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Review

Adaptation of the Vaccine Prophylaxis Strategy to Variants of the SARS-CoV-2 Virus

by
Sofia M. Gulova
,
Uliana S. Veselkina
and
Irina V. Astrakhantseva
*
Department of Immunobiology and Biomedicine, Sirius University of Science and Technology, 354349 Sirius, Krasnodarsky Krai, Russia
*
Author to whom correspondence should be addressed.
Vaccines 2025, 13(7), 761; https://doi.org/10.3390/vaccines13070761
Submission received: 30 April 2025 / Revised: 14 July 2025 / Accepted: 14 July 2025 / Published: 17 July 2025
(This article belongs to the Special Issue COVID Vaccines: Design, Development, and Immune Response Studies: 2nd Edition)
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Abstract

The emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus closely related to SARS-CoV and officially known as Betacoronavirus pandemicum precipitated a substantial surge in vaccine development that culminated during the global COVID-19 pandemic. At present, there are dozens of vaccines for the prevention of SARS-CoV-2 being utilized across the globe. However, only 10 of these vaccines have been authorized by the World Health Organization (WHO). These include mRNA-based, viral vector, subunit and whole-virion inactivated vaccines. At the current end of the pandemic, there has been a decline in the global vaccination rate, both for the general population and for those most at risk of severe illness from the virus. This suggests that the effectiveness of the vaccines may be waning. The decline occurs alongside a decrease in testing and sequencing for SARS-CoV-2. Furthermore, the process of tracking viruses becomes increasingly complex, thereby providing a selective advantage for SARS-CoV-2 and allowing it to evolve stealthily. In this review, we provide a comprehensive overview of viral evolution and vaccine development. We also discuss ways to overcome viral variability and test universal vaccines for all SARS-CoV-2 variants.

1. Introduction

The emergence of the novel SARS-CoV-2 virus, which is closely related to the SARS-CoV virus and officially known as Betacoronavirus pandemium, caused a global pandemic in 2019 [1,2]. This event has led many research institutions and biotechnology companies to develop different vaccines. These vaccines differ in the platforms on which they are based and their effectiveness [3,4].
The viral protein of SARS-CoV-2 responsible for the cell entry process via ACE2 receptor is the spike (S) protein, which is a target for neutralizing antibodies and is the main protein for the vaccine design [5,6,7,8]. The S protein also contains a variety of epitopes that are recognized by CD4+ and CD8+ T cells, and, generally, is more immunogenic compared to other SARS-CoV-2 proteins [9]. Consequently, that protein is under constant evolutionary pressure. It should also be noted that the evolution of SARS-CoV-2, resulting in variants that effectively evade the immune response, almost always involves a mutation in the S protein. Despite the initiation of a widespread vaccination campaign against the SARS-CoV-2 a year after its identification, mutations in the pathogen have been identified and have eventually led to new waves of infection [10]. It is also evident that prior to the emergence of Omicron, the reinfection rate remained low, and the number of circulating variants was found to be limited in comparison to the number of new cases. However, the Omicron-era high reinfection rate could be indicative of the transmissibility and immune evasion capabilities of Omicron. It is suggestive of its capacity to circumvent both natural immunity and vaccine-induced protection [11].
As most authorized vaccines target the production of neutralizing antibodies against the S protein to prevent infection with the SARS-CoV-2 virus, multivalent or updated vaccines have been suggested with the introduction of new variants including those of the Omicron family [12,13,14,15].
In the present moment, we find ourselves amid the onset of the low epidemic state of SARS-CoV-2 [16]. However, despite a decline in the number of new cases of infection, dominant variants are changing rapidly, approximately every two to three months, reflecting the ongoing strong competition within the viral population [17]. Consequently, there is an urgent need for a re-evaluation of current vaccination strategies and regulatory frameworks.
The present review aims to draw attention to the significant period of evolution of SARS-CoV-2 virus, and to consider the factors that have led to the erosion of the vaccine’s effectiveness. In addition to this, the current state of research in the field of universal vaccine design will be summarized.

2. Pre-Omicron Era: The Race Between Vaccine Development and SARS-CoV-2 Evolution

The majority of vaccines against COVID-19 use S protein as main immune-inductive agent since it is highly immunogenic thanks to a glycoprotein nature. However, new variants of SARS-CoV-2 are usually distinguished by specific S protein mutations. Additionally a number of bioinformatic articles describe changes in other structural proteins, and these changes should also influence viral properties as well as vaccine effectiveness [18,19].
The first significant mutation of the SARS-CoV-2 virus was D614G located in the B cell epitope of the S1 subunit of S protein. That mutation is now one of the main variants utilized in studies as a reference for the pre-Omicron era. The D614G mutation first appeared in April 2020 and rapidly became the most prevalent form within the viral population [20,21]. It has been demonstrated that the G614 S protein exhibited enhanced binding affinity to the ACE2 receptor. Furthermore, it was observed to elevate viral loads within the respiratory tract, thereby enhancing its transmissibility. However, no significant change in susceptibility for the neutralization of a virus was observed [22,23,24]. So, G614 did not drastically mitigate efficacy of the first developed vaccines based on the Wuhan variant [20,22].
Among all pre-Omicron variants, the Alpha (lineage B.1.1.7), Gamma (lineage P.1), Beta (lineage B.1.351) and Delta (lineage B.1.617.2) variants caused the most concern [25]. It was demonstrated that all of the variants exhibited a greater degree of affinity for the ACE2 receptor in comparison to the D614G variant (see all significant viral changes in Table 1) [26].
The Alpha variant was the first variant of concern (VOC) following the emergence of D614G in October 2020. This variant was first identified in the United Kingdom, and its key mutation, N501Y, was located in the RBD [27]. The mutation in this variant led to significantly increased transmissibility and fusogenicity [26]. That variant had been persisting mostly in Europe so was thoroughly examined. Despite the enhanced transmissibility of Alpha variant and more severe disease outcome, it was not able to escape from neutralizing antibody (nAb) activity elicited by vaccines or natural infection [28,29,30,31,32].
Table 1. The key mutations of SARS-CoV-2 in more prevalent variants.
Table 1. The key mutations of SARS-CoV-2 in more prevalent variants.
VariantDate of EmergenceKey MutationReferenceKey Features
G614April 2020D614G *[23,33]Enhanced viral replication by increased infectivity and stability of virion-ACE2 interaction
Alpha (B.1.1.7)October 2020 (UK)D614G, N501Y, P681H, R203K, G204R, D1118H, ΔH69/V70, ∆Y144 (+IE), A570D[26,27,34,35]Higher viral load
Increased infectivity and infectiousness
Improved binding to ACE2 receptor
Enhanced S protein cleavage
Beta (B.1.351)September 2020 (South Africa)D614G, D215G, K417N (+IE), E484K, N501Y[36]Enhanced transmissibility
Resistance to neutralizing antibodies
Gamma (P.1)November 2020 (Brazil)D614G, N501Y, E484K, K417T[37,38]Increased RBD affinity to ACE2
Increased transmissibility and virulence
Immune evasion
Delta (B.1.617.2)October 2020 (India)D614G, L452R, T478K, P681R[37,39,40]Increased fusogenicity and infectivity
60% more transmissible than the Alpha variant
Improved furin site recognition by proteases
Omicron BA.1
(B.1.1.529.1)		November 2021
(South Africa)		D614G, E484A, N501Y, Q493K, Q498R, K417N, S477N, Y505H, G496S, T478K, L452R
S375F, S371L		[39,41,42,43,44]Diminished fusogenicity, pathogenicity and cleavage efficacy (relative to Delta variant)
Heightened transmissibility and infectivity
Higher reinfection possibility
Immune evasion
BA.2 (B.1.1.529.2)November 2021
(India)		BA.1+
T19I, ∆PPA25–27, G142D, V231G, S371F, T376A, D405N, R408S		[45,46,47]Increased transmissibility
Improved fusogenicity
Better S protein cleavage and ACE2 affinity
(compared to BA.1)
XBBAugust 2022
(India)		∆Y144 (+IE), P681H
V83A (+IE), H146Q, Q183E, V213E, R346T (+IE), N460K
G339H, R368I, V445P, G446S, F490S, F486S (+IE)		[48,49,50]Increasing its fitness through recombination rather than substitutions.
(recombination of BJ.1 and BM.1.1.1)
Improved transmissibility and
Enhanced immune evasion
(relative to BA.1 Omicron)
XBB.1August 2022
(India)		XBB+
G252V		[49]Greater fusogenicity (in comparison to BA.2.75)
Profound resistance to antiviral humoral immunity induced by prior Omicron subvariants
XBB.1.5—KrakenDecember 2022XBB.1+
S486P		[51]Enhanced binding affinity to ACE2 receptor (compared to XBB.1)
Increased transmissibility
Immune evasion capabilities are the same as XBB.1
BA.2.86July 2023
(Israel, Denmark)		∆Y144 (+IE)
F157S, P681R, G339H, N460K, F486P, A484K, L452W (+IE), A445H (+IE), N450D, ∆N211, A264D, S50L, L216F, K356T (+IE), R403K		[52,53]Substantial antigenic drift
Enhanced receptor affinity
JN.1September 2023
(India)		BA.2.86+
L455S		[54,55]Significantly improved fusogenicity
Increased infectivity
SLip  JN.1+
F456L (Flip mutation)		[56,57]Decreased infectivity and membrane fusion
Declined spike processing compared to JN.1
Immune evasion
FLiRT SLip+
R346T		[57]Immune evasion
Decreased infectivity, cell-cell fusion, and spike processing relative to JN.1
KP.2January 2024Flirt+
V1140L		[58]Immune evasion
Decreased infectivity, cell-cell fusion, and spike processing relative to JN.1
HK.3January 2023
(East Asia)		EG.5.1+
L455F (Flip mutation)		[54]Enhanced immune evasion
Increased fusogenicity
(compared with EG.5.1)
KP.3February 2024JN.1+
Q493E		[59,60,61]Diminished infectivity and affinity to ACE2
Immune evasion
KP.3.1.1March 2024KP.3+
ΔS31		[61]KP.3, KP.3.1.1 and XEC showed a significant increase in ACE2-Spike binding affinity compared with JN.1; no significant changes in the receptor binding of KP.3.1.1 and XEC relative to KP.3
XECJune 2024KP.3+
F59S, T22N		[61,62]Enhanced binding affinity to ACE2 receptor in comparison to JN.1, but not to KP.3
Reduced cell–cell fusion relative to its parental KP.3
* improvement in cleavage, improvement in affinity/fusogenicity, decrease in affinity/fusogenicity. IE—immune evasion.
In September 2020, a novel variant was identified in South Africa. This variant was subsequently designated as Beta (B.1.351) and possessed five additional mutations in the S protein: D80A, D215G, E484K, N501Y and A701V. Subsequent to this identification, three further mutations were identified in November 2020, L18F, R246I and K417N, in conjunction with a deletion at position 242 to 244. This lineage underwent rapid proliferation, ultimately achieving a predominant status within South Africa [63]. The literature regarding the efficacy of mRNA vaccines in combating the Beta variant has yielded conflicting results. One study has documented a substantial decline in the neutralization titer of vaccine-induced antibodies against the Beta variant in sera from individuals vaccinated with the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) vaccines [64]. The other studies have shown that mRNA vaccines demonstrated an efficacy against the Beta variant equivalent to that against the Alpha variant [65,66]. A significant decrease in the neutralizing effectiveness of inactivated whole-virion, vector and subunit recombinant vaccines was observed [28,31,32]. For instance, subunit vaccine NVX-CoV2373 (Novavax) has demonstrated drastically reduced efficacy against the Beta variant relative to the Alpha variant (49,4% and 85,6% respectively) [32]. Furthermore, the clinical trial for the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca) did not demonstrate protection against mild to moderate cases of SARS-CoV-2 due to the B.1.351 variant [67,68].
The emergence of the Gamma variant at the end of 2020 in Brazil is of particular interest. This variant harbors 17 mutations; 10 of them were located in the S protein and displayed significantly increased transmissibility compared to the other local viral variants, higher pathogenicity independent of sex and age and increased lethality [69,70]. The mRNA vaccines (mRNA-1273 and BNT162b2) had failed to protect against the Gamma variant. In contrast, studies conducted on the whole-virion inactivated vaccine CoronoVac (by Sinovac Biotech) have indicated an efficacy rate of approximately 50% [70,71]. Notably, the ChAdOx1 nCoV-19 vaccine of Oxford-AstraZeneca demonstrated a 77.9% efficiency against the Gamma variant, which is the highest among all other vaccines [72].
Despite the variable neutralizing abilities of antibodies induced by vaccine against early variants of SARS-CoV-2, the analysis of CD8+ T cells response in convalescent individuals of the North American population has revealed conserved CD8 epitopes non-affected by mutation [73].
The Delta variant first appeared in India in October 2020 and then spread rapidly around the world. It showed extremely increased transmissibility and lethality compared to previous VOCs [26,74]. It had overtaken other VOCs and persisted in populations for a longer period of time, as all mutations (in both N-terminal domain (NTD) and RBD, the most notable being L452R, E484Q and P681R) contributed to the increased fitness of the variant [75,76]. The S protein vaccines such as BNT162b2, ChAdOx1 nCoV-19 and Ad.26.COV.2.S (Janssen/Johnson & Johnson) showed reduced efficacy against Delta variant compared to the Alpha, but still provided protection; however, breakthrough infections were observed [77,78]. Whole-virion inactivated vaccines, for example, Covaxin (Bharat Biotech), displayed lowered efficiency against VOCs, yet still provided robust immune memory with a modest impact on the humoral response against Delta and Gamma variant [79]. The indisputable advantage of the whole-virion inactivated vaccines over other types is a wide variety of induced antibodies (which, overall, should increase protection against virus) as well as broad B- and T-cell response [79]. However, a lot of whole-virion vaccines are now discontinued as they have shown low efficiency against Omicron variants and were not updated. Recombinant S protein vaccine SCB-2019 (Clover Biopharmaceuticals) is of particular interest since it has displayed increased efficacy against Delta variant—79%, compared to 67,2% against the initial Wuhan variant [13]. Overall, recombinant vaccines showed reduced efficacy against the Delta variant; however, sera from vaccinated individuals demonstrated neutralizing activity higher than that of convalescent sera [13]. The studies reviewed in [9] have demonstrated that CD4+ and CD8+ T-cell responses induced by SARS-CoV-2 infection or vaccination with various types of vaccine are able to recognize all circulating SARS-CoV-2 variants at that time, regardless of geographic location.
Other VOCs, including Epsilon, Zeta, Eta, Theta, Iota, Kappa, Lambda and Mu, appeared in late 2020 and the first half of 2021. These variants are characterized by various changes in viral properties, but all were eventually replaced by the Delta variant [76,80].

3. Vaccine Efficiency in the Omicron Landscape

The substantial evolutionary progression of the SARS-CoV-2 virus was marked by the emergence of the Omicron variant in late 2021 in South Africa, a development that occurred as a consequence of recombination and an antigenic shift [27,35]. One of the main concerns was the propensity of Omicron to reinfection. At the same time, Omicron variants are associated with a significantly reduced pathogenicity and hospitalization rate due to the lowered fusogenicity of their S protein [27].
The emergence of the BA.1 and BA.2 variants was precipitated by mutations in the Omicron lineage. As can be deduced from the available data, both have approximately 30 mutations in their spike proteins. These mutations result in increased transmissibility and increased fusogenecity, with the consequent effect of a reduction in the number of severe cases (Table 1) [76]. Both variants strongly resist neutralization with the sera of people immunized with any type of WT vaccine [81,82,83]. Starting from these variants, a three-dose vaccination schedule was recommended for better protection [84]. Two bivalent boosters have been developed, each containing the BA.1 variant. These boosters were derived from the BNT162b2 and mRNA-1273 vaccines, and both have been shown to elicit a robust humoral and T cell response against BA.1, BA.2 and the later-emerging BA.4/BA.5 variants [85]. Notably, three doses of NVX-CoV2373 vaccine elicited responses similar to mRNA vaccines and provided protection against BA.4/5 variants as well [86].
The XBB variant first emerged in India in 2022 as a result of recombination between two variants of the BA.2 sublineages. XBB sublineages have reduced antigenicity compared to BA.2.86 but slightly increased antigenicity compared to pre-XBB Omicron variants [87,88,89]. It is imperative to note that key point mutations of XBB sublineages are R346T and G252V and they provide partial S309 monoclonal antibody (mAb) evasion; S486P mutation of XBB.1.5 variant enhances binding to ACE2 receptor and increases the antigenicity of the virus. Finally, the L455F and F456L mutations contributed to the emergence of the FLip variant and have also been observed as mutation spots in the JN.1 lineage [57,88]. Interestingly, no mutations of XBB subvariants resulted in complete evasion from S309 mAb, in contrast to the BA.2.86 sublineage, which demonstrated robust resistance towards S309 therapy [87,88]. A bivalent mRNA vaccine containing WT and BA.4/5 S protein (Pfizer BioNTech) had proved its efficacy against the XBB.1 variant (G252V mutation) [90,91]. Further XBB subvariants exhibited no significant resistance to neutralization in a cohort vaccinated with three doses of the WT mRNA vaccine. As expected, neutralization was better in the cohort that showed breakthrough infection and the effect was demonstrated not only against XBB subvariants but also BA.2.86 [89]. Yet, still, Xun Wang et al. observed that vaccination with a quadrivalent peptide booster SCTV01E (SinocellTech), which contains BA.1 S protein, provided a neutralizing antibodies (nAbs) titer that was even higher relative to the breakthrough infection group [89]. What is more, SCTV01E provided cross-protectivity against both BA.2.86 and XBB sublineages [89,92]. Currently, this vaccine is undergoing phase III clinical trials and has been approved for emergency use in China [92]. A paucity of data exists regarding the efficiency of SCTV01E when employed against the contemporary variant of interest (VOI)—JN.1 and its subvariants. However, the XBB.1.5 mRNA monovalent vaccine booster by Moderna and Pfizer BioNTech is more accessible on the market and has proved its efficacy against XBB sublineages and BA.2.86 [87,88,93]. This vaccine demonstrated advantages over the bivalent BA.4/5 mRNA vaccine in terms of the neutralization of BA.2.86 and XBB sublineages since the titers of nAbs in human sera were higher [88,94]. It is important to note that all studies conducted during the circulation of the XBB sublineages and the BA.2.86 variant worldwide had demonstrated a robust immune response to the WT SARS-CoV-2 and D614G strain [87,88,89,90,93]. Novavax has also released the vaccine NVX-CoV2601, updated for the XBB.1.5 variant, which was proven to be effective and safe, and demonstrated cross-reactivity against late Omicron variants such as JN.1 and BA.2.86 [95]. These examples, once again, clearly demonstrate how good vaccine formulation design may possibly impact the population immunity and the importance of updating vaccines against the SARS-CoV-2 virus.
The BA.2.86 variant emerged in the summer 2023 and successfully co-circulated with the XBB lineages. The BA.2.86 S protein was highly mutated compared to its ancestor BA.2 or XBB lineages, with a total mutation count exceeding 30 (Table 1) [87]. BA.2.86 had demonstrated a lack of resistance to neutralization in the sera of individuals who had received a bivalent mRNA vaccine booster (containing BA.4/5 S protein), similar to XBB variants [87]. In contrast, BA.2.86 harbors S protein mutations attributed to increased pathogenicity and displayed a complete evasion from S309 mAb, a trait that is not shared by XBB.1 and XBB.1.5 [87]. Nesamari et al. studied the T-cell response to different viral variants in a group of medical workers from South Africa who had hybrid immunity against SARS-CoV-2 as they previously been vaccinated and infected. The study showed that the S-specific CD4+ T-cell response was highly preserved (≥90%) against the S protein of the ancestral and the Omicron variants, including BA.1, XBB.1 and even BA.2.86. However, the preservation of CD8+ T-cell responses was more variable across the individuals [96]. Further mutation of BA.2.86 in the L455 residue led to the current VOI—JN.1, which completely took over the XBB sublineages [97].
As mentioned before, L455 and F456 residues of RBD have become key mutation spots not only for FLip variants of XBB lineage but also for JN.1 sublineages. JN.1 variant emerged in late 2023 and harbors single S protein mutation—L455S, relative to its ancestor—BA.2.86 (Table 1). The L455S mutation in JN.1 had been shown to reduce its binding affinity to the human ACE2 receptor compared to BA.2.86 [57,98]. Subsequent variants of JN.1, such as Slip (L455S, F456L), FLiRT (R346T) and KP.2 (V1140L), demonstrated even lower infectivity and cell–cell fusion activity, which, overall, reduce viral fitness [57,94,98]. However, these mutations have created significant opportunities for SARS-CoV-2 to evade the immune system, enabling it to spread on a global scale. As of today, the JN.1 variant and its FLiRT subvariant prevail above others [99]. Research groups had investigated JN.1 for nAbs in vaccinated humans and immunized hamsters. It was shown that the bivalent BA.4/5 mRNA vaccine, given together with the WT mRNA vaccine, generates a pool of nAbs for the XBB.1.5 and JN.1 lineages. However, for the JN.1 variant line, the NT50 is reduced [57,94]. There are also data showing an increase in JN.1 variants nAbs titers when a monovalent XBB.1.5 vaccine booster is taken. It is concordant with in vivo studies, which demonstrated robust neutralization against FLip, HK.3 (L455F) and JN.1 subvariants, including FLiRT, SLip and KP.2 with XBB.1.5-monovalent immunized hamster sera, albeit with a reduced efficiency [57,94,100]. Altogether, it proves the necessity of including JN.1 S protein in upcoming vaccine formulations. Currently, there are two JN.1 updated mRNA monovalent vaccines: Bretamoveran by Moderna and Pfizer-BioNTech and the JN.1 vaccine booster by Japanese pharmaceutical company Daiichi-Sankyo. Both treatments induce immunity against JN.1 and provide cross-protectivity for BA.5 and XBB sublineages [101,102]. Interestingly, according to the study by C. Happle et al., Bretamoveran did not appear to be effective for the current variant under monitoring (VUM)—KP.3— whereas K. Uriu et al. reported robust neutralizing activity for KP.3 after a booster. In this study, Bretamoveran shows strong neutralizing activity for KP.3.1.1 and XEC variants (VUMs on February 2025), but Daiichi-Sankyo’s JN.1 booster showed better results. It is important to note the significant differences between the two cohorts of participants in the K. Uriu study in terms of age, sex and previous vaccination status, as these factors may significantly influence the results of the study. One of the key points of both studies is the shift in immunological imprinting towards Omicron variants. This suggests the need to update further vaccine formulations [101,102].
The whole-virion inactivated vaccine has demonstrated its capacity to offer protection against the SARS-CoV-2 ancestral Wuhan variant and other VOCs. This finding signifies its potential for cross-variant protection. However, the vaccine’s effectiveness in preventing infection was significantly lower than that of biotechnology vaccines [103,104,105,106,107]. The emergence of vaccine-evasive variants, such as Omicron lineages, has been accompanied by a noted reduction in neutralization efficacy [79,103,108,109,110]. A proposal has been made to update the whole-virion vaccine, but this appears to be challenging due to the intricate nature of the process and the low yield of production of Omicron subvariants. Notwithstanding the substantial decline in efficacy in preventing infection by SARS-CoV-2, the whole-virion vaccine has demonstrated the capacity to broaden and enhance the quality of SARS-CoV-2-specific immunity, including cellular immunity, and highlights the role of non-neutralizing antibodies in viral elimination [111,112].
As noted above, the Omicron variants do indeed form a distinct phylogenetic clade, and as evolution continues, different Omicron lineages accumulate genomic changes to form another genetically and phenotypically distinct lineage. For example, the characteristics of the BA.2.86 lineage differ significantly from those of the XBB lineage. However, both lineages continue to circulate around the world. Perhaps, subsequent studies and observations on SARS-CoV-2 will shed light on whether it would be advisable to apply serotypes to SARS-CoV-2.

4. Prospects for Pan-Coronaviral Antivirals: The S2 Subunit in the Spotlight

The shift in immune imprinting towards Omicron, combined with the antigenic drift of SARS-CoV-2 variants, has led to a decrease in vaccine efficacy against SARS-CoV-2 infection, which could potentially compromise public health. Consequently, there has been a surge in research and development efforts to engineer a next generation of SARS-CoV-2 vaccines that exhibit enhanced breadth and effectiveness in confronting the infection. Morens et al. posit that a pan-coronavirus vaccine should possess the following five ideal properties: (1) the prevention of SARS-CoV-2 infections and breakthrough infections, (2) the induction of long-term mucosal and systemic immunity, (3) the prevention of community transmission, (4) the establishment of durable herd immunity and (5) the provision of universal coverage of Betacoronaviruses [113]. To induce a broad response, antibodies will need to target conserved regions of the S protein. Epitope mapping of broad nAbs identified a class of such antibodies targeting the stem-helix bundle of the S2 in prefusion S trimers that are predicted to disrupt S-mediated membrane fusion. Critically, these antibodies cross-neutralize the human-infecting Betacoronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and human coronaviruses (HCoVs) HKU1 and OC43. Notably, these stem helix-targeting broad nAbs failed to neutralize the Alphacoronaviruses NL63 and 229E [114,115,116,117].
The S2 subunit of the S protein plays a crucial role in the virus’s internalization process. This process occurs after the RBD binds to the ACE2 receptor [34,118,119]. The S2 subunit consist of regions that are essential for the overall stability of the S protein and that makes the S2 subunit a highly conserved region of the S protein (Figure 1) [34]. It shares up to 90% homology with SARS-CoV with a 100% match for the heptad repeat 2 (HR2) region of SARS-CoV Tor2 strain and MERS-CoV [120]. All those facts make it a prime candidate for further vaccine development. The use of the S2 subunit is intended to generate broadly neutralizing antibodies (bnAbs) that provide protection against multiple variants of SARS-CoV-2 and other Betacoronaviruses [117,121]. For instance, several studies have found cross-reactive antibodies in patients without prior exposure to SARS-CoV-2. These antibodies can efficiently neutralize SARS-CoV-2, although with a reduced efficiency, and have demonstrated binding with the S protein, but not with the S1 subunit alone [117,121]. Similar findings were demonstrated for the T-cell immune response. Memory CD4+ T-cell lines were found to be able to react with SARS-CoV-2. It is noteworthy that there is a positive correlation between the sequence similarity between SARS-CoV-2 and other coronaviruses and the extent of cross-reactivity of CD4+ T cells [121]. The induction of CD4+ T cells is crucial in the development of the vaccine, as T cells have been shown to provide long-lasting protection. In contrast, the levels of nAbs have been observed to decline over a period of several months [121].
In the pre-Omicron era of the pandemic, utilizing the LIBRA-seq approach on a peripheral blood mononuclear cell (PBMC) sample from a donor who was infected with SARS-CoV more than 10 years before the samples were collected, several antibodies were identified. These antibodies bind not only to the S protein of SARS-CoV and SARS-CoV-2 but also to the S proteins of the endemic HCoV-OC43 and HCoV-HKU1, but at lower levels. It was observed that these antibodies targeted cross-reactive epitopes on S2 but could not neutralize SARS-CoV or SARS-CoV-2. However, two of the antibodies showed an ability to cause cross-coronavirus phagocytosis, and four antibodies were found to be capable of mediating trogocytosis. Additionally, two of these antibodies were tested in vivo and exhibited a reduction in lung hemorrhage score, although the impact on viral load remained inconclusive [127]. The 86% of individuals infected with 229E and OC43 coronaviruses exhibited IgG against the S2 subunit of the S protein of SARS-CoV-2 [128]. Additionally, it has been demonstrated that S2-reactive CD4+ T cells with a predominantly Th1 memory phenotype are present in seronegative SARS-CoV-2-unexposed donors and S2 T-cell epitopes have been shown to exhibit a higher degree of similarity to the human endemic coronaviruses 229E, NL63, OC43 and HKU1 with regard to the SARS-CoV MHC-II epitopes, in comparison to the S1 T-cell epitopes [129]. In the other cohort of samples also collected prior to the emergence of SARS-CoV-2 (2011 to 2019), which encompassed healthy donors, pregnant women and young, healthy donors, a range of 3 to 43% exhibited detectable levels of SARS-CoV-2 S protein cross-reactive IgG antibodies, accompanied by the presence of virus-neutralizing activities [130]. The infection of SARS-CoV-2 resulted in a significant increase in the circulation of cross-specific antibodies for the closely related HCoVs. A depletion experiment with soluble monomeric SARS-CoV-2 S1 or S2 subdomains indicates that S2-specific antibodies have a greater contribution to cross-reactivity than S1-specific antibodies, which is in accordance with the higher conservation of the S2 subdomain compared to the S1 subdomain [131]. The discovery of monoclonal antibodies specific to the S2′ cleavage site, which is essential for viral entry into the host cell, was soon made (COV44–62 and COV44–79). These antibodies were also found to be capable of neutralizing Alpha- and Betacoronaviruses, including the Omicron subvariants BA.2 and BA.4/5 of SARS-CoV-2 [118]. However, their potency was determined to be lower compared to RBD-specific antibodies [115]. The other anti-S2 mAb CV804 demonstrated binding activity against multiple variants, including various Omicron subvariants (BA.2.75, BA.4.1, BA.4.6, BE.1, BA.5.2.1, BQ.1.1, XBB.1, XE, BF.7 and BF.7.4.1); however it was not able to neutralize SARS-CoV-2 in a virus neutralization test. In addition, its therapeutic effect in mouse SARS-CoV-2 infection was also limited [132]. It is important to note that the antibody response to linear peptides derived from conserved areas of the SARS-CoV-2 virus in the S2 C-terminal region is significantly increased in infected individuals when compared to vaccinated individuals [133].
The S2 subunit serves as a stalk of spike protein and includes multiple α-helical structures (Figure 1B) [119]. Altogether, it forms the machinery essential for the viral entry to the cell. The formation of the six-helix bundle (6-HB) by the interaction between HR1 and HR2 domains brings viral and cellular membranes together for subsequent fusion, resulting in viral entry into host cells. The Q954H and N969K mutations, which are present in the HR1 domain of all Omicron subvariants (Figure 1B), do not appear to be involved in the HR1–HR2 interaction, suggesting that these HR1 mutations have a minimal impact on viral fusogenicity or the efficacy of fusion inhibitors targeting HR1. Consequently, the HR1 and HR2 domains have been identified as main targets in the development of broad-spectrum HCoVs fusion inhibitors. Synthetic peptides, derived from the HR2 region, have been shown to competitively hinder the interaction between viral HR2 and the HR1 domain, thereby preventing the formation of viral 6-HB and hindering viral fusion and infection [133,134,135].
So, since the onset of the SARS-CoV-2 outbreak, it has been established that a peptide derived from the HR2 domain of the S2 subunit, named 2019-nCoV-HR2P, exhibits significant inhibitory activity against SARS-CoV-2 pseudovirus infection and S protein-mediated cell-to-cell fusion [125]. The fusion inhibitor targeting the HR2 domain (EK1) has been shown to disrupt viral 6-HB formation and inhibit viral fusion and entry (Figure 1B). Intranasal administration of EK1 to hACE2-transgenic mice has been shown to provide effective protection against SARS-CoV-2 infection by different SARS-CoV-2 VOCs, particularly the Omicron variant, which was resistant to most SARS-CoV-2 nAbs. EK1C4, a PEGylated, cholesterol-modified EK1 peptide, has been found to be able to inhibit the XBB sublineage of SARS-CoV-2 [123]. A similar peptide fusion inhibitor, P3, targeting HR1, including its modification P315V3, demonstrated the most efficient antiviral activity against SARS-CoV-2 variants and several other Sarbecoviruses, as well as other HCoVs. Furthermore, P315V3 demonstrated effective prophylactic efficacy against the SARS-CoV-2 Delta and Omicron variants in mice via intranasal administration [122]. Wang et al. has presented a self-assembling recombinant protein named HR1LS that contains three linked structural domains of the S2 subunit of the S protein: HR1, CH and SH domains. The construction was found capable of binding with HR2 domain of the S2 subunit of SARS-CoV-2 as well as other coronaviruses such as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and MjHKU4r-CoV-1 (a bat MERS-like coronavirus) thus showing itself as a potential entry and fusion inhibitor. Moreover, HR1LS combined with CF501 adjuvant induced the production of broad-spectrum nAbs against multiple variants of SARS-CoV-2 and other aforementioned coronaviruses in immunized BALB/c mice [126]. The other membrane fusion-inhibitory lipopeptide, designated IPB29, was also HR2-derived. In vitro experiments have previously shown that IPB29 effectively neutralizes two viral panels. Panel 1 included the previously circulated variants (D614G, Alpha, Beta, Gamma, Delta, Lamda and several mutants with specific substitutions (K417N, E484K, N501Y, P681R, N501Y/Δ69–70 and N501Y/P681H)). Panel 2 represented divergent Omicron sublineages, including the recently emerged BF.7. BQ.1.1, XBB, XBB.1.5, CH.1.1 and EG.5.1 variants. In a Syrian hamster model of SARS-CoV-2 infection, nebulized IPB29 has been shown to be highly effective against both the Delta and Omicron variants [124].
Based on previous studies exploring the potential of broad-neutralizing antibodies, a hypothesis was proposed that a multivalent S2 subunit vaccine, incorporating S2 from SARS-CoV, Bat-CoV RsSHC014 and SARS-CoV-2 S2mut, would provide extensive protection against human Betacoronaviruses [136,137]. As demonstrated in in vivo infection models, the vaccine in question was found to have a significant impact on virus titers in the lungs of immunized mice challenged with XBB, Pangolin-GD, BANAL-236, WIV1 and RsSHC014. It is interesting to note that the role of the effector T cells in S2-based protection is not pivotal. Virus titers in immunized mice challenged with mouse adapted SARS-CoV-2 virus (MA10) were similar to those in a group of mice preliminary treated with the anti-CD8 antibody. The vaccine-induced antibodies were shown to be non-neutralizing but broadly binding. Other findings of the study by P. J. Halfmann et.al. indicate that FcγR KO mice immunized with a multivalent S2 subunit vaccine exhibited a mean virus titer significantly higher than that observed in control group of immunized wild-type mice (mice were challenged with MA10). This observation suggests that antibody-dependent cellular effector mechanisms play a crucial role in the protection provided by immunization [136]. The S2-binding antibody, which was isolated from human B cells, binds to an epitope at the apex of S2 that is highly conserved among Betacoronaviruses. It was also non-neutralizing, but it was capable of inducing Fc-dependent antiviral responses in vitro, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [138].
Attempts to develop the pan-CoV vaccine or a universal cross-reactive vaccine antigen have been made since the very beginning of the pandemic. Many unique and original approaches have taken to create an effective vaccine. However, not all of them have made it to the world market or passed clinical trials. For example, X. Ma et al. designed several nanoparticle vaccines consisting of 24 copies of the RBD or RBD-HR protein subunit covalently conjugated to self-assembling non-haem ferritin from H. pylori. Both RBD and RBD-HR nanoparticles induced nAbs and promoted type-1 T-cell response in in vivo models and also provided protection in mice challenged with SARS-CoV-2. Notably, the conjunction of RBD or RBD-HR copies to ferritin increased the level of nAbs in animal sera compared to the monomeric protein subunit. RBD-HR, in particular, led to the production of broadly neutralizing antibodies that are capable of neutralizing other coronaviruses (SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43 and RATG13) and demonstrated a stronger T-cell response in a BALB/c mice model [139]. Another example is the novel antibody HR-based vaccine designated HR121. HR121 is designed from the HR1–HR2–HR1 domains of the Wuhan-Hu-1 variant linked with peptides. HR121 has shown itself as a mimic of the native HR1 domain of the fusion-intermediate conformation of the S2 subunit and, thus, acted as a strong fusion inhibitor. It is important to note that HR121 exhibited broadly neutralizing activities against multiple variants of SARS-CoV-2 both in vitro and in vivo, especially against Omicron sublineages. HR121 provided long-term protection against SARS-CoV-2 Omicron infection after intranasal administration to Syrian golden hamsters [140,141]. A similar case is a vaccine candidate MSU-CoV-4/5 based on three SARS-CoV-2 antigen fragments (containing RBD and conserved regions of the S protein across SARS-related coronaviruses) and a novel adjuvant—spherical particles, originating from structurally modified tobacco mosaic virus. Despite the fact that the Wuhan-Hu-1 variant served as a matrix for recombinant antigens, sera obtained from animals vaccinated with MSU-CoV-4/5 has demonstrated broad neutralization activity against Omicron variants in vitro. MSU-CoV-4/5 has shown itself as a biologically safe vaccine candidate providing protection against WT SARS-CoV-2 in immunized golden Syrian hamsters [142,143]. Generally, the approach of utilizing highly conserved regions of the spike protein has once again proved itself promising as both HR121 and MSU-CoV4/5 are based on the WT SARS-CoV-2 variant; however, they provided strong protection against Omicron sublineages.
Given the continuous evolution of SARS-CoV-2, it is essential to develop novel and pragmatic vaccine design strategies to ensure long-term herd immunity and prevent the occurrence of a new pandemic or high-intensity epidemic. The use of pan-coronavirus vaccines is proposed to induce a cross-protective immune response against a range of Betacoronaviruses. However, developing such a universal vaccine is a significant challenge, given the RNA genomic structure of coronaviruses. This is especially true in light of the notable example of universal influenza vaccines (UIV), which have yet to be implemented in clinical practice [144]. As with UIV, selecting the appropriate target is essential. In the case of coronaviruses, the S2 subunit of the S protein could be an ideal candidate. This protein is a component of the immunogenic surface protein, which has a high degree of conservation [34,118,119,121,138,145]. Ideally, such a vaccine would provide long-lasting protection against SARS-CoV-2 as well as cross-protection against other coronaviruses.

5. Conclusions and Future Outlook

It has been over five years since the onset of the pandemic of SARS-CoV-2 that caused COVID-19, and the disease has now reached a low epidemic state [16]. The continuous evolution of SARS-CoV-2 has resulted in the emergence of a phylogeographically distinct clade of variants, designated Omicron, and these variants have become predominant. Despite its low pathogenicity, the infection still could be fatal, and this fact should be taken into consideration [146]. At present, there is an ongoing debate regarding the appropriate classification of the SARS-CoV-2 virus, specifically, whether serotypes should be assigned to it [147,148]. Moreover, the tools employed for the estimation of the direction of SARS-CoV-2 evolution are in a state of development [149,150,151]. The main feature of the evolution of SARS-CoV-2 was indicated as large “jumps” instead of gradual changing, which could be due to animal reservoirs, or a result of an evolution in immunocompromised individuals [152,153,154,155,156]. Considering these points, it is important to pay special attention to the vaccination of people with compromised health in order to limit the spread of the virus as well as monitoring the viral spread to the farm or domesticated animals.
The development of a pan-coronavirus vaccine could encompass broad-spectrum protection against the emerging viral variants. There are several strategies to achieve that goal. In order to strengthen the immune response to diversity of SARS-CoV-2 variants and related viruses, the development of a multivalent vaccine would require the inclusion of the spike protein (S protein) from several different viral strains [12,14,157,158]. The second approach that has received a spotlight in research is the use of heterologous booster vaccines. These vaccines have been shown to stimulate various branches of the immune response, including the broadening of T-cell responses [159,160,161,162]. The heterology of the vaccination regimen has the potential not only to involve the use of multiple vaccine platforms but also to use various methods for vaccine administration, such as the implementation of intranasal boosters [163]. These approaches were thoroughly reviewed by Saha et al. [164].
The current review, alongside the viral and vaccine coevolution, also discusses the possible use of the S2 subunit as a highly conserved region of the S protein for the development of a pan-coronavirus vaccine. It should be noted that the most widely used vaccines contain the full-length S protein, which includes the S2 subunit as well. However, previous research had shown that the levels of anti-S2 antibodies in vaccinated individuals were lower than in infected individuals or in individuals with hybrid immunity [165]. Additionally, the mRNA vaccine have been shown to induce a more robust response against the S2 subunit compared to vector-based vaccine [165,166]. This might be due to differences in the conformation of the S protein used in vaccine design and the conformation of the S protein present on the surface of intact and inactivated virions [167,168,169,170]. So, despite the presence of S2-subunits, the vaccine-induced response is probably shifted more towards anti-S1 epitopes. Despite the limited effectiveness of anti-S2 antibodies in neutralizing the virus, their broad cross-reactivity and capacity to trigger alternative antiviral defense mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), coupled with the significance of the S2 subunit in the viral architecture, make anti-S2 agents a promising candidate for developing a universal vaccine against all coronaviruses.
The limitation of this review is that we did not focus closely on the effectiveness of vaccine-induced cellular immunity against emergent viral variants, as this can be found in the review by J. Liu et al. [171].

Author Contributions

Conceptualization, I.V.A.; writing—original draft preparation, S.M.G.; writing—review and editing, I.V.A., U.S.V.; visualization, U.S.V.; supervision, I.V.A.; project administration, I.V.A.; funding acquisition, I.V.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Russian Science Foundation, grant number 24-25-20139.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors grateful for support and scientific guidance the head of Department of Immunobiology and Biomedicine S. A. Nedospasov.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Gorbalenya, A.E.; Baker, S.C.; Baric, R.S.; de Groot, R.J.; Drosten, C.; Gulyaeva, A.A.; Haagmans, B.L.; Lauber, C.; Leontovich, A.M.; Neuman, B.W.; et al. The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-NCoV and Naming It SARS-CoV-2. Nat. Microbiol. 2020, 5, 536–544. [Google Scholar] [CrossRef]
  2. National Library for Medicine. Available online: https://www.ncbi.nlm.nih.gov/datasets/taxonomy/3418604/ (accessed on 8 July 2025).
  3. Soheili, M.; Khateri, S.; Moradpour, F.; Mohammadzedeh, P.; Zareie, M.; Mortazavi, S.M.M.; Manifar, S.; Kohan, H.G.; Moradi, Y. The Efficacy and Effectiveness of COVID-19 Vaccines around the World: A Mini-Review and Meta-Analysis. Ann. Clin. Microbiol. Antimicrob. 2023, 22, 42. [Google Scholar] [CrossRef] [PubMed]
  4. Sharif, N.; Alzahrani, K.J.; Ahmed, S.N.; Dey, S.K. Efficacy, Immunogenicity and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis. Front. Immunol. 2021, 12, 714170. [Google Scholar] [CrossRef] [PubMed]
  5. Wan, Y.; Shang, J.; Graham, R.; Baric, R.S.; Li, F. Receptor Recognition by the Novel Coronavirus from Wuhan: An Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J. Virol. 2020, 94, e00127-20. [Google Scholar] [CrossRef] [PubMed]
  6. Walls, A.C.; Park, Y.-J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020, 181, 281–292.e6. [Google Scholar] [CrossRef] [PubMed]
  7. Ju, B.; Zhang, Q.; Ge, J.; Wang, R.; Sun, J.; Ge, X.; Yu, J.; Shan, S.; Zhou, B.; Song, S.; et al. Human Neutralizing Antibodies Elicited by SARS-CoV-2 Infection. Nature 2020, 584, 115–119. [Google Scholar] [CrossRef] [PubMed]
  8. Papageorgiou, A.C.; Mohsin, I. The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies. Cells 2020, 9, 2343. [Google Scholar] [CrossRef] [PubMed]
  9. Grifoni, A.; Sette, A. From Alpha to Omicron: The Response of T Cells. Curr. Res. Immunol. 2022, 3, 146–150. [Google Scholar] [CrossRef] [PubMed]
  10. Gushchin, V.A.; Pochtovyi, A.A.; Kustova, D.D.; Ogarkova, D.A.; Tarnovetskii, I.Y.; Belyaeva, E.D.; Divisenko, E.V.; Vasilchenko, L.A.; Shidlovskaya, E.V.; Kuznetsova, N.A.; et al. Dynamics of SARS-CoV-2 Major Genetic Lineages in Moscow in the Context of Vaccine Prophylaxis. Int. J. Mol. Sci. 2022, 23, 14670. [Google Scholar] [CrossRef] [PubMed]
  11. Malheiro, D.T.; Parreira, K.C.J.; Celeghini, P.D.; Callado, G.Y.; Cotia, A.L.F.; Cendoroglo Neto, M.; Bragatte, M.A.S.; Negretto Schrarstzhaupt, I.; Sampaio, V.; Kobayashi, T.; et al. COVID-19 Reinfections in the City of São Paulo, Brazil: Prevalence and Socioeconomic Factors. Open Forum Infect. Dis. 2025, 12, ofaf181. [Google Scholar] [CrossRef] [PubMed]
  12. He, C.; Yang, J.; He, X.; Hong, W.; Lei, H.; Chen, Z.; Shen, G.; Yang, L.; Li, J.; Wang, Z.; et al. A Bivalent Recombinant Vaccine Targeting the S1 Protein Induces Neutralizing Antibodies against Both SARS-CoV-2 Variants and Wild-Type of the Virus. MedComm 2021, 2, 430–441. [Google Scholar] [CrossRef] [PubMed]
  13. Heidary, M.; Kaviar, V.H.; Shirani, M.; Ghanavati, R.; Motahar, M.; Sholeh, M.; Ghahramanpour, H.; Khoshnood, S. A Comprehensive Review of the Protein Subunit Vaccines Against COVID-19. Front. Microbiol. 2022, 13, 927306. [Google Scholar] [CrossRef] [PubMed]
  14. Ye, Z.-W.; Fan, Y.; Tang, K.; Ong, C.P.; Luo, C.; Chung, H.-L.; Leong, T.-L.; Liang, R.; Lui, W.-Y.; Zhou, R.; et al. Cross-Variant Protection against SARS-CoV-2 Infection in Hamsters Immunized with Monovalent and Bivalent Inactivated Vaccines. Int. J. Biol. Sci. 2022, 18, 4781–4791. [Google Scholar] [CrossRef] [PubMed]
  15. Chalkias, S.; Harper, C.; Vrbicky, K.; Walsh, S.R.; Essink, B.; Brosz, A.; McGhee, N.; Tomassini, J.E.; Chen, X.; Chang, Y.; et al. A Bivalent Omicron-Containing Booster Vaccine against Covid-19. N. Engl. J. Med. 2022, 387, 1279–1291. [Google Scholar] [CrossRef] [PubMed]
  16. Liu, B.; Wang, Z.; Lu, S.; Qi, Z.; Zhang, Z.; Luan, J.; Ba, J. Monitoring Reported SARS-CoV-2 Variants to Assess the Status of COVID-19 Epidemics in the Low Epidemic State. Sci. Rep. 2025, 15, 10169. [Google Scholar] [CrossRef] [PubMed]
  17. Awasthi, S.; Dehkharghani, M.Z.; Fudolig, M. Emergence to Dominance: Estimating Time to Dominance of SARS-CoV-2 Variants Using Nonlinear Statistical Models. PLoS ONE 2025, 20, e0311459. [Google Scholar] [CrossRef] [PubMed]
  18. Abavisani, M.; Rahimian, K.; Mahdavi, B.; Tokhanbigli, S.; Mollapour Siasakht, M.; Farhadi, A.; Kodori, M.; Mahmanzar, M.; Meshkat, Z. Mutations in SARS-CoV-2 Structural Proteins: A Global Analysis. Virol. J. 2022, 19, 220. [Google Scholar] [CrossRef] [PubMed]
  19. Hossain, A.; Akter, S.; Rashid, A.A.; Khair, S.; Alam, A.S.M.R.U. Unique Mutations in SARS-CoV-2 Omicron Subvariants’ Non-Spike Proteins: Potential Impacts on Viral Pathogenesis and Host Immune Evasion. Microb. Pathog. 2022, 170, 105699. [Google Scholar] [CrossRef] [PubMed]
  20. Koyama, T.; Weeraratne, D.; Snowdon, J.L.; Parida, L. Emergence of Drift Variants That May Affect COVID-19 Vaccine Development and Antibody Treatment. Pathogens 2020, 9, 324. [Google Scholar] [CrossRef] [PubMed]
  21. Koyama, T.; Platt, D.; Parida, L. Variant Analysis of SARS-CoV-2 Genomes. Bull. World Health Organ. 2020, 98, 495–504. [Google Scholar] [CrossRef] [PubMed]
  22. Plante, J.A.; Liu, Y.; Liu, J.; Xia, H.; Johnson, B.A.; Lokugamage, K.G.; Zhang, X.; Muruato, A.E.; Zou, J.; Fontes-Garfias, C.R.; et al. Spike Mutation D614G Alters SARS-CoV-2 Fitness. Nature 2021, 592, 116–121. [Google Scholar] [CrossRef] [PubMed]
  23. Korber, B.; Fischer, W.M.; Gnanakaran, S.; Yoon, H.; Theiler, J.; Abfalterer, W.; Hengartner, N.; Giorgi, E.E.; Bhattacharya, T.; Foley, B.; et al. Tracking Changes in SARS-CoV-2 Spike: Evidence That D614G Increases Infectivity of the COVID-19 Virus. Cell 2020, 182, 812–827.e19. [Google Scholar] [CrossRef] [PubMed]
  24. Hou, Y.J.; Chiba, S.; Halfmann, P.; Ehre, C.; Kuroda, M.; Dinnon, K.H., 3rd; Leist, S.R.; Schäfer, A.; Nakajima, N.; Takahashi, K.; et al. SARS-CoV-2 D614G Variant Exhibits Efficient Replication Ex Vivo and Transmission in Vivo. Science 2020, 370, 1464–1468. [Google Scholar] [CrossRef] [PubMed]
  25. Morbidity and Mortality Weekly Report (MMWR). Available online: https://www.cdc.gov/mmwr/volumes/70/wr/mm7003e2.htm?utm_source=mp-fotoscapes#suggestedcitation (accessed on 25 April 2025).
  26. Rajah, M.M.; Hubert, M.; Bishop, E.; Saunders, N.; Robinot, R.; Grzelak, L.; Planas, D.; Dufloo, J.; Gellenoncourt, S.; Bongers, A.; et al. SARS-CoV-2 Alpha, Beta, and Delta Variants Display Enhanced Spike-mediated Syncytia Formation. EMBO J. 2021, 40, e108944. [Google Scholar] [CrossRef] [PubMed]
  27. Telenti, A.; Hodcroft, E.B.; Robertson, D.L. The Evolution and Biology of SARS-CoV-2 Variants. Cold Spring Harb. Perspect. Med. 2022, 12, a041390. [Google Scholar] [CrossRef] [PubMed]
  28. Ikegame, S.; Siddiquey, M.N.A.; Hung, C.-T.; Haas, G.; Brambilla, L.; Oguntuyo, K.Y.; Kowdle, S.; Chiu, H.-P.; Stevens, C.S.; Vilardo, A.E.; et al. Neutralizing Activity of Sputnik V Vaccine Sera against SARS-CoV-2 Variants. Nat. Commun. 2021, 12, 4598. [Google Scholar] [CrossRef] [PubMed]
  29. Muik, A.; Wallisch, A.-K.; Sänger, B.; Swanson, K.A.; Mühl, J.; Chen, W.; Cai, H.; Maurus, D.; Sarkar, R.; Türeci, Ö.; et al. Neutralization of SARS-CoV-2 Lineage B.1.1.7 Pseudovirus by BNT162b2 Vaccine–Elicited Human Sera. Science 2021, 371, 1152–1153. [Google Scholar] [CrossRef] [PubMed]
  30. Shen, X.; Tang, H.; McDanal, C.; Wagh, K.; Fischer, W.; Theiler, J.; Yoon, H.; Li, D.; Haynes, B.F.; Sanders, K.O.; et al. SARS-CoV-2 Variant B.1.1.7 Is Susceptible to Neutralizing Antibodies Elicited by Ancestral Spike Vaccines. Cell Host Microbe 2021, 29, 529–539.e3. [Google Scholar] [CrossRef] [PubMed]
  31. Chen, Y.; Shen, H.; Huang, R.; Tong, X.; Wu, C. Serum Neutralising Activity against SARS-CoV-2 Variants Elicited by CoronaVac. Lancet Infect. Dis. 2021, 21, 1071–1072. [Google Scholar] [CrossRef] [PubMed]
  32. Mohammadi, M.; Shayestehpour, M.; Mirzaei, H. The Impact of Spike Mutated Variants of SARS-CoV2 [Alpha, Beta, Gamma, Delta, and Lambda] on the Efficacy of Subunit Recombinant Vaccines. Brazilian J. Infect. Dis. 2021, 25, 101606. [Google Scholar] [CrossRef] [PubMed]
  33. Plante, J.; Liu, Y.; Liu, J.; Xia, H.; Johnson, B.; Lokugamage, K.; Zhang, X.; Muruato, A.; Zou, J.; Fontes-Garfias, C.; et al. Spike Mutation D614G AltersSARS-CoV-2 Fitness and Neutralization Susceptibility. Nature 2020, 592, 116–121. [Google Scholar] [CrossRef] [PubMed]
  34. Jackson, C.B.; Farzan, M.; Chen, B.; Choe, H. Mechanisms of SARS-CoV-2 Entry into Cells. Nat. Rev. Mol. Cell Biol. 2022, 23, 3–20. [Google Scholar] [CrossRef] [PubMed]
  35. Markov, P.V.; Ghafari, M.; Beer, M.; Lythgoe, K.; Simmonds, P.; Stilianakis, N.I.; Katzourakis, A. The Evolution of SARS-CoV-2. Nat. Rev. Microbiol. 2023, 21, 361–379. [Google Scholar] [CrossRef] [PubMed]
  36. Wang, Y.; Xu, C.; Wang, Y.; Hong, Q.; Zhang, C.; Li, Z.; Xu, S.; Zuo, Q.; Liu, C.; Huang, Z.; et al. Conformational Dynamics of the Beta and Kappa SARS-CoV-2 Spike Proteins and Their Complexes with ACE2 Receptor Revealed by Cryo-EM. Nat. Commun. 2021, 12, 7345. [Google Scholar] [CrossRef] [PubMed]
  37. Cheng, M.H.; Krieger, J.M.; Banerjee, A.; Xiang, Y.; Kaynak, B.; Shi, Y.; Arditi, M.; Bahar, I. Impact of New Variants on SARS-CoV-2 Infectivity and Neutralization: A Molecular Assessment of the Alterations in the Spike-Host Protein Interactions. iScience 2022, 25, 103939. [Google Scholar] [CrossRef] [PubMed]
  38. Padilha, D.A.; Benetti Filho, V.; Moreira, R.S.; Soratto, T.A.; Maia, G.A.; Christoff, A.P.; Barazzetti, F.H.; Schörner, M.A.; Ferrari, F.L.; Martins, C.L.; et al. Emergence of Two Distinct SARS-CoV-2 Gamma Variants and the Rapid Spread of P.1-like-II SARS-CoV-2 during the Second Wave of COVID-19 in Santa Catarina, Southern Brazil. Viruses 2022, 14, 695. [Google Scholar] [CrossRef] [PubMed]
  39. Zhang, Y.; Zhang, T.; Fang, Y.; Liu, J.; Ye, Q.; Ding, L. SARS-CoV-2 Spike L452R Mutation Increases Omicron Variant Fusogenicity and Infectivity as Well as Host Glycolysis. Signal Transduct. Target. Ther. 2022, 7, 76. [Google Scholar] [CrossRef] [PubMed]
  40. Planas, D.; Veyer, D.; Baidaliuk, A.; Staropoli, I.; Guivel-Benhassine, F.; Rajah, M.M.; Planchais, C.; Porrot, F.; Robillard, N.; Puech, J.; et al. Reduced Sensitivity of SARS-CoV-2 Variant Delta to Antibody Neutralization. Nature 2021, 596, 276–280. [Google Scholar] [CrossRef] [PubMed]
  41. Syed, A.M.; Ciling, A.; Taha, T.Y.; Chen, I.P.; Khalid, M.M.; Sreekumar, B.; Chen, P.-Y.; Kumar, G.R.; Suryawanshi, R.; Silva, I.; et al. Omicron Mutations Enhance Infectivity and Reduce Antibody Neutralization of SARS-CoV-2 Virus-like Particles. Proc. Natl. Acad. Sci. USA 2022, 119, e2200592119. [Google Scholar] [CrossRef] [PubMed]
  42. Chakraborty, C.; Bhattacharya, M.; Sharma, A.R.; Mallik, B. Omicron (B.1.1.529)—A New Heavily Mutated Variant: Mapped Location and Probable Properties of Its Mutations with an Emphasis on S-Glycoprotein. Int. J. Biol. Macromol. 2022, 219, 980–997. [Google Scholar] [CrossRef] [PubMed]
  43. Shi, G.; Li, T.; Lai, K.K.; Johnson, R.F.; Yewdell, J.W.; Compton, A.A. Omicron Spike Confers Enhanced Infectivity and Interferon Resistance to SARS-CoV-2 in Human Nasal Tissue. Nat. Commun. 2024, 15, 889. [Google Scholar] [CrossRef] [PubMed]
  44. Shrestha, L.B.; Foster, C.; Rawlinson, W.; Tedla, N.; Bull, R.A. Evolution of the SARS-CoV-2 Omicron Variants BA.1 to BA.5: Implications for Immune Escape and Transmission. Rev. Med. Virol. 2022, 32, e2381. [Google Scholar] [CrossRef] [PubMed]
  45. Li, L.; Liao, H.; Meng, Y.; Li, W.; Han, P.; Liu, K.; Wang, Q.; Li, D.; Zhang, Y.; Wang, L.; et al. Structural Basis of Human ACE2 Higher Binding Affinity to Currently Circulating Omicron SARS-CoV-2 Sub-Variants BA.2 and BA.1.1. Cell 2022, 185, 2952–2960.e10. [Google Scholar] [CrossRef] [PubMed]
  46. Izumi, K.; Daichi, Y.; Hesham, N.; Hayato, I.; Jiri, Z.; Jiaqi, W.; Shigeru, F.; Keiya, U.; Jiei, S.; Tomokazu, T.; et al. Multiple Mutations of SARS-CoV-2 Omicron BA.2 Variant Orchestrate Its Virological Characteristics. J. Virol. 2023, 97, e01011-23. [Google Scholar] [CrossRef]
  47. Kannan, S.R.; Spratt, A.N.; Sharma, K.; Goyal, R.; Sönnerborg, A.; Apparsundaram, S.; Lorson, C.L.; Byrareddy, S.N.; Singh, K. Complex Mutation Pattern of Omicron BA.2: Evading Antibodies without Losing Receptor Interactions. Int. J. Mol. Sci. 2022, 23, 5534. [Google Scholar] [CrossRef] [PubMed]
  48. Chakraborty, C.; Bhattacharya, M.; Chopra, H.; Islam, M.A.; Saikumar, G.; Dhama, K. The SARS-CoV-2 Omicron Recombinant Subvariants XBB, XBB.1, and XBB.1.5 Are Expanding Rapidly with Unique Mutations, Antibody Evasion, and Immune Escape Properties—An Alarming Global Threat of a Surge in COVID-19 Cases Again? Int. J. Surg. 2023, 109, 1041–1043. [Google Scholar] [CrossRef] [PubMed]
  49. Tamura, T.; Ito, J.; Uriu, K.; Zahradnik, J.; Kida, I.; Anraku, Y.; Nasser, H.; Shofa, M.; Oda, Y.; Lytras, S.; et al. Virological Characteristics of the SARS-CoV-2 XBB Variant Derived from Recombination of Two Omicron Subvariants. Nat. Commun. 2023, 14, 2800. [Google Scholar] [CrossRef] [PubMed]
  50. Giancotti, R.; Lomoio, U.; Puccio, B.; Tradigo, G.; Vizza, P.; Torti, C.; Veltri, P.; Guzzi, P.H. The Omicron XBB.1 Variant and Its Descendants: Genomic Mutations, Rapid Dissemination and Notable Characteristics. Biology 2024, 13, 90. [Google Scholar] [CrossRef] [PubMed]
  51. Criscuolo, E.; Giuliani, B.; Castelli, M.; Cavallaro, M.; Sisti, S.; Burioni, R.; Ferrari, D.; Mancini, N.; Locatelli, M.; Clementi, N. Single Spike Mutation Differentiating XBB.1 and XBB.1.5 Enhances SARS-CoV-2 Cell-to-Cell Transmission and Facilitates Serum-Mediated Enhancement. Front. Immunol. 2024, 15, 1501200. [Google Scholar] [CrossRef] [PubMed]
  52. Wang, X.; Lu, L.; Jiang, S. SARS-CoV-2 Omicron Subvariant BA.2.86: Limited Potential for Global Spread. Signal Transduct. Target. Ther. 2023, 8, 439. [Google Scholar] [CrossRef] [PubMed]
  53. Tamura, T.; Mizuma, K.; Nasser, H.; Deguchi, S.; Padilla-Blanco, M.; Oda, Y.; Uriu, K.; Tolentino, J.E.M.; Tsujino, S.; Suzuki, R.; et al. Virological Characteristics of the SARS-CoV-2 BA.2.86 Variant. Cell Host Microbe 2024, 32, 170–180.e12. [Google Scholar] [CrossRef] [PubMed]
  54. Liu, Y.; Zhao, X.; Shi, J.; Wang, Y.; Liu, H.; Hu, Y.-F.; Hu, B.; Shuai, H.; Yuen, T.T.-T.; Chai, Y.; et al. Lineage-Specific Pathogenicity, Immune Evasion, and Virological Features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3. Nat. Commun. 2024, 15, 8728. [Google Scholar] [CrossRef] [PubMed]
  55. Selvavinayagam, S.T.; Sankar, S.; Yong, Y.K.; Murugesan, A.; Suvaithenamudhan, S.; Hemashree, K.; Rajeshkumar, M.; Kumaresan, A.; Pandey, R.P.; Shanmugam, S.; et al. Emergence of SARS-CoV-2 Omicron Variant JN.1 in Tamil Nadu, India—Clinical Characteristics and Novel Mutations. Sci. Rep. 2024, 14, 17476. [Google Scholar] [CrossRef] [PubMed]
  56. Focosi, D.; Spezia, P.G.; Gueli, F.; Maggi, F. The Era of the FLips: How Spike Mutations L455F and F456L (and A475V) Are Shaping SARS-CoV-2 Evolution. Viruses 2024, 16, 3. [Google Scholar] [CrossRef] [PubMed]
  57. Li, P.; Faraone, J.N.; Hsu, C.C.; Chamblee, M.; Zheng, Y.; Carlin, C.; Bednash, J.S.; Horowitz, J.C.; Mallampalli, R.K.; Saif, J.; et al. Neutralization Escape, Infectivity, and Membrane Fusion of JN.1-Derived SARS-CoV-2 SLip, FLiRT, and KP.2 Variants. Cell Rep. 2024, 44, 114520. [Google Scholar] [CrossRef]
  58. Li, P.; Faraone, J.N.; Hsu, C.C.; Chamblee, M.; Zheng, Y.-M.; Carlin, C.; Bednash, J.S.; Horowitz, J.C.; Mallampalli, R.K.; Saif, L.J.; et al. Characteristics of JN.1-Derived SARS-CoV-2 Subvariants SLip, FLiRT, and KP.2 in Neutralization Escape, Infectivity and Membrane Fusion. bioRxiv Prepr. Serv. Biol. 2024. preprint. [Google Scholar] [CrossRef]
  59. Xu, K.; An, Y.; Liu, X.; Xie, H.; Li, D.; Yang, T.; Duan, M.; Wang, Y.; Zhao, X.; Dai, L.; et al. Neutralization of SARS-CoV-2 KP.1, KP.1.1, KP.2 and KP.3 by Human and Murine Sera. Npj Vaccines 2024, 9, 215. [Google Scholar] [CrossRef] [PubMed]
  60. Kaku, Y.; Uriu, K.; Kosugi, Y.; Okumura, K.; Yamasoba, D.; Uwamino, Y.; Kuramochi, J.; Sadamasu, K.; Yoshimura, K.; Asakura, H.; et al. Virological Characteristics of the SARS-CoV-2 KP.2 Variant. Lancet Infect. Dis. 2024, 24, e416. [Google Scholar] [CrossRef] [PubMed]
  61. Liu, J.; Yu, Y.; Jian, F.; Yang, S.; Song, W.; Wang, P.; Yu, L.; Shao, F.; Cao, Y. Enhanced Immune Evasion of SARS-CoV-2 Variants KP.3.1.1 and XEC through N-Terminal Domain Mutations. Lancet Infect. Dis. 2025, 25, e6–e7. [Google Scholar] [CrossRef] [PubMed]
  62. Li, P.; Faraone, J.N.; Hsu, C.C.; Chamblee, M.; Liu, Y.; Zheng, Y.-M.; Xu, Y.; Carlin, C.; Horowitz, J.C.; Mallampalli, R.K.; et al. Role of Glycosylation Mutations at the N-Terminal Domain of SARS-CoV-2 XEC Variant in Immune Evasion, Cell-Cell Fusion, and Spike Stability. J. Virol. 2025, 99, e00242-25. [Google Scholar] [CrossRef] [PubMed]
  63. Tegally, H.; Wilkinson, E.; Giovanetti, M.; Iranzadeh, A.; Fonseca, V.; Giandhari, J.; Doolabh, D.; Pillay, S.; San, E.J.; Msomi, N.; et al. Detection of a SARS-CoV-2 Variant of Concern in South Africa. Nature 2021, 592, 438–443. [Google Scholar] [CrossRef] [PubMed]
  64. Widera, M.; Wilhelm, A.; Hoehl, S.; Pallas, C.; Kohmer, N.; Wolf, T.; Rabenau, H.F.; Corman, V.M.; Drosten, C.; Vehreschild, M.J.G.T.; et al. Limited Neutralization of Authentic Severe Acute Respiratory Syndrome Coronavirus 2 Variants Carrying E484K In Vitro. J. Infect. Dis. 2021, 224, 1109–1114. [Google Scholar] [CrossRef] [PubMed]
  65. Chemaitelly, H.; Yassine, H.M.; Benslimane, F.M.; Al Khatib, H.A.; Tang, P.; Hasan, M.R.; Malek, J.A.; Coyle, P.; Ayoub, H.H.; Al Kanaani, Z.; et al. MRNA-1273 COVID-19 Vaccine Effectiveness against the B.1.1.7 and B.1.351 Variants and Severe COVID-19 Disease in Qatar. Nat. Med. 2021, 27, 1614–1621. [Google Scholar] [CrossRef] [PubMed]
  66. Singer, S.R.; Angulo, F.J.; Swerdlow, D.L.; McLaughlin, J.M.; Hazan, I.; Ginish, N.; Anis, E.; Mendelson, E.; Mor, O.; Zuckerman, N.S.; et al. Effectiveness of BNT162b2 MRNA COVID-19 Vaccine against SARS-CoV-2 Variant Beta (B.1.351) among Persons Identified through Contact Tracing in Israel: A Prospective Cohort Study. eClinicalMedicine 2021, 42, 101190. [Google Scholar] [CrossRef] [PubMed]
  67. Madhi, S.A.; Baillie, V.; Cutland, C.L.; Voysey, M.; Koen, A.L.; Fairlie, L.; Padayachee, S.D.; Dheda, K.; Barnabas, S.L.; Bhorat, Q.E.; et al. Efficacy of the ChAdOx1 NCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N. Engl. J. Med. 2021, 384, 1885–1898. [Google Scholar] [CrossRef] [PubMed]
  68. Zhou, D.; Dejnirattisai, W.; Supasa, P.; Liu, C.; Mentzer, A.J.; Ginn, H.M.; Zhao, Y.; Duyvesteyn, H.M.E.; Tuekprakhon, A.; Nutalai, R.; et al. Evidence of Escape of SARS-CoV-2 Variant B.1.351 from Natural and Vaccine-Induced Sera. Cell 2021, 184, 2348–2361.e6. [Google Scholar] [CrossRef] [PubMed]
  69. Faria, N.R.; Mellan, T.A.; Whittaker, C.; Claro, I.M.; da S Candido, D.; Mishra, S.; Crispim, M.A.E.; Sales, F.C.S.; Hawryluk, I.; McCrone, J.T.; et al. Genomics and Epidemiology of the P.1 SARS-CoV-2 Lineage in Manaus, Brazil. Science 2021, 821, 815–821. [Google Scholar] [CrossRef] [PubMed]
  70. Luna-Muschi, A.; Borges, I.C.; de Faria, E.; Barboza, A.S.; Maia, F.L.; Leme, M.D.; Guedes, A.R.; Mendes-Correa, M.C.; Kallas, E.G.; Segurado, A.C.; et al. Clinical features of COVID-19 by SARS-CoV-2 Gamma variant: A prospective cohort study of vaccinated and unvaccinated healthcare workers. J. Infect. 2022, 84, 248–288. [Google Scholar] [CrossRef]
  71. Banho, C.A.; Sacchetto, L.; Rodrigues, G.; Campos, F.; Bittar, C.; Possebon, F.S.; Ullmann, L.S.; Marques, B.D.C.; Ceslestino, G.; Moraes, M.M.; et al. Impact of SARS-CoV-2 Gamma Lineage Introduction and COVID-19 Vaccination on the epidemiological landscape of a Brazilian city. Commun. Med. 2022, 2, 41. [Google Scholar] [CrossRef] [PubMed]
  72. Hitchings, M.D.T.; Ranzani, O.T.; Dorion, M.; D’aGostini, T.L.; de Paula, R.C.; de Paula, O.F.P.; Villela, E.F.d.M.; Torres, M.S.S.; de Oliveira, S.B.; Schulz, W.; et al. Effectiveness of ChAdOx1 Vaccine in Older Adults. Nat. Commun. 2021, 12, 15–22. [Google Scholar] [CrossRef] [PubMed]
  73. Redd, A.D.; Nardin, A.; Kared, H.; Bloch, E.M.; Pekosz, A.; Laeyendecker, O.; Abel, B.; Fehlings, M.; Quinn, T.C.; Tobian, A.A.R. CD8+ T-Cell Responses in COVID-19 Convalescent Individuals Target Conserved Epitopes From Multiple Prominent SARS-CoV-2 Circulating Variants. Open Forum Infect. Dis. 2021, 8, ofab143. [Google Scholar] [CrossRef] [PubMed]
  74. Hart, W.S.; Miller, E.; Andrews, N.J.; Waight, P.; Maini, P.K.; Funk, S.; Thompson, R.N. Generation Time of the Alpha and Delta SARS-CoV-2 Variants: An Epidemiological Analysis. Lancet Infect. Dis. 2022, 22, 603–610. [Google Scholar] [CrossRef] [PubMed]
  75. Liu, Y.; Liu, J.; Johnson, B.A.; Xia, H.; Ku, Z.; Schindewolf, C.; Widen, S.G.; An, Z.; Weaver, S.C.; Menachery, V.D.; et al. Delta Spike P681R Mutation Enhances SARS-CoV-2 Fitness over Alpha Variant. Cell Rep. 2022, 39, 110829. [Google Scholar] [CrossRef] [PubMed]
  76. Hattab, D.; Amer, M.F.A.; Al-Alami, Z.M.; Bakhtiar, A. SARS-CoV-2 Journey: From Alpha Variant to Omicron and Its Sub-Variants. Infection 2024, 52, 767–786. [Google Scholar] [CrossRef] [PubMed]
  77. Pouwels, K.B.; Pritchard, E.; Matthews, P.C.; Stoesser, N.; Eyre, D.W.; Vihta, K.D.; House, T.; Hay, J.; Bell, J.I.; Newton, J.N.; et al. Effect of Delta Variant on Viral Burden and Vaccine Effectiveness against New SARS-CoV-2 Infections in the UK. Nat. Med. 2021, 27, 2127–2135. [Google Scholar] [CrossRef] [PubMed]
  78. Eyre, D.W.; Taylor, D.; Purver, M.; Chapman, D.; Fowler, T.; Pouwels, K.B.; Walker, A.S.; Peto, T.E.A. Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants. N. Engl. J. Med. 2022, 386, 744–756. [Google Scholar] [CrossRef] [PubMed]
  79. Vikkurthi, R.; Ansari, A.; Pai, A.R.; Jha, S.N.; Sachan, S.; Pandit, S.; Nikam, B.; Kalia, A.; Jit, B.P.; Parray, H.A.; et al. Inactivated Whole-Virion Vaccine BBV152/Covaxin Elicits Robust Cellular Immune Memory to SARS-CoV-2 and Variants of Concern. Nat. Microbiol. 2022, 7, 974–985. [Google Scholar] [CrossRef] [PubMed]
  80. Bai, H.; Zhang, X.; Gong, T.; Ma, J.; Zhang, P.; Cai, Z.; Ren, D.; Zhang, C. A Systematic Mutation Analysis of 13 Major SARS-CoV-2 Variants. Virus Res. 2024, 345, 199392. [Google Scholar] [CrossRef] [PubMed]
  81. Chemaitelly, H.; Ayoub, H.H.; AlMukdad, S.; Coyle, P.; Tang, P.; Yassine, H.M.; Al-Khatib, H.A.; Smatti, M.K.; Hasan, M.R.; Al-Kanaani, Z.; et al. Duration of MRNA Vaccine Protection against SARS-CoV-2 Omicron BA.1 and BA.2 Subvariants in Qatar. Nat. Commun. 2022, 13, 3082. [Google Scholar] [CrossRef] [PubMed]
  82. Ai, J.; Wang, X.; He, X.; Zhao, X.; Zhang, Y.; Jiang, Y.; Li, M.; Cui, Y.; Chen, Y.; Qiao, R.; et al. Antibody Evasion of SARS-CoV-2 Omicron BA.1, BA.1.1, BA.2, and BA.3 Sub-Lineages. Cell Host Microbe 2022, 30, 1077–1083.e4. [Google Scholar] [CrossRef] [PubMed]
  83. Seki, Y.; Yoshihara, Y.; Nojima, K.; Momose, H.; Fukushi, S.; Moriyama, S.; Wagatsuma, A.; Numata, N.; Sasaki, K.; Kuzuoka, T.; et al. Safety and Immunogenicity of the Pfizer/BioNTech SARS-CoV-2 MRNA Third Booster Vaccine Dose against the BA.1 and BA.2 Omicron Variants. Med 2022, 3, 406–421.e4. [Google Scholar] [CrossRef] [PubMed]
  84. Petrelli, F.; Luciani, A.; Borgonovo, K.; Ghilardi, M.; Parati, M.C.; Petrò, D.; Lonati, V.; Pesenti, A.; Cabiddu, M. Third Dose of SARS-CoV-2 Vaccine: A Systematic Review of 30 Published Studies. J. Med. Virol. 2022, 94, 2837–2844. [Google Scholar] [CrossRef] [PubMed]
  85. Vasin, A.V.; Stukova, M.A. Bivalent Omicron (BA.1) Booster Vaccination against SARS-CoV-2. Lancet Infect. Dis. 2023, 23, 880–881. [Google Scholar] [CrossRef] [PubMed]
  86. Bhiman, J.N.; Richardson, S.I.; Lambson, B.E.; Kgagudi, P.; Mzindle, N.; Kaldine, H.; Crowther, C.; Gray, G.; Bekker, L.-G.; Koen, A.; et al. Novavax NVX-COV2373 Triggers Neutralization of Omicron Sub-Lineages. Sci. Rep. 2023, 13, 1222. [Google Scholar] [CrossRef] [PubMed]
  87. Qu, P.; Xu, K.; Faraone, J.N.; Goodarzi, N.; Zheng, Y.M.; Carlin, C.; Bednash, J.S.; Horowitz, J.C.; Mallampalli, R.K.; Saif, L.J.; et al. Immune Evasion, Infectivity, and Fusogenicity of SARS-CoV-2 BA.2.86 and FLip Variants. Cell 2024, 187, 585–595.e6. [Google Scholar] [CrossRef] [PubMed]
  88. Qu, P.; Faraone, J.N.; Evans, J.P.; Zheng, Y.M.; Carlin, C.; Anghelina, M.; Stevens, P.; Fernandez, S.; Jones, D.; Panchal, A.R.; et al. Enhanced Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1, and CA.3.1 Variants. Cell Rep. 2023, 42, 112443. [Google Scholar] [CrossRef] [PubMed]
  89. Wang, X.; Jiang, S.; Ma, W.; Li, X.; Wei, K.; Xie, F.; Zhao, C.; Zhao, X.; Wang, S.; Li, C.; et al. Enhanced Neutralization of SARS-CoV-2 Variant BA.2.86 and XBB Sub-Lineages by a Tetravalent COVID-19 Vaccine Booster. Cell Host Microbe 2024, 32, 25–34.e5. [Google Scholar] [CrossRef] [PubMed]
  90. Yang, J.; Hong, W.; Shi, H.; He, C.; Lei, H.; Zhou, Y.; Yang, H.; Alu, A.; Chen, Z.; Yang, Y.; et al. Trivalent Recombinant Protein Vaccine Induces Cross-Neutralization against XBB Lineage and JN.1 Subvariants: Preclinical and Phase 1 Clinical Trials. Nat. Commun. 2024, 15, 10778. [Google Scholar] [CrossRef] [PubMed]
  91. Klotz, S.A.; Yates, S.; Smith, S.L.; Dudley, S.; Schmidt, J.O.; Shirazi, F.M. Neutralization of BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine. N. Engl. J. Med. 2023, 388, 853–854. [Google Scholar] [CrossRef] [PubMed]
  92. Zhang, R.; Zhao, J.; Zhu, X.; Guan, Q.; Liu, S.; Li, M.; Gao, J.; Tan, J.; Cao, F.; Gan, B.; et al. Efficacy of the Tetravalent Protein COVID-19 Vaccine, SCTV01E: A Phase 3 Double-Blind, Randomized, Placebo-Controlled Trial. Nat. Commun. 2024, 15, 6255. [Google Scholar] [CrossRef] [PubMed]
  93. Chenchula, S.; Karunakaran, P.; Sharma, S.; Chavan, M. Current Evidence on Efficacy of COVID-19 Booster Dose Vaccination against the Omicron Variant: A Systematic Review. J. Med. Virol. 2022, 94, 2969–2976. [Google Scholar] [CrossRef] [PubMed]
  94. Wang, Q.; Guo, Y.; Bowen, A.; Mellis, I.A.; Valdez, R.; Gherasim, C.; Gordon, A.; Liu, L.; Ho, D.D. XBB.1.5 Monovalent MRNA Vaccine Booster Elicits Robust Neutralizing Antibodies against XBB Subvariants and JN.1. Cell Host Microbe 2024, 32, 315–321.e3. [Google Scholar] [CrossRef] [PubMed]
  95. Alves, K.; Kotloff, K.; McClelland, R.S.; Kouassi, A.; Plested, J.S.; Kalkeri, R.; Zhu, M.; Cloney-Clark, S.; Cai, Z.; Smith, K.; et al. Immunogenicity and Safety of a Monovalent Omicron XBB.1.5 SARS-CoV-2 Recombinant Spike Protein Vaccine as a Heterologous Booster Dose in US Adults: Interim Analysis of a Single-Arm Phase 2/3 Study. Lancet Infect. Dis. 2025, 25, 585–594. [Google Scholar] [CrossRef] [PubMed]
  96. Nesamari, R.; Omondi, M.A.; Baguma, R.; Höft, M.A.; Ngomti, A.; Nkayi, A.A.; Besethi, A.S.; Magugu, S.F.J.; Mosala, P.; Walters, A.; et al. Post-Pandemic Memory T Cell Response to SARS-CoV-2 Is Durable, Broadly Targeted, and Cross-Reactive to the Hypermutated BA.2.86 Variant. Cell Host Microbe 2024, 32, 162–169.e3. [Google Scholar] [CrossRef] [PubMed]
  97. Jian, F.; Wang, J.; Yisimayi, A.; Song, W.; Xu, Y.; Chen, X.; Niu, X.; Yang, S.; Yu, Y.; Wang, P.; et al. Evolving Antibody Response to SARS-CoV-2 Antigenic Shift from XBB to JN.1. Nature 2025, 637, 921–929. [Google Scholar] [CrossRef] [PubMed]
  98. Kaku, Y.; Okumura, K.; Padilla-Blanco, M.; Kosugi, Y.; Uriu, K.; Hinay, A.A.; Chen, L.; Plianchaisuk, A.; Kobiyama, K.; Ishii, K.J.; et al. Virological Characteristics of the SARS-CoV-2 JN.1 Variant. Lancet Infect. Dis. 2024, 24, e82. [Google Scholar] [CrossRef] [PubMed]
  99. CDC COVID Data Tracker. Available online: https://covid.cdc.gov/covid-data-tracker/#variant-summary (accessed on 23 March 2025).
  100. Kosugi, Y.; Plianchaisuk, A.; Putri, O.; Uriu, K.; Kaku, Y.; Hinay, A.A.; Chen, L.; Kuramochi, J.; Sadamasu, K.; Yoshimura, K.; et al. Characteristics of the SARS-CoV-2 Omicron HK.3 Variant Harbouring the FLip Substitution. Lancet Microbe 2024, 5, e313. [Google Scholar] [CrossRef] [PubMed]
  101. Happle, C.; Hoffmann, M.; Kempf, A.; Nehlmeier, I.; Stankov, M.V.; Calderon Hampel, N.; Witte, T.; Pöhlmann, S.; Behrens, G.M.N.; Dopfer-Jablonka, A. Humoral Immunity after MRNA SARS-CoV-2 Omicron JN.1 Vaccination. Lancet Infect. Dis. 2024, 24, 674–676. [Google Scholar] [CrossRef] [PubMed]
  102. Uriu, K.; Kaku, Y.; Uwamino, Y.; Fujiwara, H.; Saito, F.; Sato, K. Antiviral Humoral Immunity Induced by JN.1 Monovalent MRNA Vaccines against SARS-CoV-2 Omicron Subvariants Including JN.1, KP.3.1.1, and XEC. Lancet Infect. Dis. 2025, 25, e61. [Google Scholar] [CrossRef] [PubMed]
  103. Pérez-Then, E.; Miric, M.; Qian, H.-Z.; Chen, Y.Q.; Wang, Y.; Vallejo, V.; Quezada, W.; Flaquer, M.; Olivo, J.; Castillo, J.; et al. Population-Level Effectiveness of an Inactivated Whole-Virion COVID-19 Vaccine: A Test Negative Case-Control Study in the Dominican Republic. Open Forum Infect. Dis. 2023, 10, ofad075. [Google Scholar] [CrossRef] [PubMed]
  104. Hitchings, M.D.T.; Ranzani, O.T.; Torres, M.S.S.; de Oliveira, S.B.; Almiron, M.; Said, R.; Borg, R.; Schulz, W.L.; de Oliveira, R.D.; da Silva, P.V.; et al. Effectiveness of CoronaVac among Healthcare Workers in the Setting of High SARS-CoV-2 Gamma Variant Transmission in Manaus, Brazil: A Test-Negative Case-Control Study. Lancet Reg. Health Am. 2021, 1, 100025. [Google Scholar] [CrossRef] [PubMed]
  105. Li, X.-N.; Yong, H.; Wen, W.; Qin-Long, J.; Chun-Huan, Z.; Peng-Zhe, Q.; Wei-Jie, G.; Lin, G.; Yi-Lan, L.; Wen-Hui, L.; et al. Effectiveness of Inactivated SARS-CoV-2 Vaccines against the Delta Variant Infection in Guangzhou: A Test-Negative Case–Control Real-World Study. Emerg. Microbes Infect. 2021, 10, 1751–1759. [Google Scholar] [CrossRef] [PubMed]
  106. Jeewandara, C.; Aberathna, I.S.; Danasekara, S.; Gomes, L.; Fernando, S.; Guruge, D.; Ranasinghe, T.; Gunasekera, B.; Kamaladasa, A.; Kuruppu, H.; et al. Comparison of the Immunogenicity of Five COVID-19 Vaccines in Sri Lanka. Immunology 2022, 167, 263–274. [Google Scholar] [CrossRef] [PubMed]
  107. Law, M.; Ho, S.S.H.; Tsang, G.K.C.; Ho, C.M.Y.; Kwan, C.M.; Yan, V.K.C.; Yiu, H.H.E.; Lai, F.T.T.; Wong, I.C.K.; Chan, E.W.Y. Efficacy and Effectiveness of Inactivated Vaccines against Symptomatic COVID-19, Severe COVID-19, and COVID-19 Clinical Outcomes in the General Population: A Systematic Review and Meta-Analysis. Lancet Reg. Health West. Pacific 2023, 37, 100788. [Google Scholar] [CrossRef] [PubMed]
  108. Jara, A.; Undurraga, E.A.; González, C.; Paredes, F.; Fontecilla, T.; Jara, G.; Pizarro, A.; Acevedo, J.; Leo, K.; Leon, F.; et al. Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. N. Engl. J. Med. 2021, 385, 875–884. [Google Scholar] [CrossRef] [PubMed]
  109. Svetlova, J.; Gustin, D.; Manuvera, V.; Shirokov, D.; Shokina, V.; Prusakov, K.; Aldarov, K.; Kharlampieva, D.; Matyushkina, D.; Bespyatykh, J.; et al. Microarray Profiling of Vaccination-Induced Antibody Responses to SARS-CoV-2 Variants of Interest and Concern. Int. J. Mol. Sci. 2022, 23, 13220. [Google Scholar] [CrossRef] [PubMed]
  110. Leung, D.; Mu, X.; Duque, J.S.R.; Cheng, S.M.S.; Wang, M.; Zhang, W.; Zhang, Y.; Tam, I.Y.S.; Lee, T.S.S.; Lam, J.H.Y.; et al. Safety and Immunogenicity of 3 Doses of BNT162b2 and CoronaVac in Children and Adults with Inborn Errors of Immunity. Front. Immunol. 2022, 13, 982155. [Google Scholar] [CrossRef] [PubMed]
  111. Rakshit, S.; Babji, S.; Parthiban, C.; Madhavan, R.; Adiga, V.; J, S.E.; Kumar, N.C.; Ahmed, A.; Shivalingaiah, S.; Shashikumar, N.; et al. Polyfunctional CD4 T-Cells Correlating with Neutralising Antibody Is a Hallmark of COVISHIELDTM and COVAXIN® Induced Immunity in COVID-19 Exposed Indians. Npj Vaccines 2023, 8, 134. [Google Scholar] [CrossRef] [PubMed]
  112. Kruglov, A.A.; Bondareva, M.A.; Gogoleva, V.S.; Semin, I.K.; Astrakhantseva, I.V.; Zvartsev, R.; Lunin, A.S.; Apolokhov, V.D.; Shustova, E.Y.; Volok, V.P.; et al. Inactivated Whole Virion Vaccine Protects K18-HACE2 Tg Mice against the Omicron SARS-CoV-2 Variant via Cross-Reactive T Cells and Nonneutralizing Antibody Responses. Eur. J. Immunol. 2024, 54, e2350664. [Google Scholar] [CrossRef] [PubMed]
  113. Morens, D.M.; Taubenberger, J.K.; Fauci, A.S. Universal Coronavirus Vaccines—An Urgent Need. N. Engl. J. Med. 2022, 386, 297–299. [Google Scholar] [CrossRef] [PubMed]
  114. Pinto, D.; Sauer, M.M.; Czudnochowski, N.; Low, J.S.; Alejandra Tortorici, M.; Housley, M.P.; Noack, J.; Walls, A.C.; Bowen, J.E.; Guarino, B.; et al. Broad Betacoronavirus Neutralization by a Stem Helix–Specific Human Antibody. Science 2021, 373, 1109–1116. [Google Scholar] [CrossRef] [PubMed]
  115. Dacon, C.; Tucker, C.; Peng, L.; Lee, C.C.D.; Lin, T.H.; Yuan, M.; Cong, Y.; Wang, L.; Purser, L.; Williams, J.K.; et al. Broadly Neutralizing Antibodies Target the Coronavirus Fusion Peptide. Science 2022, 377, 728–735. [Google Scholar] [CrossRef] [PubMed]
  116. Hicks, J.; Klumpp-Thomas, C.; Kalish, H.; Shunmugavel, A.; Mehalko, J.; Denson, J.P.; Snead, K.R.; Drew, M.; Corbett, K.S.; Graham, B.S.; et al. Serologic Cross-Reactivity of SARS-CoV-2 with Endemic and Seasonal Betacoronaviruses. J. Clin. Immunol. 2021, 41, 906–913. [Google Scholar] [CrossRef] [PubMed]
  117. Ladner, J.T.; Henson, S.N.; Boyle, A.S.; Engelbrektson, A.L.; Fink, Z.W.; Rahee, F.; D’ambrozio, J.; Schaecher, K.E.; Stone, M.; Dong, W.; et al. Epitope-Resolved Profiling of the SARS-CoV-2 Antibody Response Identifies Cross-Reactivity with Endemic Human Coronaviruses. Cell Reports Med. 2021, 2, 100189. [Google Scholar] [CrossRef] [PubMed]
  118. Takeda, M. Proteolytic Activation of SARS-CoV-2 Spike Protein. Microbiol. Immunol. 2022, 66, 15–23. [Google Scholar] [CrossRef] [PubMed]
  119. Guo, L.; Lin, S.; Chen, Z.; Cao, Y.; He, B.; Lu, G. Targetable Elements in SARS-CoV-2 S2 Subunit for the Design of Pan-Coronavirus Fusion Inhibitors and Vaccines. Signal Transduct. Target. Ther. 2023, 8, 197. [Google Scholar] [CrossRef] [PubMed]
  120. Hatmal, M.M.; Alshaer, W.; Al-Hatamleh, M.A.I.; Hatmal, M.; Smadi, O.; Taha, M.O.; Oweida, A.J.; Boer, J.C.; Mohamud, R.; Plebanski, M. Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and Their Interactions with ACE2. Cells 2020, 9, 2638. [Google Scholar] [CrossRef] [PubMed]
  121. Shah, P.; Canziani, G.A.; Carter, E.P.; Chaiken, I. The Case for S2: The Potential Benefits of the S2 Subunit of the SARS-CoV-2 Spike Protein as an Immunogen in Fighting the COVID-19 Pandemic. Front. Immunol. 2021, 12, 637651. [Google Scholar] [CrossRef] [PubMed]
  122. Wu, L.; Zheng, A.; Tang, Y.; Chai, Y.; Chen, J.; Cheng, L.; Hu, Y.; Qu, J.; Lei, W.; Liu, W.J.; et al. A Pan-Coronavirus Peptide Inhibitor Prevents SARS-CoV-2 Infection in Mice by Intranasal Delivery. Sci. China Life Sci. 2023, 66, 2201–2213. [Google Scholar] [CrossRef] [PubMed]
  123. Xia, S.; Jiao, F.; Wang, L.; Yu, X.; Lu, T.; Fu, Y.; Huang, Z.; Li, X.; Huang, J.; Wang, Q.; et al. SARS-CoV-2 Omicron XBB Subvariants Exhibit Enhanced Fusogenicity and Substantial Immune Evasion in Elderly Population, but High Sensitivity to Pan-Coronavirus Fusion Inhibitors. J. Med. Virol. 2023, 95, e28641. [Google Scholar] [CrossRef] [PubMed]
  124. Zhu, Y.; Gao, Z.; Feng, X.; Cheng, L.; Liu, N.; Liu, C.; Han, S.; Yang, Q.; Zou, Q.; Chong, H.; et al. Development of Potent Pan-Coronavirus Fusion Inhibitors with a New Design Strategy. MedComm 2024, 5, e666. [Google Scholar] [CrossRef] [PubMed]
  125. Xia, S.; Zhu, Y.; Liu, M.; Lan, Q.; Xu, W.; Wu, Y.; Ying, T.; Liu, S.; Shi, Z.; Jiang, S.; et al. Fusion Mechanism of 2019-NCoV and Fusion Inhibitors Targeting HR1 Domain in Spike Protein. Cell. Mol. Immunol. 2020, 17, 765–767. [Google Scholar] [CrossRef] [PubMed]
  126. Wang, X.; Sun, L.; Liu, Z.; Xing, L.; Zhu, Y.; Xu, W.; Xia, S.; Lu, L.; Jiang, S. An Engineered Recombinant Protein Containing Three Structural Domains in SARS-CoV-2 S2 Protein Has Potential to Act as a Pan-Human Coronavirus Entry Inhibitor or Vaccine Antigen. Emerg. Microbes Infect. 2023, 12, 2244084. [Google Scholar] [CrossRef] [PubMed]
  127. Shiakolas, A.R.; Kramer, K.J.; Wrapp, D.; Richardson, S.I.; Schäfer, A.; Wall, S.; Wang, N.; Janowska, K.; Pilewski, K.A.; Venkat, R.; et al. Cross-Reactive Coronavirus Antibodies with Diverse Epitope Specificities and Fc Effector Functions. Cell Reports Med. 2021, 2, 100313. [Google Scholar] [CrossRef] [PubMed]
  128. Nguyen-Contant, P.; Embong, A.K.; Kanagaiah, P.; Chaves, F.A.; Yang, H.; Branche, A.R.; Topham, D.J.; Sangster, M.Y.; Ellebedy, A.; Schultz-Cherry, S. S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit. MBio 2020, 11, e01991-20. [Google Scholar] [CrossRef] [PubMed]
  129. Braun, J.; Loyal, L.; Frentsch, M.; Wendisch, D.; Georg, P.; Kurth, F.; Hippenstiel, S.; Dingeldey, M.; Kruse, B.; Fauchere, F.; et al. SARS-CoV-2-Reactive T Cells in Healthy Donors and Patients with COVID-19. Nature 2020, 587, 270–274. [Google Scholar] [CrossRef] [PubMed]
  130. Ng, K.W.; Faulkner, N.; Cornish, G.H.; Rosa, A.; Harvey, R.; Hussain, S.; Ulferts, R.; Earl, C.; Wrobel, A.G.; Benton, D.J.; et al. Preexisting and de Novo Humoral Immunity to SARS-CoV-2 in Humans. Science 2020, 370, 1339–1343. [Google Scholar] [CrossRef] [PubMed]
  131. Grobben, M.; Van Der Straten, K.; Brouwer, P.J.; Brinkkemper, M.; Maisonnasse, P.; Dereuddre-Bosquet, N.; Appelman, B.; Ayesha Lavell, A.H.; Van Vught, L.A.; Burger, J.A.; et al. Cross-Reactive Antibodies after Sars-Cov-2 Infection and Vaccination. Elife 2021, 10, e70330. [Google Scholar] [CrossRef] [PubMed]
  132. Tsugawa, Y.; Furukawa, K.; Ise, T.; Takayama, M.; Ota, T.; Kuroda, T.; Shano, S.; Hashimoto, T.; Konishi, H.; Ishihara, T.; et al. Discovery of Anti-SARS-CoV-2 S2 Protein Antibody CV804 with Broad-Spectrum Reactivity with Various Beta Coronaviruses and Analysis of Its Pharmacological Properties in Vitro and in Vivo. PLoS ONE 2024, 19, e0300297. [Google Scholar] [CrossRef] [PubMed]
  133. Felbinger, N.; Trudil, D.; Loomis, L.; Ascione, R.; Siragusa, G.; Haba, S.; Rastogi, S.; Mucci, A.; Claycomb, M.; Snowberger, S.; et al. Epitope Mapping of SARS-CoV-2 Spike Protein Differentiates the Antibody Binding Activity in Vaccinated and Infected Individuals. Front. Virol. 2023, 3, 988109. [Google Scholar] [CrossRef]
  134. Forni, D.; Filippi, G.; Cagliani, R.; De Gioia, L.; Pozzoli, U.; Al-Daghri, N.; Clerici, M.; Sironi, M. The Heptad Repeat Region Is a Major Selection Target in MERS-CoV and Related Coronaviruses. Sci. Rep. 2015, 5, srep14480. [Google Scholar] [CrossRef] [PubMed]
  135. Liu, S.; Xiao, G.; Chen, Y.; He, Y.; Niu, J.; Escalante, C.R.; Xiong, H.; Farmar, J.; Debnath, A.K.; Tien, P.; et al. Interaction between Heptad Repeat 1 and 2 Regions in Spike Protein of SARS-Associated Coronavirus: Implications for Virus Fusogenic Mechanism and Identification of Fusion Inhibitors. Lancet 2004, 363, 938–947. [Google Scholar] [CrossRef] [PubMed]
  136. Halfmann, P.J.; Patel, R.S.; Loeffler, K.; Yasuhara, A.; Van De Velde, L.A.; Yang, J.E.; Chervin, J.; Troxell, C.; Huang, M.; Zheng, N.; et al. Multivalent S2 Subunit Vaccines Provide Broad Protection against Clade 1 Sarbecoviruses in Female Mice. Nat. Commun. 2025, 16, 462. [Google Scholar] [CrossRef] [PubMed]
  137. Halfmann, P.J.; Frey, S.J.; Loeffler, K.; Kuroda, M.; Maemura, T.; Armbrust, T.; Yang, J.E.; Hou, Y.J.; Baric, R.; Wright, E.R.; et al. Multivalent S2-Based Vaccines Provide Broad Protection against SARS-CoV-2 Variants of Concern and Pangolin Coronaviruses. eBioMedicine 2022, 86, 104341. [Google Scholar] [CrossRef] [PubMed]
  138. Johnson, N.V.; Wall, S.C.; Kramer, K.J.; Holt, C.M.; Periasamy, S.; Richardson, S.I.; Manamela, N.P.; Suryadevara, N.; Andreano, E.; Paciello, I.; et al. Discovery and Characterization of a Pan-Betacoronavirus S2-Binding Antibody. Structure 2024, 32, 1893–1909.e11. [Google Scholar] [CrossRef] [PubMed]
  139. Ma, X.; Zou, F.; Yu, F.; Li, R.; Yuan, Y.; Zhang, Y.; Zhang, X.; Deng, J.; Chen, T.; Song, Z.; et al. Nanoparticle Vaccines Based on the Receptor Binding Domain (RBD) and Heptad Repeat (HR) of SARS-CoV-2 Elicit Robust Protective Immune Responses. Immunity 2020, 53, 1315–1330.e9. [Google Scholar] [CrossRef] [PubMed]
  140. Lu, Y.; Shen, F.; He, W.-Q.; Li, A.-Q.; Li, M.-H.; Feng, X.-L.; Zheng, Y.-T.; Pang, W. HR121 Targeting HR2 Domain in S2 Subunit of Spike Protein Can Serve as a Broad-Spectrum SARS-CoV-2 Inhibitor via Intranasal Administration. Acta Pharm. Sin. B 2023, 13, 3339–3351. [Google Scholar] [CrossRef] [PubMed]
  141. Pang, W.; Lu, Y.; Zhao, Y.-B.; Shen, F.; Fan, C.-F.; Wang, Q.; He, W.-Q.; He, X.-Y.; Li, Z.-K.; Chen, T.-T.; et al. A Variant-Proof SARS-CoV-2 Vaccine Targeting HR1 Domain in S2 Subunit of Spike Protein. Cell Res. 2022, 32, 1068–1085. [Google Scholar] [CrossRef] [PubMed]
  142. Evtushenko, E.; Ryabchevskaya, E.; Kovalenko, A.; Granovskiy, D.; Arkhipenko, M.; Vasiliev, Y.; Nikitin, N.; Karpova, O. Wuhan Sequence-Based Recombinant Antigens Expressed in E. Coli Elicit Antibodies Capable of Binding with Omicron S-Protein. Int. J. Mol. Sci. 2024, 25, 9016. [Google Scholar] [CrossRef] [PubMed]
  143. Kovalenko, A.O.; Ryabchevskaya, E.M.; Evtushenko, E.A.; Kondakova, O.A.; Ivanov, P.A.; Arkhipenko, M.V.; Nikitin, N.A.; Karpova, O. V Dataset on Safety and Protective Efficacy Studies of COVID-19 Vaccine Candidates Based on Structurally Modified Plant Virus in Female Hamsters. Data Br. 2023, 48, 109158. [Google Scholar] [CrossRef] [PubMed]
  144. Wang, W.-C.; Sayedahmed, E.E.; Sambhara, S.; Mittal, S.K. Progress towards the Development of a Universal Influenza Vaccine. Viruses 2022, 14, 1684. [Google Scholar] [CrossRef] [PubMed]
  145. Cai, Z.; Ni, W.; Li, W.; Wu, Z.; Yao, X.; Zheng, Y.; Zhao, Y.; Yuan, W. SARS-CoV-2 S Protein Disrupts the Formation of ISGF3 Complex through Conserved S2 Subunit to Antagonize Type I Interferon Response. J. Virol. 2025, 99, e0151624. [Google Scholar] [CrossRef] [PubMed]
  146. Xin, H.; Law, A.H.T.; Cheung, J.K.; Lin, Y.; Wu, P.; Li, Z.; Cowling, B.J.; Yang, W.; Wong, J.Y. Comparison of Excess Deaths and Laboratory-Confirmed COVID-19 Deaths during a Large Omicron Epidemic in 2022 in Hong Kong. J. Glob. Health 2025, 15, 4105. [Google Scholar] [CrossRef] [PubMed]
  147. Hu, S.; Wu, C.; Wu, X.; Ma, X.; Shu, C.; Chen, Q.; Zheng, A.; Yang, H.; Lu, J.; Du, P.; et al. Classification of Five SARS-CoV-2 Serotypes Based on RBD Antigenicities. Sci. Bull. 2023, 68, 3003–3012. [Google Scholar] [CrossRef] [PubMed]
  148. Simon-Loriere, E.; Schwartz, O. Towards SARS-CoV-2 Serotypes? Nat. Rev. Microbiol. 2022, 20, 187–188. [Google Scholar] [CrossRef] [PubMed]
  149. Hou, M.; Shi, J.; Gong, Z.; Wen, H.; Lan, Y.; Deng, X.; Fan, Q.; Li, J.; Jiang, M.; Tang, X.; et al. Intra- vs. Interhost Evolution of SARS-CoV-2 Driven by Uncorrelated Selection—The Evolution Thwarted. Mol. Biol. Evol. 2023, 40, msad204. [Google Scholar] [CrossRef] [PubMed]
  150. Hamelin, D.J.; Scicluna, M.; Saadie, I.; Mostefai, F.; Grenier, J.C.; Baron, C.; Caron, E.; Hussin, J.G. Predicting Pathogen Evolution and Immune Evasion in the Age of Artificial Intelligence. Comput. Struct. Biotechnol. J. 2025, 27, 1370–1382. [Google Scholar] [CrossRef] [PubMed]
  151. Tai, J.-H.; Lee, D.-C.; Lin, H.-F.; Chao, T.-L.; Ruan, Y.; Cheng, Y.-W.; Chou, Y.-C.; Lin, Y.-Y.; Chang, S.-Y.; Chen, P.-J.; et al. Tradeoffs between Proliferation and Transmission in Virus Evolution– Insights from Evolutionary and Functional Analyses of SARS-CoV-2. Virol. J. 2025, 22, 107. [Google Scholar] [CrossRef] [PubMed]
  152. Nielsen, B.F.; Saad-Roy, C.M.; Li, Y.; Sneppen, K.; Simonsen, L.; Viboud, C.; Levin, S.A.; Grenfell, B.T. Host Heterogeneity and Epistasis Explain Punctuated Evolution of SARS-CoV-2. PLOS Comput. Biol. 2023, 19, e1010896. [Google Scholar] [CrossRef] [PubMed]
  153. Hammer, A.S.; Quaade, M.L.; Rasmussen, T.B.; Fonager, J.; Rasmussen, M.; Mundbjerg, K.; Lohse, L.; Strandbygaard, B.; Jørgensen, C.S.; Alfaro-Núñez, A.; et al. SARS-CoV-2 Transmission between Mink (Neovison Vison) and Humans, Denmark. Emerg. Infect. Dis. 2021, 27, 547–551. [Google Scholar] [CrossRef] [PubMed]
  154. Fang, R.; Yang, X.; Guo, Y.; Peng, B.; Dong, R.; Li, S.; Xu, S. SARS-CoV-2 Infection in Animals: Patterns, Transmission Routes, and Drivers. Eco-Environ. Health 2024, 3, 45–54. [Google Scholar] [CrossRef] [PubMed]
  155. Raglow, Z.; Surie, D.; Chappell, J.D.; Zhu, Y.; Martin, E.T.; Kwon, J.H.; Frosch, A.E.; Mohamed, A.; Gilbert, J.; Bendall, E.E.; et al. SARS-CoV-2 Shedding and Evolution in Patients Who Were Immunocompromised during the Omicron Period: A Multicentre, Prospective Analysis. Lancet Microbe 2024, 5, e235–e246. [Google Scholar] [CrossRef] [PubMed]
  156. Marques, A.D.; Graham-Wooten, J.; Fitzgerald, A.S.; Leonard, A.S.; Cook, E.J.; Everett, J.K.; Rodino, K.G.; Moncla, L.H.; Kelly, B.J.; Collman, R.G.; et al. SARS-CoV-2 Evolution during Prolonged Infection in Immunocompromised Patients. MBio 2024, 15, e00110-24. [Google Scholar] [CrossRef] [PubMed]
  157. Du, P.; Li, N.; Xiong, X.; Tang, S.; Dai, Q.; Liu, Z.; Wang, T.; Gu, X.; Zhou, Z. A Bivalent Vaccine Containing D614G and BA.1 Spike Trimer Proteins or a BA.1 Spike Trimer Protein Booster Shows Broad Neutralizing Immunity. J. Med. Virol. 2022, 94, 4287–4293. [Google Scholar] [CrossRef] [PubMed]
  158. Launay, O.; Gupta, R.; Machabert, T.; Konate, E.; Rousseau, A.; Vigne, C.; Beckers, F.; Devlin, L.; Botelho-Nevers, E.; Cachanado, M.; et al. Beta-Variant Recombinant SARS CoV-2 Vaccine Induces Durable Cross-Reactive Antibodies against Omicron BA Variants. Commun. Med. 2025, 5, 21. [Google Scholar] [CrossRef] [PubMed]
  159. Park, H.-S.; Matsuoka, Y.; Santos, C.; Luongo, C.; Liu, X.; Yang, L.; Kaiser, J.A.; Duncan, E.F.; Johnson, R.F.; Teng, I.-T.; et al. Intranasal Parainfluenza Virus-Vectored Vaccine Expressing SARS-CoV-2 Spike Protein of Delta or Omicron B.1.1.529 Induces Mucosal and Systemic Immunity and Protects Hamsters against Homologous and Heterologous Challenge. PLoS Pathog. 2025, 21, e1012585. [Google Scholar] [CrossRef] [PubMed]
  160. Perez Marc, G.; Coria, L.M.; Ceballos, A.; Rodriguez, J.M.; Lombardo, M.E.; Bruno, L.; Páez Córdoba, F.; Fascetto Cassero, C.G.; Salvatori, M.; Rios Medrano, M.; et al. Immunogenicity and Safety of Monovalent and Bivalent SARS-CoV-2 Variant Adapted RBD-Based Protein Booster Vaccines in Adults Previously Immunized with Different Vaccine Platforms: A Phase II/III, Randomized Clinical Trial. Vaccine 2025, 54, 127045. [Google Scholar] [CrossRef] [PubMed]
  161. Ao, D.; Peng, D.; He, C.; Ye, C.; Hong, W.; Huang, X.; Lu, Y.; Shi, J.; Zhang, Y.; Liu, J.; et al. Correction: A Promising MRNA Vaccine Derived from the JN.1 Spike Protein Confers Protective Immunity against Multiple Emerged Omicron Variants. Mol. Biomed. 2025, 6, 13. [Google Scholar] [CrossRef] [PubMed]
  162. Piano Mortari, E.; Ferrucci, F.; Zografaki, I.; Carsetti, R.; Pacelli, L. T and B Cell Responses in Different Immunization Scenarios for COVID-19: A Narrative Review. Front. Immunol. 2025, 16, 1535014. [Google Scholar] [CrossRef] [PubMed]
  163. Kobayashi, M.; Kobayashi, N.; Deguchi, K.; Omori, S.; Ichinohe, T. SARS-CoV-2 Infection Primes Cross-Protective Respiratory IgA in a MyD88- and MAVS-Dependent Manner. Npj Vaccines 2025, 10, 40. [Google Scholar] [CrossRef] [PubMed]
  164. Saha, A.; Ghosh Roy, S.; Dwivedi, R.; Tripathi, P.; Kumar, K.; Nambiar, S.M.; Pathak, R. Beyond the Pandemic Era: Recent Advances and Efficacy of SARS-CoV-2 Vaccines Against Emerging Variants of Concern. Vaccines 2025, 13, 424. [Google Scholar] [CrossRef] [PubMed]
  165. Grant, M.D.; Bentley, K.; Fielding, C.A.; Hatfield, K.M.; Ings, D.P.; Harnum, D.; Wang, E.C.; Stanton, R.J.; Holder, K.A. Combined Anti-S1 and Anti-S2 Antibodies from Hybrid Immunity Elicit Potent Cross-Variant ADCC against SARS-CoV-2. JCI Insight 2023, 8, e170681. [Google Scholar] [CrossRef] [PubMed]
  166. Astrakhantseva, I.V.; Krut’, V.G.; Chuvpilo, S.A.; Shevyrev, D.V.; Shumeev, A.N.; Rybtsov, S.A.; Nedospasov, S.A. On Immunological Studies at Sirius University of Science and Technology. Mol. Biol. 2023, 57, 225–234. [Google Scholar] [CrossRef] [PubMed]
  167. Hsieh, C.-L.; Goldsmith, J.A.; Schaub, J.M.; DiVenere, A.M.; Kuo, H.-C.; Javanmardi, K.; Le, K.C.; Wrapp, D.; Lee, A.G.; Liu, Y.; et al. Structure-Based Design of Prefusion-Stabilized SARS-CoV-2 Spikes. Science 2020, 369, 1501–1505. [Google Scholar] [CrossRef] [PubMed]
  168. Watanabe, Y.; Mendonça, L.; Allen, E.R.; Howe, A.; Lee, M.; Allen, J.D.; Chawla, H.; Pulido, D.; Donnellan, F.; Davies, H.; et al. Native-like SARS-CoV-2 Spike Glycoprotein Expressed by ChAdOx1 NCoV-19/AZD1222 Vaccine. ACS Cent. Sci. 2021, 7, 594–602. [Google Scholar] [CrossRef] [PubMed]
  169. Ke, Z.; Oton, J.; Qu, K.; Cortese, M.; Zila, V.; McKeane, L.; Nakane, T.; Zivanov, J.; Neufeldt, C.J.; Cerikan, B.; et al. Structures and Distributions of SARS-CoV-2 Spike Proteins on Intact Virions. Nature 2020, 588, 498–502. [Google Scholar] [CrossRef] [PubMed]
  170. Kordyukova, L.V.; Moiseenko, A.V.; Serebryakova, M.V.; Shuklina, M.A.; Sergeeva, M.V.; Lioznov, D.A.; Shanko, A. V Structural and Immunoreactivity Properties of the SARS-CoV-2 Spike Protein upon the Development of an Inactivated Vaccine. Viruses 2023, 15, 480. [Google Scholar] [CrossRef] [PubMed]
  171. Liu, J.; Wu, Y.; Gao, G.F. A Structural Voyage Toward the Landscape of Humoral and Cellular Immune Escapes of SARS-CoV-2. Immunol. Rev. 2025, 330, e70000. [Google Scholar] [CrossRef] [PubMed]
Vaccines 13 00761 g001
Figure 1. The schematic of the S2 structure of the SARS-CoV-2 S protein. (A). 3D Structure of the SARS-CoV-2 S protein on the left; monomeric S2 subunit in the prefusion state on the right. 3D protein structure visualization was obtained using the RSCB Protein Data Bank; data for 8VKK were used to create this figure (B). Domain arrangement of S2 subunit of SARS-CoV-2 S protein. S1/S2—furin cleavage site between S1 and S2 domains of the spike protein; S2′—protease furin cleavage site; FP—fusion peptide; HR1—heptad repeats 1; CH—central helices; CD—connector domain; SH—stem helix; HR2—heptad repeats 2; TM -transmembrane domain; CT—cytoplasmic tail. Inhibitory pan-coronavirus agents reviewed in the text are depicted in bright blue; hallmark SARS-CoV-2 mutations featured in the text are depicted in red [122,123,124,125,126].
Figure 1. The schematic of the S2 structure of the SARS-CoV-2 S protein. (A). 3D Structure of the SARS-CoV-2 S protein on the left; monomeric S2 subunit in the prefusion state on the right. 3D protein structure visualization was obtained using the RSCB Protein Data Bank; data for 8VKK were used to create this figure (B). Domain arrangement of S2 subunit of SARS-CoV-2 S protein. S1/S2—furin cleavage site between S1 and S2 domains of the spike protein; S2′—protease furin cleavage site; FP—fusion peptide; HR1—heptad repeats 1; CH—central helices; CD—connector domain; SH—stem helix; HR2—heptad repeats 2; TM -transmembrane domain; CT—cytoplasmic tail. Inhibitory pan-coronavirus agents reviewed in the text are depicted in bright blue; hallmark SARS-CoV-2 mutations featured in the text are depicted in red [122,123,124,125,126].
Vaccines 13 00761 g001
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Gulova, S.M.; Veselkina, U.S.; Astrakhantseva, I.V. Adaptation of the Vaccine Prophylaxis Strategy to Variants of the SARS-CoV-2 Virus. Vaccines 2025, 13, 761. https://doi.org/10.3390/vaccines13070761

AMA Style

Gulova SM, Veselkina US, Astrakhantseva IV. Adaptation of the Vaccine Prophylaxis Strategy to Variants of the SARS-CoV-2 Virus. Vaccines. 2025; 13(7):761. https://doi.org/10.3390/vaccines13070761

Chicago/Turabian Style

Gulova, Sofia M., Uliana S. Veselkina, and Irina V. Astrakhantseva. 2025. "Adaptation of the Vaccine Prophylaxis Strategy to Variants of the SARS-CoV-2 Virus" Vaccines 13, no. 7: 761. https://doi.org/10.3390/vaccines13070761

APA Style

Gulova, S. M., Veselkina, U. S., & Astrakhantseva, I. V. (2025). Adaptation of the Vaccine Prophylaxis Strategy to Variants of the SARS-CoV-2 Virus. Vaccines, 13(7), 761. https://doi.org/10.3390/vaccines13070761

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