Spike protein 1-77: a potential “magic bullet” for coronavirus disease 2019? Single antibody with broad neutralizing activity against all known coronavirus disease 2019 variants—a commentary

In December 2019, an unprecedented virus outbreak emerged in Wuhan, China, rapidly spreading across the globe and leading to the declaration of coronavirus disease 2019 (COVID-19) as a global health emergency by the World Health Organization in January 2020. By July 12, 2023, the number of confirmed COVID-19 cases worldwide reached about 767million, with 6.95 million deaths recorded. The disease manifests with symptoms, such as fever, cough, fatigue, and impaired senses of smell and taste, whereas severe cases are associated with respiratory distress and chest pain. Despite the World Health Organization’s announcement on May 5, 2023, regarding the end of the public health emergency, COVID-19 continues to pose a significant threat, causing widespread infections and fatalities worldwide. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an envelopedRNA virus that employs the spike protein (S protein) on its surface to invade host cells. The interaction between the S protein and the angiotensin-converting enzyme-2 (ACE-2) receptor is critical for viral entry, making it an essential target for antibody interventions. Presently, treatment strategies primarily focus on symptom management, ranging from self-care measures for mild cases to hospitalization with advanced respiratory support, oxygen supplementation, and fluid therapy for severe cases. Intensive care units also utilize corticosteroids and low-dose antiviral medications. Vaccination campaigns have demonstrated significant efficacy in reducing disease severity and transmission rates. This commentary highlights the production process, distinctive mechanism of action, and implications for future vaccine development associated with S protein 1-77 (SP1-77), a promising antibody that can effectively neutralize all variants of COVID-19.


Introduction
In December 2019, an unprecedented virus outbreak emerged in Wuhan, China, rapidly spreading across the globe and leading to the declaration of coronavirus disease 2019 (COVID-19) as a global health emergency by the World Health Organization in January 2020.By July 12, 2023, the number of confirmed COVID-19 cases worldwide reached about 767 million, with 6.95 million deaths recorded [1] .The disease manifests with symptoms, such as fever, cough, fatigue, and impaired senses of smell and taste, whereas severe cases are associated with respiratory distress and chest pain [2] .Despite the World Health Organization's announcement on May 5, 2023, regarding the end of the public health emergency, COVID-19 continues to pose a significant threat, causing widespread infections and fatalities worldwide.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an enveloped RNA virus that employs the spike protein (S protein) on its surface to invade host cells.The interaction between the S protein and the angiotensin-converting enzyme-2 (ACE-2) receptor is critical for viral entry, making it an essential target for antibody interventions [3] .Presently, treatment strategies primarily focus on symptom management, ranging from self-care measures for mild cases to hospitalization with advanced respiratory support, oxygen supplementation, and fluid therapy for severe cases.Intensive care units also utilize corticosteroids and low-dose antiviral medications [4] .Vaccination campaigns have demonstrated significant efficacy in reducing disease severity and transmission rates [5] .This commentary highlights the production process, distinctive mechanism of action, and implications for future vaccine development associated with S protein 1-77 (SP1-77), a promising antibody that can effectively neutralize all variants of COVID-19.

The potential of spike protein 1-77 antibody
Antibodies are proteins produced by the immune system to recognize and counteract foreign substances called antigens.They play a critical role in protecting the body against infections and diseases by tagging antigens for elimination or directly neutralizing their harmful effects [6] .However, the coronavirus has undergone mutations, rendering the previously formed antibodies against vaccines less effective for the new variants [7,8] .
A groundbreaking development in the fight against COVID-19, SP1-77, an innovative antibody developed at Boston Children's Hospital, exhibits extraordinary capabilities in neutralizing all known variants of the virus, including the highly transmissible Omicron variant.To generate SP1-77, researchers modified a mouse model that was previously utilized for generating antibodies against the human immunodeficiency virus, a virus renowned for its frequent mutational propensity.The process involved introducing 2 specific human gene segments, namely a heavy VH1-2 chain, and a light Vκ1-33 chain, into the mouse model.Through a mechanism called "variable, diversity and joining" gene recombination, this led to the production of a humanized B-cell receptor (BCR) in the mouse model.BCRs, like immunoglobulins, consist of 2 heavy chains and 2 light chains.In this case, the diversity of the humanized BCR stems from the heavy and light chains, which contain various complement-determining regions (CDRs), with a particular emphasis on CDR-3.It is important to note that the mouse model lacks its native heavy chains and expresses only a single human VH1-2 heavy chain associated with a highly diverse CDR-3 region.In addition, the deletion of the Immunoglobulin-containing and cysteine-rich receptor 1 gene in the corresponding allele led to the rapid production of a wide range of human antibodies by B cells.Through this process, the mouse model yielded nine lineages of antibodies that bind to the S protein, with the SP1-77 lineage demonstrating broad-spectrum activity in neutralizing the alpha, beta, gamma, delta, and all omicron SARS-CoV-2 variants.Unlike most antibodies that target the receptor binding domain (RBD) of the S protein to impede viral attachment to ACE-2 receptors, cryoelectron microscopy studies revealed that SP1-77 binds to a distinct site on the RBD through CDR-3.This binding event effectively inhibits the fusion of the virus's outer membrane with the host cell membrane, as confirmed by lattice light-sheet microscopy studies [9] .
The S protein of SARS-CoV-2 comprises 2 subunits, S1 and S2, with the RBD located within S1.The S2 subunit facilitates viral fusion with host cell membranes during the process of viral entry [10,11] .RBD binds to the ACE-2 receptor, subsequently exposing the S2 cleavage site to transmembrane protease, serine 2, which exposes fusion peptides on the S2 subunit, thereby initiating the fusion process and viral entry into host cells [12,13] .The ability of SP1-77 to bind to an unmutated site on the S protein enables its neutralization of all existing variants of the virus.This wide-ranging neutralization potential and unique mode of action position SP1-77 as a promising therapeutic candidate and a potential integral component of future vaccines.

Implications and future directions
The emergence of SP1-77 and its binding epitopes carries substantial implications for the management of COVID-19 and the production of vaccines [9] .Vaccination serves as a crucial tool in combating viral transmission and mitigating disease severity.The prospect of a universal vaccine capable of protecting against current and future variants, without requiring frequent updates, would significantly bolster global vaccination efforts [14] .Incorporating SP1-77 epitopes into vaccine formulations and conducting rigorous clinical trials to assess their efficacy in human populations are crucial steps toward this goal.Such vaccines could have a transformative impact, particularly in regions with limited resources and challenges in administering regular booster doses.Further investigations are necessary to ascertain the durability of immunity conferred by SP1-77-based vaccines and to identify additional broadly neutralizing antibodies, thus fortifying our ability to effectively combat evolving SARS-CoV-2 variants.

Conclusion
The identification of SP1-77, an antibody capable of neutralizing all known variants of COVID-19, marks a significant milestone in the fight against this global health crisis.With its unique mechanism of action and potential integration into future vaccines, there is renewed hope for mitigating the devastating impact of the pandemic and preventing its future recurrence.It is imperative for vaccine production organizations to integrate this newfound knowledge into their efforts, whereas robust clinical trials are necessary to validate the efficacy of both the antibody and potential vaccines in human populations.By harnessing the potential of SP1-77 and developing comprehensive vaccines, we can effectively manage the current and future subvariants of the coronavirus obviating the need for recurrent vaccine updates, ultimately bringing an end to this unparalleled health crisis.

Ethical approval
Ethics approval was not required for this short communication article.