An overview of spike protein antigen COVID-19 vaccine candidates

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still causing immense devastation worldwide. Control strategies are often limited by the need for personal compliance. In the absence of effective therapeutic strategies, vaccines are perceived to be the only way out.

A new paper in the journal Reviews in Medical Virology provides a perspective on current vaccine development strategies and tools, which may allow the production of safe and effective vaccines.

The spike protein

The SARS-CoV-2 virus enters the target host cell by means of its spike glycoprotein. This surface protein is composed of two subunits, the S1 and the S2.  The S1 mediated viral attachment to the host cell receptor, the angiotensin‐converting enzyme 2 (ACE2), while the S2 follows this up by viral-membrane fusion, allowing internalization of the virus.

The spike is a major focus of neutralizing antibodies and therefore of vaccine development efforts. The S1 subunit makes contact with the receptor via its receptor-binding domain (RBD). Compared to the earlier SARS-CoV, the RBD in the currently circulating virus binds with 10-20-fold higher efficacy. This may account for its higher spread, along with the novel polybasic furin cleavage site at the S1/S2 interface.

The metastable conformation of the prefusion spike occurs following S1-ACE2 binding, capable of switching between the ‘up’ and ‘down’ conformation, in which the protein is accessible and inaccessible to the receptor, respectively. The partially ‘up’ state appears to be the norm in highly pathogenic coronaviruses (CoVs), in contrast to the mostly ‘down’ state in the human seasonal CoVs.

Glycosylation is a critical functional feature of the SARS-CoV-2 spike, both facilitating its proper folding and immune escape by preventing specific neutralizing epitopes from being bound by their antibodies. Some can mask the RBD as well, especially if the RBD is in the ‘down’ conformation.

The spike protein, particularly the RBD, is therefore the main antigenic target for vaccine formulation.

The spike also activates CD4 and CD8 T cells from anywhere beyond 70% of COVID-19 patients. T cell responses are not only cross-reactive but can induce long-term protection. These cells have specificity against the virus, and high cytotoxicity, in acute SARS-CoV-2 infection.

The CD4-associated responses induce strong IgA and IgG antibody production. The T cell responses are strongly associated with neutralizing antibody titers. The strong Th1 bias seen with these cellular responses makes antibody-mediated enhancement of disease unlikely.

The SARS-CoV-2 virus enters the target host cell by means of its spike glycoprotein. Image Credit: Juan Gaertner / Shutterstock
The SARS-CoV-2 virus enters the target host cell by means of its spike glycoprotein. Image Credit: Juan Gaertner / Shutterstock

Vaccine development platforms

Earlier vaccines against the SARS-CoV were based on whole inactivated or attenuated virus. These were associated with antibody-dependent enhancement (ADE) of disease, or exaggerated immune responses.

To avoid this with vaccines built around the new virus, second- and third-generation vaccines use only viral antigens, especially the spike antigen. These use platforms like viral vectors, both replication-competent and replication-incompetent, DNA and RNA.

Other approaches make use of recombinant proteins and virus-like particles (VLPs) formulated in nanoparticles based on lipids (LNPs) or on polymers that encapsulate the nucleic acid.  These formulations may make use of adjuvants based on aluminum or saponin, as well as some compounds that use Toll‐like receptor (TLR) agonists.

Segments of the spike have often been preferred for vaccine development due to the occurrence of ADE in animal models following vaccination with SARS-CoV vaccines expressing fusogenic spike protein.

Full-length spike vaccines

Several vaccines that incorporate the full-length spike include the Oxford/Astra-Zeneca adenovirus vector vaccine (ChAdOx1 nCoV‐19), Ad5 vector, the LNP- encapsulated mRNA vaccines from Pfizer/BioNTech (BNT162b2) and Moderna (mRNA‐1273), and the Novavax vaccine that uses the recombinant spike protein (NVX‐CoV2373).

RBD-based vaccines

The presence of B cell epitopes on the RBD that can elicit neutralizing antibodies, and the strong protection conferred by human IgGs against the RBD, led to the development of vaccines based on the RBD. When RBD-encoding mRNA is used, it is often modified in various ways to enhance its immunogenicity and increase the translation to RBD protein.

Other platforms used for RBD-based neutralization include the protein subunit itself, plasmid DNA, and VLP vaccines, besides a replication-competent influenza vector vaccine. These may be both effective and avoid the risk of ADE.

NTD-based vaccines

The N-terminal domain (NTD) of the SARS-CoV-2 vaccine has been shown to act as an RBD, mediated by binding to glycosylation sites. Though this is not as immunogenic as the full-length spike, the S1 subunit and the RBD, it is still capable of eliciting antibodies that bind specific entry receptors. This has fueled interest in the potential of NTD-based vaccines to counter COVID-19.

S1-based vaccines

The S1 subunit has a unique advantage as a potential vaccine candidate, in that both the RBD and the NTD are located on this subunit. It is strongly immunogenic and induces neutralizing antibodies. Candidate vaccines using the S1 subunit include one using a microneedle array using recombinant S1-Fc fusion protein (Fc being an immunoglobulin component), and one based on a recombinant inactivated rabies virus platform.


The importance of the spike protein in viral entry and infection of the host cell, coupled with the many epitopes it contains for both B and T cells, has led to its being treated as a primary antigen for vaccine development. The vaccines being currently rolled out in many countries are based on the full-length spike protein.

The development of ADE in some volunteers has caused researchers to explore other antigens or segments of this antigen in novel formulations. LNP-mRNA and protein subunit vaccines are now in late clinical trials, and have shown them to be capable of eliciting powerful neutralizing antibodies and cellular responses.

S1, S2 and NTD-based vaccines may also enter clinical trials in the near future, allowing access to a range of safe and effective vaccines that may help to contain this modern-day scourge.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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