Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a devastating global pandemic for 4 years and is now an endemic disease. With the emergence of new viral variants, COVID-19 is a continuing threat to public health despite the wide availability of vaccines. The virus-encoded trimeric spike protein (S protein) mediates SARS-CoV-2 entry into host cells and also induces strong immune responses, making it an important target for development of therapeutics and vaccines. In this Review, we summarize our latest understanding of the structure and function of the SARS-CoV-2 S protein, the molecular mechanism of viral entry and the emergence of new variants, and we discuss their implications for development of S protein-related intervention strategies.

SARS-CoV-2 causes an acute respiratory tract infection that resolves in most people in less than a month. Yet some people with severely weakened immune systems fail to clear the virus, leading to persistent infections with high viral titres in the respiratory tract. In a subset of cases, persistent SARS-CoV-2 replication results in an accelerated accumulation of adaptive mutations that confer escape from neutralizing antibodies and enhance cellular infection. This may lead to the evolution of extensively mutated SARS-CoV-2 variants and introduce an element of chance into the timing of variant evolution, as variant formation may depend on evolution in a single person. Whether long COVID is also caused by persistence of replicating SARS-CoV-2 is controversial. One line of evidence is detection of SARS-CoV-2 RNA and proteins in different body compartments long after SARS-CoV-2 infection has cleared from the upper respiratory tract. However, thus far, no replication competent virus has been cultured from individuals with long COVID who are immunocompetent. In this Review, we consider mechanisms of viral persistence, intra-host evolution in persistent infections, the connection of persistent infections with SARS-CoV-2 variants and the possible role of SARS-CoV-2 persistence in long COVID. Understanding persistent infections may therefore resolve much of what is still unclear in COVID-19 pathophysiology, with possible implications for other emerging viruses.

The persistence of SARS-CoV-2 infections at a global level reflects the repeated emergence of variant strains encoding unique constellations of mutations. These variants have been generated principally because of a dynamic host immune landscape, the countermeasures deployed to combat disease, and selection for enhanced infection of the upper airway and respiratory transmission. The resulting viral diversity creates a challenge for vaccination efforts to maintain efficacy, especially regarding humoral aspects of protection. Here, we review our understanding of how SARS-CoV-2 has evolved during the pandemic, the immune mechanisms that confer protection, and the impact viral evolution has had on transmissibility and adaptive immunity elicited by natural infection and/or vaccination. Evidence suggests that SARS-CoV-2 evolution initially selected variants with increased transmissibility but currently is driven by immune escape. The virus likely will continue to drift to maintain fitness until countermeasures capable of disrupting transmission cycles become widely available.

With the continuous emergence of novel SARS-CoV-2 variants, long-lasting and broadly reactive cellular and humoral immunity is critical for durable protection from COVID-19. We investigated SARS-CoV-2-specific T cell immunity in relation to antibodies, infection outcome and disease severity and assessed its durability in a longitudinal cohort over a three-year time course. We identified pre-existing T cells reactive to the seasonal coronavirus (CoV) OC43 that cross-react with the conserved SARS-CoV-2 spike S813-829 peptide. These cross-reactive T cells increased in frequency following SARS-CoV-2 infection or vaccination and correlated with enhanced spike-specific T cell responses and significantly reduced viral loads. Furthermore, our data revealed that CoV-cross-reactive T cells were maintained as part of the long-lasting memory response, contributing to increased T cell frequencies against omicron variants. These findings suggest a functional role of CoV-cross-reactive T cells that extends beyond the initial SARS-CoV-2 exposure, contributing to enhanced immunity against highly mutated SARS-CoV-2 variants.

Identifying immune-protective biomarkers is crucial for the effective management and mitigation of current and future COVID-19 outbreaks, particularly in preventing or counteracting the immune evasion exhibited by the Omicron variants. The emergence of SARS-CoV-2 variants, especially those within the Omicron lineage, has highlighted their capacity to evade neutralizing antibodies, emphasizing the need to understand the role of antibody-dependent cell-mediated cytotoxicity (ADCC) in combating these infections.

This study, conducted in Qichun City, Hubei province, from December 2021 to March 2023, involved 50 healthy Chinese adults who had received two doses of inactivated vaccines and had subsequently experienced mild infections with the Omicron BA.5 variant. Blood samples from these 50 healthy Chinese adults were collected at six distinct time points: at baseline and at the 1st, 3rd, 6th, and 9th months following the third dose of the inactivated vaccine, as well as 3 months post-breakthrough infection. Their sera were analyzed to assess ADCC and neutralization effects.

The results indicated that the antibodies elicited by the inactivated SARS-CoV-2 vaccine targeted the spike protein, exhibiting both pre-existing neutralizing and ADCC activities against Omicron variants BA.5 and XBB.1.5. Notably, the ADCC activity demonstrated greater stability compared to that of the neutralizing effects, persisting for at least 15 months post-vaccination, and could be augmented by additional vaccine doses and breakthrough infections. The ADCC effect associated with hybrid immunity effectively targets a spectrum of prospective Omicron variants, including BA.2.86, CH.1.1, EG.5.1, and JN.1.

In light of its stability and broad-spectrum efficacy, we recommend the use of the ADCC effect as a biomarker for assessing protective immunity and guiding the development of vaccines and monoclonal antibodies.

Background/Objectives: Metabolic syndrome (MetS) is a predisposing factor for severe COVID-19. The effectiveness of COVID-19 vaccines in patients with MetS has been poorly investigated. The aim of this study was to evaluate the effectiveness of COVID-19 vaccination before (BO) and after the Omicron (AO) SARS-CoV-2 variant in patients with MetS. Methods: This retrospective observational study was carried out in a total of 3194 patients with MetS and a COVID-19 PCR or rapid antigen test. The main outcomes were vaccine effectiveness against infection, hospitalization and death resulting from COVID-19. Results: BO, only two doses of BNT162b2 were effective against infection, this effectiveness was lost AO. Also, with two doses, BNT162b2, ChAdOx1 and CoronaVac were effective against hospitalization BO; however, AO, only BNT162b2 and CoronaVac were effective. Regarding death as an outcome of COVID-19, two doses of BNT162b2 were effective BO, whereas AO, BNT162b2 and CoronaVac were 100% effective. BO the presentation of a sore throat increased after two doses of COVID-19 vaccine regardless of the type, and the presentation of dyspnea diminished after two doses of BNT162b2 and CoronaVac. Conclusions: The SARS-CoV-2 Omicron variant has impacted vaccines' effectiveness against hospitalization and death in patients with MetS. A tailored vaccination scheme for patients with MetS should be implemented due to the varying effectiveness rates observed in our study.

The durability of Hybrid immunity induced by natural infection and/or COVID-19 vaccines and evidence supporting further booster vaccination are crucial factors for pandemic response, yet remain poorly understood.

We measured the durability of immune response and neutralizing capacity of antibodies following Homologous/Heterologous vaccination by mRNA-based vaccines (Pfizer-BioNTech BNT162b2) or (Moderna mRNA-1273) and viral vector-based vaccines (ChAdox1 nCoV-19-Oxford-AstraZeneca) in infected and non-infected patients. We also evaluated the long-lasting specific humoral IgG levels and T-cell immunity of the Memory CD8 cells.

We found that heterologous prime boosters led to significantly higher IgG antibody levels)9.09(than homologous boosters)5.236) one year after vaccination. We measured SARS-CoV-2 anti-S IgG antibodies and then assessed their neutralizing capacity to inhibit the receptor-binding domain (RBD) of the SARS-CoV-2 wild-type strain and omicron B.1.1.529/BA.2 variants from binding to the ACE2 receptors. The heterologous regiment demonstrated superior ACE2-binding inhibition and consistently had higher mean ACE2-receptor binding inhibition across all dose regimens without the need for further doses. The CD8+ T cells producing IFN-γ to various COVID-19 vaccine dose regimens were evaluated. We found that robust T cell mediated immune responses were preserved and largely induced by a heterogeneous vaccination eliciting a significantly higher CD8+ T cells IFN-γ response in 100% of vaccinees regardless of previous natural infection. Indeed, the difference between infected and naïve groups was less pronounced suggesting a reduced infection-related response.

Across three layers of evidence, this study showed that heterologous vaccination provides longer-lasting immunity than homologous doses, regardless of prior natural infection.

SARS-CoV-2 virus variants continue to emerge at an alarming rate due to spontaneous genetic mutations, particularly in the spike protein receptor-binding domain (RBD) portion, which render the virus more likely to escape immunity. So far, the immunity obtained through global primary and/or booster immunisation campaigns has been sufficient to protect the population from new emerging variants of the Omicron lineage. The current approach to update vaccines' antigen composition to new variants to boost immunity may not be sustainable in the long term. It might also be potentially redundant if the mutations are giving rise to variants which induce milder infections and existing vaccines, such as Bimervax®, are still sufficiently protective, as Covid is slowly becoming a seasonal illness. Through measuring neutralising antibody titres in sera from subjects boosted with Bimervax®, we have demonstrated the ability of Bimervax® to induce immune responses against a variety of SARS-CoV-2 variants, ranging from earlier variants inducing more serious infections to more recent variants which have been found to produce milder infections.

The continual emergence of highly pathogenic novel coronaviruses and their variants has underscored the importance of neutralizing monoclonal antibodies (mAbs) as a pivotal therapeutic approach. In the present study, we report the specific neutralizing antibodies 13H7 and 9G11, which target the N-terminal domain (NTD) and receptor-binding domain (RBD) of the SARS-CoV-2, respectively. The comparative analysis observed that 13H7 not only neutralizes early variants of concern (VOCs) but also exhibits neutralizing activity against the Omicron sublineage, including BA.4, BA.5, BQ.1, and BQ.1.1. 9G11, as an RBD antibody, also demonstrated remarkable neutralizing efficacy. A cocktail antibody combining 13H7 and 9G11 with the previously reported 3E2 broaden the neutralization spectrum against new variants of the SARS-CoV-2. We elucidated the cryo-EM structure of the complex, clarifying the mechanism of action of the cocktail antibody combination. Additionally, we also emphasized the molecular mechanism between 13H7 and SARS-CoV-2 NTD, revealing the impact of Y144 and H146 residue deletions and mutations on the neutralizing efficacy of 13H7. Taken together, our findings not only offer novel insights into the combination therapy of NTD and RBD neutralizing mAbs but also lay a theoretical foundation for the development of vaccines targeting NTD antibodies, thus providing valuable understanding of alleviating the emergence of SARS-CoV-2 variants.

The COVID-19 pandemic has emphasised the importance of vaccines and preparedness against viral threats crossing species barriers. In response, a worldwide vaccination campaign targeting SARS-CoV-2 was implemented, which provides some cross-protective immunological memory to other coronavirus species with zoonotic potential. Following a vaccination regimen against SARS-CoV-2 spike in a preclinical mouse model, we were able to demonstrate the induction of neutralizing antibodies towards multiple human ACE2 (hACE2)-binding Sarbecovirus spikes. Importantly, compared to vaccines based on the SARS-CoV-2 Reference strain, vaccines based on Omicron spike sequences induced drastically less broadly cross-protective neutralizing antibodies against other hACE2-binding sarbecoviruses. This observation remained true whether the vaccination regimens were based on protein subunit or mRNA / LNP vaccines. Overall, while it may be necessary to update vaccine antigens to combat the evolving SARS-CoV-2 virus for enhanced protection from COVID-19, Reference-based vaccines may be a more valuable tool to protect against novel coronavirus zoonoses.

The pediatric community is considered a suitable target for controlling the spread and mortality of viral diseases. In late December 2019, a respiratory disease due to the novel coronavirus, later COVID-19, hit the globe. The COVID-19 global disruption had direct and indirect impacts on different aspects of child health. Therefore, surveillance, preventive approaches, and treatment plans for children came into the spotlight.

This study aims to discuss the clinical pictures as well as laboratory and radiological findings of the infected children during the COVID-19 pandemic. The focus of this study is to express the clinical manifestations of respiratory disease in pediatric SARS-CoV-2, available therapeutic options, vaccine recommendations, and long COVID sequelae in affected children. This review could serve as a hint for upcoming challenges in pediatric care during future pandemics.

The clinical presentation of COVID-19 in pediatrics can range from mild pulmonary disease to acute respiratory distress syndrome (ARDS). Supportive care is a crucial component of the management of pediatric COVID-19. However, the importance of specializing in how to treat patients with more severe conditions cannot be overstated. Additionally, clinicians must consider prevention strategies as well as potential complications.

Although the infected patients are dipping day by day, there is a lack of clinical guidelines for pediatric SARS-CoV-2-associated pulmonary diseases. Understanding of the physicians about all aspects of pediatric care during the COVID-19 pandemic could lead to enhanced quality of future patient care and safety, reduced costs of health policies, and surveil the risk that patients with respiratory viruses can expose to society.

Previous SARS-CoV-2 infection provides some level of protection against reinfection. However, few studies have evaluated the neutralizing antibody (NAb) response after Delta variant infection and its ability to prevent reinfection with Omicron BA.5 one year later.

This prospective cohort study included 431 patients who recovered from Delta variant infection. We measured their serum NAb titers against both Delta and Omicron BA.5 using microneutralization tests.

Over a 17-month follow-up, 17.9% of the participants were reinfected with Omicron BA.5. Younger adults (18-65 years) and individuals who did not receive booster immunization had significantly higher reinfection rates than older adults (>65 years) and those who received boosters (p < 0.05). Notably, reinfection rates were higher in post-vaccination breakthrough cases than in individuals who were naturally infected. However, booster immunization reduced reinfection rates within the breakthrough group. We found no significant association between Delta NAb levels and protection against Omicron BA.5 reinfection (p > 0.05). Cross-neutralization assays showed a 7.1-fold reduction in NAb efficacy against Omicron BA.5.

Delta-variant infection-induced NAbs did not strongly predict protection against Omicron BA.5 reinfection. However, booster immunization effectively reduced the reinfection rate approximately one year after the initial Delta infection.

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Some studies suggest that the monovalent mRNA-1273 vaccine is more effective than BNT162b2 in producing higher levels of antibodies. However, limited data are available, and the methods used are not directly comparable.

Blood samples were obtained before the booster (third dose) and after 14, 90, and 180 days in two similar cohorts who received the original BNT162b2 or mRNA-1273 vaccine designed to target wild type SARS-CoV-2. The aim of our study is to compare their effectiveness by assessing the levels of binding and neutralizing antibodies specifically against each of the BA.1 variant, BA.5 variant, and the XBB.1.5 subvariant.

Once the peak was reached after two weeks, a drastic decline in binding and neutralizing antibodies was observed up to 6 months after the homologous booster administration. The humoral response was however more sustained with the mRNA-1273 booster, with half-lives of 167, 55, and 48 days for binding, BA.1, and BA.5 neutralizing antibodies compared to 144, 30, and 29 days for the BNT162b2 booster, respectively. Compared to the BA.1 variant, the neutralizing capacity was significantly decreased at 6 months with the BA.5 variant (fold-decrease: 1.67 to 3.20) and the XBB.1.5. subvariant (fold-decrease: 2.86 to 5.48).

Although the decrease in the humoral response was observed with both mRNA vaccines over time, a more sustained response was observed with the mRNA-1273 vaccine. Moreover, the emergence of Omicron-based variants causes a reduced neutralizing capacity, notably with the XBB.1.5. subvariant. The administration of subsequent boosters would therefore be needed to restore a sufficiently high neutralizing response.

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evaded the efficacy of previously developed antibodies and vaccines, thus remaining a significant global public health threat. Therefore, it is imperative to develop additional antibodies that are capable of neutralizing emerging variants. Nanobodies, as the smallest functional single-domain antibodies, exhibit enhanced stability and penetration ability, enabling them to recognize numerous concealed epitopes that are inaccessible to conventional antibodies. Herein, we constructed an immune library based on the immunization of alpaca with the S1 subunit of the SARS-CoV-2 spike protein, from which two nanobodies, Nb1 and Nb2, were selected using phage display technology for further characterization. Both nanobodies, with the binding residues residing within the receptor-binding domain (RBD) region of the spike, exhibited high affinity toward the S1 subunit. Moreover, they displayed cross-neutralizing activity against both wild-type SARS-CoV-2 and 10 ο variants, including BA.1, BA.2, BA.3, BA.5, BA.2.75, BF.7, BQ.1, EG.5.1, XBB.1.5, and JN.1. Molecular modeling and dynamics simulations predicted that both nanobodies interacted with the viral RBD through their complementarity determining region 1 (CDR1) and CDR2. These two nanobodies are novel tools for the development of therapeutic and diagnostic countermeasures targeting SARS-CoV-2 variants and potentially emerging coronaviruses.

Background: Several COVID-19 vaccines were developed and approved in China. Of these, the BIBB-CorV and CoronaVac inactivated whole-virion vaccines were widely distributed in China and developing countries. However, the performance of the two vaccines in the real world has not been summarized. Methods: A living systematic review based on findings from ongoing post-licensure studies was conducted, applying standardized algorithms. Articles published between 1 May 2020 and 31 May 2022 in English and Chinese were searched for in Medline, Embase, WanFang Data, medRxiv, bioRxiv, arXiv, SSRN, and Research Square, using SARS-CoV-2, COVID-19, and vaccine as the MeSH terms. Studies with estimates of safety, immunogenicity, and effectiveness from receiving the BIBB-CorV or CoronaVac vaccine that met the predefined screening criteria underwent a full-text review. The Joanna Briggs Institute's Critical Appraisal Checklist and the Cochrane risk of bias were used for assessment of the quality. A random-effects meta-regression model was applied to identify the potential impact factors on the vaccines' effectiveness. Results: In total, 32578 articles were identified, of these, 770 studies underwent a full-text review. Eventually, 213 studies were included. The pooled occurrence of solicited and unsolicited adverse events after any dose of either vaccine varied between 10% and 40%. The top five commonly reported rare adverse events were immunization stress-related responses (211 cases, 50.0%), cutaneous responses (43 cases, 10.2%), acute neurological syndrome (39 cases, 9.2%), anaphylaxis (17 cases, 4.0%), and acute stroke (16 cases, 3.8%). The majority (83.3%) recovered or were relieved within several days. The peak neutralization titers against the ancestral strain was found within 1 month after the completion of the primary series of either vaccine, with a GMT (geometric mean titer) of 43.7 (95% CI: 23.2-82.4), followed by a dramatic decrease within 3 months. At Month 12, the GMT was 4.1 (95% CI: 3.8-4.4). Homologous boosting could restore humoral immunity, while heterologous boosting elicited around sixfold higher neutralization titers in comparison with homologous boosting. The effectiveness of receiving either vaccine against death and severe disease was around 85% for both shortly after the primary series. At Month 12, the protection against death did not decline, while the protection against severe disease decreased to ~75%. Conclusions: Both the BIBP-CorV and CoronaVac inactivated vaccines are safe. Sustained vaccine effectiveness against death was determined 12 months after the primary series, although protection against severe disease decreased slightly over time. A booster dose could strengthen the waning effectiveness; however, the duration of the incremental effectiveness and the additional benefit provided by a heterologous booster need to be studied.

Pathogenic infections cause thymic atrophy, perturb thymic T-cell development, and alter immunological response. Previous studies reported dysregulated T-cell function and lymphopenia in coronavirus disease-19 (COVID-19). However, immunopathological changes in the thymus associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have not been elucidated. Here, we report that SARS-CoV-2 infects thymocytes, and induces CD4+CD8+ (double positive; DP) T-cell apoptosis leading to thymic atrophy and loss of peripheral TCR repertoire in K18-hACE2 transgenic mice. Infected thymus led to increased CD44+CD25- T-cells, indicating an early arrest in the T-cell maturation pathway. Thymic atrophy was notably higher in male hACE2-Tg mice than in females and involved an upregulated de-novo synthesis pathway of thymic glucocorticoid. Further, IFN-γ was crucial for thymic atrophy, as anti-IFN-γ -antibody neutralization blunted thymic involution. Therapeutic use of Remdesivir also rescued thymic atrophy. While the Omicron variant and its sub-lineage BA.5 variant caused marginal thymic atrophy, the delta variant of SARS-CoV-2 exhibited severe thymic atrophy characterized by severely depleted DP T-cells. Recently characterized broadly SARS-CoV-2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore the thymic maturation pathway of T-cells. Together, we report SARS-CoV-2-associated thymic atrophy resulting from impaired T-cell maturation pathway which may contribute to dyregulated T cell response during COVID-19.

We sought to investigate the incidence of severe COVID-19 outcomes after treatment with antivirals and neutralising monoclonal antibodies, and estimate the comparative effectiveness of treatments in community-based individuals. We conducted a retrospective cohort study investigating clinical outcomes of hospitalisation, intensive care unit admission and death, in those treated with antivirals and monoclonal antibodies for COVID-19 in Scotland between December 2021 and September 2022. We compared the effect of various treatments on the risk of severe COVID-19 outcomes, stratified by most prevalent sub-lineage at that time, and controlling for comorbidities and other patient characteristics. We identified 14,365 individuals treated for COVID-19 during our study period, some of whom were treated for multiple infections. The incidence of severe COVID-19 outcomes (inpatient admission or death) in community-treated patients (81% of all treatment episodes) was 1.2% (n = 137/11894, 95% CI 1.0-1.4), compared to 32.8% in those treated in hospital for acute COVID-19 (re-admissions or death; n = 40/122, 95% CI 25.1-41.5). For community-treated patients, there was a lower risk of severe outcomes (inpatient admission or death) in younger patients, and in those who had received three or more COVID-19 vaccinations. During the period in which BA.2 was the most prevalent sub-lineage in the UK, sotrovimab was associated with a reduced treatment effect compared to nirmaltrelvir + ritonavir. However, since BA.5 has been the most prevalent sub-lineage in the UK, both sotrovimab and nirmaltrelvir + ritonavir were associated with similarly lower incidence of severe outcomes than molnupiravir. Around 1% of those treated for COVID-19 with antivirals or neutralising monoclonal antibodies required hospital admission. During the period in which BA.5 was the prevalent sub-lineages in the UK, molnupiravir was associated with the highest incidence of severe outcomes in community-treated patients.

Immunosuppressed individuals, such as people living with HIV (PLWH), remain vulnerable to severe COVID-19. We analyzed the persistence of specific SARS-CoV-2 humoral and cellular immune responses in a retrospective, cross-sectional study in PLWH on antiretroviral therapy. Among 104 participants, 70.2% had anti-S IgG antibodies, and 55.8% had significant neutralizing activity against the Omicron variant in a surrogate virus neutralization test. Only 38.5% were vaccinated (8.76 ± 4.1 months prior), all displaying anti-S IgG, 75% with neutralizing antibodies and anti-S IgA. Overall, 29.8% of PLWH had no SARS-CoV-2 serologic markers; they displayed significantly lower CD4 counts and higher HIV viral load. Severe immunosuppression (present in 12.5% of participants) was linked to lower levels of detectable anti-S IgG (p = 0.0003), anti-S IgA (p < 0.0001) and lack of neutralizing activity against the Omicron variant (p < 0.0001). T-cell responses were present in 86.7% of tested participants, even in those lacking serological markers. In PLWH without severe immunosuppression, neutralizing antibodies and T-cell responses persisted for up to 9 months post-infection or vaccination. Advanced immunosuppression led to diminished humoral immune responses but retained specific cellular immunity.

The rapid emergence of multiple strains of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has sparked profound concerns regarding the ongoing evolution of the virus and its potential impact on global health. Classified by the World Health Organization (WHO) as variants of concern (VOC), these strains exhibit heightened transmissibility and pathogenicity, posing significant challenges to existing vaccine strategies. Despite widespread vaccination efforts, the continual evolution of SARS-CoV-2 variants presents a formidable obstacle to achieving herd immunity. Of particular concern is the coronavirus spike (S) protein, a pivotal viral surface protein crucial for host cell entry and infectivity. Mutations within the S protein have been shown to enhance transmissibility and confer resistance to antibody-mediated neutralization, undermining the efficacy of traditional vaccine platforms. Moreover, the S protein undergoes rapid molecular evolution under selective immune pressure, leading to the emergence of diverse variants with distinct mutation profiles. This review underscores the urgent need for vigilance and adaptation in vaccine development efforts to combat the evolving landscape of SARS-CoV-2 mutations and ensure the long-term effectiveness of global immunization campaigns.

Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves.

To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization Western Pacific Region.

We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants.

Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) seriously threatens public health and safety. Genetic variants determine the expression of SARS-CoV-2 structural proteins, which are associated with enhanced transmissibility, enhanced virulence, and immune escape. Vaccination is encouraged as a public health intervention, and different types of vaccines are used worldwide. However, new variants continue to emerge, especially the Omicron complex, and the neutralizing antibody responses are diminished significantly. In this review, we outlined the uniqueness of SARS-CoV-2 from three perspectives. First, we described the detailed structure of the spike (S) protein, which is highly susceptible to mutations and contributes to the distinct infection cycle of the virus. Second, we systematically summarized the immunoglobulin G epitopes of SARS-CoV-2 and highlighted the central role of the nonconserved regions of the S protein in adaptive immune escape. Third, we provided an overview of the vaccines targeting the S protein and discussed the impact of the nonconserved regions on vaccine effectiveness. The characterization and identification of the structure and genomic organization of SARS-CoV-2 will help elucidate its mechanisms of viral mutation and infection and provide a basis for the selection of optimal treatments. The leaps in advancements regarding improved diagnosis, targeted vaccines and therapeutic remedies provide sound evidence showing that scientific understanding, research, and technology evolved at the pace of the pandemic.

An unprecedented surge of Omicron infections appeared nationwide in China in December 2022 after the adjustment of the COVID-19 response policy. Here, we report the clinical and genomic characteristics of SARS-CoV-2 infections among children in Shanghai during this outbreak.

A total of 64 children with symptomatic COVID-19 were enrolled. SARS-CoV-2 whole genome sequences were obtained using next-generation sequencing (NGS) technology. Patient demographics and clinical characteristics were compared between variants. Phylogenetic tree, mutation spectrum, and the impact of unique mutations on SARS-CoV-2 proteins were analysed in silico.

The genomic monitoring revealed that the emerging BA.5.2.48 and BF.7.14 were the dominant variants. The BA.5.2.48 infections were more frequently observed to experience vomiting/diarrhea and less frequently present cough compared to the BF.7.14 infections among patients without comorbidities in the study. The high-frequency unique non-synonymous mutations were present in BA.5.2.48 (N:Q241K) and BF.7.14 (nsp2:V94L, nsp12:L247F, S:C1243F, ORF7a:H47Y) with respect to their parental lineages. Of these mutations, S:C1243F, nsp12:L247F, and ORF7a:H47Y protein were predicted to have a deleterious effect on the protein function. Besides, nsp2:V94L and nsp12:L247F were predicted to destabilize the proteins.

Further in vitro to in vivo studies are needed to verify the role of these specific mutations in viral fitness. In addition, continuous genomic monitoring and clinical manifestation assessments of the emerging variants will still be crucial for the effective responses to the ongoing COVID-19 pandemic.

A nasally delivered chimpanzee adenoviral-vectored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (ChAd-SARS-CoV-2-S) is currently used in India (iNCOVACC). Here, we update this vaccine by creating ChAd-SARS-CoV-2-BA.5-S, which encodes a prefusion-stabilized BA.5 spike protein. Whereas serum neutralizing antibody responses induced by monovalent or bivalent adenoviral vaccines were poor against the antigenically distant XBB.1.5 strain and insufficient to protect in passive transfer experiments, mucosal antibody and cross-reactive memory T cell responses were robust, and protection was evident against WA1/2020 D614G and Omicron variants BQ.1.1 and XBB.1.5 in mice and hamsters. However, depletion of memory CD8+ T cells before XBB.1.5 challenge resulted in loss of protection against upper and lower respiratory tract infection. Thus, nasally delivered vaccines stimulate mucosal immunity against emerging SARS-CoV-2 strains, and cross-reactive memory CD8+ T cells mediate protection against lung infection by antigenically distant strains in the setting of low serum levels of cross-reactive neutralizing antibodies.

EPOCH-US is an ongoing, retrospective, observational cohort study among individuals identified in the Healthcare Integrated Research Database (HIRD®) with ≥ 12 months of continuous health plan enrollment. Data were collected for the HIRD population (containing immunocompetent and immunocompromised [IC] individuals), individual IC cohorts (non-mutually exclusive cohorts based on immunocompromising condition and/or immunosuppressive [IS] treatment), and the composite IC population (all unique IC individuals). This study updates previous results with addition of the general population cohort and data specifically for the year of 2022 (i.e., Omicron wave period). To provide healthcare decision-makers the most recent trends, this study reports incidence rates (IR) and severity of first SARS-CoV-2 infection; and relative risk, healthcare utilization, and costs related to first COVID-19 hospitalizations in the full year of 2022 and overall between April 2020 and December 2022.

These updated results showed a 2.9% prevalence of immune compromise in the population. From April 2020 through December 2022, the overall IR of COVID-19 was 115.7 per 1000 patient-years in the composite IC cohort and 77.8 per 1000 patient-years in the HIRD cohort. The composite IC cohort had a 15.4% hospitalization rate with an average cost of $42,719 for first COVID-19 hospitalization. Comparatively, the HIRD cohort had a 3.7% hospitalization rate with an average cost of $28,848 for first COVID-19 hospitalization. Compared to the general population, IC individuals had 4.3 to 23 times greater risk of hospitalization with first diagnosis of COVID-19. Between January and December 2022, hospitalizations associated with first COVID-19 diagnosis cost over $1 billion, with IC individuals (~ 3% of the population) generating $310 million (31%) of these costs.

While only 2.9% of the population, IC individuals had a higher risk of COVID-19 hospitalization and incurred higher healthcare costs across variants. They also disproportionately accounted for over 30% of total costs for first COVID-19 hospitalization in 2022, amounting to ~ $310 million. These data highlight the need for additional preventive measures to decrease the risk of developing severe COVID-19 outcomes in vulnerable IC populations.

The 2002 SARS outbreak, the 2019 emergence of COVID-19, and the continuing evolution of immune-evading SARS-CoV-2 variants together highlight the need for a broadly protective vaccine against ACE2-utilizing sarbecoviruses. While updated variant-matched formulations are a step in the right direction, protection needs to extend beyond SARS-CoV-2 and its variants to include SARS-like viruses. Here, we introduce bivalent and trivalent vaccine formulations using our spike protein nanoparticle platform that completely protect female hamsters against BA.5 and XBB.1 challenges with no detectable virus in the lungs. The trivalent cocktails elicit highly neutralizing responses against all tested Omicron variants and the bat sarbecoviruses SHC014 and WIV1. Finally, our 614D/SHC014/XBB trivalent spike formulation completely protects human ACE2-transgenic female hamsters against challenges with WIV1 and SHC014 with no detectable virus in the lungs. Collectively, these results illustrate that our trivalent protein-nanoparticle cocktail can provide broad protection against SARS-CoV-2-like and SARS-CoV-1-like sarbecoviruses.

The development of effective SARS-CoV-2 vaccines has been essential to control COVID-19, but significant challenges remain. One problem is intramuscular administration, which does not induce robust mucosal immune responses in the upper airways-the primary site of infection and virus shedding. Here we compare the efficacy of a mucosal, replication-competent yet fully attenuated virus vaccine, sCPD9-ΔFCS, and the monovalent mRNA vaccine BNT162b2 in preventing transmission of SARS-CoV-2 variants B.1 and Omicron BA.5 in two scenarios. Firstly, we assessed the protective efficacy of the vaccines by exposing vaccinated male Syrian hamsters to infected counterparts. Secondly, we evaluated transmission of the challenge virus from vaccinated and subsequently challenged male hamsters to naïve contacts. Our findings demonstrate that the live-attenuated vaccine (LAV) sCPD9-ΔFCS significantly outperformed the mRNA vaccine in preventing virus transmission in both scenarios. Our results provide evidence for the advantages of locally administered LAVs over intramuscularly administered mRNA vaccines in preventing infection and reducing virus transmission.

In the context of continuous emergence of SARS-CoV-2 variants of concern (VOCs), one strategy to prevent the severe outcomes of COVID-19 is developing safe and effective broad-spectrum vaccines. Here, we present preclinical studies of a RBD vaccine derived from the Gamma SARS-CoV-2 variant adjuvanted with Alum. The Gamma-adapted RBD vaccine is more immunogenic than the Ancestral RBD vaccine in terms of inducing broader neutralizing antibodies. The Gamma RBD presents more immunogenic B-cell restricted epitopes and induces a higher proportion of specific-B cells and plasmablasts than the Ancestral RBD version. The Gamma-adapted vaccine induces antigen specific T cell immune responses and confers protection against Ancestral and Omicron BA.5 SARS-CoV-2 challenge in mice. Moreover, the Gamma RBD vaccine induces higher and broader neutralizing antibody activity than homologous booster vaccination in mice previously primed with different SARS-CoV-2 vaccine platforms. Our study indicates that the adjuvanted Gamma RBD vaccine is highly immunogenic and a broad-spectrum vaccine candidate.