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The COVID-19 pandemic has highlighted the need to use infection testing databases to rapidly estimate effectiveness of prior infection in preventing reinfection (⁠|$P{E}_S$|⁠) by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Mathematical modeling was used to demonstrate a theoretical foundation for applicability of the test-negative, case–control study design to derive |$P{E}_S$|⁠. Apart from the very early phase of an epidemic, the difference between the test-negative estimate for |$P{E}_S$| and true value of |$P{E}_S$| was minimal and became negligible as the epidemic progressed. The test-negative design provided robust estimation of |$P{E}_S$| and its waning. Assuming that only 25% of prior infections are documented, misclassification of prior infection status underestimated |$P{E}_S$|⁠ , but the underestimate was considerable only when > 50% of the population was ever infected. Misclassification of latent infection, misclassification of current active infection, and scale-up of vaccination all resulted in negligible bias in estimated |$P{E}_S$|⁠. The test-negative design was applied to national-level testing data in Qatar to estimate |$P{E}_S$| for SARS-CoV-2. |$P{E}_S$| against SARS-CoV-2 Alpha and Beta variants was estimated at 97.0% (95% CI, 93.6-98.6) and 85.5% (95% CI, 82.4-88.1), respectively. These estimates were validated using a cohort study design. The test-negative design offers a feasible, robust method to estimate protection from prior infection in preventing reinfection. [ABSTRACT FROM AUTHOR]

This study evaluated the potential for antibody‐dependent enhancement (ADE) in serum samples from patients exposed to Middle East respiratory syndrome coronavirus (MERS‐CoV). Furthermore, we evaluated the effect of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination on ADE in individuals with a MERS infection history. We performed ADE assay in sera from MERS recovered and SARS‐CoV‐2‐vaccinated individuals using BHK cells expressing FcgRIIa, SARS‐CoV‐2, and MERS‐CoV pseudoviruses (PVs). Further, we analyzed the association of ADE to serum IgG levels and neutralization. Out of 16 MERS patients, nine demonstrated ADE against SARS‐CoV‐2 PV, however, none of the samples demonstrated ADE against MERS‐CoV PV. Furthermore, out of the seven patients exposed to SARS‐CoV‐2 vaccination after MERS‐CoV infection, only one patient (acutely infected with MERS‐CoV) showed ADE for SARS‐CoV‐2 PV. Further analysis indicated that IgG1, IgG2, and IgG3 against SARS‐CoV‐2 S1 and RBD subunits, IgG1 and IgG2 against the MERS‐CoV S1 subunit, and serum neutralizing activity were low in ADE‐positive samples. In summary, samples from MERS‐CoV‐infected patients exhibited ADE against SARS‐CoV‐2 and was significantly associated with low levels of neutralizing antibodies. Subsequent exposure to SARS‐CoV‐2 vaccination resulted in diminished ADE activity while the PV neutralization assay demonstrated a broadly reactive antibody response in some patient samples. [ABSTRACT FROM AUTHOR]

Background: Priming with ChAdOx1 followed by heterologous boosting is considered in several countries. Nevertheless, analyses comparing the immunogenicity of heterologous booster to homologous primary vaccination regimens and natural infection are lacking. In this study, we aimed to conduct a comparative assessment of the immunogenicity between homologous primary vaccination regimens and heterologous prime‐boost vaccination using BNT162b2 or mRNA‐1273. Methods: We matched vaccinated naïve (VN) individuals (n = 673) with partial vaccination (n = 64), primary vaccination (n = 590), and primary series plus mRNA vaccine heterologous booster (n = 19) with unvaccinated naturally infected (NI) individuals with a documented primary SARS‐CoV‐2 infection (n = 206). We measured the levels of neutralizing total antibodies (NTAbs), total antibodies (TAbs), anti‐S‐RBD IgG, and anti‐S1 IgA titers. Results: Homologous primary vaccination with ChAdOx1 not only showed less potent NTAb, TAb, anti‐S‐RBD IgG, and anti‐S1 IgA immune responses compared to primary BNT162b2 or mRNA‐1273 vaccination regimens (p < 0.05) but also showed ~3‐fold less anti‐S1 IgA response compared to infection‐induced immunity (p < 0.001). Nevertheless, a heterologous booster led to an increase of ~12 times in the immune response when compared to two consecutive homologous ChAdOx1 immunizations. Furthermore, correlation analyses revealed that both anti‐S‐RBD IgG and anti‐S1 IgA significantly contributed to virus neutralization among NI individuals, particularly in symptomatic and pauci‐symptomatic individuals, whereas among VN individuals, anti‐S‐RBD IgG was the main contributor to virus neutralization. Conclusion: The results emphasize the potential benefit of using heterologous mRNA boosters to increase antibody levels and neutralizing capacity particularly in patients who received primary vaccination with ChAdOx1. [ABSTRACT FROM AUTHOR]

Homocystinuria is a rare disease caused by mutations in the CBS gene that results in a deficiency of cystathionine γ-synthase (CBS). CBS is an essential pyridoxal 50-phosphate (PLP)-dependent enzyme in the transsulfuration pathway, responsible for combining serine with homocysteine to produce cystathionine, whose activity is enhanced by the allosteric regulator S-adenosylmethionine (SAM). CBS also plays a role in generating hydrogen sulfide (H2S), a gaseous signaling molecule with diverse regulatory functions within the vascular, nervous, and immune systems. In this study, we present the clinical and biochemical characterization of two novel CBS missense mutations that do not respond to pyridoxine treatment, namely c.689T > A (L230Q) and 215A > T (K72I), identified in a Chinese patient. We observed that the disease-associated K72I genetic variant had no apparent effects on the spectroscopic and catalytic properties of the full-length enzyme. In contrast, the L230Q variant expressed in Escherichia coli did not fully retain heme and when compared with the wild-type enzyme, it exhibited more significant impairments in both the canonical cystathionine-synthesis and the alternative H2S-producing reactions. This reduced activity is consistent with both in vitro and in silico evidence, which indicates that the L230Q mutation significantly decreases the overall protein's stability, which in turn, may represent the underlying cause of its pathogenicity. [ABSTRACT FROM AUTHOR]

Neutralizing antibodies (NAbs) are elicited after infection and vaccination and have been well studied. However, their antibody‐dependent cellular cytotoxicity (ADCC) functionality is still poorly characterized. Here, we investigated ADCC activity in convalescent sera from infected patients with wild‐type (WT) severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) or omicron variant compared with three coronavirus disease 2019 (COVID‐19) vaccine platforms and postvaccination breakthrough infection (BTI). We analyzed ADCC activity targeting SARS‐CoV‐2 spike (S) and nucleocapsid (N) proteins in convalescent sera following WT SARS‐CoV‐2‐infection (n = 91), including symptomatic and asymptomatic infections, omicron‐infection (n = 8), COVID‐19 vaccination with messenger RNA‐ (mRNA)‐ (BNT162b2 or mRNA‐1273, n = 77), adenovirus vector‐ (n = 41), and inactivated virus‐ (n = 46) based vaccines, as well as post‐mRNA vaccination BTI caused by omicron (n = 28). Correlations between ADCC, binding, and NAb titers were reported. ADCC was elicited within the first month postinfection and ‐vaccination and remained detectable for ≥3 months. WT‐infected symptomatic patients had higher S‐specific ADCC levels than asymptomatic and vaccinated individuals. Also, no difference in N‐specific ADCC activity was seen between symptomatic and asymptomatic patients, but the levels were higher than the inactivated vaccine. Notably, omicron infection showed reduced overall ADCC activity compared to WT SARS‐CoV‐2 infection. Although post‐mRNA vaccination BTI elicited high levels of binding and NAbs, ADCC activity was significantly reduced. Also, there was no difference in ADCC levels across the four vaccines, although NAbs and binding antibody titers were significantly higher in mRNA‐vaccinated individuals. All evaluated vaccine platforms are inferior in inducing ADCC compared to natural infection with WT SARS‐CoV‐2. The inactivated virus‐based vaccine can induce N‐specific ADCC activity, but its relevance to clinical outcomes requires further investigation. Our data suggest that ADCC could be used to estimate the extra‐neutralization level against COVID‐19 and provides evidence that vaccination should focus on other Fc‐effector functions besides NAbs. Also, the decreased susceptibility of the omicron variant to ADCC offers valuable guidance for forthcoming efforts to identify the specific targets of antibodies facilitating ADCC. [ABSTRACT FROM AUTHOR]

Background The epidemiology of the SARS-CoV-2 B.1.1.7 (or Alpha) variant is insufficiently understood. This study's objective was to describe the introduction and expansion of this variant in Qatar and to estimate the efficacy of natural infection against reinfection with this variant. Methods and findings Reinfections with the B.1.1.7 variant and variants of unknown status were investigated in a national cohort of 158,608 individuals with prior PCR-confirmed infections and a national cohort of 42,848 antibody-positive individuals. Infections with B.1.1.7 and variants of unknown status were also investigated in a national comparator cohort of 132,701 antibody-negative individuals. B.1.1.7 was first identified in Qatar on 25 December 2020. Sudden, large B.1.1.7 epidemic expansion was observed starting on 18 January 2021, triggering the onset of epidemic's second wave, 7 months after the first wave. B.1.1.7 was about 60% more infectious than the original (wild-type) circulating variants. Among persons with a prior PCR-confirmed infection, the efficacy of natural infection against reinfection was estimated to be 97.5% (95% CI: 95.7% to 98.6%) for B.1.1.7 and 92.2% (95% CI: 90.6% to 93.5%) for variants of unknown status. Among antibody-positive persons, the efficacy of natural infection against reinfection was estimated to be 97.0% (95% CI: 92.5% to 98.7%) for B.1.1.7 and 94.2% (95% CI: 91.8% to 96.0%) for variants of unknown status. A main limitation of this study is assessment of reinfections based on documented PCR-confirmed reinfections, but other reinfections could have occurred and gone undocumented. Conclusions In this study, we observed that introduction of B.1.1.7 into a naïve population can create a major epidemic wave, but natural immunity in those previously infected was strongly associated with limited incidence of reinfection by B.1.1.7 or other variants., Author(s): Laith J. Abu-Raddad 1,2,3,*, Hiam Chemaitelly 1,2, Houssein H. Ayoub 4, Peter Coyle 5,6,7, Joel A. Malek 8,9, Ayeda A. Ahmed 8, Yasmin A. Mohamoud 8, Shameem Younuskunju 8, [...]

Small molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the BCR::ABL1 kinase and inhibit downstream signaling pathways. However, therapy failure may be seen in 20-25% of CML patients due to intolerance or inadequacy related to BCR::ABL1 dependent or independent mechanisms. This review aimed to summarize current treatment options involving TKIs, resistance mechanisms and the prospective approaches to overcome TKI resistance. We highlight BCR::ABL1-dependent mechanisms of TKI resistance by reviewing clinically-documented BCR::ABL1 mutations and their consequences for TKI binding. In addition, we summarize BCR::ABL1 independent pathways, including the relevance of drug efflux, dysregulation of microRNA, and the involvement of alternative signaling pathways. We also discuss future approaches, such as gene-editing techniques in the context of CML, as potential therapeutic strategies. [ABSTRACT FROM AUTHOR]