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"Evans, John P."
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SARS-CoV-2 spreads through cell-to-cell transmission
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell–cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell–cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.
Journal Article
Rexodus
\"With the aid of Kelvin, a dinosaur from the past, Amber must save her father--and the rest of us--from the very same danger that caused the dinosaurs to flee--and from the dinosaurs themselves as they return to Earth\"-- Back cover.
Book
Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants
After two doses of mRNA vaccine, health care workers had less viral neutralizing-antibody activity against the BA.4/5 and BA.2.12.1 omicron subvariants than against the BA.1 and BA.2 subvariants, but titers increased significantly with a booster dose.
Journal Article
Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants
After a third (booster) dose of SARS-CoV-2 vaccine, immunity waned more slowly than after two doses and even more slowly in persons with breakthrough Covid-19. Neutralization of subvariant BA.4–BA.5 was particularly resistant to vaccine-induced immunity.
Journal Article
Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants
Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and reduced disease severity; however, the underlying mechanism is not fully understood. In addition, whether the most recent Omicron subvariants, including BA.5 and BA.2.75, use the same pathway as their ancestor for entry is currently not known. The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced S1 shedding of their reversion mutants K547T and Y655H in viral producer cells. Importantly, the H655Y mutation also determines the low fusogenicity and enhanced dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5, and BA.2.75. Together, these results uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis. IMPORTANCE Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and reduced disease severity; however, the underlying mechanism is not fully understood. In addition, whether the most recent Omicron subvariants, including BA.5 and BA.2.75, use the same pathway as their ancestor for entry is currently not known. In this study, we show that T547K and H655Y mutations in the C terminus of the S1 subunit critically determine the enhanced dependence on the endosomal entry pathway as well as the reduced cell-cell fusion activity of Omicron BA.1, BA.1.1, and other subvariants. Further experiments and molecular modeling suggest that H655Y and K547T stabilize the spike trimer conformation, likely contributing to the decreased fusogenicity and endosomal entry. Our work uncovers novel mechanisms underlying the distinct entry pathway of Omicron subvariants and advances our understanding of their biological characteristics.
Journal Article
Neutralization of SARS-CoV-2 Variants of Concern Harboring Q677H
SARS-CoV-2, the causative agent of COVID-19, is rapidly evolving to be more transmissible and to evade acquired immunity. To date, most investigations of SARS-CoV-2 variants have focused on RBD mutations. The sensitivity of SARS-CoV-2 variants of concern (VOCs) to neutralizing antibodies has largely been studied in the context of key receptor binding domain (RBD) mutations, including E484K and N501Y. Little is known about the epistatic effects of combined SARS-CoV-2 spike mutations. We now investigate the neutralization sensitivity of variants containing the non-RBD mutation Q677H, including B.1.525 (Nigerian isolate) and Bluebird (U.S. isolate) variants. The effect on neutralization of Q677H was determined in the context of the RBD mutations and in the background of major VOCs, including B.1.1.7 (United Kingdom, Alpha), B.1.351 (South Africa, Beta), and P1-501Y-V3 (Brazil, Gamma). We demonstrate that the Q677H mutation increases viral infectivity and syncytium formation, as well as enhancing resistance to neutralization for VOCs, including B.1.1.7 and P1-501Y-V3. Our work highlights the importance of epistatic interactions between SARS-CoV-2 spike mutations and the continued need to monitor Q677H-bearing VOCs. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, is rapidly evolving to be more transmissible and to evade acquired immunity. To date, most investigations of SARS-CoV-2 variants have focused on RBD mutations. However, the impact of non-RBD mutations and their synergy with studied RBD mutations are poorly understood. Here, we examine the role of the non-RBD Q677H mutation arising in many SARS-CoV-2 lineages, including VOCs. We demonstrate that the Q677H mutation enhances viral infectivity and confers neutralizing antibody resistance, particularly in the background of other SARS-CoV-2 VOCs.
Journal Article
Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology
Background
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy.
Methods
Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19.
Results
Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8
+
T cells, CD4
+
T cells, and CD56
+
natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis.
Conclusions
Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.
Journal Article
Three SARS-CoV-2 spike protein variants delivered intranasally by measles and mumps vaccines are broadly protective
As the new SARS-CoV-2 Omicron variants and subvariants emerge, there is an urgency to develop intranasal, broadly protective vaccines. Here, we developed highly efficacious, intranasal trivalent SARS-CoV-2 vaccine candidates (TVC) based on three components of the MMR vaccine: measles virus (MeV), mumps virus (MuV) Jeryl Lynn (JL1) strain, and MuV JL2 strain. Specifically, MeV, MuV-JL1, and MuV-JL2 vaccine strains, each expressing prefusion spike (preS-6P) from a different variant of concern (VoC), were combined to generate TVCs. Intranasal immunization of IFNAR1
−/−
mice and female hamsters with TVCs generated high levels of S-specific serum IgG antibodies, broad neutralizing antibodies, and mucosal IgA antibodies as well as tissue-resident memory T cells in the lungs. The immunized female hamsters were protected from challenge with SARS-CoV-2 original WA1, B.1.617.2, and B.1.1.529 strains. The preexisting MeV and MuV immunity does not significantly interfere with the efficacy of TVC. Thus, the trivalent platform is a promising next-generation SARS-CoV-2 vaccine candidate.
In this study, the authors developed intranasal measles virus and mumps virus-based trivalent vaccines, each expressing three distinct SARS-CoV-2 stabilized prefusion spike proteins. They show that the intranasal vaccines provide protection against infection of SARS-CoV-2 variants in small animal models.
Journal Article
Impaired neutralizing antibody response to COVID-19 mRNA vaccines in cancer patients
There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin’s lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT
50
) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT
50
levels, with 50-60% of them below the detection limit; (3) mean NT
50
levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT
50
levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies.
Journal Article