Little data exist on the COVID-19 vaccine response in African countries who despite having high disease burden, have low COVID-19 mortality rates. We investigated the longitudinal immune response in a West-African urban population upon COVID-19 vaccination, two years after the start of the pandemic.

The HERITAGE study is a prospective cohort study of 301 residents of Accra, Ghana. Participants received two doses of a COVID-19 vaccine (AZD1222 or BNT162b2) from December 2021 and were followed-up for 12 months. COVID-19 status was determined by RT-PCR at seven time points. Serological responses, including anti-Nucleocapsid IgG, anti-Spike IgG and live-virus neutralisation were determined at four time points during the 12 months follow-up.

COVID-19 positivity was 19.3% at baseline and reduced rapidly upon vaccination. Serological analyses indicated previous exposure to SARS-CoV-2 in 80.5% of the HERITAGE participants. After vaccination, neutralising antibody titres (NAbTs) against six different SARS-CoV-2 variants significantly (p < 0.001) increased, with fold changes (FC) ranging from 1.87 to 4.59. Highest NAbTs were recorded in the previously exposed group. Participants without prior exposure showed a continues increase in NAbTs between months 3 and 12 for circulating variants (Omicron B.A2 (FC 2.44, p < 0.001) and XBB.1.5 (FC 1.91, p = 0.05)). By comparison a matched cohort from the UK-based LEGACY study showed generally lower NAbTs at baseline (HERITAGE vs LEGACY for Wild-type: 250.3 vs 141.3, p < 0.0001, for A.27 84.6 vs 43.2, p = 0.0129, for Eta 159.7 vs 118.1, p = 0.3428, for Delta 158.6 vs 10.0, p < 0.0001, for Omicron B.A2 153.7 vs 10.0, p < 0.0001) and after receiving the vaccine (HERITAGE vs LEGACY for Wild-type: 882.6 vs 337.7, p < 0.0001, for A.27 552.0 vs 227.7, p = 0.0001, for Eta 682.2 vs 295.3, p < 0.0001, for Delta 557.6 vs 165.1, p < 0.0001, for Omicron B.A2 283.3 vs 124.2, p < 0.0001). NAbTs kinetics between the two cohorts were more similar when analysis was restricted to previously unexposed participants when adjusted for circulating variants during the sampling period.

Two doses of AZD1222 or BNT162b2 significantly increased existing NAbTs against SARS-CoV-2 in a highly exposed population, showing durable boosting of pre-existing infection-induced immunity. This indicates the importance of considering local population exposure in vaccination design and deployment.

The emergence of SARS-CoV-2 variants of concern (VOCs), particularly Omicron, has challenged the efficacy of initial COVID-19 vaccination strategies. Booster immunizations, especially with mRNA vaccines, were introduced to enhance and prolong immune protection. However, the underlying mechanisms of humoral and cellular immunity induced by homologous versus heterologous vaccination regimens remain incompletely understood. This study aimed to elucidate the immune responses, including B cell, plasmacytoid dendritic cell (pDC), and T cell activation, following mRNA booster vaccination.

In a longitudinal cohort study, 136 individuals received three different vaccination regimens: homologous mRNA, heterologous vector-mRNA-mRNA, or heterologous vector-vector-mRNA vaccinations. Serum and peripheral blood mononuclear cells (PBMCs) were collected at multiple time points up to 64 weeks after initial vaccination. Anti-SARS-CoV-2 IgG titers and neutralization capacity against the wildtype virus and Omicron variant were measured using ELISA and cPass assays. Cellular immunity was assessed by IFN-γ release assays, and flow cytometry was employed to analyze B cell and pDC frequencies, viability, and activation markers. Functional pDC-mediated T cell activation was evaluated in mixed lymphocyte cultures.

mRNA booster vaccination stabilized high anti-SARS-CoV-2 IgG titers and neutralizing activity against wildtype virus across all regimens, with the homologous mRNA group showing the highest antibody titers and Omicron neutralization capacity. Peripheral B cell frequencies and activation markers (MHC class I/II, CD86) were significantly upregulated post-booster. pDCs demonstrated enhanced antigen-presenting capacity and significantly promoted SARS-CoV-2-specific T cell IFN-γ responses in vitro. Despite differences in humoral responses between regimens, breakthrough infection rates up to 25 weeks post-booster were comparable across cohorts, suggesting compensatory mechanisms via cellular immunity.

Our findings highlight the pivotal role of pDCs and T cells in sustaining effective immunity following mRNA booster vaccination. While homologous mRNA regimens induce superior humoral responses, robust cellular immunity in heterologous regimens may balance protection levels against breakthrough infections. The study underscores the importance of integrated humoral and cellular immune responses, suggesting potential for optimized booster strategies and pDC-targeted vaccine designs to enhance long-term protection against SARS-CoV-2 and emerging variants.

The effectiveness of multiple COVID-19 vaccinations in individuals with a history of SARS-CoV-2 infection remains unclear; specifically, elucidation of the durability of anti-viral antibody responses could provide important insights for epidemiological applications. We utilized the BU ELISA protocol to measure the circulating SARS-CoV-2 receptor-binding domain (RBD) and nucleocapsid (N) specific IgG and IgA antibody levels in a cohort of individuals infected with SARS-CoV-2 in the spring of 2020, with the sample collection spanning six months to two years post-symptom onset. Further, we interrogated the neutralization activity of these samples against the ancestral SARS-CoV-2 (WA-1) and Delta and Omicron (BA.1) variants. Consistent with previous studies, we found a more rapid waning of anti-N compared to anti-RBD antibodies in months prior to the first vaccinations. Vaccine-induced antibody responses in individuals previously infected with SARS-CoV-2 were elevated and sustained for more than one year post-vaccination. Similarly, neutralization activity against WA-1, Delta, and Omicron increased and remained higher than pre-vaccination levels for one year after the first COVID-19 vaccine dose. Collectively, these results indicate that infection followed by vaccination yields robust antibody responses against SARS-CoV-2 that endure for one year. These results suggest that an annual booster would stably boost anti-SARS-CoV-2 antibody responses, preventing infection and disease.

Identifying immune markers driving early and effective antibody response in patients with severe coronavirus disease 2019 (COVID-19) is critical due to the threat of future coronavirus pandemics, incomplete global vaccination, and suboptimal booster coverage. Patients with life-threatening severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by dysregulated thromboinflammation and cytokine storm that could influence the isotype virus-specific antibody response and the subsequent clinical outcome. We investigated the association between COVID-19-related mortality with the dynamics, magnitude, and relative avidity of nucleoprotein (N), spike (S), and receptor-binding domain (RBD)-specific IgM, IgA, and IgG in circulation. We also assessed the relationship between the virus-specific antibody responses and cytokine patterns, as well as systemic and pulmonary thromboinflammation markers. This multicenter study included COVID-19 patients hospitalized early in the pandemic, classified as survivors (n=62) and non-survivors (n=17). We developed indirect enzyme-linked immunosorbent assays (ELISAs) to evaluate each virus-specific isotype using well-characterized outpatient COVID-19 (n=180) and pre-pandemic cohorts (n=111). The pro-inflammatory interleukin (IL)-6 and tumor necrosis factor (TNF)-α, as well as the regulatory IL-10, transforming growth factor (TGF)-β1, and soluble tumor necrosis factor receptor I (sTNFRI) levels were evaluated. The ELISAs performed highly for all virus-specific isotypes, although modest for IgM-N. Non-survivors increased N-specific, but no S-specific, IgM and IgA responses throughout the disease course and, more notably, a delayed class switching to IgG-S and IgG-RBD compared to survivors. No differences were observed in the virus-specific IgG relative avidity. Survivors exhibited an antibody response proportional to the degree of systemic and pulmonary thromboinflammation, whereas non-survivors showed those dissociated because of their uncontrolled severe thromboinflammation. Only the survivors showed a dominant regulatory cytokine pattern in the early phase of infection (<10 days after symptoms onset), which strongly correlated with developing IgG-S and IgG-RBD protective antibodies. We developed easy-to-use immune assays that enable patient monitoring and identify at-risk populations in low- to middle-income regions. Non-survivors displayed an ineffective N-mediated antibody response, marked by an inability to control inflammation and a compromised time-dependent class switching toward S and RBD-specific IgG. The regulatory cytokine axis, including TGF-β1, maybe a critical immune correlate of effective antibody-mediated immunity in COVID-19.

The pathogenesis of COVID-19 highlights a complex relationship between disease severity and neutralizing antibodies (NAbs). We aimed to investigate the relationships among the total NAb (tNAb) levels, the presence of potential neutralization antibodies (pNAbs), and the clinical outcomes of COVID-19 patients. Patients aged ≥18 years diagnosed between October 2021 and September 2022 were grouped by symptom severity. Blood samples were taken at two time points and data on demographics, epidemiology, and vaccination were recorded. The tNAbs and pNAbs were measured by an enhanced chemiluminescence assay and a surrogate virus neutralization test, respectively. The tNAbs of 68 and the pNAbs of 52 patients were analyzed. Twenty-six (38.2%) patients had severe infection. The 28-day mortality rate was 16.2% (n = 11). The tNAb levels in the control blood samples (CBSs) were significantly higher than those of the admission blood samples (ABSs) (p < 0.001). The statistical analysis showed no relationship between disease severity and pNAbs. Vaccinated patients had significantly higher tNAbs in the ABSs and CBSs (p < 0.001 and p < 0.001, respectively). The presence of pNAbs in the ABSs was correlated with a lower 28-day mortality (p = 0.026) and a milder disease course (p = 0.041). Although these findings support a correlation between tNAbs and disease severity and mortality, their presence seems to be unrelated to favorable clinical outcomes.

We performed a retrospective immunological analysis of the antibody response in serum and in nasopharyngeal swabs (NPS) obtained from 46 individuals infected with ancestral SARS-CoV-2 Wuhan-Hu-1 strain during the first COVID-19 wave in Cagliari (Sardinia, Italy), with a 4-month follow-up after the hospital admission. We implemented a comprehensive antibody response in serum and in mucosal samples using assays established in our laboratories. In NPS we evaluated the viral load by real time PCR, presence and kinetics of anti-Spike IgG and IgA by ELISA as well as their anti-Wuhan neutralization activity, showing induction and persistence of anti-viral immunity at the mucosal level. Neutralizing antibodies were measured in serum and NPS using a safe pseudovirus-based assay validated after comparison with a standard neutralization test using live SARS-CoV-2. We evaluated cross-neutralizing antibodies against all the major early variants of concerns (VoC) in sera. Of note, we detected a remarkable reduction of neutralizing activity against BA.1 compared to BA.2 and BA.5 Omicron subvariants, which was confirmed in sera from an analogous cohort of patients at the San Raffaele hospital in Milan, a geographically distant region of Italy, infected with the ancestral virus during the same period of time.

Background/Objectives: Virus-like particles (VLPs) represent an attractive platform for delivering vaccine formulations, combining a high biosafety profile with a potent immune-stimulatory ability. VLPs are non-infectious, non-replicating, self-assembling nanostructures that can be exploited to efficiently expose membrane-tethered glycoproteins such as the SARS-CoV-2 Spike (S) protein, the main target of approved preventive vaccines. Here, we describe the development and preclinical validation of Simian Immunodeficiency Virus (SIV)-based GFP-labeled VLPs displaying S from the B.1.617.2 (Delta) variant (VLP/S-Delta) for inducing persistent anti-SARS-CoV-2 neutralizing antibodies (nAbs) and S-specific T cell responses in mice. Methods: SIV-derived VLP/S-Delta were produced by co-transfecting a plasmid expressing SIVGag-GFP, required for VLP assembly and quantification by flow virometry, a plasmid encoding the Delta S protein deleted in the cytoplasmic tail (CT), to improve membrane binding, and a VSV.G-expressing plasmid, to enhance VLP uptake. Recovered VLPs were titrated by flow virometry and characterized in vitro by transmission electron microscopy (TEM) and confocal microscopy (CLSM). BALB/c mice were immunized intramuscularly with VLP/S-Delta following a prime-boost regimen, and humoral and cellular immune responses were assessed. Results: VLP/S-Delta were efficiently pseudotyped with CT-truncated S-Delta. After BALB/c priming, VLP/S-Delta elicited both specific anti-RBD IgGs and anti-Delta nAbs that significantly increased after the boost and were maintained over time. The prime-boost vaccination induced similar levels of cross-nAbs against the ancestral Wuhan-Hu-1 strain as well as cross-nAbs against Omicron BA.1, BA.2 and BA.4/5 VoCs, albeit at lower levels. Moreover, immunization with VLP/S-Delta induced S-specific IFNγ-producing T cells. Conclusions: These data suggest that SIV-based VLPs are an appropriate delivery system for the elicitation of efficient and sustained humoral and cellular immunity in mice, paving the way for further improvements in the immunogen design to enhance the quality and breadth of immune responses against different viral glycoproteins.

The global dissemination of SARS-CoV-2 led to a worldwide pandemic in March 2020. Even after the official downgrading of the COVID-19 pandemic, infection with SARS-CoV-2 variants continues. The rapid development and deployment of SARS-CoV-2 vaccines helped to mitigate the pandemic to a great extent. However, the current vaccines are suboptimal; they elicit incomplete and short-lived protection and are ineffective against evolving virus variants. Updating the spike antigen according to the prevailing variant and repeated boosters is not the long-term solution. We have designed a lipopeptide-based, mucosal, pan-coronavirus vaccine candidate, derived from highly conserved and/or functional regions of the SARS-CoV-2 spike, nucleocapsid, and membrane proteins. Our studies demonstrate that the designed lipopeptides (LPMix) induced both cellular and humoral (mucosal and systemic) immune responses upon intranasal immunization in mice. Furthermore, the antibodies bound to the wild-type and mutated S proteins of SARS-CoV-2 variants of concern, including Alpha, Beta, Delta and Omicron, and also led to efficient neutralization in a surrogate viral neutralization assay. Our sequence alignment and 3-dimensional molecular modeling studies demonstrated that spike-derived epitopes, P1 and P2, are sequentially and/or structurally conserved among the SARS-CoV-2 variants. The addition of a novel mucosal adjuvant, heat-killed Caulobacter crescentus, to the lipopeptide vaccine significantly bolstered mucosal antibody responses. Finally, the lipopeptide-based intranasal vaccine demonstrated significant improvement in lung pathologies in a hamster model of SARS-CoV-2 infection. These studies are fundamentally important and open new avenues in the investigation of an innovative, broadly protective intranasal vaccine platform for SARS-CoV-2 and its variants.

It is important to be able to retrospectively determine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections with high accuracy, both for post-coronavirus disease 2019 (COVID-19) epidemiological studies, and to distinguish between Long COVID and other multi-syndromic diseases that have overlapping symptoms. Although serum antibody levels can be measured to retrospectively diagnose SARS-CoV-2 infections, peptide stimulation of memory T cell responses is a more sensitive approach. This is because robust memory T cells are generated after SARS-CoV-2 infection and persist even after antibodies wane below detectability thresholds. In this study, we compare T cell responses using FluoroSpot-based methods and overnight stimulation of whole blood with SARS-CoV-2 peptides followed by an ELISA. Both approaches have comparable sensitivity and specificity but require different equipment and samples to be used. Furthermore, the elimination of peptides that cross-react with other coronaviruses increases the assay specificity but trades off some sensitivity. Finally, this approach can be used on archival, cryopreserved PBMCs. This work shows comparative advantages for several methods to measure SARS-CoV-2 T cell responses that could be utilized by any laboratory studying the effects of the coronavirus disease 2019 pandemic.

COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) represents the biggest global health emergency in recent decades. The host immune response to SARS-CoV-2 seems to play a key role in disease pathogenesis and clinical manifestations, with Natural Killer (NK) lymphocytes being among the targets of virus-induced regulation.

This study performed a single-cell multi-omics analysis of transcripts and proteins of NK lymphocytes in COVID-19 patients, for the characterization of the innate immunological response to infection. NK cells were isolated from peripheral blood samples collected from adult subjects divided into 3 study groups: (1) non-infected subjects (Naïve group, n = 3), (2) post COVID-19 convalescent subjects (Healed group, n = 3) and (3) patients that were vaccinated against SARS-CoV-2 (Vaccine group, n = 3). Cells were then analysed by the BD Rhapsody System for the single-cell multi-omics investigation of transcriptome and membrane proteins.

The bioinformatic analysis identified 5 cell clusters which differentially expressed gene/protein markers, defining NK cell subsets as "Active NK cells" and "Mature NK cells". Calculating the relative proportion of each cluster within patient groups, more than 40% of the Naïve group cell population was found to belong to Mature NKs, whereas more than 75% of the Vaccine group cell population belonged to the cluster of Active NKs. Regarding the Healed group, it seemed to show intermediate phenotype between Active and Mature NK cells. Differential expression of specific genes, proteins and signaling pathways was detected comparing the profile of the 3 experimental groups, revealing a more activated NK cell phenotype in vaccinated patients versus recovered individuals.

The present study detected differential expression of NK cell markers in relation to SARS-CoV-2 infection and vaccine administration, suggesting the possibility to identify key molecular targets for clinical-diagnostic use of the individual response to viral infection and/or re-infection.

The emergence of hitherto unknown viral pathogens presents a great challenge for researchers to develop effective therapeutics and vaccines within a short time to avoid an uncontrolled global spread, as seen during the coronavirus disease 2019 (COVID-19) pandemic. Therefore, rapid and simple methods to identify immunogenic antigens as potential therapeutical targets are urgently needed for a better pandemic preparedness. To address this problem, we chose the well-characterized Modified Vaccinia virus Ankara (MVA)-T7pol expression system to establish a workflow to identify immunogens when a new pathogen emerges, generate candidate vaccines, and test their immunogenicity in an animal model. By using this system, we detected severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) nucleoprotein (N)-, and spike (S)-specific antibodies in COVID-19 patient sera, which is in line with the current literature and our observations from previous immunogenicity studies. Furthermore, we detected antibodies directed against the SARS-CoV-2-membrane (M) and -ORF3a proteins in COVID-19 patient sera and aimed to generate recombinant MVA candidate vaccines expressing either the M or ORF3a protein. When testing our candidate vaccines in a prime-boost immunization regimen in humanized HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice, we were able to demonstrate M- and ORF3a-specific cellular and humoral immune responses. Hence, the established workflow using the MVA-T7pol expression system represents a rapid and efficient tool to identify potential immunogenic antigens and provides a basis for future development of candidate vaccines.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

COVID-19 remains a significant threat, particularly to vulnerable populations. The emergence of new variants necessitates the development of treatments and vaccines that induce both humoral and cellular immunity. This study aimed to identify potentially immunogenic SARS-CoV-2 peptides and to explore the intricate host-pathogen interactions involving peripheral immune responses, memory profiles, and various demographic, clinical, and lifestyle factors. Using in silico and experimental methods, we identified several CD8-restricted SARS-CoV-2 peptides that are either poorly studied or have previously unreported immunogenicity: fifteen from the Spike and three each from non-structural proteins Nsp1-2-3-16. A Spike peptide, LA-9, demonstrated a 57% response rate in ELISpot assays using PBMCs from 14 HLA-A*02:01 positive, vaccinated, and mild-COVID-19 recovered subjects, indicating its potential for diagnostics, research, and multi-epitope vaccine platforms. We also found that younger individuals, with fewer vaccine doses and longer intervals since infection, showed lower anti-Spike (ELISA) and anti-Wuhan neutralizing antibodies (pseudovirus assay), higher naïve T cells, and lower central memory, effector memory, and CD4hiCD8low T cells (flow cytometry) compared to older subjects. In our cohort, a higher prevalence of Vδ2-γδ and DN T cells, and fewer naïve CD8 T cells, seemed to correlate with strong cellular and lower anti-NP antibody responses and to associate with Omicron infection, absence of confusional state, and habitual sporting activity.

Although some immune protection from close contact with individuals who have coronavirus disease 2019 (COVID-19) has been documented, there is limited data on the seroprevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals who were in lockdown with confirmed COVID-19 cases. This study investigated immunogenicity against SARS-CoV-2 in household members and people who lived near home-quarantined patients with COVID-19.

This cross-sectional study was conducted during the community-based care that took place during lockdowns in District 10, Ho Chi Minh City, Vietnam from July to September 2021. SARS-CoV-2 antibody levels were determined in index cases of COVID-19, household contacts, and a no-contact group from the same area.

A total of 770 participants were included (355 index cases, 103 household contacts, and 312 no contacts). All index cases were unvaccinated, but >90% of individuals in the household and no-contact groups had received ≥1 vaccine dose. SARS-CoV-2 neutralizing antibodies (Nabs) were present in >77% of unvaccinated index cases versus 64%/65.4% in the household/no-contact groups (p=0.001). Antibody concentrations in unvaccinated index cases were significantly higher than those in household contacts and no contacts, with no difference between the latter groups. In all cases, antibody levels declined markedly ≥6 weeks after infection, and failed to persist beyond this time in the household and no-contact groups.

Community-based care may have helped to create community immunogenicity, but Nabs did not persist, highlighting a need for vaccination for all individuals before, or from 6 weeks after, infection with SARS-CoV-2.

COVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2-78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival (p = 0.0001). Comparing 2022 with 2020-2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed.

The IgG response against SARS-CoV-2 infection can persist for over six months (long response; LR). However, among 30% of those infected, the duration can be as short as three months or less (short response; SR). The present study assembled serological data on the anti-SARS-CoV-2 IgG response duration of two previous studies and integrated these results with the plasmatic cytokine levels and genetic profile of 10 immune-relevant SNPs that were also previously published, along with the plasmatic total IgG, IgA, and IgM levels, allowing for the genetic, clinical, immunological, and epidemiological aspects of the post-COVID-19 IgG response duration to be understood. The SR was associated with previous mild acute COVID-19 and with an SNP (rs2228145) in IL6R related to low gene expression. Additionally, among the SR subgroup, no statistically significant Spearman correlations were observed between the plasma levels of IL-17A and the Th17 regulatory cytokines IFN-γ (rs = 0.2399; p = 0.1043), IL-4 (rs = 0.0273; p = 0.8554), and IL-2 (rs = 0.2204; p = 0.1365), while among the LR subgroup, weaker but statistically significant Spearman correlations were observed between the plasma levels of IL-17A and IFN-γ (rs = 0.3873; p = 0.0016), IL-4 (rs = 0.2671; p = 0.0328), and IL-2 (rs = 0.3959; p = 0.0012). These results suggest that the Th17 response mediated by the IL-6 pathway has a role in the prolonged IgG response to SARS-CoV-2 infection.

COVID-19 convalescent plasma (CCP) is an important therapeutic option for immunocompromised patients with COVID-19. Such patients are at increased risk for serious complications of infection and may also develop a unique syndrome of persistent infection. This article reviews the rationale for CCP utilization in immunocompromised patients and the evidence for its value in immunosuppressed patients with both acute and persistent COVID-19. Both historical precedence and understanding of the mechanisms of action of antibody treatment support this use, as do several lines of evidence derived from case series, comparative studies, randomized trials, and systematic reviews of the literature. A summary of recommendations from multiple practice guidelines is also provided.

In December 2019, Corona Virus Disease 2019 (COVID-19) was first identified and designated as a pandemic in March 2020 due to rapid spread of the virus globally. At the beginning of the pandemic, only a few treatment options, mainly focused on supportive care and repurposing medications, were available. Due to its effects on immune system, vitamin D was a topic of interest during the pandemic, and researchers investigated its potential impact on COVID-19 outcomes. However, the results of studies about the impact of vitamin D on the disease are inconclusive. In the present narrative review, different roles of vitamin D regarding the COVID-19 have been discussed to show that vitamin D supplementation should be recommended carefully.

Antibodies against SARS-CoV-2 spike (anti-S) may confer protection against symptomatic COVID-19. Whether their level predicts progression among those with COVID-19 pneumonia remains unclear.

We conducted a retrospective cohort study to assess predictors of anti-S levels and whether anti-S titer is associated with death or mechanical ventilation (MV). Adults hospitalized for COVID-19 pneumonia between July 2021 and July 2022 were enrolled if anti-S had been measured within 72 h of admission. Predictors of anti-S level were explored using multivariable quantile regression. The association between anti-S levels and 30-day death/MV was investigated via multivariable logistic regression. Analyses were stratified by vaccine status.

The median anti-S level was 1370 BAU/ml in 328 vaccinated and 15.5 BAU/ml in 206 unvaccinated individuals. Among the vaccinated, shorter symptom duration (p = 0.001), hematological malignancies (p = 0.002), and immunosuppressive therapy (p = 0.004) were associated with lower anti-S levels. In the unvaccinated group, symptom duration was the only predictor of anti-S levels (p < 0.001). After 30 days, 134 patients experienced death or MV. Among vaccinated individuals, higher anti-S levels correlated significantly with lower death/MV risk (per log2 increase, OR 0.88, 95%CI 0.81-0.97), irrespective of age and solid malignancies. Among unvaccinated, a marginally protective effect was observed (OR 0.86, 95%CI 0.73-1.01), independent of age, immunosuppressive therapy, and diabetes. Adjustment for monoclonal antibody treatment strengthened the association (OR 0.81, 95%CI 0.68-0.96).

This study suggests that levels of anti-S antibodies can predict critical or fatal outcomes in COVID-19 pneumonia patients, regardless of vaccination. Whether anti-S Ab could guide risk assessment and vaccination boosting merits further evaluation.

SARS-CoV-2 pandemic still poses a significant burden on global health and economy, especially for symptoms persisting beyond the acute disease. COVID-19 manifests with various degrees of severity and the identification of early biomarkers capable of stratifying patient based on risk of progression could allow tailored treatments.

We longitudinally analyzed 67 patients, classified according to a WHO ordinal scale as having Mild, Moderate, or Severe COVID-19. Peripheral blood samples were prospectively collected at hospital admission and during a 6-month follow-up after discharge. Several subsets and markers of the innate and adaptive immunity were monitored as putative factors associated with COVID-19 symptoms.

More than 50 immunological parameters were associated with disease severity. A decision tree including the main clinical, laboratory, and biological variables at admission identified low NK-cell precursors and CD14+CD91+ monocytes, and high CD8+ Effector Memory T cell frequencies as the most robust immunological correlates of COVID-19 severity and reduced survival. Moreover, low regulatory B-cell frequency at one month was associated with the susceptibility to develop long COVID at six months, likely due to their immunomodulatory ability.

These results highlight the profound perturbation of the immune response during COVID-19. The evaluation of specific innate and adaptive immune-cell subsets allows to distinguish between different acute and persistent COVID-19 symptoms.

The potency of antibody neutralization in cell culture has been used as the key criterion for selection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for clinical development. As other aspects may also influence the degree of protection in vivo, we compared the efficacy of two neutralizing monoclonal antibodies (TRES6 and 4C12) targeting different epitopes of the receptor binding domain (RBD) of SARS-CoV-2 in a prophylactic setting in rhesus monkeys. All four animals treated with TRES6 had reduced viral loads in the upper respiratory tract 2 days after naso-oropharyngeal challenge with the Alpha SARS-CoV-2 variant. Starting 2 days after challenge, mutations conferring resistance to TRES6 were dominant in two of the rhesus monkeys, with both animals failing to maintain reduced viral loads. Consistent with its lower serum neutralization titer at the day of challenge, prophylaxis with 4C12 tended to suppress viral load at day 2 less efficiently than TRES6. However, a week after challenge, mean viral loads in the lower respiratory tract in 4C12-treated animals were lower than in the TRES6 group and no mutations conferring resistance to 4C12 could be detected in viral isolates from nasal or throat swabs. Thus, genetic barrier to resistance seems to be a critical parameter for the efficacy of prophylaxis with monoclonal antibodies against SARS-CoV-2. Furthermore, comparison of antibody concentrations in respiratory secretions to those in serum shows reduced distribution of the 4C12 antibody into respiratory secretions and a delay in the appearance of antibodies in bronchoalveolar lavage fluid compared to their appearance in secretions of the upper respiratory tract.IMPORTANCEMonoclonal antibodies are a powerful tool for the prophylaxis and treatment of acute viral infections. Hence, they were one of the first therapeutic agents licensed for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oftentimes, the main criterion for the selection of antibodies for clinical development is their potency of neutralization in cell culture. By comparing two antibodies targeting the Spike protein of SARS-CoV-2, we now observed that the antibody that neutralized SARS-CoV-2 more efficiently in cell culture suppressed viral load in challenged rhesus monkeys to a lesser extent. Extraordinary rapid emergence of mutants of the challenge virus, which had lost their sensitivity to the antibody, was identified as the major reason for the reduced efficacy of the antibody in rhesus monkeys. Therefore, the viral genetic barrier to resistance to antibodies also affects their efficacy.

Long-acting passive immunization strategies are needed to protect immunosuppressed vulnerable groups from infectious diseases. To further explore this concept for COVID-19, we constructed Adeno-associated viral (AAV) vectors encoding the human variable regions of the SARS-CoV-2 neutralizing antibody, TRES6, fused to murine constant regions. An optimized vector construct was packaged in hepatotropic (AAV8) or myotropic (AAVMYO) AAV capsids and injected intravenously into syngeneic TRIANNI-mice. The highest TRES6 serum concentrations (511 µg/ml) were detected 24 weeks after injection of the myotropic vector particles and mean TRES6 serum concentrations remained above 100 µg/ml for at least one year. Anti-drug antibodies or TRES6-specific T cells were not detectable. After injection of the AAV8 particles, vector mRNA was detected in the liver, while the AAVMYO particles led to high vector mRNA levels in the heart and skeletal muscle. The analysis of the Fc-glycosylation pattern of the TRES6 serum antibodies revealed critical differences between the capsids that coincided with different binding activities to murine Fc-γ-receptors. Concomitantly, the vector-based immune prophylaxis led to protection against SARS-CoV-2 infection in K18-hACE2 mice. High and long-lasting expression levels, absence of anti-drug antibodies and favourable Fc-γ-receptor binding activities warrant further exploration of myotropic AAV vector-based delivery of antibodies and other biologicals.

The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most therapeutic mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in this study. It could effectively restore the neutralizing activity of the bsAb when any of its single mAbs is escaped by variants. This synergy is primarily attributed to the binding angle of receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking and promoting cryptic epitope exposure that classical antibody cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, and RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. This study not only shifts the paradigm in understanding antibody interactions but paves the way for developing more effective therapeutic antibodies against rapidly mutating SARS-CoV-2, with Dia-19 already showing promise against emerging variants like BA.2.86, EG.5.1, and JN.1.