key: cord-0821961-jru4zb7n authors: Atefe Hosseini, Seyede; Zahedipour, Fatemeh; Mirzaei, Hamed; Kazemi Oskuee, Reza title: Potential SARS-CoV-2 Vaccines: Concept, Progress, and Challenges date: 2021-03-29 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2021.107622 sha: 4d95b0fc98252441e34110aa4b0929d4e1984a10 doc_id: 821961 cord_uid: jru4zb7n Since September 2020, the world has had more than 28 million cases of coronavirus disease 2019 (COVID-19). Many countries are facing a second wave of the COVID-19 outbreak. A pressing need is evident for the development of a potent vaccine to control the SARS-CoV-2. Institutions and companies in many countries have announced their vaccine research programs and progress against the COVID-19. While most vaccines go through the designation and preparation stages, some of them are under evaluation for efficacy among animal models and clinical trials, and three approved vaccine candidates have been introduced for limited exploitation in Russia and China. An effective vaccine must induce a protective response of both cell-mediated and humoral immunity and should meet the safety and efficacy criteria. Although the emergence of new technologies has accelerated the development of vaccines, there are several challenges on the way, such as limited knowledge about the pathophysiology of the virus, inducing humoral or cellular immunity, immune enhancement with animal coronavirus vaccines, and lack of an appropriate animal model. In this review, we firstly discuss the immune responses against SARS-CoV-2 disease, subsequently, give an overview of several vaccine platforms for SARS-CoV-2 under clinical trials and challenges in vaccine development against this virus. New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the current coronavirus disease 2019 (COVID-19) pandemic [1] .The reproductive number (R0) estimated for SARS-CoV-2 is 2.2, which means one infected person can cause viral transmission to 2.2 other persons, thus this infection is highly transmissible with estimated 5.8-day incubation period [2] . Coronaviruses include four classes of alpha (α), beta (β), gamma (γ) and delta (δ) strains. The SARS-CoV, the SARS-CoV-2 and the Middle East respiratory syndrome coronavirus (MERS-CoV) are in beta coronavirus class. The SARS-CoV-2genome is completely sequenced and represented similarity to MERS-CoV and SARS-CoV [3, 4] . The SARS-CoV-2, like other members of Coronaviradae family, consists of an envelope surrounding a single-stranded 30-kb RNA including 14 open reading frames (ORF). Four major proteins can be found in this virus, including, nucleocapsid (N), envelope (E), membrane (M), and spike (S). The N fragment comprises T-cell epitopes [4] . The S fragment is the predominant target to synthesize the vaccine against the SARS-CoV-2, mainly because of triggering the antibodies capable of neutralizing the virus as the immune response to vaccination. The N-terminal domain of S protein sequence in the SARS-CoV-2 consists of three excess short insertions when comparing with the SARS-CoV. Moreover, the receptor-binding domain (RBD) of S fragment contains alterations in 4 out of 5 main residues [5] . Angiotensin-converting enzyme 2 (ACE2), on the cell membrane of the host, acts as a receptor for SARS-CoV-2 and SARS-CoV. The binding interaction between ACE2 and viral S protein is a central phase for triggering infection process. The primary target of SARS-CoV-2 is lower respiratory tracts, leading to pneumonia. In addition, this virus may bind to its receptor on the central nervous system (CNS), liver, kidney, gastrointestinal system and heart, resulting in multiple organ failure (MOF) [6] . Moreover, several nonstructural proteins are encoded by the viral genome such as PLpro (papainlike protease), RdRp (RNA-dependent RNA polymerase) and coronavirus main protease (3CLpro). The virus after entering to the host cell releases the genome as a +ssRNA, which is then translated to the proteins of the virus via utilizing the translation machinery of host cell. Subsequently, viral proteins are cleaved by PLpro and 3CLpro to form effector proteins. In addition, PLpro is a deubiquitinase capable of deubiquinating specific proteins in the host cell, such as NF-κB and interferon factor 3, leading to suppression of host immune system. A full-length template of minus-strand RNA of the virus is synthesized using the RdRp for the replication of more viral genome [7, 8] . Coronaviruses represent a high recombination rate because the replication of viral genome by RdRp result in increased rate of mutation thus, increasing the rate of homologous recombination. With respect to their high mutation rate coronaviruses are zoonotic pathogens that are capable of infecting humans and animals and result in extensive clinical symptoms, from asymptomatic features to severe symptoms result in the failure of many organs in the body [9] . Although, there is a need for months and probably years for knowing the complete characteristics of SARS-CoV-2 and its probable sources, symptoms, and host immune responses in the battle against infection. Studies are ongoing to produce the SARS-CoV-2 vaccines at high speed and large scale, mostly including DNA-based, mRNA-based, viral vectored, subunit and inactivated vaccines, as well as mainly based on S protein. However, in the way of producing a new vaccine there are so many challenges including poor success in developing human SARS/MERS vaccines, lack of appropriate animal models, limited knowledge of the SARS-CoV-Russian Federation, on 11 August 2020, approved the vaccine Gam-COVID-Vac (Sputnik V) produced by the Gamaleya Research Institute in Moscow. Scientists have raised great concern about the safety and efficacy of this vaccine because has not yet entered Phase 3 clinical trials. It should be noted that 234 vaccine candidates were being developed as of September 2020, 38 of which in clinical trials and 33 of these in Phase I-II trials and 6 in Phase II-III trials (11) . The current review aimed to briefly overview the host immune response to SARS-CoV-2, various vaccine candidates (mainly in clinical trials) and the challenges of implementing vaccine strategies. At present the information about the host immune response to COVID-19 is very limited. According to the cumulative empirical and clinical evidence on the study coronaviruses, it is possible to predict the mechanism of host immune system to combat this virus and the viral strategy to induce these immune responses [11] . Numerous studies illustrate important changes in the innate and adaptive immunity in SARS-CoV-2 patients. Clinically, the COVID-19 infection mediated immune responses are in two stages. There is a need for specific response of adaptive immunity within the incubation period and nonsevere phases to remove the virus and inhibit the disease progression to severe phases. Thus, the pathways to improve immune responses (pegylated or anti-sera IFNα) are course essential during this period [12] . Although, the first protective line to control the viral infection is a fast and wellcoordinated immune response, strong inflammation of innate immunity and dysregulated protection of host adaptive immunity can develop tissue damages either at the virus entry site or at whole body. In this regard, the excessive cytokine and chemokine release, named as "cytokine storm", is defined as uncontrolled dysregulation of immune defense in the host. Therefore, due to the main function of immune responses in SARA-CoV-2, knowing the process underlying immune dysregulation as well as the mechanisms of SARS-CoV-2 to escape from immune response help us to clinically manage the acute conditions and prevent the mild-to-severe stage transition [13] . An endogenous protective immune response can be established at the non-severe and incubation stages if the host has a suitable genetic history (e.g. HLA) and good general health eliciting a special antiviral immune response. The differences in genetic history in terms of the immune reactions against the pathogens can establish the individual alterations. However, in the impaired protective immunity, the viruses spread and the tissue is destroyed massively, particularly in organs with greater expression level of ACE2, including kidneys and intestines. Innate lung inflammation occurs in the damaged cells, predominantly due to proinflammatory granulocytes and macrophages. Therefore, during the severe stages in COVID-19 patients, the absolute number of natural killer (NK) cells, B cells, and CD4 + and CD8 + cells is significantly reduced in the circulation [4, 14, 15] , and also a reduction in basophils, eosinophils and monocytes has been reported [15] [16] [17] . furthermore, most of severe COVID-19 patients showed substantially increase in proinflammatory cytokines (e.g. TNFα, CCL3, IP-10, MCP-1, GM-CSF, G-CSF, IL-17, IL-6, IL-8, IL-1β and IL-2) in the serum [17, 18] . The inflammation of lungs is the major reason for the deadly respiratory diseases [14] . Suitable status of general health may therefore not be beneficial for the cases progressed to severe degree. If the lung damage develops significantly, the examinations should be directed to inhibit the inflammatory reaction and control the illness signs. Alarmingly, some patients remain/return positive for the SARS-CoV-2 and others even relapse after discharge from hospital. This means that it may be difficult to trigger a SARS-CoV-2 viruseliminating immune response probably in several cases, and these patients may not response to the vaccines. The survivors from non-severe condition must be checked for the presence of virus and the responses of B/T cells, especially when determining vaccine production strategies. Additionally, several coronavirus types or subtypes have been introduced. Therefore, if the vaccines that specifically target SARS-CoV-2 are found to face problems for production, the Edward Jenner approach should be considered [12] . A new infection of SARS-CoV-2 has been demonstrated in children in a recent study, associated with a remarkable inflammatory response. This condition has been known as pediatric inflammatory, multisystem syndrome temporally associated with COVID-19 (PIMS-TS). The new syndrome was temporally associated with recent exposure to SARS-CoV-2. PIMS-TS is an acute presentation of the virus in children and needs to be detected early to prevent its development and probable adverse impacts [19] . The primary signs of PIMS-TS are fever, inflammation marks (rash, oral mucosal changes, and conjunctivitis), cardiac dysfunction, and gastrointestinal symptoms. These characteristics are associated with laboratory evidence of remarkable inflammation: lymphopenia, neutrophilia, higher ferritin concentrations, and serum CRP; non-ST elevation pancarditis, and hypercoagulable state. Besides, echocardiograms usually show hyperechoic coronary arteries and left ventricular dysfunction [20] . PIMS-TS complications are systemic thrombosis and coronary artery aneurysms in nearly 13% of children in some published cohorts [21] . Approximately 2% of these children have died [22] . Retarded clearance of the SARS-CoV-2, which resulted in unchecked inflammation, is a potential mechanism for PIMS-TS [23] . Serum concentrations of proinflammatory interleukins (IL-1 beta, IL-17, IL-6, and IL-8) were very high in children with PIMS-TS. It was accompanied by monocytes and neutrophils activation [24] . However, in viral clearance, there is a handful of data on the anti-viral interferons' function (alpha, beta, and lambda). It also has been suggested that antibody-dependent enhancement (ADE), with the host cells' invasion amplified by serum proteases, antibody, or auto-antibody induced disease [25] . Nevertheless, PIMS-TS seem to affect only young adults and children, and ADE would be anticipated in older adults (with higher prevalence before exposure to other coronaviruses). The adult patient's treatment with COVID-19 recovering plasma has also not been correlated with hyperinflammation. The extensive effects of intravenous immunoglobulins via Fcγ-receptors, diminishing lymphocyte apoptosis, scavenging of inflammatory mediators, and preventing hypothesizing for the PIMS-TS' pathobiology [20] . Today, limited data are available on the host innate immune responses in the patients with SARS-CoV-2. In a study on the cases (n=99) examined in Wuhan, total neutrophils were elevated (38%), total lymphocytes were decreased (35%), the IL-6 level was increased in serum (52%) and creactive protein was increased (84%) [4] . Reduced lymphocytes and increased neutrophils correlate also with the seriousness of disease and death [26] . Furthermore, the ICU patients had greater serum levels of innate cytokines such as, TNFα, MIP-1A, MCP-1, and IP-10 [4] . These clinical characteristics proposed a potential role of hyperinflammatory responses in COVID-19 pathogenesis. Efficient innate immunity against the viral infectious diseases is highly dependent on the IFN I (interferon type I) responses and their downstream cascade which eventually results in the control of viral replication and the provocation of strong adaptive immunity. The SARS-CoV has been reported to directly infect T cells and macrophages, a key feature in pathogenesis mediated by SARS-CoV, which induces delayed but increased proinflammatory chemokines and cytokines. The ACE2 is a receptor minimally expressed in T cells, monocytes and macrophages in the lungs. However the strategy of SARS-CoV2 for directly infect any immune cells is still unknown [14] . A suitable antiviral response can be created by recognizing the invasion of viruses via innate immune cells, mostly through the pathogen-associated molecular pattern, PAMP. It is known for RNA viruses, including coronavirus, that PAMPs as viral genomic RNA or dsRNA (an intermediate produced within the viral replication), are identified by cytosolic RNA sensor, TLR7 and TLR3 as well as the endosomal RNA receptors, MDA5/RIG-I. Such identification process activates the downstream signaling pathway, such as IRF3 and NF-κB transcription factors, with the nuclear translocation. Such nuclear factors trigger the expression of IFN I and some proinflammatory cytokines. These primary reactions constitute the first protective line to control the viral infection at the penetration site [27] . In turn, the IFN-I uses the IFNAR to activate the JAK-STAT pathway in which the STAT1 and STAT2 are phosphorylated by JAK1 and TYK2 kinases. After form complex of STAT/2 with IRF9, they underwent nuclear shift for starting the IFN-stimulated gene (ISG) transcription supervised by promoters-containing IFN-stimulated response element (ISRE) [11] . According to the collected data from previous coronavirus infections, the innate immunity is important in protective or destructive reactions, opening a gate for the intervention immune. Later on, active viral replication leads to the overproduction of IFN I and the release of macrophages and neutrophils as the key resources of proinflammatory cytokine. During COVID19, the SARS-CoV-2 is capable of provoking delayed IFN I and viral control loss in an early infection with related alterations in overall lymphocytes and neutrophils [4] . Several approaches may be suggested about the key role of innate immunity, including some antagonists of key antiviral agents and proinflammatory cytokines such as IFN I. In the use of IFN I as the treatment, timing of administration in a murine models of SARS-CoV infection is crucial to providing protective response [28] . In general, T helper type 1 (Th1) immune response plays is important for the adaptive immune As regards adaptive immunity, the novel SARS-CoV-2 mainly affects the counting and balance of lymphocytes. The T cell response was extensively investigated in SARS-CoV. In a cohort study in Wuhan involving 452 patients with COVID-19, the patients with severe COVID-19 reported a smaller count of total T cells (suppressor and helper T cells) [17] . Reduced regulatory T cells was observed among Th cells, with highly decrease depending on the illness intensity of patients, and in memory T cells, while the percent of naïve T cells was elevated [17] . In another study using 128 convalescent samples, CD8-positive T cell responses were prevalent higher than CD4-positive T cell reactions. In addition, specific viral T cells from the patients with severe condition appeared to be a main memory phenotype having a markedly greater number of polyfunctional CD4positive T cells (TNFα, IFNγ, and IL-2) and CD8-positive T cells (TNFα, IFNγ, and degranulated state) when comparing with the mild-moderate patients. Potent T-cell responses significantly associated with greater neutralizing antibodies whereas higher Th2 cytokines (IL4 , IL5, IL10) in the serum were identified in the fatal patients group [31] . Memory and naïve T cells are necessary for the immune system, whose equilibrium plays a pivotal role to maintain an effective defensive system. The naïve T cells activate a large and closely coordinated release of cytokines to defend against new and previously unrecognized infections, while memory T cells induce the antigenspecific immunity. Dysregulated balance in favor of naïve T cell over regulatory T cells may significantly develop the hyperinflammation [32, 33] . A majority of responses (70%) induced versus structural proteins (nucleocapsid, spike, shell and membrane) was found for epitope mapping. Reportedly, the Th1 responses can effectively control the SARSCoV and MERSCoV, and probably the SARS-CoV-2. However, the critical CD8positive T cell response must be regulated in order to prevent lung pathology. Because a majority of epitopes for both MERSCoV and SARSCoV are concentrated on the structural proteins of the virus, it is useful to map those epitopes of MERSCoV/SARSCoV with the epitopes of SARSCoV-2. Concerning the overlapped epitopes of these viruses, the convalescent serum of recovered MERS or SARS cases can be used in the passive immunization. For epitopes of T cell, it will facilitate to develop cross-reactive vaccines which will protect against all 3 human coronaviruses in future [11] . As far as B cells are concerned, Wen et al found significant B cell changes exploiting single-cell RNA sequencing (scRNA-seq) for the characterization of transcriptome landscape of immune cell subtypes during the recovery stage of COVID-19. In particular, the plasma cells are elevated in peripheral blood mononuclear cells, while the naïve B cells are decreased [34] . In addition, numerous novel B cell-receptor alterations (e.g. IGHV3-23 and IGHV3-7) were identified. Moreover, isotypes have been confirmed, including IGKV3-11, IGHV3-15, and IGHV3-30, previously used for the development of virus vaccines. The highest frequencies of pairing, IGHV3-23-IGHJ4, was suggested for the recognition of monoclonal status of SARS-CoV-2 particularity [34] . In addition, the antibody seroconversion response must be importantly tracked to clinically evaluate the infections, considering the pivotal function of B cells to manage the infection. While the serum samples of patients with COVID-19 had no S1 subunit cross-binding with the SARS-CoV spike antigen, several cross-reactivity was observed in the serum specimens of patients with COVID-19 to the nucleocapsid antigens of SARS-CoV [35] . According to the findings from this study, most patients Poor and delayed responses of antibodies are related with the severe results for both types of coronavirus infections. A limited detail of SARS-CoV-2 serology was found. A pilot study reported a peak-specific IgM on the ninth day after the illness onset and a switch to IgG at the second week in one patient [4] . The serum samples of five patients with definitive COVID-19 exhibited cross-reactivity with the SARS-CoV, but not with other coronaviruses. In addition, all serum samples neutralized the COVID-19 in an in vitro plaque assay, offering a potential for successfully loading of humoral reactions [4] . However, the specific antibody titer/kinetic property associated with the severity of disease must be checked Most of the mechanisms rely on inhibiting innate immune responses, particularly the recognition [43, 44] . In addition, the PLpro possesses deubiquitinase(DUB) potential within the cells infected with virus, as well as inactivates IRF3 in either SARS-CoV or MERS-CoV [45] [46] [47] .  Suppressed IFN signaling: the interferon signaling pathway is directly inhibited by the viruses. SARS-CoV nsp6 and nsp1 block STAT1/STAT2/IRF9 complex translocation and STAT1phosphorylation, respectively, inactivating the antiviral conditions in infected cell and inducing the IFN response [48, 49] . According to the above contents, SARS-CoV-2 can activate the host adaptive and innate immunities and generated long-lasting protective immunity against them. Therefore, the creation of an effective vaccine considers as a promising approach for inhibiting pandemic COVID-19. The aim of all vaccination is to expose the body to an antigen that will not cause disease but will stimulate an immune response that can suppress or kill the viruses if a person becomes infected. There are at least eight types of vaccines being tried against the SARS-CoV-2. They rely on viral parts or different viruses that we have mentioned to them at below. Since efficacious vaccines and protective medications have been introduced for COVID-19, demand is likely to outrun the supply. Thus a prioritizing strategy for vaccination is needed to reach the highest level of public health. The Joint Committee on Vaccination and Immunization's provisional advice stated that adults over 65 years old, people in shielding groups, and health workers are the priority for COVID vaccination [50] . According to an at-risk population analysis, Hassan-Smith et al. [50] suggested a draft plan for prioritizing the vaccines and protective medications. These groups include people with severe infection, such as those with non-communicable diseases (e.g., cardiovascular disease, hypertension, diabetes, and obesity) who should also be prioritized. Next, the high-risk job-related groups comprising those working in customer-facing roles, such as security and transport worker, should also be involved. Socioeconomic factors related to adverse effects in COVID-19 should also be evaluated. Moreover, a functional strategy would consider vaccination of those living in overcrowded situations or organizations such as care homes [50] . Besides, developing clinical prediction tools could be applied to notify further risk stratification [51] . Based on CDC reports, persons of any age with the hereunder conditions are at higher risk of severe illness caused by COVID-19 and should be potentially prioritized for COVID-19 vaccination: 1)cancer, 2) chronic kidney disease, 3)COPD (chronic obstructive pulmonary disease), 4)down syndrome, heart conditions, 5)immunocompromised state from a solid organ transplant, 6)obesity, 7)sickle cell disease, 8)smoking, and 9)type 2 diabetes mellitus [52]. A conventional way for viral vaccination is the use of live-attenuated vaccines or inactivated vaccines. Attenuated virus vaccines mainly induce mucosal immunity to reduce the mucosal infection of the virus. A live influenza vaccine expressing the proteins of SARS-CoV-2 has been developed by the scientists from the University of Hong Kong. A "codon deoptimization" technology, developed by Codagenix, strives to discover the SARS-CoV-2 vaccine technologies to produce attenuated virus vaccine [53, 54] . The main advantage of inactivated or attenuated vaccines is intrinsic immunogenicity and capacity to trigger the toll-like receptors (such as TLR 9, TLR 7/8 and TLR 3). Other advantages include: fast development, excellent neutralizing Ab, viral structure preservation, induction formulated with different adjuvants, excellent T/B cell response induction, and site-directed mutagenesis performed easily to improve their features. It should be noted that the live virus vaccines mostly need further experiment to ensure the safety. According to the findings from the elevated infectivity following the immunization using killed or live SARS-CoV vaccines, safety is an issue in the development of new vaccine. Moreover, these vaccines are inappropriate for sensitive individuals, including elderly people, immunocompromised individuals and infants [16, 55] . The Chinese company (Sinovac Biotech) is trying to develop an inactivated vaccine named CoronaVac in the phase I,II, and III, reached emergency approval for limited use in July [56] . Table 1 contains several clinical trials on SARS-COV-2 live inactivated or attenuated vaccines. Protein-based subunit vaccines comprise of the minimum SARS-CoV-2 structural parts capable of triggering the host protective immunity, required to be used along with molecular adjuvants to increase their immunogenicity. Subunit vaccines against the SARS-CoV depend on stimulating the anti-S protein immunity to inhibit its attachment on host ACE2 receptor [55] . The University of Queensland is trying to achieve the viral surface proteins for presenting to immune system. Clover Biopharmaceuticals has designed and developed a trimerized protein subunit vaccine by utilizing their patented Trimer-Tag technology. However, they detected eosinophilic infiltration and enhanced infectivity while using some full-length viral S proteins. Novavax has produced a virus-like particle that express the recombinant S protein as a vaccine candidate [57, 58] . Another subunit vaccine has been produced by Texas Children's Hospital decrease the host immunopotentiation [59, 60] . In general, subunit vaccines have advantages including, excellent safety, continuous production, and capability of triggering both cellmediated and humoral immunities. However, they require suitable molecular adjuvants and their cost-effectiveness may vary [11] . Generex is developing and producing a SARS-CoV-2 vaccine using Ii-Key technology to activate immune system. This technology utilizes synthetic peptides mimicking important viral protein fragments that are chemically attach to the 4 Ii-Key amino acids to make sure that it will effectively activate the immune system. The Ii-Key technology ensures strong CD4 + T cells activation, therefore facilitates antibody production to combat the infection. GlaxoSmithKline (GSK) in patent application WO2010063685 describes a vaccine that contains one soluble S protein (an engineered ectodomain S protein) as an immunogen as well as an oil-in-water emulsion as an adjuvant. This vaccine is able to trigger neutralizing antibody responses as well as IgG2a or IgG2b antibody reactions in response to the SARS-CoV-2 in the animal models. Recently, GSK is working with Clover Biopharmaceuticals (Chinese firm) to produce its++ candidate vaccine for SARS-CoV-2 . Pharmaceuticals explores a DNA-based vaccine. The of pGX9501 plasmid, which is able to express the full-length SARS-CoV-2 S protein [66] . Table Table 4 The CoV-2 antibodies in mice and primates. ARCoV is stable at an ambient temperature for minimally a week and is produced in liquid formulation, which is currently in phase I clinical trial [72] . Indeed, human DNA-and mRNA-based vaccine candidates may be unable to trigger a protective immunity after a single immunization because they, like recombinant and inactivated subunit protein-based vaccines, need to be administered in several times over prolonged duration to have immunogenicity [73] . Table 5 contains an update list of several RNA vaccines in clinical trials. Besides, a review of the adverse outcomes and the licensed SARS-CoV-2 vaccines' participants were summarized in Table 6 . Virus-like particle (VLP) is a nanostructure with self-assembly feature that contains structural proteins of virus. Molecular and morphological characteristics of VLP are similar to authentic viruses. Due to lack of genetic materials, VLP is not able to replicate or cause infection and does not require biosafety protection and specific laboratory settings. Thus, VLP is a suitable and safe model for viral molecular studies and vaccine design [74, 75] . Xu et al revealed that the presence of M and E proteins are essential for effectively assembly and release of VLPs from the SARS-CoV-2. They suggest that SARS-CoV-2 VLPs mimic native virion particles molecularly and morphologically, which not only provides incentives for viral morphological studies but also offer a possible vaccine for SARS-CoV-2 [76] . CoV-2 on CuMV TT VLP (cucumber mosaic virus) and evaluated the immunogenicity of all vaccines in mouse models. CuMV TT VLPs contain one tetanus toxin-originated universal T cell epitope. Moreover, these VLPs package bacterial RNA during the synthesis process that acts as potent adjuvants as a ligand for TLR 7/8. Via coupling of SARS-CoV-2 RBD to these VLPs, the RBD immunogenicity significantly increased and the triggered antibodies could inhibit the RBD binding to the ACE2 viral receptor [79] . A phase I clinical trial recruiting in Canada evaluates the tolerability, immunogenicity and safety of a plant-derived recombinant coronavirus-like particle. The Medicago VLP vaccine was produced by plants as bioreactors to synthesize the S protein of SARS-CoV-2. Subsequently, these proteins assemble to form VLPs that resemble the virus, without showing any of the infectious features, which are easily detected by the immune system of the host. Figure 1 shows a schematic of several vaccine platforms designed for SARS-CoV-2, which activate the immune response of the host. In December 2020, an unforeseen rise occurred in COVID-19 cases. That was assigned to the appearance of the new SARS-CoV-2 variants 501Y.V2 (B.1.351) in South Africa and 501Y.V1 (B.1.1.7) in the UK [80, 81] . In South Africa, high transmission and high herd immunity may have supported the appearance and the following spread of the variant. Both variants showed a mutation (N501Y) on the spike protein's receptor-binding domain that is suggested to participate in higher transmission [82] . It is estimated that the transmission rate is between 40 and 70% [81] . Furthermore, the 501Y.V2 variant shows two additional mutations (K417N and E484K) in the spike protein that allow a possible immune escape from antibodies [83] . Additionally, another set of mutations (N501Y, K417T, and E484K) in a new P.1 (501Y.V3) lineage has been characterized in Manaus, Brazil [84] . Also, L452R is another mutation that was observed to be increased. It was recently associated with a significant breakout in California, but health professionals stated that it's not clear if it caused more infections [85] . Besides, initial clinical trial findings of ChAdOx1 nCoV-19 suggested 74% efficacy in the UK3 but only 22% in South Africa. In contrast, NVX-CoV2373, a protein-based COVID-19 vaccine, demonstrated 89% efficacy in the UK, but in South Africa, where the 501Y.V2 variant predominates, the effectiveness was only 49% [89, 90] . Similarly, efficacy differences in South Africa and the USA (57% vs. 72%) were observed for the Ad26COV2.S COVID-19 vaccine [91] . Promisingly, in South Africa, 85% protection against COVID-19 for the Ad26COV2.S vaccine has been shown. However, we are not sure about the precision estimated value released by the press [92] . A confirmed vaccine strategy that targets at risk of severe COVID-19 might be effective even in the presence of variants [93] . After a period of genetic stability, the new variants of SARS-CoV-2 caused concern since multiple new immune escape variants could be emerged in the future and resulted in a severe epidemic return, as observed in South Africa. The higher viral transmission provides a greater chance for occurring SARS-CoV-2 variants. Therefore, ending the pandemic disease is only possible when effective vaccines against new variants are administered across the world fairly. While highincome countries compete to vaccinate their people within months, they leave themselves unprotected to new variants of SARS-CoV-2 evolving in lower-income countries that vaccines could not protect them [93] . To control new variants of SARS-CoV-2, formulating new vaccines may be often required [81] . Along with the increased primary reproduction number of variants with more transmissible SARS-CoV-2, more vaccine coverage will be needed to achieve population immunity, and vaccinating children might also be critical to obtaining this coverage [93] . A few weeks after infection with SARS-CoV-2, patients develop antibodies against viral proteins [94] [95] [96] [97] . Some weeks after symptom initiation, most infected individuals' serum can attach to the viral spike protein and neutralize it in vitro [94, 98, 99] . The serum' reciprocal dilution can inhibit the viral infection up to 50% (neutralizing antibody titer at 50% inhibition [NT50]). It is generally between 100-200 at 3-4 weeks following the symptom occurrence [100] ; however, the range of neutralizing titers is undetectable to more than 10000 [98, 99, 101] . There is currently limited data on the neutralizing antibody dynamics in the months following recovery from SARS-CoV-2. In severe viral infections, antibody neutralization rises quickly after infection due to a sudden increase of short-lived antibody-secreting cells. Then diminishing this peak before reaching a stable plateau and it can be kept for years to some decades via memory B cells and long-lived plasma [102, 103] . The dynamics mentioned above have been reported for many viruses, such as respiratory syncytial virus, influenza, Middle East respiratory syndrome coronavirus, seasonal human coronavirus 229E, and the SARS coronavirus 1 [104] [105] [106] [107] [108] . Various studies followed up antibody levels in recovered individuals from SARS-CoV-2 infection for the first few months following the symptom occurrence [94, 95, 98, 101, 109, 110] . After the first three months, most of them have reported, those antibodies that target the spike protein reduced several-times from the peak [94, 98, 110] . This finding suggests the similar early dynamics of the antibody response to SARS-CoV-2 and other acute viral infections. In 2021, Crawford et al. [111] evaluated both the binding and neutralizing antibody levels in serial samples of plasma from 32 SARS-CoV-2-infected persons with a range of disease severity follow-up as long as 152 days after symptom initiation. They reported that, on average, neutralizing titers declined about four folds from approximately 30 to more than 90 days after symptom beginning. This reduction in neutralizing titers was accompanied with a decline in antibodies level that attaches to the spike protein and its receptor-binding domain (RBD). However, most convalesced individuals still had significant neutralizing titers at 3-4 months after symptom start [111] . In another study, lyer, and colleagues in 2020 quantified plasma and/or serum antibody responses to the receptor-binding domain of SARS-CoV-2 'S protein in 343 North American people infected with SARS-CoV-2 (of which 93% were hospitalized) up to 122 days following symptom initiation [112] . Next, they compared the results with responses of 1548 individuals whose blood samples were taken before the pandemic. This investigation's findings were also added to rising evidence on the perseveration and decay of antibody responses after SARS-CoV-2 infection. IgA and IgM responses to RBD were short-lived, and most patients seroreverted within 2.5 months following the beginning of the illness. However, IgG antibodies were preserved at detectable levels in individuals more than 90 days after symptom start, and seroreversion was only reported in a small part of patients. These anti-RBD IgG antibodies' concentration was also highly associated with pseudo-virus NAb titers, which also showed minimal decay. Observing the persistence of IgG and neutralizing antibody responses is promising and displays the robust systemic immune memory development in patients with acute infection. These results were identical to those observed in a study on anti-RBD antibodies in 121 North American convalescent plasma donors up to 82 days from symptom onset [113] and a research work of 1,197 Icelanders who stayed seropositive by two pan-IgG SARS-CoV-2 antibody assays 120 days following the qPCR diagnosis of SARS-CoV-2 (9). These results differed from other new studies that demonstrated a more quick waning in anti-RBD titers after asymptomatic or mild SARS-CoV-2 infection [109, 114] . Antibody levels declined with time, but few researchers studied the quality and nature of the memory B cells that would be needed to generate antibodies upon reinfection has not been investigated yet. Gaebler et al. [115] [116] . The monkeys readministered with the similar SARS-CoV-2 strain could not generate detectable viral spreading, clinical demonstration, and histopathological alteration. This study showed that a significant neutralizing antibody response might be involved in protecting the rhesus macaques from SARS-CoV-2 reinfection. They concluded that primary SARS-CoV-2 infection maybe protects from following reinfection [116] . However, more studies are yet needed. Most respiratory viruses lead in immunoglobulin concentrations that persist for a few months, whereas neutralizing immunoglobulin against SARS-CoV-2 lasts only for about 40 days [117] . On the other hand, unlike seropositivity for IgG following the primary infection, positive RNA tests have been reported [118] . Nonetheless, such cases have been explained as sampling errors, silent carriers, or low commercial kits' accuracy. In some cases, the time window between the first infection and the second positive RNA test, which is approximately two months, may indicate reinfection or reactivity of a latent infection with the virus [119] . Studies are still encouraged to develop a more efficient vaccine. Current challenges raise some concerns that vaccination may not lead to a long-term and effective immunity against SARS-CoV-2. These concerns are the existence of more than 80 genotypical variants of the SARS-CoV-2, the likelihood of reinfection, and the short-lived seropositivity for neutralizing antibodies. Moreover, Ig levels may not be associated with the risk of transmissibility of SARS-CoV-2 and viral shedding [118] . Also, the short-lasting immunity against the virus may prevent the improved homogeneity of affected individuals in a certain time frame. Thus, population immunity may not be obtained; because reinfection may happen even in the presence of neutralizing antibodies. These challenges led to the concern that abolishing the COVID-19 pandemic may not be as practical as assumed. Thus, we must rely more on transmission prevention until virus features are more characterized [120] and more effective anti-SARS-CoV-2 drugs are developed. In COVID-19 infection, the host immune cellular and antibody response and post infection protection are highly limited. In order to find a suitable antibody marker for protection and evaluation of vaccine efficacy, better characterization of the SARS-CoV-2 is required. There are important issues that should be considered for the development of a potent vaccine including the viral genetic changes, immune enhancement, immunosenescence in the elderly as well as decreased in antibody content over time. For testing the vaccine efficacy, suitable immunological and clinical markers required to be identified. Moreover, the cold chain storage conditions also should be taken into account to prevent the challenges like the Ebola vaccine challenge (its optimal storage temperature is under -60 °C) [10, 121] . Although the S protein is targeted by multiple vaccine platforms against the SARS-CoV-2 infection, the main elements of a defensive immune response should be considered. These elements include: 1) The function of neutralizing antibodies in the host protection, specific epitopes that may targeted by neutralizing antibodies, and threshold neutralizing antibody reaction against the SARS-CoV-2. 2) The function of anti-S protein non-neutralizing antibodies attaching the infected cell membrane. 3) The function of mucosal immune response to infection or viral spread in the respiratory system. 4) The possible importance of humoral immunity against other viral ORFs to induce the immune response, mainly those located on the cell surface or secreted to extracellular environment that immune antagonist activity. 5) The importance of CD4 + and CD8 + T cell responses to the induction of protective immunity by a vaccine. A major challenge with SARS-CoV-2 vaccine candidates is the lack of high-throughput animal disease models for the selection of candidate vaccines and the detailed study of vaccine immunogenicity. Evaluation of immune response and pathogenesis in various animal models including primates and non-primates is still in its early stages. Bao et al reported that the laboratory species of mouse are not prone to COVID-19 [122] . In addition, the immunogen structure, vaccine formulation, and age of vaccination can affect the immune system and the consequence of naturally occurring infection, though all of these issues about COVID-19 should be studied extensively. Although several vaccine candidates have been developed for COVID19, there is still a considerable distance to achieve one ready for public use. However, low efficiency, immune adaptability, tolerability, and safety are the major weaknesses of current vaccine candidates. In addition, the alteration that occurs in the host during viral replication fails to resolve by most of the vaccines. All of these weak spots are major impediments for preclinical and clinical research of promising vaccine candidates. In this regard, there are some recommendations that may help to overcome these barriers. The polymeric antigen-based nanocapsules are very interstin to promote the vaccines as an antigen-adjuvant delivery complex for targeting the main cells of the immune system, especially in the liver. To overcome the previous mentioned limitations, induction of long-lasting and potent TH1-oriented immunity via single-dose vaccination as well as the production of immunogenic and safe nanocapsules is a promising approach. Nanoparticles derived from viruses are mainly attractive to novel vaccine formulations, producing strong biodegradable protein nanocapsules generated from the pathogen-specific antigen. The preparation of hydrophilic nanocontainers through water-in-oil mini-emulsions and then delivery to an aqueous solution is greatly important, as it allows hydrophilic payloads to be encapsulated efficiently in large quantities. The NS5A protein was used to produce the vaccine candidates for the hepatitis C virus. Accurately adjustable size and the surface properties of the nanocapsules, the simultaneous prescription of vaccineantigen and vaccine -adjuvant and therefore the probability of targeting specific immune system cells, are the major benefits of synthetic particulate vaccines [124] . The whole cell vaccines are classified into two groups of autologous and allogenic types, which are genetically modified to induce the production of chemokines, cytokines and co-stimulatory molecules reinforcing the immune stimulation. Using the immune cells extracted from the patient, specially their DCs, is another type of cellular-based vaccination. The DCs are formulated by loading the autologous DCs of patient co-treated by immunoadjuvants using nucleic material or spike antigens. Then, the DCs loaded with antigen are re-prescribed to the patient for the in induction of the immunity against viruses. Liposomes are composed of biocompatible phospholipids that form spherical vesicles. They are used as either delivery vesicles or adjuvants in vaccinology [125] . Plasticity and versatility are the major strengths reported for the liposomes. It is possible to control the antigen charge, incorporation, location and size by selecting lipids and their formulation technique. Antigens linked with the surface, integrated with the lipid bilayer, or encapsulated within the liposome. The antigen site in the liposome determines the type of vaccine-induced immune responses. Encapsulated and surface-linked antigens induce T cell response, while surface-linked antigens induced the responses of B cells. The CD4 Th cell epitope inclusion induces a potent antibody reaction to the B cell antigen target. Also, the immunity on the T cell epitope is reduced via fully spatial separation of the two antigens through the liposomal bilayer, reducing the immunity on the T cell epitope. The liposomal capacity for carrying cargoes enables immunostimulatory molecules to be simultaneously transferred to the target immune cells, including cytokines or TLR agonists, thus minimizing the systemic sensitivity to such adjuvants. The first approved liposomal vaccines were diphtheria toxin (1974) . Subsequently, the liposomal vaccines of Epaxal and Inflexal V were approved for hepatitis A and influenza with human use, respectively [126] [127] [128] . According to computational studies, the engineered multi-epitope vaccine has stable structure, which induces particular immunity and thus can be a possible option for the SARS-CoV-2 vaccine. Immunoinformatic tools have been employed to generate such SARS-CoV-2 vaccine that consists of IFN-γ, HTL and CTL epitopes capable of inducing robust immunity. It has been found that these vaccines are both antigenic and immunogenic. The simulation method of molecular dynamics (MD) has ensured the stable engineered vaccine and Molecular Docking studies verified a robust interaction between the immune receptors and the vaccine. Based on the in silico expression finding, the vaccine's expression has been verified in the bacterial host. In addition, Immune Simulation studies validated the effectiveness of the vaccine in triggering an immune response [129] . In an experimental study, the vaccine peptide platforms from the SARS-CoV-2 S protein were selected for the immunization of the mice, followed by testing the antigenic B/T-cell epitopes in all proteins encoded by SARS-CoV-2, and fabricating a new multi-epitope peptide virus vaccine. The results showed a significantly higher serum IgG level and elevated ILN CD19 cells in peptideimmunized animals in comparison with controls. Also, the density of lymphocytes secreting IFN-γ in CD8 + /CD4 + cells were higher in the peptides-immunized animals when comparing with the controls. The count of splenic IFN-γ-secreting T cells was larger in the intervention group. Specific cell-mediated and humoral immunity in the animals were successfully elicited by the obtained vaccine peptides. However, there is a need for primate tests and clinical trials for the confirmation of the safety and efficacy of such vaccine peptides [130] . The accessibility to an efficient and safe COVID-19 vaccine is well-confirmed as an essential tool to control the pandemic. Therefore, the efforts and strategies are required to rapidly develop, evaluate, and create the large scale are enormous. It is necessary that as many vaccines as possible are evaluated because we cannot predict how many would be viable. To raise the success chances (due to the high attrition level during the vaccine development), all vaccine candidates should test until exclusion. World Health Organization facilitates collaboration and accelerates efforts on a scale which has not been seen before [45] . When candidate vaccines are used in human trials, they first undergo phase trials primarily to test the safety of vaccine, determine dosages and identify adverse side effects in a limited number of participants. Phase trials further analyze safety and begin investigating efficacy on bigger groups. The final phase, phase 3 trials, that few vaccines ever enter, is much larger, involving thousands of people, to confirm and evaluate the vaccine's effectiveness and to test whether there are any rare adverse effects that only appear in large groups. If a candidate for vaccine is confirmed successful in human clinical trials, the developers can seek approval by a national regulatory agency, including the U.S. Food and Drug Administration and the European Medicines Agency. The unprecedented speed and scale of the epidemic COVID-19 has forced us to make a substantial alteration in the conventional vaccine generation route that takes an average of more than 10 years, even in comparison with an accelerated 5-year period to develop the first Ebola vaccine, to produce a novel vaccine using patterns like manufacturing capacity scaling, adaptive and parallel production stages and innovative regulatory processes. Furthermore, preclinical studies of the SAR-CoV-2 vaccine candidates may require parallel clinical trials. Considering the speed imperative, the vaccines are said to be available for emergency application or such cases by early 2021 [64] . The fundamental data collection to develop and test the COVID-19 vaccines should be well defined in order to make a vaccine possible. These data include determining target antigen, correlated immune protection, immunization route, target product profile, production facility, animal models, scalability, target community and outbreak prediction. An essential parameter in the "certainty of success" in progression of human SARS-CoV-2 vaccine is proposed infectious inoculum intensity at a personal level, and infectious force at a population level. Reducing the intensity of infectious inoculum (and infection force at population level) is predicted to prolong the incubation period, which in turn is predicted to decrease the severity of the disease, and increase the chance of anamnestic reaction when exposed to the circulating virus [35] . The COVID-19 Humanitarian and Economic Impact Scale is a rapid assessment of next-generation vaccine production strategies via novel patterns for faster development. Very little information is currently available on the host immune response to SARS-CoV-2, although some investigations have reported certain alterations in the innate and adaptive immunity in patients with COVID-19. According to studies, a candidate for the COVID-19 vaccine should induce a strong and persistent response that includes both T cell responses and neutralizing antibodies to trigger a satisfactory protective level [131] . A prominent characteristic of COVID-19 vaccine development is the presence of various strategies such as inactivated virus methods, live attenuated virus approaches, recombinant protein, replicating and non-replicating viral vector, peptide, virus-like particle and nucleic acid vaccines [64] . The DNA/mRNA-based vaccine platforms provide a high flexibility for rapid designation and antigen manipulation. The viral vector vaccines provide a great protein expression level, prolonged stability, and a robust immunity. There is little knowledge about the specific SARS-CoV-2 antigen (s) employed in the vaccine to the SARS-CoV-2 is a major challenge. Moreover, viral genetic changes, immune enhancement, vaccine formulation, and age of vaccine recipient are other important challenges to generate an efficient candidate of vaccine for COVID-19 that need to be studied more extensively. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia Genetic Recombination, and Pathogenesis of Coronaviruses A pneumonia outbreak associated with a new coronavirus of probable bat origin Progress and Concept for COVID-19 Vaccine Development SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Virus-encoded proteinases and proteolytic processing in the Nidovirales The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds MERS, SARS and other coronaviruses as causes of pneumonia COVID-19 vaccine development and the way forward Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic A Novel Coronavirus from Patients with Pneumonia in China Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2 Pathological findings of COVID-19 associated with acute respiratory distress syndrome Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19 Dysregulation of Immune Response in Patients With Coronavirus COVID-19: consider cytokine storm syndromes and immunosuppression Severe coronavirus disease-2019 in children and young adults in the Washington, DC, metropolitan region. The Journal of pediatrics Paediatric Inflammatory Multisystem Syndrome Temporally-Associated with SARS-CoV-2 Infection: An Overview Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic COVID-19 and multisystem inflammatory syndrome in children and adolescents. The Lancet Infectious Diseases Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection The immunology of multisystem inflammatory syndrome in children with COVID-19 A new coronavirus associated with human respiratory disease in China SARS and MERS: recent insights into emerging coronaviruses Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome T cell responses to whole SARS coronavirus in humans Recurrence of positive SARS-CoV-2 RNA in COVID-19: A case report Cause analysis and treatment strategies of "recurrence Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing Antibody responses to SARS-CoV-2 in patients with COVID-19 Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PLoS One Modulation of the immune response by Middle East respiratory syndrome coronavirus Cytokine responses in severe acute respiratory syndrome coronavirusinfected macrophages in vitro: possible relevance to pathogenesis Interferon-stimulated genes: a complex web of host defenses Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum Expression and Cleavage of Middle East Respiratory Syndrome Coronavirus nsp3-4 Polyprotein Induce the Formation of Double-Membrane Vesicles That Mimic Those Associated with Coronaviral RNA Replication Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3 Middle East respiratory syndrome coronavirus accessory protein 4a is a type I interferon antagonist Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6 Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists Who should be prioritised for COVID-19 vaccines? Protocol for the development and evaluation of a tool for predicting risk of short-term adverse outcomes due to COVID-19 in the general UK population. medRxiv, 2020. 52. CDC, People with Certain Medical Conditions China coronavirus: Hong Kong researchers have already developed vaccine but need time to test it, expert reveals. South China Morning Post Codagenix raises $20 million for a new flu vaccine and other therapies Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac -PROFISCOV: A structured summary of a study protocol for a randomised controlled trial Clover initiates development of recombinant subunit-trimer vaccine for wuhan coronavirus (2019-ncov) Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine Optimization of the Production Process and Characterization of the Yeast-Expressed SARS-CoV Recombinant Receptor-Binding Domain (RBD219-N1), a SARS Vaccine Candidate Yeast-expressed recombinant protein of the receptor-binding domain in SARS-CoV spike protein with deglycosylated forms as a SARS vaccine candidate Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis. Vaccine The COVID-19 vaccine development landscape The SARS-CoV-2 Vaccine Pipeline: an Overview Current Trend in Treatments and Vaccines Development of Novel COVID 19. 67. NCT04276896, C., Immunity and Safety of Covid-19 Synthetic Minigene Vaccin A leading coronavirus vaccine trial is on hold: scientists react Subscribe to our informative Newsletter & get Nature's Evidence-Based Pharmacy Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults A Thermostable mRNA Vaccine against COVID-19 The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines Tauroursodeoxycholic acid (TUDCA) inhibits influenza A viral infection by disrupting viral proton channel M2 Effect of a Chikungunya Virus-Like Particle Vaccine on Safety and Tolerability Outcomes: A Randomized Clinical Trial Construction of SARS-CoV-2 Virus-Like Particles by Mammalian Expression System A COVID-19 mRNA vaccine encoding SARS-CoV-2 virus-like particles induces a strong antiviral-like immune response in mice Virus-like particles as vaccine Development of a COVID-19 vaccine based on the receptor binding domain displayed on virus-like particles. bioRxiv Emergence and rapid spread of a new severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv Transmission of SARS-CoV-2 Lineage B. 1.1. 7 in England: Insights from linking epidemiological and genetic data. medRxiv Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy SARS-CoV-2 501Y. V2 escapes neutralization by South African COVID-19 donor plasma Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. Virological Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation. medRxiv mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants SARS-CoV-2 B. 1.1. 7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies. medRxiv Antibody Resistance of SARS-CoV-2 Variants B. 1.351 and B Novavax vaccine delivers 89% efficacy against COVID-19 in UKbut is less potent in South Africa South Africa suspends use of AstraZeneca's COVID-19 vaccine after it fails to clearly stop virus variant One-dose of COVID-19 vaccine offers solid protection against severe disease Johnson COVID-19 Vaccine Authorized by U.S. FDA For Emergency Use -First Single-Shot Vaccine in Fight Against Global Pandemic SARS-CoV-2 variants and ending the COVID-19 pandemic. The Lancet Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature medicine Neutralizing and binding antibody kinetics of COVID-19 patients during hospital and convalescent phases. medRxiv Rapid generation of neutralizing antibody responses in COVID-19 patients Convergent antibody responses to SARS-CoV-2 in convalescent individuals Duration of humoral immunity to common viral and vaccine antigens The multifaceted B cell response to influenza virus The time course of the immune response to experimental coronavirus infection of man Neutralizing antibody response and SARS severity MERS-CoV antibody responses 1 year after symptom onset Impaired antibody-mediated protection and defective IgA B-cell memory in experimental infection of adults with respiratory syncytial virus. American journal of respiratory and critical care medicine Antibody dynamics of 2009 influenza A (H1N1) virus in infected patients and vaccinated people in China Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nature medicine Decline of humoral responses against SARS-CoV-2 spike in convalescent individuals Dynamics of neutralizing antibody titers in the months after severe acute respiratory syndrome coronavirus 2 infection. The Journal of infectious diseases Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients SARS-CoV-2 infection induces robust, neutralizing antibody responses that are stable for at least three months. medRxiv (2020) Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19 Evolution of antibody immunity to SARS-CoV-2 Lack of reinfection in rhesus macaques infected with SARS-CoV-2. BioRxiv COVID-19 and postinfection immunity: limited evidence, many remaining questions COVID-19 reinfection: myth or truth? SN Comprehensive Clinical Medicine Herd immunity: understanding COVID-19 With Risk of Reinfection, Is COVID-19 Here to Stay? Disaster medicine and public health preparedness Effectiveness of influenza vaccines in preventing severe influenza illness among adults: A systematic review and meta-analysis of test-negative design case-control studies The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice Engineered human mesenchymal stem cells as new vaccine platform for COVID-19. bioRxiv Novel strategies in vaccine design: can nanocapsules help prevent and treat hepatitis B? Nanomedicine (Lond) Liposomes as vaccine delivery systems: a review of the recent advances Liposomes containing monophosphoryl lipid A: a potent adjuvant system for inducing antibodies to heroin hapten analogs. Vaccine Co-delivery of a CD4 T cell helper epitope via covalent liposome attachment with a surface-arrayed B cell target antigen fosters higher affinity antibody responses. Vaccine Liposomes as immunological adjuvants A candidate multi-epitope vaccine against SARS-CoV-2. 2020 Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus in China (SARS-CoV-2). bioRxiv Immunological considerations for COVID-19 vaccine strategies Not applicable. Not relevant. Not applicable. Not applicable. The researcher's declaration implies lack of conflict of interest.