The Use of SARS-CoV-2-Positive Donors in Hematopoietic Stem Cell Transplantation.

BACKGROUND: Since 2019, the SARS-CoV-2 pandemic has become a global issue due to its high fatality rate. Over time, the characteristics of the virus have evolved and led to the creation of an omicron strain with higher infectivity but a significantly decreased fatality rate. For patients in urgent need of hematopoietic stem cell transplantation (HSCT), whether the SARS-CoV-2 infection status of donors has a significant impact on HSCT recipients should be clarified. METHODS: To estimate the transplantation risk of SARS-CoV-2-positive donors, 24 patients who underwent HSCT from December 1, 2022 to January 30, 2023 were retrospectively included. The ratio of the observation group (SARS-CoV-2-positive donors, n = 12) to the control group (SARS-CoV-2-negative donors, n = 12) was 1:1. We observed the time of hematopoietic reconstruction, donor chimerism, severe infection, acute graft vs host disease, and hepatic vein occlusion disease during hematopoietic reconstruction. RESULTS: In the observation group, the average time of myeloid hematopoietic reconstruction was 11.58 days, and in the control group, it was 12.17 days (P = .3563 [>.05]). On average, all patients achieved a 90% donor chimerism rate of +13.58 (±4.5) days (P = .5121 [>.05]). The average percentage of patients that achieved successful hematopoietic reconstruction was 96.75% in the observation group and 96.31% in the control group (P = .7819 [>.05]). A total of 6 adverse events occurred during this study: 3 in the observation group and 3 in the control group. CONCLUSIONS: Our preliminary results showed favorable short-term outcomes in recipients of SARS-CoV-2-positive HCST donors.

Strong CD4+ T-Cell Responses to Ancestral and Variant Spike Proteins Are Established by NVX-CoV2373 SARS-CoV-2 Primary Vaccination.

BACKGROUND: NVX-CoV2373 is an efficacious COVID-19 vaccine comprising full-length 5-µg recombinant SARS-CoV-2 spike (rS) glycoprotein and Matrix-M™ adjuvant. Phase 2 of a randomized, placebo-controlled, phase 1/2 trial in healthy adults (18-84 years) previously reported good safety/tolerability and robust humoral immunogenicity. METHODS: Participants were randomized to placebo or 1 or 2 doses of 5-µg or 25-µg rS with 50 µg Matrix-M adjuvant 21 days apart. CD4+ T-cell responses to SARS-CoV-2 intact S or pooled peptide stimulation (with ancestral or variant S sequences) were measured via enzyme-linked immunosorbent spot (ELISpot) assay and intracellular cytokine staining (ICCS). RESULTS: A clearly discernable spike antigen-specific CD4+ T-cell response was induced after 1 dose, but markedly enhanced after 2 doses. Counts and fold-increases in cells producing Th1 cytokines exceeded those secreting Th2 cytokines, although both phenotypes were clearly present. Interferon-γ responses to rS were detected in 93.5% of 2-dose 5-µg recipients. A polyfunctional CD4+ T-cell response was cross-reactive and of equivalent magnitude to all tested variants, including Omicron BA.1/BA.5. CONCLUSIONS: NVX-CoV2373 elicits a moderately Th1-biased CD4+ T-cell response that is cross-reactive with ancestral and variant S proteins after 2 doses. CLINICAL TRIAL REGISTRATION: NCT04368988.

Utilization of SARS-CoV-2-positive donors in hematopoietic stem cell transplantation

Background Since 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a global issue due to its high fatality rate. Over time, the characteristics of the virus have evolved and led to the creation of an omicron strain with higher infectivity but a significantly decreased fatality rate. For patients in urgent need of hematopoietic stem cell transplantation (HSCT), whether the SARS-CoV-2 infection status of donors has a significant impact on HSCT recipients should be clarified. Methods To estimate the transplantation risk of SARS-CoV-2-positive donors, 24 patients who underwent HSCT from December 1, 2022, to January 30, 2023, were retrospectively included. The ratio of the observation group (SARS-CoV-2-positive donors, n=12) to the control group (SARS-CoV-2-negative donors, n=12) was 1:1. We observed the time of hematopoietic reconstruction, donor chimerism, severe infection, acute graft versus host disease (aGVHD) and hepatic vein occlusion disease (VOD) during hematopoietic reconstruction. Results In the observation group, the average time of myeloid hematopoietic reconstruction was 11.58 d, and in the control group, it was 12.17 d. P= 0.3563 (>0.05)). On average, all patients achieved a 90% donor chimerism rate of +13.58 (±4.5) d. P=0.5121 (>0.05). The average percentage of patients that achieved successful hematopoietic reconstruction was 96.75% in observation group and 96.31% in control group. P=0.7819 (P>0.05). A total of 6 adverse events occurred during this study: 3 in the observation group and 3 in the control group. Conclusions Our preliminary results showed favorable short-term outcomes in recipients of SARS-CoV-2-positive HCST donors.

Immunogenicity and protection of a variant nanoparticle vaccine that confers broad neutralization against SARS-CoV-2 variants.

SARS-CoV-2 variants have emerged with elevated transmission and a higher risk of infection for vaccinated individuals. We demonstrate that a recombinant prefusion-stabilized spike (rS) protein vaccine based on Beta/B.1.351 (rS-Beta) produces a robust anamnestic response in baboons against SARS-CoV-2 variants when given as a booster one year after immunization with NVX-CoV2373. Additionally, rS-Beta is highly immunogenic in mice and produces neutralizing antibodies against WA1/2020, Beta/B.1.351, and Omicron/BA.1. Mice vaccinated with two doses of Novavax prototype NVX-CoV2373 (rS-WU1) or rS-Beta alone, in combination, or heterologous prime-boost, are protected from challenge. Virus titer is undetectable in lungs in all vaccinated mice, and Th1-skewed cellular responses are observed. We tested sera from a panel of variant spike protein vaccines and find broad neutralization and inhibition of spike:ACE2 binding from the rS-Beta and rS-Delta vaccines against a variety of variants including Omicron. This study demonstrates that rS-Beta vaccine alone or in combination with rS-WU1 induces antibody-and cell-mediated responses that are protective against challenge with SARS-CoV-2 variants and offers broader neutralizing capacity than a rS-WU1 prime/boost regimen alone. Together, these nonhuman primate and murine data suggest a Beta variant booster dose could elicit a broad immune response to fight new and future SARS-CoV-2 variants.

Cryoelectron microscopy structures of a human neutralizing antibody bound to MERS-CoV spike glycoprotein.

Neutralizing monoclonal antibodies (mAbs) against highly pathogenic coronaviruses represent promising candidates for clinical intervention. Here, we isolated a potent neutralizing monoclonal antibody, MERS-S41, from a yeast displayed scFv library using the S protein as a bait. To uncover the neutralization mechanism, we determined structures of MERS-S41 Fab in complex with the trimeric spike glycoprotein by cryoelectron microscopy (cryo-EM). We observed four distinct classes of the complex structure, which showed that the MERS-S41 Fab bound to the "up" receptor binding domain (RBD) with full saturation and also bound to an accessible partially lifted "down" RBD, providing a structural basis for understanding how mAbs bind to trimeric spike glycoproteins. Structure analysis of the epitope and cell surface staining assays demonstrated that virus entry is blocked predominantly by direct competition with the host receptor, dipeptidyl peptidase-4 (DPP4).

Cryoelectron microscopy structures of a human neutralizing antibody bound to MERS-CoV spike glycoprotein

Neutralizing monoclonal antibodies (mAbs) against highly pathogenic coronaviruses represent promising candidates for clinical intervention. Here, we isolated a potent neutralizing monoclonal antibody, MERS-S41, from a yeast displayed scFv library using the S protein as a bait. To uncover the neutralization mechanism, we determined structures of MERS-S41 Fab in complex with the trimeric spike glycoprotein by cryoelectron microscopy (cryo-EM). We observed four distinct classes of the complex structure, which showed that the MERS-S41 Fab bound to the “up” receptor binding domain (RBD) with full saturation and also bound to an accessible partially lifted “down” RBD, providing a structural basis for understanding how mAbs bind to trimeric spike glycoproteins. Structure analysis of the epitope and cell surface staining assays demonstrated that virus entry is blocked predominantly by direct competition with the host receptor, dipeptidyl peptidase-4 (DPP4).

Comparison of the safety and immunogenicity of a novel Matrix-M-adjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in older adults: a phase 3 randomised controlled trial.

BACKGROUND: Improved seasonal influenza vaccines for older adults that can induce broadly cross-reactive antibodies and enhanced T-cell responses, particularly against A H3N2 viruses, while avoiding egg-adaptive antigenic changes, are needed. We aimed to show that the Matrix-M-adjuvanted quadrivalent nanoparticle influenza vaccine (qNIV) was immunologically non-inferior to a licensed, standard-dose quadrivalent inactivated influenza vaccine (IIV4) in older adults. METHODS: This was a phase 3 randomised, observer-blinded, active-comparator controlled trial done across 19 US community-based clinical research sites during the 2019-20 influenza season. Participants were clinically stable and community-dwelling, aged at least 65 years, and were randomised in a 1:1 ratio using an interactive web response system to receive a single intramuscular dose of qNIV or IIV4. The primary objective was to describe safety and show that qNIV was immunologically non-inferior to IIV4. The primary outcomes were adverse events by treatment group and comparative haemagglutination-inhibiting antibody responses (assayed with egg-propagated virus) on day 28, summarised in terms of the ratio of geometric mean titres (GMTRqNIV/IIV4) and seroconversion rate (SCR) difference between participants receiving qNIV or IIV4 for all four vaccine homologous influenza strains. The immunogenicity outcome was measured in the per-protocol population. Non-inferiority was shown if the lower bound of the two-sided 95% CI on the GMTRqNIV/IIV4 was at least 0·67 and the lower bound of the two-sided 95% CI on the SCR difference -was at least -10%. The study is registered with clinicaltrials.gov, NCT04120194, and is active and not recruiting. FINDINGS: 2742 adults were assessed for eligibility and 2654 were enrolled and randomised between Oct 14, 2019, and Oct 25, 2019; 1333 participants were randomised to the qNIV group and 1319 to the IIV4 group (two participants withdrew consent before being assigned to a group). qNIV showed immunological non-inferiority to IIV4: GMTRqNIV/IIV4 for the four vaccine homologous influenza strains was A/Brisbane 1·09 (95% CI 1·03 to 1·15), A/Kansas 1·19 (1·11 to 1·27), B/Maryland 1·03 (0·99 to 1·07), and B/Phuket 1·23 (1·16 to 1·29); and SCR difference was A/Brisbane 5·0 (95% CI 1·9 to 8·1), A/Kansas 7·3 (3·6 to 11·1), B/Maryland 0·5 (-1·9 to 2·9), and B/Phuket 8·5 (5·0 to 11·9). 659 (49·4%) of 1333 of participants in the qNIV group and 551 (41·8%) of 1319 participants in the IIV4 group had at least one treatment-emergent adverse event. More solicited adverse events were reported by participants in the qNIV group (551 [41·3%] of 1333) than in the IIV4 group (420 [31·8%] of 1319), and were comprised primarily of mild to moderate transient injection site pain (341 [25·6%] in the qNIV group vs 212 [16·1%] in the IIV4 group). INTERPRETATION: qNIV was well tolerated and produced qualitatively and quantitatively enhanced humoral and cellular immune response in older adults compared with IIV4. qNIV might enhance the effectiveness of seasonal influenza vaccination, and future studies to show clinical efficacy are planned. FUNDING: Novavax.

Prevalence of mental health problems among children and adolescents during the COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis examined the prevalence of depression, anxiety, sleep disorders, and posttraumatic stress symptoms among children and adolescents during global COVID-19 pandemic in 2019 to 2020, and the potential modifying effects of age and gender. METHODS: A literature search was conducted in PubMed, Web of Science, PsycINFO, and two Chinese academic databases (China National Knowledge Infrastructure and Wanfang) for studies published from December 2019 to September 2020 that reported the prevalence of above mental health problems among children and adolescents. Random-effects meta-analyses were used to estimate the pooled prevalence. RESULTS: Twenty-three studies (21 cross-sectional studies and 2 longitudinal studies) from two countries (i.e., China and Turkey) with 57,927 children and adolescents were identified. Depression, anxiety, sleep disorders, and posttraumatic stress symptoms were assessed in 12, 13, 2, and 2 studies, respectively. Meta-analysis of results from these studies showed that the pooled prevalence of depression, anxiety, sleep disorders, and posttraumatic stress symptoms were 29% (95%CI: 17%, 40%), 26% (95%CI: 16%, 35%), 44% (95%CI: 21%, 68%), and 48% (95%CI: -0.25, 1.21), respectively. The subgroup meta-analysis revealed that adolescents and females exhibited higher prevalence of depression and anxiety compared to children and males, respectively. LIMITATIONS: All studies in meta-analysis were from China limited the generalizability of our findings. CONCLUSIONS: Early evidence highlights the high prevalence of mental health problems among children and adolescents during the COVID-19 pandemic, especially among female and adolescents. Studies investigating the mental health of children and adolescents from countries other than China are urgently needed.

SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice.

The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) from the full-length spike (S) protein that is stable in the prefusion conformation. NVX-CoV2373 S form 27.2-nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicit high titer anti-S IgG that blocks hACE2 receptor binding, neutralize virus, and protects against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. NVX-CoV2373 also elicits multifunctional CD4+ and CD8+ T cells, CD4+ follicular helper T cells (Tfh), and antigen-specific germinal center (GC) B cells in the spleen. In baboons, low-dose levels of NVX-CoV2373 with Matrix-M was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that block S-protein binding to hACE2 and neutralize virus infection and antigen-specific T cells. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2373 with Matrix-M (NCT04368988).

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine.

BACKGROUND: NVX-CoV2373 is a recombinant severe acute respiratory syndrome coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. METHODS: We initiated a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-µg and 25-µg doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults. In phase 1, vaccination comprised two intramuscular injections, 21 days apart. The primary outcomes were reactogenicity; laboratory values (serum chemistry and hematology), according to Food and Drug Administration toxicity scoring, to assess safety; and IgG anti-spike protein response (in enzyme-linked immunosorbent assay [ELISA] units). Secondary outcomes included unsolicited adverse events, wild-type virus neutralization (microneutralization assay), and T-cell responses (cytokine staining). IgG and microneutralization assay results were compared with 32 (IgG) and 29 (neutralization) convalescent serum samples from patients with Covid-19, most of whom were symptomatic. We performed a primary analysis at day 35. RESULTS: After randomization, 83 participants were assigned to receive the vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose-sparing, and induced a T helper 1 (Th1) response. The two-dose 5-µg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic Covid-19 patients (8344 and 983, respectively). CONCLUSIONS: At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in Covid-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).