scholarly journals Structure and computation-guided design of a mutation-integrated trimeric RBD candidate vaccine with broad neutralization against SARS-CoV-2

2021 ◽  
Author(s):  
Yu Liang ◽  
Jing Zhang ◽  
Run Yu Yuan ◽  
Mei Yu Wang ◽  
Peng He ◽  
...  

The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 is an attractive target for COVID-19 vaccine developments, which naturally exists in a trimeric form. Here, guided by structural and computational analyses, we present a mutation-integrated trimeric form of RBD (mutI tri-RBD) as a broadly protective vaccine candidate, in which three RBDs were individually grafted from three different circulating SARS-CoV-2 strains including the prototype, Beta (B.1.351) and Kappa (B.1.617). The three RBDs were then connected end-to-end and co-assembled to possibly mimic the native trimeric arrangements in the natural S protein trimer. The recombinant expression of the mutI tri-RBD, as well as the homo-tri-RBD where the three RBDs were all truncated from the prototype strain, by mammalian cell exhibited correct folding, strong bio-activities, and high stability. The immunization of both the mutI tri-RBD and homo-tri-RBD plus aluminum adjuvant induced high levels of specific IgG and neutralizing antibodies against the SARS-CoV-2 prototype strain in mice. Notably, regarding to the immune-escape Beta (B.1.351) variant, mutI tri-RBD elicited significantly higher neutralizing antibody titers than homo-tri-RBD. Furthermore, due to harboring the immune-resistant mutations as well as the evolutionarily convergent hotspots, the designed mutI tri-RBD also induced strong broadly neutralizing activities against various SARS-CoV-2 variants, especially the variants partially resistant to homo-tri-RBD. Homo-tri-RBD has been approved by the China National Medical Products Administration to enter clinical trial (No. NCT04869592), and the superior broad neutralization performances against SARS-CoV-2 support the mutI tri-RBD as a more promising vaccine candidate for further clinical developments.

2020 ◽  
Author(s):  
Alexander Kwarteng ◽  
Ebenezer Asiedu ◽  
Augustina Angelina Sylverken

Abstract Recently, several mutations in the SARS-CoV-2 genome have been identified and reported. However, little is currently known about the influence of these mutations on the infectivity, transmissibility and antigenicity of the virus. Here, using an integrative computational approach, we characterized the G476S variant of SARS-CoV-2 focusing on interactions with ACE-2 and neutralizing antibodies. The substitution of Gly-476 to Ser-476 in the SARS-CoV-2 Receptor-binding domain (RBD) largely affected the structural dynamics of the S-protein leading to significant influence on the interactions with ACE-2 and neutralizing antibodies. Structural properties of the S-protein such as conformation changes, residual fluctuations and residue surface area largely varied between the wild-type and G476S variant, especially in the RBD. Analyses of the interaction energies between S-protein and ACE-2 suggest that the G476S variant may have enhanced interactions with ACE-2 compared to the wild-type. The G476S variant was found to have weaker interactions with the neutralizing antibody H014 compared to the wild-type. Collectively, our findings have implications for the infectivity and antigenicity of the G476S variant of SARS-CoV-2.


2021 ◽  
Author(s):  
Yong Yang ◽  
Jinkai Zang ◽  
Shiqi Xu ◽  
Xueyang Zhang ◽  
Sule Yuan ◽  
...  

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current SARS-CoV-2 vaccines are based on spike (S) protein, S1 subunit, or receptor-binding domain (RBD) of prototype strain. Emergence of several novel SARS-CoV-2 variants has raised concern about potential immune escape. In this study, we performed an immunogenicity comparison of ancestral RBD, S1, and S ectodomain trimer (S-trimer) antigens and tested the efficacy of these prototype vaccines against the circulating variants, especially B.1.617 that has been linked to India's current COVID-19 surge. We found that RBD and S-trimer proteins could induce significantly higher neutralizing antibody titers than S1 protein. For the three vaccines, the neutralizing titers decreased over time, but still remained high for at least five months after immunization. Importantly, the three prototype vaccines were still effective in neutralizing the variants of concern, although B.1.351 and B.1.617.1 lineages showed varying degrees of reduction in neutralization by the immune sera. The vaccines-induced sera were shown to block receptor binding and inhibit S protein-mediated membrane fusion. In addition, the immune sera did not promote antibody-dependent enhancement (ADE) in vitro. Our work provides valuable information for development of SARS-CoV-2 subunit vaccines and also supports the continued use of ancestral RBD or S-based vaccines to fight the COVID-19 epidemic.


2021 ◽  
Vol 118 (12) ◽  
pp. e2026153118
Author(s):  
Mijia Lu ◽  
Piyush Dravid ◽  
Yuexiu Zhang ◽  
Sheetal Trivedi ◽  
Anzhong Li ◽  
...  

The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR−/−mice, IFNAR−/−-hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2–specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine.


Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1421
Author(s):  
Yong Yang ◽  
Jinkai Zang ◽  
Shiqi Xu ◽  
Xueyang Zhang ◽  
Sule Yuan ◽  
...  

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most of the currently approved SARS-CoV-2 vaccines use the prototype strain-derived spike (S) protein or its receptor-binding domain (RBD) as the vaccine antigen. The emergence of several novel SARS-CoV-2 variants has raised concerns about potential immune escape. In this study, we performed an immunogenicity comparison of prototype strain-derived RBD, S1, and S ectodomain trimer (S-trimer) antigens and evaluated their induction of neutralizing antibodies against three circulating SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.617.1. We found that, at the same antigen dose, the RBD and S-trimer vaccines were more potent than the S1 vaccine in eliciting long-lasting, high-titer broadly neutralizing antibodies in mice. The RBD immune sera remained highly effective against the B.1.1.7, B.1.351, and B.1.617.1 variants despite the corresponding neutralizing titers decreasing by 1.2-, 2.8-, and 3.5-fold relative to that against the wild-type strain. Significantly, the S-trimer immune sera exhibited comparable neutralization potency (less than twofold variation in neutralizing GMTs) towards the prototype strain and all three variants tested. These findings provide valuable information for further development of recombinant protein-based SARS-CoV-2 vaccines and support the continued use of currently approved SARS-CoV-2 vaccines in the regions/countries where variant viruses circulate.


2005 ◽  
Vol 86 (5) ◽  
pp. 1435-1440 ◽  
Author(s):  
Milosz Faber ◽  
Elaine W. Lamirande ◽  
Anjeanette Roberts ◽  
Amy B. Rice ◽  
Hilary Koprowski ◽  
...  

Foreign viral proteins expressed by rabies virus (RV) have been shown to induce potent humoral and cellular immune responses in immunized animals. In addition, highly attenuated and, therefore, very safe RV-based vectors have been constructed. Here, an RV-based vaccine vehicle was utilized as a novel vaccine against severe acute respiratory syndrome coronavirus (SARS-CoV). For this approach, the SARS-CoV nucleocapsid protein (N) or envelope spike protein (S) genes were cloned between the RV glycoprotein G and polymerase L genes. Recombinant vectors expressing SARS-CoV N or S protein were recovered and their immunogenicity was studied in mice. A single inoculation with the RV-based vaccine expressing SARS-CoV S protein induced a strong SARS-CoV-neutralizing antibody response. The ability of the RV-SARS-CoV S vector to confer immunity after a single inoculation makes this live vaccine a promising candidate for eradication of SARS-CoV in animal reservoirs, thereby reducing the risk of transmitting the infection to humans.


2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Yuan Liu ◽  
Lianpan Dai ◽  
Xiaoli Feng ◽  
Ran Gao ◽  
Nan Zhang ◽  
...  

AbstractIn the face of the emerging variants of SARS-CoV-2, there is an urgent need to develop a vaccine that can induce fast, effective, long-lasting and broad protective immunity against SARS-CoV-2. Here, we developed a trimeric SARS-CoV-2 S protein vaccine candidate adjuvanted by PIKA, which can induce robust cellular and humoral immune responses. The results showed a high level of neutralizing antibodies induced by the vaccine was maintained for at least 400 days. In the study of non-human primates, PIKA adjuvanted S-trimer induced high SARS-CoV-2 neutralization titers and protected from virus replication in the lung following SARS-CoV-2 challenge. In addition, the long-term neutralizing antibody response induced by S-trimer vaccine adjuvanted by PIKA could neutralize multiple SARS-CoV-2 variants and there is no obvious different among the SARS- CoV-2 variants of interest or concern, including B.1.351, B.1.1.7, P.1, B.1.617.1 and B.1.617.2 variants. These data support the utility of S-trimer protein adjuvanted by PIKA as a potential vaccine candidate against SARS-CoV-2 infection.


2021 ◽  
Author(s):  
Yiwei Cao ◽  
Yeol Kyo Choi ◽  
Martin Frank ◽  
Hyeonuk Woo ◽  
Sang-Jun Park ◽  
...  

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 (ACE2) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.


2021 ◽  
Vol 5 (1) ◽  
pp. 077-086
Author(s):  
Nikhra Vinod

Introduction - evolution of SARS-CoV-2 variants: With the unrestrained pandemic for over last one-and-half year, SARS-CoV-2 seems to have adapted to its habitat, the human host, through mutations that facilitate its replication and transmission. The G variant incorporating D614G mutation, potently more transmissible than the ancestral virus arose during January 2020 and spread widely. Since then, various SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with higher infectivity or virulence or both, have evolved on the background of G variant, and spread widely. SARS-CoV-2 infection and the immunodynamics: As the virus becomes more transmissible, its lethality may drop. Apart from the humoral immunity, T-cell recognition from a previous SARS-CoV-2 infection or vaccination may modify the disease transmission correlates and its clinical manifestations. On the other hand, the immunity generated may reduce probability of re-infection as well as limit evolution of adaptive mutations, and emergence of highly infectious and immune-escape variants. There are complex issues related to the SARS-CoV-2 evolutionary dynamics and host’s immunodynamics. Trending etiopathoimmunological correlates: The evolution potential of SARS-CoV-2 is limited because of proofreading function of nsp14. The S protein mutations affect transmissibility, virulence, and vaccine efficacy. The D614G mutation in G variant with higher infectivity has turned the Chinese epidemic into a pandemic. Other SARS-CoV-2 variants, such as Alpha, Beta, Gamma, and Delta seem to have evolved as result of adaptation to selective pressures during periods of prolonged infections and subsequent transmission. Further, there is issue of convergent association of mutations. Basics of immunity and immune system failure: The nature of the immune response after natural SARS-CoV-2 infection is variable and diverse. There are pre-existing neutralizing antibodies and sensitized T cells elicited during previous infection with seasonal CoVs influencing the disease susceptibility and course. The virus has evolved adaptive mechanisms to reduce its exposure to IFN-I and there are issues related to erratic and overactive immune response. The altered neutralizing epitopes in the S protein in SARS-CoV-2 variants modify the immune landscapes and clinical manifestations. Conclusion: current scenarios and prospects: Presently, the SARS-CoV-2 infection is widespread with multiple evolving infectious variants. There is probability of its transition from epidemic to endemic phase in due course manifesting as a mild disease especially in the younger population. Conversely, the pandemic may continue with enhanced disease severity due to evolving variants, expanded infection pool, and changing immunity landscape. There is need to plan for the transition and continued circulation of the virus during the endemic phase or continuing pandemic for indefinite period.


2021 ◽  
Author(s):  
George W. Carnell ◽  
Katarzyna A. Ciazynska ◽  
David A. Wells ◽  
Xiaoli Xiong ◽  
Ernest T. Aguinam ◽  
...  

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.


2021 ◽  
Author(s):  
Neeltje van Doremalen ◽  
Robert Fischer ◽  
Jonathan Schulz ◽  
Myndi Holbrook ◽  
Brian Smith ◽  
...  

Many different vaccine candidates against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of COVID-19, are currently approved and under development. Vaccine platforms vary from mRNA vaccines to viral-vectored vaccines, and several candidates have been shown to produce humoral and cellular responses in small animal models, non-human primates and human volunteers. In this study, six non-human primates received a prime-boost intramuscular vaccination with 4 μg of mRNA vaccine candidate CV07050101, which encodes a pre-fusion stabilized spike (S) protein of SARS-CoV-2. Boost vaccination was performed 28 days post prime vaccination. As a control, six animals were similarly injected with PBS. Humoral and cellular immune responses were investigated at time of vaccination, and two weeks afterwards. No antibodies could be detected two and four weeks after prime vaccination. Two weeks after boost vaccination, binding but no neutralizing antibodies were detected in 4 out of 6 non-human primates. SARS-CoV-2 S protein specific T cell responses were detected in these 4 animals. In conclusion, prime-boost vaccination with 4 μg of vaccine candidate CV07050101 resulted in limited immune responses in 4 out of 6 non-human primates.


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