IgA, and neutralizing antibody against wild-type SARS-CoV-2 in a cohort of patients who were previously infected with SARS-CoV-2. Between March and May 2020, 531 individuals with virologically confirmed cases of SARS-CoV-2 infection were enrolled in our immunological study. The neutralizing titers against SARS-CoV-2 were detected in 95.2%, 86.7%, 85.0%, and 85.4% of recovered COVID-19 patients at 3, 6, 9, and 12 months after symptom onset, respectively. The seropositivity rate of anti-S1 IgG, anti-RBD total Ig, anti-S1 IgA, and neutralizing titers remained at 68.6%, 89.6%, 77.1%, and 85.4%, respectively, at 12 months after symptom onset. The half-life of neutralizing titers was estimated at 100.7 days (95% confidence interval = 44.5 – 327.4 days, R2 = 0.106). These results support that the decline in serum antibody levels over time depends on the symptom severity, and the individuals with high IgG antibody titers experienced a significantly longer persistence of SARS-CoV-2-specific antibody responses than those with lower titers.

scholarly journals Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated with Delta Inulin Adjuvants Provide Enhanced Protection while Ameliorating Lung Eosinophilic Immunopathology

2014 ◽  
Vol 89 (6) ◽  
pp. 2995-3007 ◽  
Author(s):  
Yoshikazu Honda-Okubo ◽  
Dale Barnard ◽  
Chun Hao Ong ◽  
Bi-Hung Peng ◽  
Chien-Te Kent Tseng ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Case Fatality ◽  
Neutralizing Antibody ◽  
The Elderly ◽  
Spike Protein ◽  
Interleukin 4 ◽  
Unique Problem ◽  
Antibody Titers ◽  
Ifn Γ

ABSTRACTAlthough the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) epidemic was controlled by nonvaccine measures, coronaviruses remain a major threat to human health. The design of optimal coronavirus vaccines therefore remains a priority. Such vaccines present major challenges: coronavirus immunity often wanes rapidly, individuals needing to be protected include the elderly, and vaccines may exacerbate rather than prevent coronavirus lung immunopathology. To address these issues, we compared in a murine model a range of recombinant spike protein or inactivated whole-virus vaccine candidates alone or adjuvanted with either alum, CpG, or Advax, a new delta inulin-based polysaccharide adjuvant. While all vaccines protected against lethal infection, addition of adjuvant significantly increased serum neutralizing-antibody titers and reduced lung virus titers on day 3 postchallenge. Whereas unadjuvanted or alum-formulated vaccines were associated with significantly increased lung eosinophilic immunopathology on day 6 postchallenge, this was not seen in mice immunized with vaccines formulated with delta inulin adjuvant. Protection against eosinophilic immunopathology by vaccines containing delta inulin adjuvants correlated better with enhanced T-cell gamma interferon (IFN-γ) recall responses rather than reduced interleukin-4 (IL-4) responses, suggesting that immunopathology predominantly reflects an inadequate vaccine-induced Th1 response. This study highlights the critical importance for development of effective and safe coronavirus vaccines of selection of adjuvants based on the ability to induce durable IFN-γ responses.IMPORTANCECoronaviruses such as SARS-CoV and Middle East respiratory syndrome-associated coronavirus (MERS-CoV) cause high case fatality rates and remain major human public health threats, creating a need for effective vaccines. While coronavirus antigens that induce protective neutralizing antibodies have been identified, coronavirus vaccines present a unique problem in that immunized individuals when infected by virus can develop lung eosinophilic pathology, a problem that is further exacerbated by the formulation of SARS-CoV vaccines with alum adjuvants. This study shows that formulation of SARS-CoV spike protein or inactivated whole-virus vaccines with novel delta inulin-based polysaccharide adjuvants enhances neutralizing-antibody titers and protection against clinical disease but at the same time also protects against development of lung eosinophilic immunopathology. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. Thus, delta inulin adjuvants may offer a unique ability to develop safer and more effective coronavirus vaccines.

scholarly journals Defective neutralizing antibody response to SARS-CoV-2 in vaccinated dialysis patients

2021 ◽  
Author(s):  
Jessica Bassi ◽  
Olivier Giannini ◽  
Chiara Silacci-Fregni ◽  
Laura Pertusini ◽  
Paolo Hitz ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Therapeutic Strategies ◽  
Affinity Maturation ◽  
Plasma Samples ◽  
Igg Antibodies ◽  
Dialysis Patients ◽  
Antibody Avidity ◽  
Neutralizing Activity ◽  
Frail Population

Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis (HD) and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naive HD patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity, consistent with a delayed affinity maturation of SARS-CoV-2 S-specific B cells. These data indicate that dialysis patients should be considered for an additional boost and other therapeutic strategies, including early immunotherapy with monoclonal antibodies.

scholarly journals Neutralizing antibody and soluble ACE2 inhibition of a replication-competent VSV-SARS-CoV-2 and a clinical isolate of SARS-CoV-2

2020 ◽  
Author(s):  
James Brett Case ◽  
Paul W. Rothlauf ◽  
Rita E. Chen ◽  
Zhuoming Liu ◽  
Haiyan Zhao ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Neutralization Assay ◽  
Spike Protein ◽  
Glycoprotein Gene ◽  
Level 3 ◽  
Focus Reduction ◽  
High Throughput Imaging ◽  
Biosafety Level

ABSTRACTAntibody-based interventions against SARS-CoV-2 could limit morbidity, mortality, and possibly disrupt epidemic transmission. An anticipated correlate of such countermeasures is the level of neutralizing antibodies against the SARS-CoV-2 spike protein, yet there is no consensus as to which assay should be used for such measurements. Using an infectious molecular clone of vesicular stomatitis virus (VSV) that expresses eGFP as a marker of infection, we replaced the glycoprotein gene (G) with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and developed a high-throughput imaging-based neutralization assay at biosafety level 2. We also developed a focus reduction neutralization test with a clinical isolate of SARS-CoV-2 at biosafety level 3. We compared the neutralizing activities of monoclonal and polyclonal antibody preparations, as well as ACE2-Fc soluble decoy protein in both assays and find an exceptionally high degree of concordance. The two assays will help define correlates of protection for antibody-based countermeasures including therapeutic antibodies, immune γ-globulin or plasma preparations, and vaccines against SARS-CoV-2. Replication-competent VSV-eGFP-SARS-CoV-2 provides a rapid assay for testing inhibitors of SARS-CoV-2 mediated entry that can be performed in 7.5 hours under reduced biosafety containment.

scholarly journals Seroprevalence of SARS-CoV-2 IgG Antibodies After the Second BNT162b2 mRNA Vaccine in Japanese Kidney Transplant Recipients

2021 ◽  
Author(s):  
Tomoko Hamaya ◽  
Shingo Hatakeyama ◽  
Tohru Yoneyama ◽  
Yuki Tobisawa ◽  
Hirotake Kodama ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Kidney Transplant ◽  
Neutralizing Antibodies ◽  
Humoral Response ◽  
Healthy Controls ◽  
Transplant Recipients ◽  
Igg Antibodies ◽  
Kidney Transplant Recipients ◽  
Univariate Logistic Regression Analysis ◽  
Antibody Titers

Abstract We aimed to evaluate the rate of anti–SARS-CoV-2 IgG seropositivity and investigated factors associated with seropositivity after the second SARS-CoV-2 mRNA vaccination in kidney transplant (KT) recipients. This retrospective study conducted between June 2021 and November 2021 included 106 KT recipients and 127 healthy controls who received the second dose of the BNT162b2 mRNA vaccine at least seven days before the measurement of antibody titers. The titers of immunoglobulin G (IgG) antibodies against the receptor-binding domain of SARS-CoV-2 spike (S) protein were determined. Seropositivity was defined as an anti–SARS-CoV-2 IgG level of ≥15 units/mL, which was considered as the presence of sufficient neutralizing antibodies. The median ages and the seroprevalence rates of the healthy controls and KT recipients were 68 and 56 years and 98% and 22%, respectively. Univariate logistic regression analysis revealed that age >53 years, rituximab use, mycophenolate mofetil use, and KT vintage <7 years were negatively associated with anti–SARS-CoV-2 IgG seropositivity in KT recipients. Humoral response after the second BNT162b2 mRNA vaccine was greatly hindered by immunosuppression therapy in KT recipients. Older age, rituximab use, mycophenolate mofetil use, and KT vintage may play key roles in seroconversion.

scholarly journals Studies on the level of neutralizing antibodies produced by inactivated COVID-19 vaccines in the real world

2021 ◽  
Author(s):  
Haiying Zhang ◽  
Yuyuan Jia ◽  
Ying Ji ◽  
Xu Cong ◽  
Yan Liu ◽  
...  
Keyword(s):  
Real World ◽  
Linear Correlation ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Igg Antibodies ◽  
Serum Samples ◽  
The Real ◽  
Significant Difference ◽  
Positive Rate ◽  
High Linear Correlation

Background Although effective vaccines have been developed against COVID-19, the level of neutralizing antibodies (Nabs) induced after vaccination in the real world is still unknown. To evaluate the level and persistence of NAbs induced by two inactivated COVID-19 vaccines in China. Methods and findings Serum samples were collected from 1,335 people aged 18 and over who were vaccinated with COVID-19 inactivated vaccine in Peking University People's Hospital from January 19 to June 23, 2021, for detection of COVID-19 antibodies. The WHO standard of SARS-CoV-2 NAbs was detected. The coefficients of variation between the detection results and the true values of the NAbs detected by the WHO standard were all lower than the WHO international standard 3% after the dilution of the original and the dilution of the theoretical concentrations of 500 IU/mL, 250 IU/mL, 125 IU/mL, 72.5 IU/mL, 36.25 IU/mL and 18.125 IU/mL. On day 11-70, the positive rate of NAbs against COVID-19 was 82% to 100%; From day 71 to 332, the positive rate of NAbs decreased to 27%. The level of NAbs was significantly higher at 3-8 Weeks than at 0-3 Weeks. There was a high linear correlation between NAbs and IgG antibodies in 1335 vaccinated patients. NAbs levels were decreased in 31 of 38 people (81.6%) at two time points after the second dose of vaccine. There was no significant difference in age between the group with increased and decreased neutralizing antibody levels (x2 =-0.034, P>0.05). The positive rate of NAbs in the two-dose vaccine group (77.3%) was significantly higher than that in the one-dose group (18.1%), with statistical difference (x2=312.590, P<0.001). A total of 206 people who were 11-70 days after receiving the second dose were tested and divided into three groups: 18-40 years old, 41-60 years old and >60 years old. The positive rates of NAbs in three groups (18-40 years old, 41-60 years old and >60 years old) were 95.14%, 78.43% and 81.8%, respectively. The positive rate of NAbs was significantly higher in 18-40 years old than in 41-60 years old (x2=12.547, P <0.01). The titer of NAbs in 18-40 years old group was significantly higher than that in 41-60 years old group (t=-0.222, P <0.01). The positive rate of NAbs in male group (89.32%) was lower than in female (91.26%), but there was no significant difference (x2=0.222, P >0.05). Conclusions The positive rate of NAbs was the highest from 10 to 70 days after the second dose of vaccine, and the positive rate gradually decreased as time went by. There was a high linear correlation between COVID-19 NAbs and IgM/IgG antibodies in vaccinators, suggesting that in cases where NAbs cannot be detected, IgM/IgG antibodies can be detected instead. The level of NAbs produced after vaccination was affected by age, but not by gender. The highest levels of NAbs were produced between shots 21 to 56 days apart, suggesting that 21 to 56 days between shots is suitable for vaccination.

scholarly journals Modified Vaccinia Ankara Based SARS-CoV-2 Vaccine Expressing Full-Length Spike Induces Strong Neutralizing Antibody Response

2020 ◽  
Author(s):  
Nanda Kishore Routhu ◽  
Sailaja Gangadhara ◽  
Narayanaiah Cheedarla ◽  
Ayalnesh Shiferaw ◽  
Sheikh Abdul Rahman ◽  
...  
Keyword(s):  
Antibody Response ◽  
Room Temperature ◽  
Vaccine Candidate ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Full Length ◽  
Spike Protein ◽  
Strongly Correlated ◽  
Igg Antibodies ◽  
Potential Vaccine

AbstractThere is a great need for the development of vaccines for preventing SARS-CoV-2 infection and mitigating the COVID-19 pandemic. Here, we developed two modified vaccinia Ankara (MVA) based vaccines which express either a membrane anchored full-length spike protein (MVA/S) stabilized in a prefusion state or the S1 region of the spike (MVA/S1) which forms trimers and is secreted. Both immunogens contained the receptor-binding domain (RBD) which is a known target of antibody-mediated neutralization. Following immunizations with MVA/S or MVA/S1, both spike protein recombinants induced strong IgG antibodies to purified full-length SARS-CoV-2 spike protein. The MVA/S induced a robust antibody response to purified RBD, S1 and S2 whereas MVA/S1 induced an antibody response to the S1 region outside of the RBD region. Both vaccines induced an antibody response in the lung and that was associated with induction of bronchus-associated lymphoid tissue. MVA/S but not MVA/S1 vaccinated mice generated robust neutralizing antibody responses against SARS-CoV-2 that strongly correlated with RBD antibody binding titers. Mechanistically, S1 binding to ACE-2 was strong but reduced following prolonged pre-incubation at room temperature suggesting confirmation changes in RBD with time. These results demonstrate MVA/S is a potential vaccine candidate against SARS-CoV-2 infection.

scholarly journals SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses

2021 ◽  
Author(s):  
George W. Carnell ◽  
Katarzyna A. Ciazynska ◽  
David A. Wells ◽  
Xiaoli Xiong ◽  
Ernest T. Aguinam ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Protein S ◽  
Spike Protein ◽  
Receptor Binding Site ◽  
S Protein ◽  
Closed State ◽  
S Proteins ◽  
Protein Constructs

AbstractThe majority of SARS-CoV-2 vaccines in use or in advanced clinical development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described that act against both open and closed conformations. The long-term success of vaccination strategies will depend upon inducing antibodies that provide long-lasting broad immunity against evolving, circulating SARS-CoV-2 strains, while avoiding the risk of antibody dependent enhancement as observed with other Coronavirus vaccines. Here we have assessed the results of immunization in a mouse model using an S protein trimer that is arrested in the closed state to prevent exposure of the receptor binding site and therefore interaction with the receptor. We compared this with a range of other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induce a long-lived, strongly neutralizing antibody response as well as T-cell responses. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralising responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, virus-inhibiting immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.

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