The Omicron variant is rapidly becoming the dominant SARS-CoV-2 virus circulating globally. It is important to define reductions in virus neutralizing activity in the serum of convalescent or ...vaccinated individuals to understand potential loss of protection against infection by Omicron. We previously established that a 50% plaque reduction neutralization antibody titer (PRNT
) ≥25.6 in our live virus assay corresponded to the threshold for 50% protection from infection against wild-type (WT) SARS-CoV-2. Here we show markedly reduced serum antibody titers against the Omicron variant (geometric mean titer (GMT) < 10) compared to WT virus 3-5 weeks after two doses of BNT162b2 (GMT = 218.8) or CoronaVac vaccine (GMT = 32.5). A BNT162b2 booster dose elicited Omicron PRNT
titers ≥25.6 in 88% of individuals (22 of 25) who previously received 2 doses of BNT162b2 and 80% of individuals (24 of 30) who previously received CoronaVac. However, few (3%) previously infected individuals (1 of 30) or those vaccinated with three doses of CoronaVac (1 of 30) met this threshold. Our findings suggest that countries primarily using CoronaVac vaccines should consider messenger RNA vaccine boosters in response to the spread of Omicron. Studies evaluating the effectiveness of different vaccines against the Omicron variant are urgently needed.
The host interactome of influenza viral proteins is ever-expanding. In this work, we report the identification of host heterogeneous nuclear ribonucleoprotein C (hnRNP-C) as an interacting partner of ...influenza A virus nucleoprotein (NP). We confirmed that this interaction exists across different influenza A subtypes and strains. Using biochemical methods, we determined that hnRNP-C interacts with NP via its C-terminal auxiliary domain. Further, we determined that the hnRNP-C is a negative regulator of influenza viral growth. Its interaction with NP is implicated in the promotion of host cell apoptosis during viral infection. It is the first time that the interaction between influenza nucleoprotein and host heterogeneous nuclear ribonucleoprotein C is characterized in detail. Overall, these findings not only characterize the interaction between NP and its host interacting partner hnRNP-C but also clarify the functional significance of this interaction. This work may lead to a new therapeutic target for the development of anti-influenza drugs.
Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID‐19) by targeting multiple antigen ...epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal‐type carbohydrates, mainly the N‐glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3‐galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate‐N‐acetylneuraminic acid hydroxylase and α1,3‐galactosyl‐transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike receptor binding domain to produce glyco‐humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3‐galactose epitopes. Animals rapidly developed a hyperimmune response with anti‐SARS‐CoV‐2 end‐titers binding dilutions over one to a million and end‐titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV‐19, neutralized spike/angiotensin converting enzyme‐2 interaction at a concentration <1 μg/mL, and inhibited infection of human cells by SARS‐CoV‐2 in cytopathic assays. We also found that pig GH‐pAb Fc domains fail to interact with human Fc receptors, thereby avoiding macrophage‐dependent exacerbated inflammatory responses and a possible antibody‐dependent enhancement. These data and the accumulating safety advantages of using GH‐pAbs in humans warrant clinical assessment of XAV‐19 against COVID‐19.
GGTA1/CMAH double KO pigs produced high titers of XAV‐19, an anti‐SARS‐Cov‐2 RBD glyco‐humanized polyclonal antibody. XAV‐19 is presented with a high complement activation and a high neutralization potency in vitro and in cell‐based neutralization assays. XAV‐19 does not interact with human Fc gamma receptors, preventing Fc‐dependent enhancement or immune cells skewing.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, ...cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR-confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20-40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti-SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.
...easing of restrictions has contributed to the emergence of new outbreaks predominantly by the SARS-CoV-2 omicron lineages BA5.2 and BF.7 in many cities, such as Beijing.2 With suspension of mass ...testing in mainland China after adjustment of the zero-COVID policy, empirical data on the epidemic growth and transmissibility of omicron variants are scarce. ...the number of infected cases and transmission rates were usually estimated using modelling with partial data.3 Previously, we reported that presence of the ORF8 antibody in blood is one of the most accurate serological markers of SARS-CoV-2 natural infection.4,5 Because the ORF8 gene is only expressed during SARS-CoV-2 replication, this serology test can confirm whether the patient has previously been infected with the virus and help to estimate the attack ratio. After the zero-COVID policy ended, the age-specific infection attack ratio and disease transmission measures (ie, initial reproduction number and doubling time) were estimated by an age-specific renewal equation. Supplementary Material Supplementary appendix Number of samples Sampling date (2023) Median age, years (IQR) Male Female Positive rate Attack ratio (credible interval) All age groups 1500 Jan 5–14 52 (34–71) 736 (49%) 764 (51%) 922 (61·5%) 80·7% (72·2–86·8) 1–17 years 74 Jan 5–14 12 (8–15) 45 (61%) 29 (39%) 49 (66·2%) 85·1% (72·0–92·4) 18–39 years 422 Jan 5–13 30 (25–35) 184 (44%) 238 (56%) 301 (71·3%) 87·5% (83·3–90·7) 40–59 years 381 Jan 5–12 50 (45–54) 196 (51%) 185 (49%) 206 (54·1%) 74·3% (63·7–82·5) 60–79 years 412 Jan 5–14 69 (65–74) 206 (50%) 206 (50%) 230 (55·8%) 73·9% (66·7–79·9) 80–99 years 211 Jan 7–14 85 (82–88) 106 (50%) 105 (50%) 136 (64·5%) 75·2% (60·3–85·6) Table 1 Summary of ELISA test results per age group
The recent increase in zoonotic avian influenza A(H7N9) disease in China is a cause of public health concern. Most of the A(H7N9) viruses previously reported have been of low pathogenicity. We report ...the fatal case of a patient in China who was infected with an A(H7N9) virus having a polybasic amino acid sequence at its hemagglutinin cleavage site (PEVPKRKRTAR/GL), a sequence suggestive of high pathogenicity in birds. Its neuraminidase also had R292K, an amino acid change known to be associated with neuraminidase inhibitor resistance. Both of these molecular features might have contributed to the patient's adverse clinical outcome. The patient had a history of exposure to sick and dying poultry, and his close contacts had no evidence of A(H7N9) disease, suggesting human-to-human transmission did not occur. Enhanced surveillance is needed to determine whether this highly pathogenic avian influenza A(H7N9) virus will continue to spread.
Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic ...analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising 35SIRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses.
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•OTUB1 is induced during IAV infection in an IFN-I-dependent manner•OTUB1 regulates the RIG-I complex via its enzymatic and E2-repressive activities•Optimal K63 versus K48 polyubiquitin chain concentrations determine RIG-I activation•Influenza NS1 targets OTUB1 for proteasomal degradation
Jahan et al. describe the role of Otub1, a deubiquitylase that is induced during virus infection in an interferon-dependent manner to regulate optimal signaling via the RIG-I pathway. Influenza A virus NS1 is able to bind and degrade newly synthesized Otub1 as a means to evade the innate immune response.
Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses ...encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.
Background and objective
Few head‐to‐head evaluations of immune responses to different vaccines have been reported.
Methods
Surrogate virus neutralization test (sVNT) antibody levels of adults ...receiving either two doses of BNT162b2 (n = 366) or CoronaVac (n = 360) vaccines in Hong Kong were determined. An age‐matched subgroup (BNT162b2 n = 49 vs. CoronaVac n = 49) was tested for plaque reduction neutralization (PRNT) and spike‐binding antibody and T‐cell reactivity in peripheral blood mononuclear cells.
Results
One month after the second dose of vaccine, BNT162b2 elicited significantly higher PRNT50, PRNT90, sVNT, spike receptor binding, spike N‐terminal domain binding, spike S2 domain binding, spike FcR binding and antibody avidity levels than CoronaVac. The geometric mean PRNT50 titres in those vaccinated with BNT162b2 and CoronaVac vaccines were 251.6 and 69.45, while PRNT90 titres were 98.91 and 16.57, respectively. All of those vaccinated with BNT162b2 and 45 (91.8%) of 49 vaccinated with CoronaVac achieved the 50% protection threshold for PRNT90. Allowing for an expected seven‐fold waning of antibody titres over 6 months for those receiving CoronaVac, only 16.3% would meet the 50% protection threshold versus 79.6% of BNT162b2 vaccinees. Age was negatively correlated with PRNT90 antibody titres. Both vaccines induced SARS‐CoV‐2‐specific CD4+ and CD8+ T‐cell responses at 1 month post‐vaccination but CoronaVac elicited significantly higher structural protein‐specific CD4+ and CD8+ T‐cell responses.
Conclusion
Vaccination with BNT162b2 induces stronger humoral responses than CoronaVac. CoronaVac induces higher CD4+ and CD8+ T‐cell responses to the structural protein than BNT162b2.
Through the head‐to‐head comparison, vaccination with BNT162b2 induces significantly higher levels of SARS‐CoV‐2‐specific binding and neutralizing antibody responses compared to CoronaVac. CoronaVac induces higher CD4+ and CD8+ T‐cell responses to the structural protein than BNT162b2.
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